key: cord- -ejv gidp authors: coleman, kristen k; wong, chui ching; jayakumar, jayanthi; nguyen, tham t; wong, abigail w l; yadana, su; thoon, koh c; chan, kwai peng; low, jenny g; kalimuddin, shirin; dehghan, shoaleh; kang, june; shamsaddini, amirhossein; seto, donald; su, yvonne c f; gray, gregory c title: adenoviral infections in singapore: should new antiviral therapies and vaccines be adopted? date: - - journal: j infect dis doi: . /infdis/jiz sha: doc_id: cord_uid: ejv gidp background: a number of serious human adenovirus (hadv) outbreaks have been recently reported: hadv-b (israel, singapore, and usa), hadv-b d (usa and china), hadv-d , -d , and -c (japan), hadv-b p (usa, europe, and china), and hadv-b (china, singapore, and france). methods: to understand the epidemiology of hadv infections in singapore, we studied hadv-positive clinical samples collected from pediatric and adult patients in singapore from to . genome sequencing and phylogenetic analyses were performed to identify hadv genotypes, clonal clusters, and recombinant or novel hadvs. results: the most prevalent genotypes identified were hadv-b ( . %), hadv-b ( . %), and hadv-e ( . %). we detected new hadv-c strains and detected incursions with hadv-b (odds ratio [or], . ; % confidence interval [ci], . – . ) and hadv-e (or, . ; % ci, . – . ) among pediatric patients over time. in addition, immunocompromised patients (adjusted or [aor], . ; % ci, . – . ) and patients infected with hadv-c (aor, . ; % ci, . – . ), hadv-b (aor, . ; % ci, . – . ), or hadv-e (aor, . ; % ci, . – . ) were at increased risk for severe disease. conclusions: singapore would benefit from more frequent studies of clinical hadv genotypes to identify patients at risk for severe disease and help guide the use of new antiviral therapies, such as brincidofovir, and potential administration of hadv and vaccine. human adenoviruses (hadvs) cause diverse illnesses that often vary by hadv species (a-g) and type (> genotypes have been described) [ ] . human adenovirus types , , , , , and have been associated with severe acute respiratory disease [ ] [ ] [ ] [ ] . although a number of hadv vaccine types have been or are under current study, live enteric-coated vaccines against hadv-b and hadv-e have been used with remarkable effectiveness and safety among us military trainees [ ] . clinical epidemiological data regarding hadv infections are relatively sparse for southeast asia (sea). however, existing data suggest that hadv-b is ubiquitous and more often associated with milder illness when compared with recent hadv-b infections in singapore, malaysia, taiwan, and china [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . unlike hadv-b and hadv-b , outbreaks of hadv-e have not been as commonly reported globally until recently. upon its discovery in the s [ ] , hadv-e was largely considered restricted to and controlled by vaccine in the us military population, with rare detections among civilians, such as school children in the netherlands in [ ] , users of a private swimming pool in the usa in [ ] , and conjunctivitis patients in japan in [ ] . more recently, surveillance for hadv has improved, and evidence of hadv-e infections among civilian populations in the usa, italy, west africa, china, hong kong, taiwan, india, malaysia, and singapore have been increasingly reported [ , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . due to the historical lack of hadv genotyping surveillance, it is unknown whether hadv-e is a new or re-emerging pathogen in sea. in an effort to epidemiologically describe clinical hadv genotypes in singapore, we used a hexon and fiber genotyping algorithm [ ] to retrospectively and prospectively study hadv infections among patients from large public hospitals in singapore. institutional review board (cirb reference / ) to study archived and prospectively collected hadv-positive specimens. clinical samples previously collected from hadv-positive patients admitted to singapore general hospital (sgh) and kk women's and children's hospital (kkh) between and were preserved at − °c and transferred to duke-nus laboratory of one health research for study. clinical records were accessed only to determine clinical sample type. from to , informed consent was sought from all patients with laboratory-confirmed adenovirus infection at sgh and kkh. a patient with laboratory-confirmed adenovirus infection was defined as a person of any age seeking healthcare and who had evidence of adenovirus infection by polymerase chain reaction (pcr), real-time pcr, commercial direct fluorescent antibody (dfa), culture, specific monoclonal antibody assay, or other clinically approved adenovirus tests. the clinical samples (nasal, pharyngeal, nasopharyngeal, throat, bronchoalveolar, blood, serum, conjunctival, or urine) were first clinically screened with commercial dfa or seeplex rv ace pcr targeting influenza a and b virus, parainfluenza - virus, respiratory syncytial virus, metapneumovirus, rhinovirus, enterovirus, human coronavirus oc and e/nl , adenovirus, and bocavirus. residual samples were then preserved at − °c. clinical records were reviewed and specimen information forms were completed. human adenovirus-positive samples were transported on dry ice to the sgh department of microbiology where they were divided into two . -ml aliquots ( kept at sgh and transferred to duke-nus's laboratory of one health research). human adenovirus-positive patients with an influenza virus codetection were excluded from our study because these samples were required for study at singapore's national public health laboratory. human adenovirus culture was attempted at duke-nus. a -μl aliquot of each sample was inoculated into a cells with dulbecco's modified eagle's medium % (v/v) fetal bovine serum and incubated at °c while controlling for bacterial contamination. inoculated shell vials were observed for cytopathic effect hours after inoculation and daily afterward for days. observation of cytopathic effect was used to score hadv-positive culture. at duke-nus, deoxyribonucleic acid (dna) was extracted from the culture supernatants of hadv-positive samples. for culture-negative hadv samples, dna was extracted directly from the original clinical sample. total dna was extracted using the qiaamp dna blood mini kit (qiagen, inc., valentica, ca) and typed using conventional pcr [ , ] [ ] was independently performed, and in-house sequencing was performed using the bigdye terminator v . cycle sequencing kit (applied biosystems) on the abi prism genetic analyzer (applied biosystems). results from the typing efforts at each institution were then compared and the hadv genotype was confirmed. deoxyribonucleic acid extracted from culture supernatants from culture-positive hadv samples were sent for wholegenome sequencing at the duke-nus genome biology facility. a qubit high sensitivity assay was used to measure dna concentrations (ng/μl) in each sample before library preparation using the nextera xt dna library prep kit. samples were then studied using the miseq × bp ( cycle) nano kit v . the quality of short ngs reads were initially checked by fastqc and followed by the removal of the illumina adaptors using trimmomatic [ ] . the trimmed reads were then mapped against the reference genomes (hadv-c or hadv-e) using geneinous r . . (biomatters ltd., auckland, new zealand). a total of new adenovirus genomes were generated from this study and compared with all available hadv-c and hadv-e sequences of fiber, hexon, and penton base and full genomes from genbank. for each dataset, multiple sequence alignment was initially performed using mafft [ ] followed by manual alignment. gene and full genome phylogenies were initially reconstructed using fasttree [ ] , and the outliers were removed for subsequent analysis. for hadv-c viruses, final datasets were further subsampled to fiber sequences ( bp in length), hexon sequences ( bp), penton base sequences ( bp), and full genomes ( bp). for hadv-e viruses, another final datasets were also subsampled to fiber sequences ( bp in length), hexon sequences ( bp), penton base sequences ( bp) and full genomes ( bp). for each dataset, maximum likelihood (ml) phylogenies were reconstructed using raxml v . [ ] , and branch support was assessed using bootstrap (bs) replicates. to detect potential recombinant events, full genome datasets were analyzed separately for hadv-c and hadv-e, because these were the species identified from the subset of isolates (n = ) that were fully sequenced. human adenovirus-c datasets consisted of novel genomes from singapore and representative virus isolates from different genotypes (hadv-c , hadv-c , hadv-c , and hadv-c ). human adenovirus-e datasets consisted of novel genomes and representative virus isolates of hadv-e . the datasets were analyzed using different methods as implemented in recombination detection program (rdp ) [ ] . these methods included rdp, geneconv, bootscan, maxchi, chimaera, siscan, and seq and their p values estimated. the breakpoints positions and their major and minor parents were identified for putative recombination strains. for each novel genome, a subsampled dataset was subsequently analyzed in rdp to determine their recombination events. to further confirm detected recombination events, independent phylogenetic analyses were performed using ml method as described above. epidemiological data were imported and categorized for statistical analyses using stata, version . (statacorp, college station, tx). logistic regression was performed to examine hadv genotype frequencies by time period. pearson's χ and fisher's exact tests were used to examine potential risk factors (gender, age group, immunosuppression, and hadv genotype) for associations with severe disease (prolonged hospitalization, prolonged fever, or intensive care unit admission). stepwise, unconditional logistic regression using a saturated model and backward elimination (exclusion p > . ) was used to further examine these risk factors. clinical samples were studied from hadv-positive patients admitted at either of the hospitals from to . partial genome (hexon and fiber) sequencing was attempted on all samples, ( %) of which were successfully genotyped. the most prevalent genotypes identified were hadv-b ( . %), hadv-b ( . %), and hadv-e ( . %) followed by hadv-c ( . %) and hadv-c ( . %). see figure for hadv genotype frequencies by year. among the retrospective cases ( pediatric and adult), hadv-b was most prevalent from to , which was consistent with previous literature for singapore [ ] . a total of ( pediatric and adult) prospective hadvpositive patients provided informed consent, and their samples ( % respiratory) and clinical data were included in the study (table ) . twenty-two immunocompromised patients were included in the study and described separately ( table ) . human adenovirus-b ( . %) was most prevalent among prospective cases, followed by hadv-e ( . %) and hadv-b ( . %) ( table ) . lastly, immunocompromised patients (adjusted odds ratio [aor], . ; % confidence interval [ci], . - . ) and patients infected with hadv-c (aor, . ; % ci, . - . ), hadv-b (aor, . ; % ci, . - . ), hadv-e (aor, . ; % ci, . - . ), or an unknown hadv genotype (aor, . ; % ci, . - . ) were found to have an increased risk for severe disease (table ) . (table ) . overall, ( . %) of the clinical samples were collected from adults, of which genotypes hadv-b ( . %), hadv-e ( . %), and hadv-c ( . %) were most prevalent. among the adult samples, ( . %) were retrospectively collected from to , whereas the remaining ( . %) were prospective samples from to . no significant differences in hadv genotype frequencies were found between retrospective and prospective adult patients. in , we noticed an increase in hadv-e infections. to learn whether the observed increase might reflect a novel hadv-e strain, hadv-e sample genomes were sequenced ( from severe and from mildly ill patients). another hadv species c samples were chosen for sequencing based on their discrepant hexon and fiber genotyping results between laboratories. based on the full genomes of hadv-c (figure ), isolates-sg , sg , and sg -belonged to c and were strongly monophyletic, with % bs support. these new isolates were also sister to a group of hadv strains from the united states. contrarily, isolate sg was nested within c lineage (ml bs = %) and closely related with a beijing hadv-c strain (human/chn/bj / ) collected from an infant during a hadv-c epidemic in beijing in - [ ] as well as earlier c strains from the united states isolated from to immunocompromised within months before clinical sample collection. c hospitalized for more than consecutive days. . it is notable that sg was isolated from a -year-old patient requiring oxygen therapy. hexon, fiber, and penton base topologies (supplemental figures and ) indicated that isolates sg and sg were most closely related, with strong bs support ( %, %, and %, respectively). however, penton base phylogeny (supplemental figure ) demonstrated that isolate sg was related to c lineage, although this lacks statistical support, as opposed to c based on full genomes. more notably, the penton base phylogeny demonstrated that isolates sg and sg were closely related to c and c . clinical descriptions of the singapore hadv-c isolates and their genbank accession numbers can be found in supplemental table and figure . in contrast to hadv-c, the full genomes of hadv-e ( figure ) clearly indicated new isolates (sg , sg , sg , sg , sg , and sg ) from singapore grouped within e , with strong bs support (ml bs = %). these results were concordant with fiber and penton base phylogenies (supplemental figures and ) , indicating that these e isolates were genetically identical ( % in both genes) and appeared to be clonal. however, the hadv-e hexon phylogeny (supplemental figure ) indicated that the e isolates were relatively segregated, despite being largely monophyletic. these isolates also exhibited . %- % nucleotide similarities, suggesting that some genetic variations existed among them. clinical descriptions of the hadv-e isolates and their genbank accession numbers can be found in supplemental table and figure . global mutational analysis using genome mutation mapper ([gmm]; unpublished beta software) was then used to investigate nucleotide-level variations (single-nucleotide polymorphisms and insertions/deletions) between the hadv-e isolates (sg , sg , sg , sg , sg , and sg ) and a hadv-e reference field strain [ ] . based on the genotyping failed. f gmm results, sg and sg are clones, "lineal" to sg and sg , which are clonal. clones sg and sg are also lineal to sg , which is lineal to sg . it is notable that sg has both an insertion and a deletion near the . -kda gene. in addition, to provide nexus with the earlier reports of hadv-e in the literature and to compare genome types [ , ] , in silico restriction enzyme fragment analyses were performed using snapgene (version . ), revealing that sg and sg are novel separate genome type variants, with differing drai and bamhi patterns and given designations " a drai/ bamhi v " and " a drai/bamhi v ". the others are genome typed as hadv-e a . these patterns support the lineages described by the gmm results. for reference, the hadv-e field strain is genome type hadv-e a [ ] , and the patterns for the prototype strains differ from the hadv-e a strains across all restriction enzymes applied, with one exception, a match of hadv-e p mil and the hadv-e a strains using ecori. our rdp analyses detected recombination events in new hadv-c isolates from singapore. recombination analysis of sg isolate clearly identified parental strains (bj and c ), and the estimated breakpoint was located at the position (supplemental figure a , supplemental table ). to confirm this result, phylogenetic analysis was independently performed for the gene regions before and after the breakpoint. the ml topologies (supplemental figure b) indicate that sg recombinant was descended from c , but it also comprised genetic components from the bj recombinant strain. the bj strain was crucially important [ ] because it has been shown to bear gene sequences from different genotypes: hadv-c at (position - , comprising e a, e b, penton base), hadv-c ( - , comprising hexon and fiber), and hadv-c ( -end, comprising the e gene region). the e region of sg recombinant also contained c because this region was recombined with the bj strain. another recombinant, sg , was found to be almost identical ( . % nucleotide identity) to sg , therefore they both displayed the same breakpoint location (supplemental table ) and rdp graph (data not shown) as well as the phylogenetic position as expected (supplemental figure ). these findings indicate that sg and sg isolates were recombinants of c and bj parental strains. recombination analysis of isolate sg (supplemental figure a ) suggested that this strain was recombinant of c and bj parental strains, although the sg backbone was largely derived from c . the ml phylogenies (supplemental figure b) confirmed, with strong bs support (ml bs = %), that sequence position - of sg isolate was nested within c , whereas sequence position - of sg isolate was closely related with the bj and bj strains. in contrast, the after stepwise logistic regression using saturated model and backward elimination of covariates with p > . . c immunocompromised within months before clinical sample collection. figure a ) displayed the parental c subtype as the main backbone, although recombination with c was found towards the end of the full genome. the rdp results were also concordant with the ml phylogenies that are incongruent with each other (supplemental figure b ). all recombination results were statistically significant (p < . ) (supplemental table ). in marked contrast, no recombination events were detected in the hadv-e isolates. this is the first large-scale study to systematically describe clinical hadv genotypes in singapore. our results highlight the prevalence of hadv-b and an increase in morbidity due to hadv-e and hadv-b pediatric infections in singapore. more important, patients with hadv-c , hadv-e , and hadv-b were more likely to have severe disease. hence, it seems prudent for public health officials and clinicians to consider using antiviral therapies and hadv vaccines in singapore. for instance, brincidofovir, an experimental antiviral therapy, is being used in the usa against severe hadv infections with good outcomes [ ] [ ] [ ] . in addition, a very effective "adenovirus type and type vaccine, live, oral" has been used among us military personnel since . the new version of this vaccine, used since , has resulted in a dramatic decline of respiratory infections among us military recruits [ ] . although this nonattenuated vaccine is not indicated to prevent infections for other populations (concerns for safety among the immunocompromised), other vaccines [ ] are being developed that might prove useful in singapore. given the lack of hadv surveillance in sea, it is unknown whether hadv-e is a new or re-emerging pathogen in the region. the high prevalence of hadv-e infections identified in our study is intriguing. the hadv-e genes and genome have been shown to be almost identical to several chimpanzee adenoviruses, including the sadv-e genome at % and the sadv-e at %, with the prototype as reference [ , ] . these values are consistent with hadv-e being the only hadv amongst several chimpanzee adenoviruses phylogenetically grouped within hadv species e, supporting a zoonotic origin, consistent with current hypotheses that cross-species infections may lead to the emergence of novel human pathogens [ ] . furthermore, sequence analysis of recent circulating hadv-e strains revealed a recombination event that provides a conserved dna replication motif (nf-i), likely from a respiratory pathogen of hadv species b, that is present in almost all hadvs but absent in sadvs as well as the hadv-e prototype and contemporaneously circulating isolates, including the "vaccine" strain [ , ] . this hadv-like motif, as well as the conserved core origin and nf-iii motif, were present in all of the fully sequenced singapore hadv-e genomes. the nf-i human transcription factor and its binding have been extensively characterized molecularly and biochemically as required for optimal hadv dna replication [ , ] . this putative genome-based host adaptation may be the "tipping point" that has allowed hadv-e entry into a global general population, which is presumably immunologically naive to its epsilon (hexon) antigen, because hadv-e had been known to circulate sporadically [ , [ ] [ ] [ ] . the recombination event is likely a recent one, with the earliest appearance in (kx v /france/ ) as noted in a resurvey [ ] of sets of recently released genomes that include archived and currently circulating military and civilian hadv-e isolates [ , ] , and it may be important as an example of a molecular evolution pathway by which zoonosis may be a source of emergent human pathogens [ ] . our rdp analyses detected separate recombination events in each of our hadv-c isolates, which suggests the frequent exchange of genetic components among different genotypes. sg , sg , and sg were shown to be recombinants of a clinically relevant parental strain, bj , a hadv-c strain isolated from an infant during a - epidemic in beijing [ ] . it is notable that sg was the only hadv-c strain fully sequenced in our study and was isolated in from a severely ill -year-old singapore patient requiring oxygen therapy. given the observed increased risk for severe disease among the prospective pediatric patients infected with hadv-c , infections of which occurred within a -month period, we speculate that these patients might represent a cluster. although our study revealed important findings regarding the epidemiology and clinical severity of hadvs in singapore, we were limited in our approach because we did not rule out all possible coinfections (other than influenza virus). it is also possible that some of the hadv infections were not associated with the acute clinical presentations. our study could have been strengthened by testing blood (or another sterile compartment such as csf) from all study patients or by testing matched patient controls to demonstrate a stronger probability of disease association. however, the prevalent genotypes identified (ie, hadv-b , hadv-b , and hadv-e ) were genotypes that are commonly known to cause acute respiratory infections. finally, mixed hadv infections could not be ruled out as the cause of the untypable patient samples ( %). this theory is supported by the observed increased risk for severe disease among patients infected with an "unknown" hadv genotype, as well as the high prevalence ( . %) of unknown hadv genotype infections among immunocompromised patients in our study. another reason for an untypable sample is inadequate hadv dna for amplification, resulting in an unknown hadv genotype classification. the majority of these untypable samples were adult samples, which is consistent with the theory that infected adults shed less virus when compared with children. our study demonstrates how hadv genotyping can be performed 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during a lapse in vaccination key: cord- -vs famsa authors: foley, m.; mcpherson, g.; mcgillivray, d. title: establishing singapore as the events and entertainment capital of asia: strategic brand diversification date: - - journal: international perspectives of festivals and events doi: . /b - - - - . - sha: doc_id: cord_uid: vs famsa nan contained within singapore tourism board's (stb) vision for tourism is the stated intention to establish singapore as the ' events and entertainment capital of asia ' . this strategy is part of wider economic development agency attempts to diversify singapore's brand beyond its well established reputation as a leading business destination. the city wants to capture the attention of global tourism markets by redefining itself as a vibrant cultural hub with an events and entertainment offering to rival some of the world's most attractive cities. this strategy can be viewed as a response to the intensification of global place wars for attention which have increased the pressure on destinations the world over to create unique attractions to entice valuable mobile capital. this chapter provides a critical overview of the global context for inter-urban place wars before focusing on the value of an events-led strategy in delivering competitive advantage for singapore. methodologically, it draws on elite interviews with leading singaporean cultural policy makers, observations at local, national and international events and documentary analysis of the recent strategic environment for singapore tourism. we contend that the city branding and place-making strategies employed by the singaporean state apparatus are designed to create cultural strategies which ensure the gentrification of space and place necessary for the reception of global tourism inflows. in essence, we suggest that singapore has used its events-led strategies to extend its internal processes of cultural planning, regeneration and development at the same time as securing a global position in the increasingly competitive events (and place) bidding wars. events (or culture)-led strategies in establishing competitive advantage for cities within the global economy. hall ( ) , reflecting on the growth of sports mega-events, argues that neoliberal entrepreneurial growth strategies are now regularly played out by cities around the world. in zukin's ( ) words, culture is increasingly the ' business of cities ' , an ' instrument in the entrepreneurial strategies of local governments and business alliances ' (p. ) . in urban environments across europe, the americas and asia, public and private growth coalitions come together to utilise events and festivals as a means of gaining competitive advantage in increasingly aggressive place wars ( haider, ; short and kim, ; yeoh and chang, ) with other aspiring global cities. these place wars are driven by the need to create a favourable image to tourism, migration and business marketplaces. increasingly, sporting and other cultural festivals and events represent particularly attractive communication vehicles for cities as they interact with the globalised media complex and vie for the attention of policy makers, consumers and investors, alike. in the competition for attention ( goldhaber, ) , places seek out means of differentiation and distinction; unique qualities which can attract valuable mobile capital to advance their economic standing. the decision to engage in city event branding of this sort is almost always politically motivated, rather than cultural or even economic. today, cities are under pressure to be seen to be bidding for sporting mega-events or to create large scale festivals so that they maintain position in the rankings of top global cities (shoval, ) . however, exploiting the cultural cache of festivals and events is not the only (or even the most popular) means for cities to secure attention. richards and wilson ( ) suggest that branding the built urban environment with signature or iconic buildings and cultural quarters is perhaps the most frequently used means of altering perceptions of a locale. yet, regenerative strategies based on the transformation of the builtscape ( chang and huang, ) suffer from the threat of homogeneity and serial monotony ( harvey, ) which has afflicted other destinations. moreover, in the fastpaced global economy, an over-reliance on inflexible, physical spaces of regeneration can leave destinations vulnerable to changing architectural fashions and ambitious competitors. in contrast, events and festivals ' provide a means of adding flexibility to fixed structures, supplying a source of spectacle which adds to the image value of a landmark ' ( richards and wilson, , pp. - , or of a destination. events are an attractive proposition for policy makers because they animate objects, they enliven the physical environment and, in their uniquely media-friendly form, they transcend geographical boundaries. using chang and huang's ( ) terminology, the creation of ' eventscapes ' also allows places to produce new symbolic (often contrived) meanings, catering for ' new lifestyle needs ' (p. ) . for example, reflecting on the regeneration of the singapore river, they argue that a process of ' creative destruction ' has taken place whereby the neoliberal ideological policy of the city has transformed the environment into ' an image of leisure and entertainment at the waterfront, at the expense of landscapes of past economic and social ills ' (p. ). investing in, and creating, festivals and events is doubly attractive to semi-peripheral cities and states ( whitson and horne, ) as they can use these spectacles to establish themselves on the world map. these events can also give others the impression that a city has an achievement and entrepreneurial orientation, informing potential suitors (e.g. investors) that political leaders are enterprising ( whitson and horne, ) . festivals and events permit semi-peripheral, or regional powers, to showcase their offerings through the global media to a watching audience, influencing perceptions of place identity -both externally (to the possessors of circulating capital) and internally (to members of the host population). the strategies discussed thus far only bear fruit because cities now operate in a fluid symbolic realm, where image enhancement carries a value; where the hosting of unique events helps cities express their ' personalities ' and advertise their position on the global stage ( essex and chalkley, ) . sporting and cultural events also fit with the dominant logic of consumption, providing a ' point of identification ' ( richards and wilson, , p. ) for consumers in a crowded marketplace. in discussing place images and their relationship with events, richards and wilson argue that ' events have become a particular valuable form of cultural currency ' (p. ) creating a favourable impression of the city or nation as a destination worth visiting. the proliferation of cultural and sporting festivals can be associated with, and supports, similar trends towards a cosmopolitan ethic which defines a neighbourhood or city as vibrant. when contrived or manufactured events are hosted, the façade of the city is invariably dressed is such a way as to communicate specific impressions to target audiences. events are invariably located in gentrified spaces (or in places which are undergoing gentrification processes) and help choreograph forms of cultural consumption which fit with how the city wishes to be perceived, and with the values of those people it wishes to attract (principally the incoming visitor). the visual representation of cities is particularly valuable in the dominant symbolic realm of inter-urban place marketing competition. festivals and events provide city marketers with a plethora of suitable vibrant, colourful and multicultural images which are easily packaged for global circulation. sydney has its mardi gras, rio exploits the carnival and london uses notting hill carnival to represent the city in a suitably cosmopolitan way. the process often involves recreating a sanitised historical narrative ( chang and huang, ) , one that the governing agencies can utilise to secure the consent of the host population and which is also, crucially, exploitable as a tourism resource. internationally renowned festivals, such as notting hill carnival, were often created to address the threat posed by social unrest and riots and were targeted towards a particular ethnic minority group. today, however, these events are invariably used as a clever marketing tool for civic leaders to showcase their destinations ' cultural diversity. political decision makers in cities such as rio and new orleans have continually reinvented their festivals by globalising local celebrations and selling them as unique attractions via global media networks. behind many city event-led strategies sit entrepreneurial governments seeking to attract circulating capital ( schimmel, ) which brings the ' footloose consumption ' (short and kim, , p. ) of tourists and conventions to their destinations. in the s and early s, us downtowns were transformed into packaged landscapes ( boyer, ) with cultures of consumption being defined by spectacularised urban space ( hannigan, ; harvey, ) . this format for urban growth is now replicated across the world, with cultural consumption at its core. in developing major festival and events strategies, cities tend to work to a common denominator in respect of the markets being courted. these tend to be high spending tourists, middle-class professionals and potential investors. however, the beneficiaries of these event-led strategies are not always those people to whom the city leaders are democratically accountable. it is to the politics of event-led growth that we now turn. of course, in the competition for favourable city status there are invariably winners and losers. as hall ( ) contends, pursuing a major events strategy may well produce lucrative short term gains for private interests (e.g. construction firms, advertisers or sponsors), but this can bring more negative long term consequences for other public stakeholders. this view is supported by the work of smith ( ) , macleod ( ) and others who consider the changing urban policy landscape to be defined by a dominant neoliberal logic in central and local government towards urban entrepreneurialism subsidised by the public purse, which leaves some stakeholders disempowered from decisionmaking processes and from the promulgated economic rewards. as control over content and promotion is handed over to multinational conglomerates -the driving force for many large scale events -cities and nations also risk alienating the citizens who are identified as the main beneficiaries. once sponsors have a stake in an event, the presentation of place for target market consumption is more difficult to manage and control. hall ( ) identifies the problem as being about a perceived democratic deficit, whereby local citizens are disempowered from their rights in the furtherance of a large scale events policy. alongside whitson and horne ( ) , zukin ( ) and richards and wilson ( ) , hall ( ) asserts that the dominant discourse of capital accumulation provides an ' ideological justification for place-competitive re-imaging strategies ' (p. ), and a ' competitiveness hegemony ' (p. ), which places the logic of capital central to policy discussions and decisions. gray ( ) labels this the commodification of cultural policy, where decisions on investment in forms of cultural expression are made with economic logic in mind. in pursuing an events-led regeneration strategy as a means of escaping ' routine identities ' ( richards and wilson, , p. ) , cities also face the threat of reinforcing sameness and cultural uniformity, in creating a ' homogenised uniqueness ' . furthermore, in following a strategy of creating international (or global) events for touristic consumption, the sharp contrast between the host population and the affluent tourist tribes ( schimmel, ) being targeted by city governments may also be thrown into view. for example, judd ( ) , commenting on the fallout from an overemphasis on attracting tourist dollars in the united states, warns that the islands of affluence created often hide the real material deprivation and cultural exclusion faced by some host residents. cultural and sporting events have also been employed as a means of addressing the tensions associated with multiculturalism ( zukin, ) expressed in the promotion of ' local ' ethnic uniqueness (chang, ). yet, this again can be understood as an intentional policy response to the threat posed by global (read standardised) culture, using cultural diversity as an instrumental tool to attain non-cultural aims and objectives ( gray, ) . the symbolic realm ( zukin, ) -a realm of images, signs and spaces in cities -permits the creation of collective identity forms, albeit one frequently mediated by the relationship between ' cultural symbols and entrepreneurial capital ' ( zukin, , p. ) . in implementing an events-led strategy with the discourse of enterprise at its core, debate over the appropriate use of contested public space is also brought to the fore. the loss of public space free from the logic of consumption is an issue which has attracted the attention of academic commentators and anti-globalisation prophets in recent years (see klein, ; zukin, ) . they argue that civic spaces are now colonised by private capital (e.g. sponsors), often at the bequest of the public authorities. there are a number of problems associated with this development when considered in relation to festivals and events and their projected tourism returns. first, as invented or contrived cultural events and festivities colonise civic space (e.g. squares, main avenues) the outcome can be the production of intensely regulated, or gated, communities identified by the presence of security barriers, security guards and the ubiquity of cctv cameras. regulatory control over licences, traffic management, environmental pollution and the like ensure that the civic authorities and their (growth) coalition partners can easily manage the cultural offering to produce ' safe ' spaces for tourist consumption. however, this can leave the impression of a public culture controlled and contained, managed and directed for the benefit of the footloose consumer. the implications of what gray ( ) calls an acceptance of a commodified conception of public policy is that collective space is re-conceptualised as consumable space. in focusing on the singaporean context for events and festivals over the last decade, the empirical component of this chapter will now review critically the implications of the nation's drive towards the title of ' events and entertainment capital of asia ' . since gaining independence from the united kingdom in , the singaporean government's main aim has been to maintain stability in the areas of economic and environmental development. at the same time, the government has also continued with its drive to reinforce a discourse of national identity through the development of cultural policies based on the promotion of singapore's shared values. politically, whilst the city-state is a democracy, the people's action party (pap) has been the only ruling power since it took over the reigns from the colonial governor. singapore does have a representative democracy and has official united nations ' recognition as a parliamentary republic. despite being small in physical size, singapore has a high population density of approximately . million people which in the census encompassed a multi-ethnic mix of chinese . %, malay . %, indian . % and others . % ( www.singstat.com , ) . as a post-colonial power, singapore has invested heavily in creating a sense of national identity, often using the vehicle of cultural events as a means of integrating the diverse multi-ethnic population along the lines of shared singaporean values (e.g. national day celebrations). indeed, in singapore, the debate over the need for a strong sense of national identity started at independence from british colonial rule ( kong, ) . this movement strengthened in the s and s as part of a larger nation building initiative. the pap's authoritarian regime ( tamney, ) , at least in the first three decades of independent rule, promoted a discourse of national survival and the protection of asian values in the face of the challenge posed by perceived western decadence. however, as singapore rapidly industrialised, the focus of government policy shifted from ' protection ' and the cultivation of shared national values, to the promotion and encouragement of inward investment in entrepreneurial growth strategies. the success of this strategy is illustrated by singapore's position as the most economically successful country in south east asia ( ooi, ) . singapore's rapid industrialisation in the s and s was based on the authoritarian regimes ' tight regulation and exploitation of shared national values of hard work and nation before community. however, as strong economic returns were amassed, the attention of government and citizens alike turned from necessity to luxury; from work to leisure and consumption. through the s and into the new millennium, the government has had to re-evaluate its authoritarian approach as its working population reflect upon the sacrifices made in the name of economic growth. in policy terms the government has created heritage spaces and other ' places to play ' (judd, ) whilst, at the same time, maintaining a ' hegemonic ' control over their population. however, in recent years, singapore has also sought to exploit its popularity as a travel destination, even in the face of the sars (severe acute respiratory syndrome) crisis early in the new millennium. despite this crisis, tourism has evolved into one of its largest industries, with around . million tourist visits in . the singaporean government has set a target of at least million visitor arrivals by . the orchard road district is the central retail hub in singapore but, until recently, the city has suffered from a relatively low attractions base. however, this has been addressed by the tourism authorities and the urban redevelopment authority over the past few years. these agencies have been involved in the development of two integrated resorts at marina south and sentosa island, alongside the singapore flyer, the gardens by the bay, the singapore river development and the construction of the double helix bridge connecting tourist attractions in and around the packaged landscape of marina bay. whilst the ' builtscapes ' ( chang and huang, ) have been markedly enhanced, this has gone hand-in-hand with the development of the accompanying ' eventscapes ' ( chang and huang, ) . the great singapore sales, singapore food festival, the singapore river hong bao festival, the singapore arts festival and the chingay parade represent opportunities to promote singapore to regional and international markets. add to this sporting events, like the singapore masters, the singapore marathon and the f grand prix (due to visit singapore in for the first time) , and it is clear that singapore is following a well-trodden path towards the use of events and other cultural forms as valuable commodities worth packaging and selling to the rest of asia and, increasingly, to wider tourism markets. in many respects, singapore has invested in its creative and cultural offering as much out of necessity as of choice. this need is driven by the fact that there are scant natural resources in this island nation, due to its small land mass and high population density. unlike korea and taiwan, singapore does not have ship building or agricultural activities on which to generate economic growth. however, the ruling party seized the opportunity to use ' cultural maintenance ' to both exercise power over the people and form new markets ( miller and yudice, ) . from the late s onwards, the singaporean state, through its vehicles of economic development (the ministry of trade and industry and the singaporean tourism board), has pursued an ambitious strategy to attract global tourism spend by re-branding singapore as more than a business travel destination. in recent campaigns, singapore has been labelled a ' global arts city ' , ' uniquely singapore ' , an ' eventful city ' and, most recently, the ' events and entertainment capital of asia ' . it is the final label, the events and entertainment capital of asia that will occupy our attention in the remainder of this chapter. in the furtherance of this study on the event and festival strategies being utilised in the promotion of singapore as a tourist destination, a mixed methods case study approach was employed as it ' allows an investigation to retain the holistic and meaningful characteristics of real-life events ' ( yin, , p. ). yin ( ) argues that the benefit of employing a case study approach in the contextual situation of the studied phenomena is integrated into the mode of enquiry, thereby permitting the relationship between context and phenomena to be delineated. the research strategy underpinning this chapter took two main forms. the substantive phase of fieldwork was gathered by members of the research team during a field trip to singapore in february . elite semi-structured interviews were conducted with representatives from statutory and non-statutory bodies drawn from the tourist sector, from cultural institutions and from enterprise organisations. interviews were held with individuals from the national arts council ( ), national heritage board ( ), singapore tourism board ( ), singapore sports council ( ) and the international festival and events association ( ). the research team intentionally selected interviewees who were in a position to make meaningful comment on strategic issues pertaining to events and festival policy in singapore, whether in the arts or in sport. each interviewee was asked questions around key themes concerning the rationale for investment in festivals and events and the policy outcomes sought. themes included: • the perception of events and festivities in the tourism product of singapore now and in the future. • the strategy to make singapore the events and entertainment capital of asia. • the sensitivity of multi-racial diversity issues in promoting events and festivals to tourist audiences. • placing singapore on a global map and the importance of local cultural heritage in that positioning. • the role of sports and arts events in making singapore into a global player for the events sector. • the marketing of singapore as the bridge between the east and the west for international events. • the role of local events in forming singaporean cultural identity and the promotion of this globally. given the three-year time lag since the completion of the elite interviews, an extensive desk-based research phase was also undertaken in to provide an update on the singaporean context and to investigate the policy rationale behind a significant intensification in singapore's pursuit of an eventsled strategy since . documentary analysis was carried out on a number of strategy documents pertaining to economic and tourism policy and on press coverage relating to several of singapore's renowned cultural and sporting events. the documentary analysis eschewed content analysis techniques in favour of discourse analysis. the former is a quantitative and scientific approach which focuses on the ' direct, deterministic and unilinear link ' within documents, ' from sender to communication to recipient ' ( jupp and norris, , p. ) . however, in evaluating the contents of government policy and strategy, it is more meaningful to consider the status of ' official ' documents as socially constructed entities. that withstanding, documents are subject to multiple interpretations both temporally and spatially. for this chapter, a more qualitative, discourse analysis of strategy and policy documents was undertaken, taking into consideration the distinctive political and economic context of singapore at the time of their publication. when considered alongside the views of the elite interviewees -the ' local interactional context ' ( flick, , p. ) -a more thorough evaluation of strategic rhetoric and local realities can be accessed. leisure and tourism markets represent key strands in stb's strategy to create a unique destination singapore brand identity that complements its well established reputation as a leading business destination. the stb has a professed aspiration to establish singapore as the ' events and entertainment capital of asia ' (stb, ) , attracting ' a big variety of the world's best events year round for visitors to enjoy ' . working in tandem with the principal economic development agency, the ministry for trade and industry (mita), the stb provides public subsidy and expert support to incentivise cultural and sporting festivals and events to attract tourist expenditure. this approach is in line with the city's long term goal of competing on a global level, and in presenting itself as safe asia ( foley et al., ) offering sanitised, hyper asian experiences alongside dominant western ideologies of consumption. events and festivals have become a key plank of the city's global strategy to communicate, or present, an alternative singaporean identity to the rest of the world. chang and huang ( ) suggest that the singaporean authorities are pursuing a strategy of ' forgetting to remember ' , a ' strategic undertaking that streamlines the past in ways that are coherent to the present and profitable for the future ' (p. ). chang and yeoh ( ) also suggest that singapore's cultural landscapes are repackaged as marketable commodities. in the case of singapore's events-led strategy, the ' profitable future ' is build around increasing tourism spend and in creating favourable impressions of singapore as a distinctive destination to visit -a destination which is progressive and sophisticated, yet still an expression of the asian soul (e.g. the new asia marketing campaign). that it is a strategic undertaking that is evidenced in the level of g overnment support which some showcase events receive, whether that be in the arts and cultural area or in relation to large sports events. in many cities government support is forthcoming because of the projected international tourism returns accruable from events, but in recent years singapore has deliberately altered its strategy to limit the number of events it invests in. as the singapore director of the international festivals and events association (ifea) acknowledges: our strategy is now to improve on developing quality in world class activities that have got tourism appeal (wong, february , interview) . in developing events with tourism appeal, the place marketers encourage the promotion of activities which ooi ( ) argues falsify time and place; events without a past but with an exploitable future. these events overlook some elements of the rich cultural heritage of the city, in favour of marketable commodities. the promotion of what chang and yeoh ( ) call inauthentic products is apparent in singapore's recent successful attempt to attract one of the world's most lucrative transportable sporting events the f grand prix to its streets in . this event promises to be the first ever night race, designed specifically to exploit television audiences in asia, europe and the united states. the singapore government expects tourism revenues of £ million from the event (mti, ) ; however, the direct economic benefits are only a small part of the overall strategic rationale for hosting the event in singapore's recently redeveloped marina area. the principal strategic driver is to re-position singapore as a leisure and tourism destination in the minds of existing and new markets. in the intensely competitive asian region, singapore is adopting a strategy of urban entrepreneurialism, competitiveness and growth ( hall, ) . driven by its agencies of economic development, the singaporean state has engaged in a place-competitive re-imaging strategy intended to produce a ' vibrant global city that is abuzz with high quality entertainment and events ' (mita, ) . to further emphasise the strategic importance of this flagship event to the city, the stb has made a commitment to fund % of the costs from a tourism development fund, complementing private investments. this represents an example of public and private growth coalitions working in tandem to showcase an area's unique facilities and attractions, as a means of gaining valuable coverage in the global media complex. singapore's events-related investment is not, however, restricted to the realm of mediasport events. the arts and cultural field is also following what gray ( ) calls a commodified conception of public policy, the instrumental use of culture for non-cultural outcomes in its adoption of flagship arts events (e.g. singapore arts festival) to promote singapore to a watching global audience. as the director of programme development at the national arts council suggests: our mission is to develop singapore into a global arts city. so that's the way we are and so creating these events will help to put us on the world map … that sense of positioning ourselves and how we make strategic positioning of singapore … how we can use the arts to give singapore an identity and an image which i think reflects us (lee, february , interview) . much of the strategic rhetoric in singaporean policy is concerned with creating distinction within an increasingly competitive global marketplace, capitalising on a (constructed) shared heritage, unravelled cultural diversity and outstanding infrastructural hardware. as the director of special projects at the stb indicates: we would use events as a main hook, a main magnet -we have to differentiate ourselves … so what we look for as strategy for singapore is events. it is events which actually leaven what you call the bread. the bread could be baking with shopping, with a lot of lifestyle activities, but it is events which have a fantastic pulling power (khor, february , interview) . singapore is certainly using ' unique ' events to attract attention from key markets as a means of increasing its levels of tourist visitation towards its target of doubling visitor arrivals to million a year (tourism working group report, ) . the government's investment in attracting large scale regional and international sports events (e.g. singapore open golf, lexus cup golf, singapore masters golf, aviva singapore open badminton, singapore marathon) has recently been supported by the construction of the singapore sports hub, the ' hardware ' (wong, february , interview) , which is described as ' a unique cluster development of integrated world-class sports facilities within the city … it will play a critical role in accelerating the development of the sports industry ' (singapore sports council, ) . singapore clearly wishes to enhance its level of status and prestige, giving visitors a reason to identify with the city. as the stb chief executive, lim neo chian, illustrates with respect to the grand prix, singapore wants to position itself as a place to ' be in and be seen in ' (stb press release, ) . this further reinforces richards and wilson's ( ) view of the cultural currency of events in creating a favourable impression of the city or nation as a desirable destination. in referring to the importance of the chingay festival in promoting singapore to external markets, the director of ifea emphasises the: marketing value of this event being broadcast in portugal, for example, and the eyeballs that see singapore as a happening and aspirational place -it is imprinted on this individual's mind -one day i would like to go to singapore (wong, february , interview) . using hallmark or special events to manage impressions of a destination can further enhance the existing product offering, whether cultural, sporting or business. returning to the singapore grand prix, the stb believes that its presence in singapore will create ' positive energy ' , unrivalled ' exposure ' and an opportunity to showcase the city's physical, cultural, sporting, artistic and historical landmarks. events provide an unparalleled immediacy of message which makes them attractive to place marketers: branding brings in immediate returns in terms of media attention, global media attention. so we are very conscious of the branding potential of ourselves as an eventful city. but now we are going to be more strategic and discriminating in picking up the ones (events) that will attract different markets (khor, february , interview) . what is apparent in this strategy is that the government agencies are now discriminating between those events which have local value and meaning and those which will bring exposure to new audiences and lucrative broadcasting revenues. at this time, the agencies responsible for economic development are concentrating on exploiting the potential of the latter, sometimes at the expense of events with significant national (and regional) appeal: you have … events like table tennis and badminton which we are actually quite good at, in asian culture we are quite good at. we have opportunities to win gold medals at olympics or asian games, but from the commercial infrastructure perspectives it is limited because the sports are not really sexy -there isn't enough appeal (khoo, february , interview) . in this example, decisions over the support for specific sports events are made on the basis of commercial appeal and not national participation targets. this reflects the dominance of neoliberal entrepreneurial strategies and their impact on other public stakeholders within the singaporean context. the singapore sports council interviewee (khoo, february, interview) indicated a tension between the needs of the sports development agenda and the economic imperatives underpinning the international events strategy. the logic of capital certainly informs sport and arts policy in singapore, but with low levels of expressed discontent a feature of singaporean society, the outcomes of the policy drive are perhaps less noticeable than in other cities (e.g. toronto). another noticeable feature of singapore's event-led strategy is the way in which the promotion of indigenous cultural events (e.g. chingay, river hong bao festival and taipusam festival) comes together with world-class sporting spectaculars to symbolise the notion of a ' new asia ' brand, where ' east meets west, asian heritage blends with modernity and sophistication, and old world charm combined with new world vision ' (mita, ) . chang and huang ( ) argue that the creation of the new asia brand in singapore is tied up with re-fashioning the built environment (e.g. the river), the staging of events and activities (e.g. the f grand prix) and the establishment of public art installations. they also see this move as reflecting wider state attempts to create new memories and identities for singaporememories befitting its aspiration to acquire and sustain global city status through destination singapore. returning to mita's version of the new asia brand, the f grand prix epitomises the ' west ' , ' modernity ' and the ' new world vision ' . the street circuit is designed specifically to open up key landmarks to media view, animating the city's wider cultural heritage attractions to the watching world. in the singapore context, like elsewhere, events operate as brand vehicles employed to communicate visual and audio messages via the symbolic realm of inter-urban place marketing competition. however, despite singapore's apparent success in attracting the attention of the world's arts and sporting glitterati in the form of the singapore arts festival and the f grand prix, there are clear dangers associated with a rapid rise to prominence. given the earlier discussion of the dangers of serial monotony and homogenised uniqueness, it is important to subject singapore's events-led strategy to further critical scrutiny on the basis of its ongoing sustainability. in interviews with key policy makers, it was apparent that there is some concern associated with a shift away from a mainly local or regional events policy, driven by the demands of national unity towards a more abstract, place branding strategy. chang and yeoh ( ) warn of the creation of inauthenticity and the sports council representative reinforces this view in the following commentary: i think the first priority is to understand that events must be local first before you go outside. if you have a , seater and you can only fill it with , people even though it has got massive international appeal you are really losing out because international appeal takes time to build. i think for singapore, six to eight major events probably is just right for us and you can underpin that with a whole group of different events that can bring the vibrancy of a community (khoo, february , interview). this response was also repeated in interviews with the cultural agencies and with representatives of the stb. however, whilst the global place wars continue apace, it is unlikely that singapore's agents of economic development will alter their internationalisation strategies in the face of the inevitable global forces which require cities around the world to engage in interdependent transnational relationships with other aspiring contenders. singapore is often described as a ' hub ' for a variety of business and travel processes, but it is now striving to exploit its events and entertainment offering to gain recognition as a tourism destination in its own right rather than as a stopover on the journey to australia. since gaining independence from the united kingdom in , the singaporean government has undertaken a series of national unity projects designed to secure the active consent of its population around the values of hard work and thrift. however, with its rapid industrial and subsequent postindustrial growth, singapore has had to embrace the challenge of securing the valuable mobile capital of investors and tourists in the face of increasingly competitive global place wars. since the turn of the new millennium, singapore has invested heavily in an events-led strategy designed to secure its position as the events and entertainment capital of asia. in its use of sporting and cultural events to re-brand itself as a vibrant destination, singapore has sought to animate its existing attractions and landscapes to communicate positive cosmopolitan credentials to regional and international audiences. as part of this strategy, singapore has invested significant public funds to support infrastructural developments and bids for internationally recognised sporting events which bring immediate symbolic returns, in terms of the communication of managed images through the global media complex. the forthcoming singapore f grand prix is the vehicle on which singapore hopes to build an international reputation as a leisure and entertainment hub -one worth visiting as a destination in its own right. the brand identity transmitted in the interface between traditional cultural events and manufactured sporting spectacles is inseparable from the notion of singapore as new asia -a city in which tradition and modernity sit as one alongside multi-ethnic diversity and globally recognisable products and services. the old and the new, the authentic and the contrived are immutable features of the singaporean events offering. however, should the balance of power shift too far 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mega-events in canada and japan globalising singapore: debating transnational flows in the city case study research: design and methods key: cord- -utbrf ad authors: fisher, dale a; chew, madeleine h l; lim, yean‐teng; tambyah, paul a title: preventing local transmission of sars: lessons from singapore date: - - journal: med j aust doi: . /j. - . .tb .x sha: doc_id: cord_uid: utbrf ad nan has been designated as a "non-sars" hospital in singapore's health system. in theory, the hospital is to remain sars free -by instituting measures to detect cases, providing isolation for suspected cases and referring probable sars cases to tan tock seng hospital (the designated sars hospital). the intention is that nuh continues to be part of a sars-free segment of the health system. evidence to date suggests that this is not easily achievable. although the patient reported no contact history with a patient with sars, and had not been to any recognised singapore sars "hot spots", it later transpired that his brother was ill in hospital and was subsequently shown to be the index case of a sars cluster involving cases at singapore general hospital. the patient was in the emergency department (ed) for hours and the ward for hours. during this time he was not isolated, as he gave no contact history for sars and was afebrile. furthermore, at that time in singapore, gowns, gloves and masks were not consistently worn by staff, and were generally reserved for those caring for identified suspected cases. during the hours, there was disease transmission to one doctor, two nurses, three patients and a visitor (box ). other cases -a doctor, a nurse and a visitor -remain "suspect", and second generation cases are beginning to present. a total of contacts were identified for the -hour period, each person requiring varying levels of intervention from counselling through to home or hospital quarantine. unfortunately, the first doctor infected (box ) was not initially identified as a contact, as she had worn gloves, a gown and an n- mask. infection may have been a result of inadequate eye protection when transferring the patient to the intensive care unit (icu). she was in the hospital on the day of her first symptoms, and, as a result, four wards (around patients) were quarantined. community spread involving at least five individuals is now also linked to our patient before his admission. his wife and two of his three children have sars, as does a taxi driver who took him to work just before hospital presentation. the patient was a vendor at one of singapore's largest markets. as the extent of our patient's cluster became clearer, there was major concern in singapore with the identification of another market vendor and his family with sars. the ramifications of spread within a crowded market place prompted the unprecedented move by health authorities to place individuals on home quarantine orders for days. the value of quarantine is an ongoing debate, but it is one of the few measures that can be taken during an infectious disease outbreak. instituting this preventing local transmission of sars: lessons from singapore clinical record at : on april , a -year-old man presented to the national university hospital emergency department (ed) complaining of light headedness for days, and dry cough and body aches for days. his general practitioner had recorded a temperature of . Њc. on further enquiry in the ed, he described mild dyspnoea and palpitations. for over years, he had smoked cigarettes a day, and had consumed at least g of alcohol per day. he gave a history of hypertension, ischaemic heart disease and chronic atrial fibrillation. regular medications included isosorbide dinitrate, aspirin, digoxin and candesartan. he had not travelled out of singapore recently, nor did he report contact with anyone suspected of having sars. the patient's temperature was . Њc and he was noted to be "comfortable". bilateral basal crackles were audible on auscultation. his chest x-ray showed cardiomegaly and nonspecific bibasal infiltrates ( figure ). arterial blood gas measurement revealed a ph of . , po of mmhg, pco of mmhg and an arterial oxygen saturation (sao ) of %, on an oxygen mask delivering a fraction of inspired oxygen (fio ) of %. he was assessed as having cardiac failure and admitted to an open, shared ward at : . admission blood results included a normal total white-cell count ( . x /l), but lymphopenia ( . x /l), and a lactate dehydrogenase level of u/l (normal range, < u/l). other measured parameters gave unremarkable results, but in hindsight these abnormalities may have been early pointers to the ultimate diagnosis. , within hours of admission to the ward the patient's condition deteriorated rapidly. although consistently afebrile during this period, respiratory distress and worsening hypoxia ensued, with sao at % on a "non-rebreather" mask with fio close to %. echocardiography showed good ventricular function, inconsistent with heart failure. at : , he was transferred to the intensive care unit (icu), and hours after presentation a temperature of . Њc was noted. three hours later, because of further respiratory deterioration, he was intubated ( figure ). he was transferred to the designated sars hospital, and died on april. the diagnosis was confirmed later when sars coronavirus was identified in a throat swab on pcr testing, using primers developed by the bernhard nocht institute. postmortem examination showed "solid lungs" (> kg each). haemorrhagic infarcts were seen macroscopically. microscopy showed diffuse alveolar damage, with inflammation and fibrous changes of the alveolar walls. the alveolar damage was not uniform in all parts of the lungs, but showed some temporal phasing; ie, severe damage was interspersed with an intermediate degree of damage and some relatively normal alveolar air sacs. postmortem lung tissue specimens were also positive for sars coronavirus. safeguard has caused significant financial hardship to individuals and disrupted the flow of food supplies in singapore. there are numerous lessons to be learned from this case. although a contact history, by our understanding, was clearly present, our patient did not appreciate this. we would regard an unwell brother in hospital, whom he had visited a week earlier, as a significant contact. had this information been forthcoming at the initial general practitioner visit or on ed presentation, the whole scenario may have been prevented. at that time, patients "with" versus "without" a contact history were managed differently. now, in response, we have de-emphasised the importance of a lack of contact history. australia must ensure rapid identification of a potential index case at points of initial contact in hospitals, community clinics and general practices across the country. as well as giving no contact history, the patient presented afebrile and gave no history of a fever > . Њc, which many regard as essential to confirm a diagnosis. we have now learned that fever may appear later, particularly in individuals with comorbidities. our patient's other medical problems, including excess alcohol consumption and cardiac disease, may have contributed to the absence of fever. it is also possible that patients with such fulminant disease may be relatively immunocompromised, impairing their ability to mount a fever. most certainly, and with the benefit of hindsight, our patient had fulminant disease, progressing from being "comfortable" to respiratory failure requiring intubation in hours. it is probable that he had a high viral load, which would explain the rapid deterioration in his condition as well as his infectivity. fever is essential to the world health organization case definition of sars (box ), but clinicians must not confuse an epidemiologically useful definition with clinical criteria. if fever is present at admission, the situation is much clearer, but cases such as this one have prompted us to change the threshold criteria for initial isolation. at nuh, any patient with fever or respiratory symptoms or a chest x-ray abnormality not otherwise explained is initially admitted to one of our newly created "fever wards". in the first weeks of our engagement with sars, there have been admissions (including staff) to these wards, with individuals ( . %) referred as suspect or probable sars cases. such a practice consumes considerable resources with a low yield of cases. the patient described, however, demonstrates the heavy costs of not isolating. the lead time australia has to establish healthcare systems to cope with sars, as well as our geographical barriersallowing assessment of newly arrived travellers for fever and typical symptoms of sars -should provide us with a primary level of protection. , in countries with the resources to implement full and effective contact and respiratory isolation for all suspect patients, local transmission of the virus has been almost non-existent. the incubation period of around days is long enough, however, to permit a first presentation of an individual with sars anywhere in australia. early identification of potential cases requires sustained clinical vigilance at all points at which patients enter the health system. health administrations must ensure accountability of these processes nationwide. provided there is consistent early identification of imported suspect cases, then australia's healthcare system can manage these patients with appropriate isolation to prevent secondary transmission. all the nurses and patients involved with our patient were identified as contacts and isolated (box ). their quarantining possibly prevented escalation of this nosocomial outbreak. the fact that this disease presents and spreads foremost as a nosocomial infection permits us to provide community protection by focusing efforts in the health sector. our experience with this patient, and similar atypical cases, informs us that patients with sars cannot invariably be identified on admission. thus, in addition to the low clinical thresholds to isolation, nuh has instituted the wearing of masks for all staff and visitors to provide a level of protection from unidentified cases. staff with any patient contact wear a mask, gown and gloves, and sometimes eye cover as well. the documented spread to hospital visitors has seen singapore limit non-essential attendance at all hospitals and exclude children visitors. patients presenting with overt symptoms suggestive of sars, including fever, are unlikely to be the source of an outbreak. unidentified sars cases not in isolation have to date been responsible for most outbreaks. individuals requiring hospital admission who have been in affected countries in the preceding days may be infected or incubating the disease. monitoring and possible isolation of these patients should be considered. a second tier of public health protection should be invoked once secondary transmission has occurred. this will be instrumental in australia's (or a region's) chance of remaining sars free. the response will need to be in hours, not days, and must use all available epidemiological resources for contact tracing, quarantine and isolation. government, health jurisdictions, and clinicians must act collaboratively and proactively. unfortunately, experiences in singapore suggest that the spread of sars, while being somewhat controllable, is very difficult to fully extinguish once established. observations from frankfurt and vietnam, where single, imported cases led to limited secondary and no tertiary spread, suggest that preparedness, drastic measures and some luck can help "get the cat back in the bag". each health jurisdiction in australia must have a plan for managing a local sars outbreak, which should include prompt hospital and community responses, and an ability to meet potential needs at short notice. central monitoring will ensure that all jurisdictions are adequately prepared. australia's defences begin at entry points to the country and are followed up at entry points to health facilities. with local transmission, the battle turns to the wards and the community setting. our patient's unrecognised illness resulted in infection of numerous others in the community and in hospital. furthermore, it led to the closure of four hospital wards and a major produce market. contact tracing and quarantine has involved thousands of people. the economic impact on individuals and the whole country is profound, affecting tourism, education and employment. the current australian guidelines for sars prevention are a useful interim effort, but arguably could go further in some areas, as outlined above. lessons from practice ■ the clinical features used to manage suspected sars cases should not be confused with a surveillance case definition used for epidemiological purposes ■ an outbreak of sars in australia will most likely occur in a hospital after spread from an unidentified case. the extent of spread will depend on the patient's infectivity and the time to isolation ■ lowering the threshold for respiratory and contact isolation of a possible sars case allows a period of observation until the diagnosis is clarified ■ given the consequences of a major sars outbreak, resources for appropriate infection control systems must be made available a major outbreak of severe acute respiratory syndrome in hong kong coronavirus as a possible cause of severe acute respiratory syndrome identification of a novel coronavirus in patients with severe acute respiratory syndrome sars epidemic unmasks age-old quarantine conundrum global surveillance for severe acute respiratory syndrome (sars) world health organization. case definitions for surveillance of severe acute respiratory syndrome (sars) world health organization. cumulative number of reported probable cases of severe acute respiratory syndrome (sars) the sars epidemic: lessons for australia australian department of health and ageing; interim australian infection control guidelines for severe acute respiratory syndrome (sars) as of th there is no financial justification for limiting resources to avoid the establishment of sars in australia. there are substantial costs involved in preventing local disease transmission, but these will be insignificant compared with the costs of managing a sars outbreak, which will extend well beyond the health sector. every reasonable avenue must be pursued to keep australia sars free for as long as possible.addendum : at the time of publication, one of the sons of the index patient has died from sars and another patient from the same ward has become a probable sars case, with an onset of symptoms days after exposure (april ), raising concerns over a prolonged incubation or an unidentified intermediate infection.the son of the husband and wife infected via the ed is also now a probable sars case. key: cord- -mkv jc u authors: chen, yirong; badaruddin, hishamuddin; lee, vernon j.; cutter, jeffery; cook, alex r. title: the effect of school closure on hand, foot, and mouth disease transmission in singapore: a modeling approach date: - - journal: am j trop med hyg doi: . /ajtmh. - sha: doc_id: cord_uid: mkv jc u singapore implements a school closure policy for institutional hand, foot, and mouth disease (hfmd) outbreaks, but there is a lack of empirical evidence on the effect of closure on hfmd transmission. we conducted a retrospective analysis of , cases of hfmd over the period – at the national level and of , cases in , institutional outbreaks over the period – in singapore. the effects of school closure due to ) institutional outbreaks, ) public holidays, and ) school vacations were assessed using a bayesian time series modeling approach. school closure was associated with a reduction in hfmd transmission rate. during public holidays, average numbers of secondary cases having onset the week after dropped by % ( % credible interval – %), and during school vacations, the number of secondary cases dropped by % ( % credible interval – %). schools being temporarily closed in response to an institutional outbreak reduced the average number of new cases by , ( % credible interval , – , ). despite the positive effect in reducing transmission, the effect of school closure is relatively small and may not justify the routine use of this measure. hand, foot, and mouth disease (hfmd) is a common pediatric disease that is endemic in east and southeast asia , and increasingly found in north america , and europe. when caused by coxsackieviruses, hfmd usually leads to relatively mild infections with symptoms that are self-limiting. however, hfmd caused by human enterovirus may lead to complications involving the nervous system and result in reduced cognitive function, delayed neurodevelopment, and motor impairment, or death [ ] [ ] [ ] ; in china, an estimated - children die of hfmd annually. because of this potential severity, the ministry of health in singapore imposes strict control policies, especially in preschools. in preschools, daily routine health checks for all children and isolation of suspected cases are implemented for early detection and control of outbreaks. should transmission continue within an outbreak, school closure is enforced. this policy was implemented following an outbreak in in which several children died from enterovirus complications , ; the details have evolved over time, but until recently, if a school has more than cases or an attack rate more than % with a transmission period more than days, the school will be required to close for a period of days. in the most updated guideline, the policy has been relaxed somewhat, and ministry of health will consider the predominant circulating strain when assessing closure in addition to the trigger. this change provides an avenue to assess the impact of this policy. school closure as a form of social distancing intervention to mitigate transmission during an infectious disease outbreak is often found in countries' pandemic preparedness plans. the influenza literature shows that school closure may effectively reduce the spread, [ ] [ ] [ ] and school vacations have a significant impact in limiting transmission. , analyses also suggest that school closure combined with the use of antiviral agents is cost-effective and is a justifiable strategy for mitigating influenza pandemics. , there is, however, a lack of empirical evidence on the effect of school closure on hfmd transmission: one exception is a review of hfmd in hong kong that revealed fewer hfmd consultations than expected during the severe acute respiratory syndrome and the influenza pandemic, which was attributed to various control measures including school closure. , this article aimed to assess the effect of school closure on hfmd transmission. in singapore, hfmd is endemic with year-round transmission and is legally notifiable by physicians and childcare teachers, as well as actively screened for in preschool-aged children. these policies provide data that enable us to obtain three sources of information on the effect of school closure: ) the reduction in the numbers of cases after a public holiday, when childcare centers and schools close; ) the reduction during school vacations; and ) the impact within childcare centers of school closure in response to an ongoing outbreak. singapore's school closure policy for hfmd, which has been implemented for over a decade, in tandem with a comprehensive hfmd surveillance system, therefore, provides a unique opportunity to assess the impact of this important method of outbreak control. source of data. ministry of health, singapore, actively monitors and publishes the incidence of hfmd, which was made a notifiable disease in the year . two sets of data on hfmd were extracted from the ministry's records for this study. the first dataset contains aggregate reported hfmd cases from to , with the number of daily cases with onset of symptoms, stratified by age. the second dataset contains information on all hfmd outbreaks in childcare centers and kindergartens in singapore, during the period - . this provides the cumulative number of cases per day in each preschool with an outbreak, together with the school type (childcare centers or kindergarten), enrollment size, whether the schools were closed because of the outbreak, and, if so, dates of closure and reopening. data were retained at a daily resolution for two analyses but aggregated to weekly for the analysis of vacations. data were collected under singapore's infectious disease act, and because aggregate non-identifiable data were used, institutional review board approval was not deemed necessary for this study. statistical analysis. separate statistical analyses were performed to investigate the ) public holiday effect, ) school vacation effect, and ) school closure effect on hfmd transmission, as described in the following paragraphs. public holiday effect. there are typically public holidays in singapore each year, as detailed in supplemental table ; these are a mix of secular and religious holidays, some of which rotate around the year following the lunar calendar. if a public holiday falls on sunday, the following monday will be a public holiday. we derived the dates of all public holidays from to from the official listing of the ministry of manpower. the effect of public holiday on hfmd transmission was measured by quantifying the reduction attributable to the public holiday. because time points not immediately preceding or following a public holiday contribute little information to the effect of the public holiday, rather than considering a time series model, we developed a bayesian model of the time points surrounding public holidays. the number of cases in the week before the holiday i is modeled as x i ∼ poissonðα i × μÞ, and the number the week after as y i ∼ poissonðα i × ½ μ + θμÞ, or y i ∼ poissonðα i × ½ μ + θμÞ for two-day-long holidays. here, μ represents the average number of cases on a typical day; estimates of θ and a % credible interval provide a measure of the public holiday effect (i.e., À θ is the reduction in the number of infections on a public holiday compared with that on a normal day); and α i ∼ Γða,aÞ is an individual week effect which has an expected value of and allows for autocorrelation in the time series. the window length of week was selected to ensure balance in the number of weekdays in each window and to correspond roughly to the assumed incubation period of hfmd of around - days. this model assumes that the difference between the number of cases prior or after the public holidays is purely because of the difference in the number of infections happening on the public holiday, which is unobservable but indirectly represented by the change in the number of symptomatic cases in the following weeks. to assess whether there was any longer term impact, we repeated the analysis comparing incidence in the second week (days [ ] [ ] [ ] [ ] [ ] [ ] [ ] following the holiday with the week before it, as well as in the third week (days [ ] [ ] [ ] [ ] [ ] [ ] [ ] . the main analysis does not treat public holidays that were less than days apart specially. in sensitivity analysis, we removed data corresponding to both holidays from the fitting procedure if they were less than days apart. sensitivity analysis was also conducted by applying different forms of the non-informative prior distributions for the parameters to test the robustness of the inference. school vacation effect. in singapore, kindergartens, primary schools, and secondary schools have school vacations in march for week, in june for weeks, in september for week, and in november and december for - weeks. to measure the effect of school vacations on hfmd transmission, we built time series models, fit bayesianly, for the weekly number of children with hfmd aged years and younger. this has some similarities with an autoregressive time series, but the bayesian approach afforded greater flexibility in the model specification. we assumed a negative binomial distribution for the number of hfmd cases, y t , observed in week t, with mean and shape parameter p, where h t = if week t is a school holiday and otherwise, and a, b, d, p, are model parameters that needed to be estimated: b accounts for autocorrelation, whereas d determines the effect of school vacation. a negative binomial distribution is used to allow more flexibility to capture the observed variability in the data than that obtained using the poisson model originally considered. a constant b that does not vary with time was used because singapore has very little seasonality that would add forcing to the timing of epidemics of hfmd, and because it would hamper identifiability of the vacation effect. the adequacy of using a constant b was assessed and confirmed by examining the distribution of the residual of -week-ahead model forecasts. the model was fit using bayesian methods (markov chain monte carlo) with non-informative prior distributions, as described in the supplemental file. for each draw from the posterior distribution, we iteratively derived the median number of cases for the following week based on the number of cases in the current week using the formula in the aforementioned model. the number of cases in the first week of the simulations was taken to be the observed average weekly number of cases across the time horizon. this was done for weeks ( years) and only the latter weeks were kept as the number of weekly cases for a typical year. for each set of posterior values, , such simulations were performed. based on these , simulations of a typical year scenario using each of the , sets of posterior values, % prediction and credible intervals were derived for each of the time points. median values for all , simulated numbers for each set of posterior values ( , median values in total) were calculated. school closure during outbreaks effect. for each preschool that had an outbreak during the time horizon - , a period of days from the first day of case onset was considered; this was enough to span the duration of most outbreaks. the number of incident cases on day j in outbreak i, x i,j , was modeled by where c i,j is the cumulative number of cases within week before day j in outbreak i, s i,j is the number of children not yet symptomatically infected during the current outbreak by day j of outbreak i, and w i,j is the indicator for school closure on day j in outbreak i (w i,j = if the school was closed on day j in outbreak i, and otherwise). we smoothed the effect λ k of the current outbreak size k using the formula the posterior samples were used to project the number of cases that were avoided by forcing schools to close when they hit the trigger. for each draw from the posterior, simulations were performed to each of the schools with closures in our study period. in each simulation, the number of new incident cases on each day after the closure day was calculated using the model formulation and w i,j was set to be . the total number of cases was then compared with the observed number of cases when schools close and the total number of additional cases due to not closing schools for each simulation/set of posterior values was recorded. median values for all simulated numbers for each set of posterior values ( , median values in total) were calculated. we use bayesian methods to fit the models as the bayesian paradigm was considered more flexible than its frequentist analog. throughout, non-informative prior distributions were selected (detailed in supplemental file ) and models were fit, using markov chain monte carlo algorithms with burn-in periods of , and , iterations, in the r statistical environment. the posterior samples were then used to obtain posterior distributions of derived quantities. throughout, equal-tailed % credible intervals are used. model convergence was evaluated by using the gelman diagnostic tests and model validity assessed by comparing posterior predictions or simulations with the actual observed data. a total of , hfmd cases were notified to the ministry of health, singapore, from to . table shows the demographics of all notified cases. children aged less than years accounted for about % of all hfmd cases, and about % of all children with hfmd were aged years and younger; % of the cases were male, whereas % were ethnic chinese, % malay, % indian, and % others: the indian ethnic group is substantially underrepresented among cases compared with the general population ( % of singapore residents aged less than years have indian ethnicity). table shows the summary statistics for the bayesian models for the public holiday effect: the average of hfmd cases a day was reduced by % ( % confidence interval [ci]: [ %, %]) in the week following a public holiday, but only by % ( % ci: [ %, %)]) in the second week, whereas there was no reduction in the third week ( %, % ci: [− %, %]). alternative forms of non-informative prior distribution did not affect the results (not shown). during school vacations, weekly number of cases were modeled to be reduced to % ( figure shows the simulations for a typical year based on the modeled effects of school vacations on hfmd transmission, using typical timing of school holidays. both overall analysis and separate models for different age groups showed similar results and are consistent with the patterns of the data for the -year period. the temporally structured distribution of residuals in the -week-ahead model forecasts is shown in supplemental figure . no trends were observed, suggesting that the model with a constant b is adequate. from to , there were totally , school-level outbreaks involving a total of , hfmd cases in childcare centers and kindergartens, of which led to closure (table ). in all, , outbreaks including closures were included in our model: schools without accurate enrolment sizes were removed and four schools with closure falling beyond days after the first day of outbreak were categorized as no closure (detailed in supplemental file ) . the bayesian poisson model shows that the expected number of new cases decreases to % ( % ci: - %) if a school was closed on that day compared with a normal school day, after adjusting for size and duration of the outbreak. one-dayahead predictions based on the previous day's observed number of cases, shown in figure for arbitrarily selected outbreaks (more outbreaks are presented in supplemental file ), both with and without short-term school closure, demonstrate that the fitted model adequately captures the observed outbreak patterns. figure show the effect of school closure by showing the cumulative number of cases if there were no school closure for four arbitrarily selected outbreaks with closure (more outbreaks are presented in supplemental file ). the percentage of cases avoided from school closure for all closures is shown in figure . the majority of school closure events (> %) were associated with a less than % difference between observed and modeled cases, regardless of outbreak size at closure. closures that prevented more than % of total school size were generally in bigger schools (of size more than ). overall, the modeled number of infections prevented through the school closure policy from to was , ( % ci: [ , , , ] ), that is, an average % reduction compared with the total number of cases during that period. convergence of all bayesian models used was achieved according to the gelman diagnostic test. model validity assessed by comparing posterior predictions or simulations school closure is a common control measure in pandemic preparedness plans and in response to actual outbreaks, which may possibly be a high impact method of controlling an outbreak of a severe or potentially severe infectious disease. its effectiveness has been assessed in modeling studies, , , which posit that because children have closer social networks and high contact rates in schools, closing schools may substantially reduce transmission, if they do not compensate by having greater contact outside of school during a closure. the burden of school closure on families which may need to make alternative childcare arrangements means that it is imperative to have real-world evidence supporting its effectiveness. relatively little such evidence is available, though some studies in japan, france and the united states have assessed school closures in response to influenza outbreaks. , in light of this, the evidence on the effect of closure from singapore's long-standing routine school closures to control hfmd may prove valuable. this study demonstrated a consistent reduction in average numbers of hfmd cases when schools were closed, regardless of the reason for the closure. there was an estimated decrease of % in the number of cases in the week after a public holiday than the week before it, corresponding to a reduction in the number of infections that occurs on the holiday itself of %, although the effect of the holiday declines in the weeks following as infections return to baseline levels. a similar reduction in the number of infections during school vacations was also estimated (also about %). this may be an underestimate of the actual effect size because many preschool-aged children still attend preschools during school holidays. this hypothesis is supported by the slightly accentuated effect in children who have started formal schooling, with a reduction in risk around % for children aged years and older. although the reduction was statistically significant for all age groups, the difference in effect between age groups was not statistically significant. the data on school closure in response to outbreaks allowed a quasi-experimental analysis because recently the school closure policy has been reinterpreted to allow more discretion by the ministry of health whether to close the affected school or not. this led to a decrease in the number of school closures in the later periods of the study (table ) . although not randomized, this change allowed some overlap in the exposure (closure) and response (outbreak growth). the analysis showed that as with holidays and public holidays, school closure during an outbreak had the intended effect of orange line shows the cumulative number of cases if the school was not closed during the closure period. light pink and dark pink shades are % and % confidence intervals, respectively. this figure appears in color at www.ajtmh.org. mitigating transmission, but the effect was relatively small, and we estimated that only ∼ , cases were averted over the years analyzed. the high asymptomatic rate , and seroprevalence of the main causative viruses may mean that a substantial fraction of children are no longer susceptible by the time of closures in response to large outbreaks, which is currently triggered when more than cases or % of children are symptomatic. the fraction of cases prevented by outbreak-induced closure was modeled to be small in general, but larger for the larger preschools, which we attribute to the structure of the thresholds for closure: this is effected when either the fraction or the number of children in the school is notified, meaning that closure of larger schools occurs when the threshold for the number of cases is hit but the fraction is still low. given the disruptions to parents/families from unplanned closures, , outbreak-driven closures may, therefore, cause more problems than closure because of holidays. in light of the limited effect, it is not clear that this policy should be continued to be used routinely for hfmd outbreaks, but the effect of closures because of holidays suggests that a school closure policy may still be valuable for pandemic preparedness plans and needs to be carried out when there are serious outbreaks or when the outbreak is due to novel pathogens of unknown severity. although this was a retrospective study, with hfmd being a legally notifiable disease in singapore, incident data were collected in a standard way through preschools, clinics, and hospitals, and as such, the data used for this study are largely reliable indicators of symptomatic cases. however, some other limitations exist. several assumptions were made in the modeling process: the public holiday effect analysis assumed that the observed difference in the number of cases before and after the public holiday was solely attributable to the public holiday. in temperate countries, this assumption may not be tenable because of seasonal changes that drive transmission. singapore, however, lies close to the equator and has almost no seasonality-having year-round high temperature and humidity-with the effect that some virus transmission is effectively aseasonal. for the same reason, the assumption that there are no other temporal effects in the school vacation analysis may be more robust than it would in a temperate setting. these three analyses provide evidence that school closure-whether in response to an outbreak, or because of a public holiday or longer school vacation-reduces the transmission of hfmd. although we found that school closure in response to outbreaks does have a positive effect in reducing transmission, the effect is small, and given the high incidence and the fact that most of the cases of hfmd are mild and selflimiting, the evidence from this study suggests that policymakers in singapore should evaluate whether routine use of school closure outside of public health emergencies justifies the impact on families. epidemiology and control of hand, foot and mouth disease in singapore the epidemiology of hand, foot and mouth disease in asia: a systematic review and analysis notes from the field: severe 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reverse transcription-pcr with universal enterovirus and ev -specific primers mitigation of infectious disease at school: targeted class closure vs school closure effect of short-term school closures on the h n pandemic in japan: a comparative case study analysis of the effectiveness of interventions used during the a/h n influenza pandemic estimating the impact of school closure on social mixing behaviour and the transmission of close contact infections in eight european countries effect of winter school breaks on influenza-like illness school closure and mitigation of pandemic (h n ) , hong kong economic analysis of pandemic influenza mitigation strategies for five pandemic severity categories the cost effectiveness of pandemic influenza interventions: a pandemic severity based analysis changing epidemiology of hand, foot, and mouth disease in hong kong transmission of hand, foot and mouth disease and its potential driving factors in hong kong randomness of dengue outbreaks on the equator r: a language and environment for statistical computing general methods for monitoring convergence of iterative simulations projecting social contact matrices in countries using contact surveys and demographic data closure of schools during an influenza pandemic clinical features and risk factors of pulmonary oedema after enterovirus- -related hand, foot, and mouth disease seroepidemiology of enterovirus infection prior to the season in children in shanghai severity and burden of hand, foot and mouth disease in asia: a modeling study dynamic modelling of costs and health consequences of school closure during an influenza pandemic acknowledgments: we thank the data extraction team from communicable disease division, ministry of health, singapore, for their help in extracting data for our analysis. authors' addresses: yirong chen and alex r. cook, saw swee hock school of public health, national university of singapore and national university health system, singapore, e-mails: chenyirong @gmail. com and alex.richard.cook@gmail.com. hishamuddin badaruddin, vernon j. lee, and jeffery cutter, ministry of health, singapore, e-mails: drphisham@gmail.com, vernonljm@hotmail.com, and jeffery_cutter@ moh.gov.sg.this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. key: cord- -l jniccw authors: wilder-smith, annelies title: as travel medicine practitioner during the sars outbreak in singapore date: - - journal: travel medicine doi: . /b - - - - . - sha: doc_id: cord_uid: l jniccw nan common problem in singapore. he consulted a physician in new york. indeed, leukopenia and thrombocytopenia was noted, thus confirming his suspicion of dengue. however, his chest x-ray also showed pneumonia. there was no way he could have connected his symptoms with that of his patient he had seen in the previous week. this all occurred in the couple of days before the term 'sars' was coined and before the who sent out the alert on march. dr. l felt so unwell that he decided to cut short his stay in new york and he embarked on the next singapore airlines flight to return to singapore. just before he departed, he called a doctor friend in singapore to announce that he was diagnosed with pneumonia and was returning home. meanwhile, back in singapore, 'all hell' had broken loose. on friday after our morning grand rounds, several nurses, friends and visitors came down with the same symptoms -and all had been in contact with elly in the preceding week. they were admitted and immediately isolated. by the end of the weekend, we had numerous admissions and we knew that something really unusual was happening. we had staff working around the clock, we had huge media attention and atop this we received a visit by the minister of health. by early monday morning, the first list of the most common symptoms and laboratory findings was put together. i will never forget the staff meeting on that monday morning. the director of the communicable diseases center announced, "we have an outbreak at hand, and it appears to be bigger than we thought". we had no clue how big it was going to be, or what sinister effects it would have... the next two weeks, we lived with great uncertainty. these were the worst two weeks of the epidemic, for we neither knew what the causative agent was nor its mode of transmission nor its treatment. we were horrified to see one medical or nursing colleague after the other coming down with the disease. by now, the first patients that we had seen were starting to die. in the first week after our first cases, the who named the disease "sars", and they sent out global alerts. meanwhile dr. l was on his flight back to singapore, unaware of what was going on in singapore. his friend, whom he had contacted just prior to his departure, was astute enough to conclude, however, that the symptoms dr. l displayed, and his recent contact with the index case, were highly suggestive of this new disease and he alerted the ministry of health. the ministry in turn alerted singapore airlines and this led to the halt of the flight in frankfurt. to his amazement, dr. l was escorted from the airport in full protective gear, admitted to a frankfurt hospital. within hours, his name was in all the news media around the world. his pregnant wife also fell ill, but his mother-in-law for some mysterious reasons did not, although all three of them had been in close contact over a prolonged time. the passengers and crew were debriefed about sars, the recognition of its symptoms and signs, and they were given advice to seek care if they developed any such indications. four days later, a -year-old stewardess of that flight sought help at our clinic when she developed a fever and cough. during the flight, dr. l was kept isolated in the back of the plane. the stewardess had only brief contact with him while serving food, picking up trays, and the like. she kept as much distance as possible and this included minimal communication. sars was confirmed in the stewardess making her the first reported case of in-flight transmission. let me go back to the first few days when the outbreak started to unfold. as you can imagine, my travel clinic was swamped by the public demanding the flu vaccine and any other information about sars. our communicable diseases centre turned into a major screening hub. we screened hundreds of contacts in made up tents using portable x-rays. it soon became clear that as a sole department, we would not be able to cope with all the screening. the screening was therefore moved to the main building of tan tock seng hospital under the auspices of the accident & emergency department. my travel clinic was closed and my staff had a change of job: from advising travelers and administering vaccines to taking their temperatures and asking about any respiratory symptoms. march, the hard decision. close down our hospital completely. it became the designated sars hospital, admitting only probable and suspect sars cases. large numbers were seen and although we were a , bed hospital, we were soon short of isolation rooms.... sars came suddenly and caught us unaware. it's novelty, ease of transmission, and the speed of its spread, put us all in a state of fear. the epidemic progressed rapidly, and it was tragically associated with high death rates. one after another of elly's relatives and friends died: first her father, then her pastor, her mother and finally her uncle. her grandmother was also in the icu, but mysteriously she survived. elly herself survived. we kept her in hospital for a very long time, partly because we were unsure how long she would be able to transmit the disease to others, partly also to protect her from all the media attention. i often wondered how she was coping. characterized by a high rate of transmission to healthcare workers, sars struck deep and hard and affected every one of us with varying degree. the constant fear of getting infected was felt throughout. this fear intensified, as colleagues became patients and young patients died. more distressing was the fear of inadvertently transmitting the infection to loved ones, especially children. many moved out of their usual abode and did not touch their children or spouses for weeks. we became also suspicious of each other. i remember vividly how one colleague wanted to whisper something into my ear, and i jumped away out of fear of getting infected. fear of death became a daily reality. n masks soon became a shortage, and we had to learn how to use the same mask for one whole day. n masks muffled speech, hid expressions of your face, and worse, if one quickened the pace of walking, then we ended up gasping breathlessly for air. in the smouldering humid heat of singapore, the sweat would drop underneath our hair covers, soak the masks and slowly droop down our faces, leaving us in doubt whether the masks were still working. we also had to rationalize our gowns and gloves. frustrations abounded as policies were changed almost daily. we wrote so many guidelines; and every day seemed to bring up a new revision of those from the previous day. although singapore was exemplary in its transparency and abundance of information, as healthcare workers we felt we were scrambling for information. i was literally glued to the websites to gain more up-to-date information of the global outbreak. in the view of the public, the outbreak was mainly associated with our hospital. healthcare workers were shunned by the public. there were stories of nurses not being allowed to return to their rented apartments. buses would not stop at our hospital so that transportation home was not possible. taxis refused to come by. we felt stigmatized. instead of the moral support that we craved for, we felt left alone. my children were not invited to birthday parties anymore. our neighbors did not let their children play with ours. i became infuriated about the way the press dealt with elly. the media also obtained information on patient's names that were eventually published. the atmosphere in the hospital was eerie. instead of the usual buzz with visitors, restaurants and coffee shops, the hospital was empty. i only met masked healthcare workers. movements within the hospital were restricted. visitors were not allowed. every minute of the day, we were geared up. in one of my e-mails, i wrote to my friends back home: "i am masked, gloved, gowned -but not yet cloned". the end time atmosphere in the hospital was accentuated by the tv sets that aired the start of the war in iraq. in april, the previously hidden large number of sars cases in china was suddenly revealed to the world. this news made me loose all hope. i imagined that the epidemic would now turn into global proportions sweeping the world, thereby killing % of its population. i imagined my life as a doctor from now to be a life geared up physically in masks and gowns, psychologically geared for death. in singapore, the outbreak was initially only hospital based, but in april the news was out that sars had affected a large vegetable market. overnight, thousands of people had to be quarantined. the market was closed. that evening i went shopping and realized that there were no more vegetables in supply! many patients had died, but death struck really home when a young medical officer died on april. his mother, a doctor, who had cared for him initially during his illness, was also struck by the disease. she eventually died. one of my infectious disease colleagues was admitted to hospital because of fever. fortunately, her fever turned out to be due to the flu that she had caught from her kids, and she was discharged. not long after, i started feeling unwell myself. i wondered "am i going to be the next?" i was afebrile, but i decided to separate myself from my family, said farewell to my children and my dear husband from the distance, and spent the night isolated in a room. i measured my temperature every hour, ready to get myself admitted if it reached the threshold. alone like this, i reflected over my life and wondered whether i was ready to die. that night was a life-changing experience. the news of the death of carlo urbani, the italian who doctor who was instrumental in the control of sars in vietnam, sent our hospital staff into depression. there was both grief and shock in the air. the final blow came when the husband of a friend of mine contracted sars. he was a surgeon in his mid-thirties, a very bright and popular consultant. he deteriorated rapidly and because of the strict isolation regulations in practice, there was no time for adequate farewell. from his isolation room, he communicated with his wife via text messages. i was grief stricken when i later heard that he had succumbed to sars. even worse, there was no funeral, only a rushed cremation the very next day, as these were the rules for sars-related deaths. with this tragedy, my facade crumbled and i broke down, the first time during all these weeks. i sobbed. i grieved for his widow, a friend and colleague with whom i still teach in community medicine, often finding myself wakening up at night and praying for her. the worst about dying during sars was the fact that this was a lonely death. in total, we lost a total of five healthcare workers to sars in singapore: doctors, nursing officer, nursing aide and hospital attendant. there was a strong group spirit of commitment and determination amongst us, and this enabled us to continue working. voices to quit were few; almost everyone stayed on. dr. carlo urbani's words were a reality for us: "health and dignity are in-dissociable in human beings. it is a duty to stay close to victims and guarantee their rights". after the initial stigmatization, and ostracization, against healthcare workers, there was a turning point in public opinion. all of a sudden, we became the heroes of the nation. we were in a battle against sars together. we were showered with thank you cards, gifts, vitamins and herbal medicine. the walls of our hospital were plastered with well wishers comments and 'thank you' posters sent by companies, institutions, schools, churches, non-government organizations, individuals, etc. almost every day, the media highlighted a healthcare worker with a full story and pictures in the newspapers. emotional support and positive affirmations were morale boosters. the hospital management under the leadership of dr. lim suet wuen arranged frequent staff updates; and the transparency increased our trust in the authorities. our status as healthcare workers was elevated, and with it our morale. progressively stricter infection control measures were put in place. our temperatures were measured three times per day. audits were made to ensure compliance with all the measures. infection control was now part of our daily lives. two to three weeks into the epidemic it became clear, that infection control measures were effective; no more new cases occurred amongst the staff of our hospital. we started feeling safe at work. in fact, we became the safest hospital to work in as new cases continued to arise in the other hospitals in singapore. it may sound strange but because of the implemented strict infection control measures i even felt safer in the hospital than outside. never did i think that i should leave singapore. there was only one moment when i seriously considered it: the newspaper suddenly announced that doctors whose spouses were also doctors but working in different hospitals should be separated. my husband is indeed a doctor in another hospital. i thought "if they separate us, then i will separate myself from singapore". luckily, the plan was never put in action, as it turned out that a vast majority of singapore's doctors are married to other doctors who often happen to work in different hospitals or practices. by may, it became evident that sars was under control in singapore. on st may we were declared sars free. worldwide, also, cases were diminishing. my despair had turned into hope -a hope that sars will not continue to have a deathly grip on our daily lives. once we had hope, life at the sars hospital now also meant facing up to the scientific challenges of this newly emerging coronavirus. the operation center at our hospital became a large center where dozens of people sat long hours every day, even weekends, to do data entry, to analyze data and interpret new findings. i was tasked to do a seroepidemiological cohort study among healthcare workers exposed to sars in the first month of our nosocomial outbreak. the goal of the study was to investigate the incidence of and factors associated with asymptomatic sars-cov infection. while i took blood samples from the more of study subjects, i listened to heartbreaking stories. the findings were interesting. of all exposed (before infection control measures were instituted) healthcare workers, . % had asymptomatic sars (sars serology positive). multivariate analysis showed that asymptomatic sars was associated with lower sars antibody titers and higher use of masks compared to sars that presented with pneumonia. this was an interesting study, however, my main interest circled around sars and its relationship to travel. sars, travel and travel medicine were intricately interlinked. travelers belonged to those primarily affected in the early stages of the outbreak, travelers became vectors of the disease, and finally, travel and tourism themselves became the victims. in fact, travelers not only turned a newly emergent local virus into a global outbreak, but travelers were also the first to unmask the mysterious disease in southern china. i followed up all imported cases of sars, and all incoming flights to singapore with sars cases on board. of the six imported cases, which all occurred before screening measures were implemented at the airport, only the first resulted in extensive secondary transmission. none of these cases resulted in in-flight transmission. of , air passengers screened after measures were implemented, were sent to our designated hospital for further sars screening; none was diagnosed as having sars. the sars outbreak in singapore can be traced to the first imported case. the absence of transmission from the other imported cases was most likely a result of relatively prompt identification and isolation of cases. new imported sars cases therefore need not lead to major outbreaks if systems are in place to identify and isolate them early. screening at entry points is costly, has a low yield and is not sufficient in itself. however, the costs and efforts may be justified in light of the major economic, social and international impact, which even a single imported sars case can have. use of simple laboratory features to distinguish the early stage of severe acute respiratory syndrome from dengue fever experience of severe acute respiratory syndrome in singapore: importation of cases and defense strategies at the airport low risk of in-flight transmission of severe acute respiratory syndrome: the singapore experience asymptomatic sars coronavirus infection among health care workers this article is dedicated to my friend and colleague, dr. woon puay koh, who lost her surgeon husband to sars. key: cord- -jjaqlyo authors: beirman, david title: a comparative assessment of three southeast asian tourism recovery campaigns: singapore roars: post sars , bali post-the october , bombing, and wow philippines date: - - journal: tourism, security and safety doi: . /b - - - - . - sha: doc_id: cord_uid: jjaqlyo nan the advent of mass international tourism since the s stimulated rapid growth for inbound and stopover tourism in southeast asia (se asia). tourism represents one of the most lucrative economic segments for most se asian countries. the tourism industry is a major source of foreign currency earnings, creating millions of service industry jobs throughout the region. increased per capita earnings within eastern and se asia combined with the reduction of tourism prices in real terms within asia are key factors in accelerating se asia's development as one of the world's fastest growing regional tourism destinations. se asia's tourism industry was spared the most severe initial repercussions of september , the attack against the united states and the launch of the usled global "war on terror" against islamic political movements. during the months following september , , international tourism experienced a decline predicated on safety threats to long-haul air travel. se asian tourism remained relatively buoyant throughout most of partially due to the perceived isolation of se asia from the afghan and middle east trouble spots. equally relevant is the fact that most travel to se asia originates from within or near the region (koldowski, ) . the bombing of the crowded sari nightclub in denpassar, bali, on the evening of october , , resulted in the murder of tourists and wounded from countries (henderson, ) . the world's deadliest terrorist attack in recent history specifically targeting tourists placed se asia at the epicenter of the war on terror. the convicted perpetrators were members of the radical islamic group jemal islamyia with affiliated cells throughout indonesia, malaysia, thailand, singapore, and the philippines. the sari club bombing had a devastating impact on tourism to bali and throughout indonesia, causing collateral damage to the security perception of many neighboring se asian countries. although islamic organizations have been active in se asia for many years, the bali attack exacerbated fear of islamic violence in se asia. the governments of many tourist generating countries including japan, united states, united kingdom, and australia issued cautionary travel advisories which encompassed indonesia, malaysia, singapore, and the philippines. the combination of negative media coverage and negative government travel advisories was perceived as a major threat to the viability of the tourism industries in the region. southeast asian tourism was forced to respond to a further challenge in march when reports surfaced about the outbreak of a condition known as severe acute respiratory syndrome, which became known worldwide as sars. this illness has similar symptoms to pneumonia and was initially diagnosed in southern china but by march and april cases appeared in hong kong, singapore, vietnam, and canada (singapore tourist board statistics, ) . according to the world health organization, between march and july there were over , confirmed cases of sars. the deaths of people were attributed to sars. the outbreak of sars was regarded as a potentially serious public health risk. however, the actual extent of the problem was relatively minor in comparison with ongoing global epidemics including aids, malaria, cholera, and typhoid, which cause the death of millions annually. the blanket international media coverage of sars, the mysterious nature of the disease, and the absence of a known cure combined to ignite panic in the countries affected and among international travelers. media footage of people in the streets and airports of hong kong and singapore wearing surgical masks created a sense of fear among travelers who sought to avoid even transiting in cities known or even thought to have contacted the disease. although tourism to singapore and hong kong was most heavily affected by the sars scare, the tourism industries of most se asian countries were collateral victims of sars. thailand, malaysia, and the philippines had minimal exposure to sars but tourism to all these destinations was negatively affected. fear of terrorism arising from the bali bombing and the outbreak of sars in se asia, much of it magnified by media coverage in the west, was exacerbated by a series of negative travel advisories issued by the governments of many economically significant tourism source markets including the united states, united kingdom, australia, and japan. the advisories suggested that citizens defer travel to several countries in se asia, notably indonesia, the philippines, malaysia, and, for brief periods, hong kong, thailand, vietnam, and singapore (henderson, ) . although there were varying impacts on tourism within each se asian country, the regional extent of the threat to tourism industry spurred se asian nations to respond regionally. on november , , the heads of state of asean (association of south east asian nations) met in the cambodian capital phnom phenh to pledge their support for an asean tourism recovery marketing campaign (association of south east asian nations, ). an asean tourism marketing organization has theoretically been in existence since ; however, regional tourism marketing was rarely practiced. the crisis engendered by the bali bombing motivated the region's political leadership to swiftly reactivate asean tourism marketing cooperation. at the private sector level, the bangkok-headquartered pacific asia travel association (pata), the main travel industry body representing the pacific rim, placed the restoration of se asian tourism as its top priority project from the time of the bali bombing and was supported by national tourist offices and peak travel industry bodies of all se asian nations and the international air transport association (iata). in pata launched its innovative recovery campaign, project phoenix, designed to stimulate tourism recovery throughout se asia. in essence, project phoenix involved cooperation between specific media organizations, airlines, national tourist offices, tour operators, and hotel chains. the campaign involved se asian regional and destination specific marketing promotions and a range of incentive travel offers to jump-start consumer recovery post-sars. this chapter will examine the regional recovery campaigns and issues while focusing on three specific recovery campaigns representing the major challenges encountered by the tourism industry in se asia during the final quarter of , the first half of , and the varying successes of recovery strategies employed. the first specific recovery campaign discussed is bali's attempt to restore inbound tourism following the sari club bombing of october , . the restoration campaign was unusual in that it was dominated by the private sector. the balinese provincial tourism authorities were professional in their approach but there was considerable evidence that indonesian government actions did more to hinder, rather than to help, the recovery processes. bali enjoyed an unusually high degree of support from foreign tour operators and from pata in its market recovery program. the singapore roars marketing campaign was a highly professional, government initiated, and generously funded restoration marketing campaign designed to stimulate a rapid recovery of tourism to singapore following the end of the sars scare in july . an unusual feature of the singapore roars campaign was that it was conducted in selected source markets in conjunction with similar campaigns promoted by thailand and malaysia. although it emphasized singapore, the singapore roars campaign was not conducted in isolation. singapore, as a highly centralized city-state, marshaled a high level of coordination in its marketing campaign. singapore's tourism marketing is characterized by close cooperation at the leadership level between the public and private sectors of the nation's tourism industry. the philippines tourism industry has had a long history of navigating its way through a variety of crisis events since the mid- s. islamic terrorism has posed a background problem in the philippines since the early s, although occasional attacks against foreign tourists have raised the media profile of this problem. the philippines was a collateral victim of the fear of terrorism and sars. the bali attack focused global attention on the endemic issue of islamic terrorism in the philippines. despite rare attacks in manila and several well-publicized incidents of abduction and killing of tourists, islamic terrorism is primarily confined to southern mindanao. although there were no sars cases reported in the philippines, tourism suffered to a limited extent from the sars scare. from , the philippines department of tourism, under the leadership of its energetic secretary richard gordon, decided to conduct a highly visible and positive marketing campaign which directly challenged the negative stereotypes prevalent about the philippines. the wow philippines campaign was carefully targeted and designed to re-image destination philippines and to spread the benefits of tourism as widely as possible across the , island archipelago nation. while not designed as a campaign to recover from specific events such as was the case with bali, local terrorist incidents, or sars, the wow philippines campaign is designed with the longer-term goal of changing consumer and industry perceptions of the philippines and stimulating real growth for the country's tourism industry. gordon, elected chairman of pata in , also sought to incorporate the philippines recovery marketing campaign within a broader se asian tourism recovery campaign. an unusual aspect targeted the million filipino nationals living overseas to act as tourism marketing ambassadors of the philippines in their respective countries of residence. they were encouraged to make return visits and incentives were offered as motivation to nationals of their country of residence to visit the philippines. regional marketing of se asia, especially to long-and medium-haul source markets including north america, europe, australasia, and japan was an important feature of tourism marketing during the s. however, as the economies of se asian countries modernized and diversified, the major tourism destinations and stopover points in se asia increasingly sought to differentiate their marketing identities, resulting in a tendency toward competition and limited cooperation. intense competition ensued among hong kong, bangkok, kuala lumpur, and singapore as airline hub and spoke points that influenced their relative positions for stopover traffic. malaysia, thailand, indonesia (especially bali), the philippines, and vietnam all regarded tourism as strategic fulcrums for national economic expansion. consequently, their government-dominated tourism marketing bodies sought inbound tourism at the expense of neighboring nations. the highly competitive nature of tourism during the s was simply not conducive to regional tourism cooperation as each destination assiduously sought to maximize its own share of a growing international market. the asean tourism marketing body, a product of late s government policies, technically remained in existence, but in every practical sense was moribund by . during the s the tourism industry's private sector had a very different set of priorities. airlines, multinational hotel chains, cruise and tour operators servicing multiple destinations, and global financial institutions were far more amenable to regional destination marketing than the private sector during the s. the major regional travel industry association pata was, until the s, primarily oriented towards america. the relocation of its headquarters from san francisco to bangkok in represented the realization of its organizational evolution from an america-centric association in its early years to an asia-centric organization by the mid- s. pata took over the role of regional se asian tourism marketing abandoned by asean during the s (chuck and lurie, ) . although iata's global headquarters remained in switzerland, it maintained a high-profile presence in asia (interview: concil, ) . by , se asian tourism growth was increasingly sourced from within asia. during the s japan, south korea, hong kong, and taiwan (the so-called tiger economies) had become significant se asia source markets. the asian economic collapse resulted in a -year hiatus to this growth. the emergence of india and the people's republic of china as rapidly growing tourism generating markets promised long-term tourism growth for se asian tourism destinations. the quantum growth of mass chinese outbound tourism exacerbated competitive pressures largely due to the prc government policy of limiting approved destinations for chinese nationals. the criteria for a country to become an approved destination for chinese citizens included operational and political elements. murray bailey's report on the chinese outbound market commissioned by pata in provides a detailed guide to the growth forecasts and the specific qualifications for approved destination status (bailey, ) . the prevailing dissonance between the private and the government sector's approach to regional tourism marketing in se asia during the s and the early years of the twenty-first century was radically affected by the sari club bombing of october , , and the sars scare of march-june . the two events put a sudden end to the divergence between the two approaches and resulted in a rapid new convergence. regional focus on the actual and potential threat of terrorism directed at tourists highlighted by the bali bombing presented a common threat to the regional tourism industry requiring a coordinated response. the perceived threat of terrorism was compounded by a sudden upsurge in media-driven speculation concerning the potential threat to tourist security. global media networks including cnn, bbc, deutsch welle, and australian abc covered this issue extensively. simultaneously the governments of many economically significant source markets including the united states, canada, united kingdom, germany, and japan issued travel advisories recommending their citizens defer travel to several se asian countries. from the perspective of these governments, most of which had citizens who were victims of the bali attack, enhanced caution was not only deemed justified but their own societies demanded it. se asian countries, including singapore, malaysia, indonesia, the philippines, and thailand, publicly criticized these negative travel advisories and treated them as a diplomatic affront. although government travel advisories have been issued since the september , , attack their global media profile and public visibility has been substantially enhanced. outspoken former malaysian prime minister dr. mahathir mohammed, indonesian president megawati sukarnoputri, and philippine tourism secretary richard gordon (who would be elected as pata chairman in mid- ) were scathing in their condemnation of negative western and japanese government travel advisories. the australian government was the most frequent target of criticism partially due to australia's position as a country that assiduously courted inclusion within asia while being perceived as a hostile mouthpiece of the united states (wilks, ) . a relatively unrecognized development that arose from the bali bombing involved the international travel insurance industry. with few exceptions, prior to the bali bombing it was almost axiomatic that commercial travel insurance coverage for passengers was linked to the wording of government travel advisories. most insurance providers automatically excluded coverage for loss or injury from such acts as "politically motivated violence, civil disobedience, war or terrorism." the insurance industry's term for this exclusion was "the general exemption." after september there was growing consumer and stakeholder pressure placed on insurers to provide coverage for unforeseen events (exemplified by the september attack) and some insurers relaxed their adherence to the general exemption to provide coverage on a case-by-case basis. the high number of fatalities in the bali bombing placed the spotlight on insurance companies. there was intense media pressure applied on travel insurers to assist victims of the bombing. since the bali attack several major travel insurers gradually abandoned the general exemption and either provided coverage on an individual basis or factored in terrorism as optional premium coverage. concurrently there has been an erosion of the linkage between government travel advisories and insurance coverage. until the september , , attack it was a common (though not universal) practice for insurers to deny regular travel insurance coverage for travelers visiting destinations for which governments had issued an advisory to defer travel. the increased incidence of governments issuing negative travel advisories since the advent of the "war on terrorism" has led insurers to treat them less seriously as a commercially valid assessment of tourist risk and determine their coverage based on independent statistical risk assessments. the combination of negative media coverage from the west and the need to respond to what was widely perceived in se asia as diplomatic attacks (in the form of travel advisories) from the west spurred the governments of se asia to present a united front to defend regional tourism. on november , , just over three weeks after the bali incident, a summit of asean heads of states gathered in cambodia to sign a tourism marketing accord pledging a coordinated asean approach to tourism marketing, effectively marking the rebirth of asean tourism. asean tourism cooperation following the bali attack would also be reinforced and amplified during the sars crisis. by sheer coincidence, the executive of pata was in bali on the night of the bombing (october , ) for the wedding of pata vice president peter semone. the reception was due to be held at the sari club but the explosion occurred while they were en route to the club. the presence of the senior executives of pata at the scene of the bombing meant that pata was able to directly assist with the recovery and crisis communication process. pata played a significant role in mobilizing private tourism industry support for the victims of the bombing and for the balinese tourism industry. pata also pledged its cooperation with the indonesian tourism industry to assist with marketing recovery and adopted a supportive approach to regional tourism recovery in se asia (interview: semone, ) . in early pata sponsored a task force of tourism recovery experts to assist and report to the indonesian government and the balinese tourism authorities. in april , during a period in which sars was already exerting a significant impact on tourism in se asia, the annual pata conference was held in bali. although venues for pata's annual conferences are determined at least years in advance, the conference was a most propitious opportunity for the asia/pacific travel industry to express solidarity with their indonesian and balinese colleagues. pata prepared a crisis-management manual for the use of its members and affiliates (winning edge, ) . in july following the sars scare, pata launched their major tourism market recovery campaign, project phoenix, which included several major elements. it involved the tourism ministries of most se asian countries, media organizations (notably cnn), airlines, hoteliers, and major tour operators. the campaign's message was intended to reassure travelers that se asia was clear of sars and welcoming visitors. the positive messages were reinforced by a series of pull marketing incentive programs designed to lure tourists. project phoenix included broad regional promotion of se asia combined with destination-specific promotion. effectively, project phoenix was a private sector initiative involving a high level of public sector support from the tourism ministries of the major se asian tourism destinations. during the sars scare, iata relocated its asia pacific crisis communications headquarters from tokyo to singapore where it coordinated and communicated the preventative activities of airlines servicing and transiting the region in response to the sars crisis. pata, in conjunction with the world tourism organization and the asia pacific economic cooperation, jointly commissioned an extensive report entitled tourism risk management for the asia pacific region written by professor jeff wilks and supported by several other tourism scholars. wilks heads the centre for tourism and risk management at the university of queensland. professor wilks' report adopted a broad and well-structured approach to the major risk management and security issues affecting tourism in se asia. during the second half of it was clear that the convergence between the priorities of se asian governments and the tourism private sector was manifested by an increasingly cooperative approach to the restoration marketing of tourism in the region. from july the overwhelming regional priority for se asian tourism was the rapid implementation of demand recovery for the inbound tourism market. this regional priority would be complemented by the market recovery campaigns of the individual countries within se asia. singapore has earned an outstanding reputation for success in se asian tourism since the s. the opening of changi international airport km north of the center of singapore in greatly enhanced singapore's capacity to handle a massive growth in airline capacity. singapore's inbound tourism numbers in with . million arrivals represent an all-time record. by comparison, singapore's inbound tourism level was only million arrivals in . however, it must be noted that tourism in singapore is dominated by short stays and a high proportion of stopover tourism. the average length of stay in according to the singapore tourism board was only . days. although not counted in tourism statistics, transit passengers remaining at the airport or passing through singapore en route to other destinations may contribute financially to singapore, but not to its hotel revenues (singapore tourist board statistics, ). singapore's reputation as a tourist attraction is based on its shopping facilities, a concentrated range of tourist attractions, the high quality of its cuisine, hotels, and its image as being safe, clean, law abiding, free of health concerns, and tourist-friendly, are among the key attractions for visitors. according to joan henderson, tourism to singapore in contributed us$ . billion or approximately % of singapore's gdp. consequently, tourism's contribution to singapore's economy and employment creation is significant by world standards. singapore's tourism experienced a minor downturn of . % in compared with , primarily due to the global downturn in long haul flights following september , , which affected inbound tourism during the final quarter of . most of singapore's major markets remained stable during that year with the only notable downturn from japan, the united states, and taiwan. singapore was largely perceived as relatively immune from the threat of islamic terrorism and geographically removed from the epicenter of america's "war on terrorism" being fought in afghanistan during and early (henderson, ) . during inbound tourism to singapore continued to decline, although this was concentrated within the period immediately following the bali bombing in october , . singapore became a classical collateral victim of the bali terrorist incident. as discussed earlier in this chapter, the bali attack focused world attention on the potential threat of islamic terrorism in se asia. this was not a new phenomenon; but the scale of the bali attack, the fact that the majority of victims were tourists from western countries, and the intense media coverage of the incident had regional implications. in singapore, days after bali, the us, british, and australian intelligence services claimed to identify a jemayal islamiya/al qaeda plot to attack several western diplomatic legations in singapore. several suspects were arrested by singapore police and documents and videotapes were produced to support these allegations. the foreign ministries of several of singapore's main source markets including australia, united kingdom, united states, and japan issued travel advisories to defer nonessential travel to singapore. although this level of warning remained in force relatively briefly, the advisories aroused outrage throughout singapore, especially in its tourism industry. singapore was not the only se asian country subjected to negative travel advisories following the bali bombing. however, the very concept of a highly regulated and ordered society such as singapore being defined as a tourism security risk was considered by the political and business elite of singapore as a diplomatic insult and a loss of face. the first confirmed case of sars in singapore was identified in mid-march . according to the singapore ministry of tourism, a chinese doctor visiting hong kong in late february unwittingly infected several hotel guests, including a number of singaporeans who carried the disease home to singapore. at its zenith, by late may, a total of people in singapore were diagnosed with the virus, of whom died. a further people were placed under preventive quarantine. as joan henderson correctly observes, the crisis surrounding sars was one of fear rather than of substance. this is not to suggest the very real concern generated by sars, especially among those unfortunate enough to have contracted the condition. in global epidemiological terms, the sars outbreak in singapore was relatively minor compared to the s hong kong flu. the overwhelming media coverage of sars accompanied by the widespread dissemination of world health organization warnings in the media and government travel advisories created a global impression that singapore was a latter day leper colony. the psychological fear of a looming pandemic quickly descended on neighboring countries. travelers were instilled with dread about visiting or transiting singapore or even flying in aircraft that might travel in the general direction of singapore (henderson, a) . iata temporarily relocated its asia pacific crisis communications headquarters from tokyo to singapore in order to focus its attention on reassuring airline passengers of the negligible risk of contracting sars on airlines and in transit lounges in singapore or other se asian transit points. tony concil, iata's asia pacific manager of crisis communications, sent daily media releases about the sars situation as it impacted on airlines and airports. concil recalled the many occasions he fielded journalists' questions and issued media releases detailing the precautions airlines had taken to minimize the risk of the spread of sars among airline passengers (interview: concil, ) . during the height of the sars crisis in the period of march-june , singapore's government committed sid$ million to support the travel and tourism industry during a period in which tourist arrivals to the island state fell by % over the corresponding months of . a portion of these funds was devoted to maintaining employment levels in a wide range of tourism enterprises including hotels, attractions, tour operators, and the government-owned airlines. a push marketing campaign was initiated to inform and reassure the travel industry and consumers in key markets that singapore had adopted a range of measures to minimize the threat of sars. many hotels and attractions were identified as complying with a series of measures which declared them "sars safe." this was conducted under the slogan cool singapore campaign (henderson, a) . by june singapore was declared sars free by the who, enabling the singapore tourism board to instigate its major post-sars marketing recovery campaign. singapore roars referred to the national merlion symbol and the explicit connection with tourists "roaring" back to singapore. the singapore tourism board was granted a sid$ million budget increment devoted to marketing singapore toward a post-sars recovery. the primary message communicated, of singapore being sars-free, incorporated a range of inducements and discounts designed to encourage travel agents to sell and promote singapore to their clients. travelers visiting singapore were made aware of an extensive range of discounted and value-added deals on tours, hotel accommodation, access to attractions, etc. promotions targeted at the travel industry in specific source markets incorporated the singapore roars campaign as part of a cooperative marketing exercise with campaigns to visit malaysia, thailand, hong kong, and the philippines. this strategy was part of a broader asean and pata approach to tourism recovery. the singapore roars campaign marked the first occasion for singapore's tourism industry in which a destination-specific recovery campaign was conducted in conjunction with a broader regional tourism recovery campaign. the significant downturn of tourism to most of se asia irrespective of the prevalence or even presence of sars was a common factor prompting a cooperative approach. operational and budgetary benefits derived from sharing the costs between government and private sector stakeholders communicating a common regional message to the trade and consumers in key source markets were persuasive reasons to cooperate. the singapore roars campaign involved concerted media coverage in major source markets, some of it subsidized by cnn as part of a broader se asian regional project phoenix campaign coordinated along with pata. a consortium of private tour operators, hoteliers, attractions, shopping outlets, and airlines contributed marketing funds and offered a range of special deals to expand incentive arrangements designed to reactivate tourism demand for singapore. by november , it was clear statistically that the recovery process was achieving success. november arrival figures for singapore were . % up on the preceding year. however, it must be recalled that november figures were historically low due primarily to the impact of the bali incident on se asian regional tourism. the impact of sars was pronounced on the annualized figures for singapore's inbound tourism, which suffered a . % drop in compared to or . million tourists in compared to . million in (singapore tourist board statistics, . the relative speed and success of singapore's recovery exemplify the best elements of a professionally managed restoration marketing campaign. singapore roars was coordinated and centralized by the singapore tourism board involving a high level of cooperation with national carrier singapore airlines, the private sector of singapore's tourism industry, especially hoteliers, major attractions, and inbound tour operators. singapore's advantage in this achievement is largely due to the fact that it is a highly regulated and compact city-state and there is universal recognition in singapore that tourism is a strategically and economically significant industry. the eastern indonesian island of bali is traditionally promoted as a destination with little reference to the fact that it remains politically an integral part of indonesia. in the period of the late s and the beginning of the twenty-first century, the indonesian nation, which gained independence in under the slogan "unity in diversity," has experienced an upsurge of political instability accompanied by outbreaks of ethnic, religious, and nationalist separatist movements. the most significant campaign resulted in the creation of an independent east timor in following a bloody -year guerrilla war. however, from aceh in the northwest extremity of sumatra to irian jaya in western new guinea (indonesia's eastern extremity), separatist movements are now an integral part of indonesia's complex political landscape in a country with a population of million people and , islands, the sprawling archipelago dominating the region between the malay peninsula and australia. until october , bali, especially from a tourism perspective, was a superficially idyllic anomaly in indonesia. bali's population and culture are predominantly hindu, whereas % of indonesia's people are muslim. bali's distinctive culture, as the last surviving remnant of india's former cultural hegemony over the indonesian archipelago, is unique in indonesia. over the past years bali has become a popular "paradise" resort island for tourists from all over the world. beautiful scenery, a pervasive spiritualism among the traditional balinese, excellent surfing beaches, friendly people, and relatively relaxed attitudes to cultural pluralism are the elements that have resulted in bali's popularity as one of the most visited single tourist and resort destinations in se asia. bali is the most popular destination for foreign tourists in indonesia. bali's tourism infrastructure has attracted a vast amount of foreign investment and contributed to its comprehensive and diverse tourism infrastructure, with resorts ranging from the ultimate in luxury to the basic. the influx of tourists has brought a mixture of economic benefits and social and economic problems. bali's economy is heavily dependent on tourism but many balinese are exploited by the tourism-based economy. many of the resorts and hotels are owned by multinational companies and australian or western entrepreneurs. the dark side of bali's tourism success has resulted in the growth of a subculture of corruption, drug dealing, and a high rate of petty crime. the combination of unregulated capitalism and the daily influx of ten jumbo loads of foreign tourists, some of whom are totally ignorant and insensitive to traditional bali's social mores, has undermined bali's traditional society (interview: king, ) . a minority of western tourists, especially from nearby australia, treated bali as an exotic tropical "pub" and a relatively inexpensive resort island paradise to let off steam after a football season or to celebrate personal or communal events. the alcohol-and drug-induced hedonism of this section of the western market has caused offense to the traditional local hindu balinese. for the growing numbers of indonesians who have embraced islamist fundamentalism, these tourists symbolize western decadence inimical to their beliefs. since the mid- s, some islamic groups in java have attacked nightclubs and liquor outlets as part of a wider demand to impose (islamist) sharia law in indonesia. until , bali had been spared this form of violence primarily because most balinese are non-islamist and such acts would harm the lucrative tourism industry. inbound tourism to indonesia statistically peaked in with a total of , , arrivals. the main source markets in were singapore, . million tourists; japan, , ; malaysia, , ; australia, , ; taiwan, , ; south korea, , ; united kingdom, , ; united states, , ; and germany, , . malaysian and singaporean numbers were heavily inflated by their proximity to indonesia and the fact that many of these visits were essentially cross-border short trips. ne asia and japan, europe, australasia, and north america were the primary sources of high-yield tourism for indonesia and bali specifically. bali's capital, denpassar, was the port of entry for . % of foreign visitors to indonesia and the principal port of entry for inbound tourists (badan pusat statistik, bps-statistics indonesia, ) . the october , , bali bombing had a profound impact on balinese tourism but it would impact tourism broadly throughout indonesia and se asia. on that evening the crowded sari club and nearby paddy's bar were destroyed by powerful truck bombs. the convicted perpetrators, members of jemaal islamiya, a radical islamic group allegedly linked to al qaeda with a substantial presence in indonesia, readily admitted responsibility for the attack. the bombing was the deadliest attack directed against tourists in the world for many years. of the deaths, were australian, british, and indonesian, and the victims included citizens from other countries (wilks, ) . the impact of the bali bombing on tourism to the island was instantaneous. tourism demand fell and forward booking dried up. the bombing exposed a number of serious infrastructure problems, the most obvious of which was the lack of medical and hospital facilities to cope with a disaster on this unprecedented scale. the lack of mortuary facilities was a factor that contributed to the major difficulties in identifying many of the deceased. the bombing also exposed the serious security shortcomings of the entire tourism infrastructure in bali. the indonesian government does not make provisions for adequate medical facilities to cope with the general needs of locals or tourists. the balinese were unprepared and ill-equipped for an act of terrorism so alien to their way of life. many of bali's major tourism source countries immediately imposed upgraded travel advisories. australia, the united states, united kingdom, and japan advised their citizens to defer travel. garuda airlines and qantas facilitated the evacuation from bali of many travelers, especially australians. the australian government offered medical assistance to the indonesian government and sent medical and rescue teams, providing australian medical facilities and personnel to all victims of the attack. as discussed in the introduction, the executive members of the pata were in bali on the night of the sari club bombing to celebrate the wedding of pata vice president peter semone. the pata executives were to play a significant role in galvanizing regional travel industry support for bali's beleaguered tourism industry. they immediately assisted local tourist authorities in establishing a crisis communications unit. pata recruited a team of crisis management experts to assist the balinese and indonesians in planning a recovery strategy for the tourism industry. the indonesian government contracted australian tourism crisis management specialist john king, ceo of tourism and leisure and the chairman of tourism tasmania, to assist them in developing a marketing recovery strategy. king's significant involvement in tourism tasmania's highly successful campaign to restore tourism to tasmania after the port arthur massacre of tourists eminently qualified him to assist in bali catastrophe. mr. king observed that the indonesian government demonstrated minimal commitment to implementing the advice provided by him, his colleagues, or any other foreign experts. the private sector of the tourism industry within bali and regionally was characterized by a strong sense of unity of purpose. conscious of the need to reassure tourists, hoteliers, tour operators, and local attractions upgraded security. tour operators and airlines combined to introduce a range of incentive-based marketing campaigns and familiarization tours for media and travel industry leaders from source markets. pata maintained its long-term plan to hold its annual conference in bali in april . australian tourism industry organizations, including the australian institute of travel and tourism and the council of australian tour operators, chose to hold major conferences in bali as gestures of support for the balinese tourism industry. the balinese regional tourism authority produced a tourism security and safety: from theory to practice highly professional promotional film that illustrated the distinction between negative perception and the actual experience of travelers in . the film featured tourists from the main source markets telling viewers how much they were enjoying their visit and showing there was no cause for concern. the underlying theme was to communicate a message that tourism to bali was safe. major obstacles to a fully integrated tourism recovery in bali included the maintenance of negative travel advisories, negative media publicity mostly emanating from international media, and the indonesian government's decision to conduct the trial of the bali bombers in bali. according to australian, british, american, and japanese travel industry professionals invited by the indonesian government to assist in the recovery, the greatest barrier to implementing a recovery was the ineptitude and incompetence of the indonesian government and the indonesian ministry of tourism. the indonesian government ignored professional advice and implemented policies counterproductive to an effective tourism recovery campaign. the indonesian government compounded its problems from the very beginning of the bali crisis by its failure to show due concern for the welfare of the victims and launching into attacks verging on the paranoia against governments that had issued negative travel advisories after the bombing. indonesian government attacks against the australian government were especially vituperative. considering that australians accounted for almost half the victims of the sari club attack, the indonesian response to the advisories demonstrated insensitivity at best, and at worst a petulant abandonment of diplomacy. the attitude toward australia, in particular, was colored by wider strains in bilateral relations including timor's struggle for independence from indonesia in and australia's prominent military and diplomatic involvement as a guarantor of this process. the indonesian government was a vocal supporter of reconstituting the asean tourism marketing organization. during the november summit of asean leaders in phnom phenh, indonesian president megawati sukarnoputri joined many of her fellow asean leaders in criticizing western government negative travel advisories. the bali attack had led to the imposition of security-based negative travel advisories applying to several se asian countries. indonesia was strongly supported in this forum by all se asian leaders, especially malaysian prime minister dr. mohathir mohammed. the indonesian government officially committed us$ million toward bali's tourism recovery but there was little evidence of spending on any identifiable program. tourism, security and finance ministry officials undertook "fact finding marketing missions" to source markets; two were conducted in australia. the indonesian delegates involved in the second visit in november were unaware of the first one, which had taken place in may . one policy initiative widely condemned by local and overseas tourism industry stakeholders was the indonesian government's decision to impose a series of visa fees. whatever the merits of the policy, the timing of its release several weeks after the bali bombing was condemned by private sector stakeholders who viewed it as a major disincentive to tourism recovery. the decision to try the alleged bombers in bali was controversial. there were legitimate legal reasons to conduct the trial at or near the scene of the crime. however, from a tourism recovery perspective, the trial served as a painful and protracted reinforcement of the bali bombing. understandably, the trial focused far more global media coverage on bali than the issue of restoring tourism. private industry marketing campaigns led to a gradual recovery of tourism to bali from april . pata's conference during that month focused on positive tourism attention on bali. bali also figured in the broad scheme of pata's project phoenix. additionally, a range of cut-price holiday deals was successful in enticing many tourists to return to bali. the balinese tourism authorities successfully cooperated with the private sector of the tourism industry. the anniversary of the bali bombing was conducted in a manner intended to end to the formal mourning period (if not for the survivors and the families of victims) to this terrible event at least to non-balinese victims. the balinese tourism industry took almost a year to recover. australian and japanese markets have been slower to recover than se asia, the united kingdom, and the united states. the philippines tourism industry has a long history of overcoming a range of events that have restricted its potential to become a major tourism destination in se asia. political instability, aids, localized terrorism, especially in the large southern island of mindanao, natural disasters ranging from seasonal typhoons to the eruption of mount pinatubo, and the asian economic crisis all contributed to acting as a brake on tourism growth. considering all these problems, the overall trend for tourism in the philippines during the s was positive. by , inbound tourism numbers to the philippines passed million, double the level (beirman, ) . in the forced resignation of president joseph estrada led to the appointment and later election of gloria arroyo as president of the philippines. arroyo appointed richard gordon as secretary of tourism. gordon took on the position with an almost missionary zeal to advance tourism to the philippines as a major industry. an energetic and ambitious man, richard gordon sought to radically alter the tourism infrastructure and the marketing of the philippines. he also took on a high profile in supranational tourism organizations. in he was elected as chairman of pata and rapidly became a powerful regional voice within the world tourism organization. gordon rallied the philippines tourism industry by calling the first tricon (tourism related industry conference) a few months after his appointment as tourism secretary in . the underlying strategy to revitalize philippines tourism was to gather an alliance of all sectors of the tourism industry and the local and provincial political leadership. the second and third tricons in and developed the concept of a marketing campaign called wow philippines. the core strategy of the campaign was to diversify both the image and benefits of inbound tourism to encompass a wide geographical area of the country. the campaign sought to appeal to a variety of niche markets, including golfing, resorts, ecotourism, meetings and conventions, business and incentive tourism, adventure tourism, diving and water sports, cultural tourism, and to identify specific regions of the philippines as representative destinations for these activities. in the capital, manila, the department of tourism actively participated in restoring specific districts of the city, most notably intramuros (the old walled spanish quarter of manila) and manila bay's waterfront. the philippines department of tourism, in close association with major tour operators, philippine airlines, and other carriers servicing the philippines, offered tourism security and safety: from theory to practice a range of cut-price and value-added incentives for tourists. it also sought to encourage the estimated million filipinos living abroad to act as tourism ambassadors. the department of tourism, supported by the national government and the local media, instituted educational and promotional programs designed to encourage locals to adopt a welcoming attitude toward tourists and to encourage hospitality and cleanliness in the county's towns and cities. the philippines department of tourism claimed a high level of success for this program. following the bali bombing in october , there was renewed focus on islamic activists in the southern philippines by the global media and by the governments of some of the philippines' most lucrative tourism source markets, notably japan, the united states, western europe, and australia. tourism secretary richard gordon was a vocal critic of negative media coverage and government advisories. the primary basis of his criticism was that the reputation of the entire country was under attack because of activities that took place in one particular locality. gordon demanded that the media and government advisories specify the problem areas as opposed to calling the entire destination into disrepute. gordon's demand for specificity in both media coverage and government travel advisories resonated with the governments and tourism officials in many other countries in se asia that shared similar problems after the bali bombing. the philippines inbound tourism industry was a collateral victim of the sars outbreak despite the fact that the country was virtually free of the disease. media-magnified fears of se asia as a potential risk area for sars impacted se asian countries irrespective of the incidence or absence of sars. richard gordon's appointment to the chairmanship of pata in gave him a powerful voice well beyond the philippines. he used his regional power base in both pata and asean to exert pressure on the world tourism organization to take a global tourism industry approach to the issue of government travel advisories and received support from many countries that shared the problems the philippines itself had encountered. in early the wto's secretary general, francesco frangialli, called on the wto to initiate discussions through the un for a global approach to realistic government travel advisories. the wto obtained un status in , which enabled them to officially propose a global set of standards on travel advisories to the un. the wow philippines campaign involved a mixture of marketing campaigns, travel industry training and education, media and travel agency familiarization visits, and the incorporation of wow philippines within pata's project phoenix. a unique feature of the campaign was the incentive scheme offered to expatriate filipinos to make a home visit accompanied by citizens of their host nation. in effect, the more citizens filipinos could identify as visiting because of their individual promotion, the cheaper the home visit would be. the expatriate program was designed as an attractive bonus/incentive scheme for the many filipino citizens working abroad on low incomes with families in the philippines. provided they could identify a given number of tourists, the home visit for the expatriate would be free of charge. as filipino nationals traditionally represented % of the inbound tourist market during the s, the bonus scheme was a potentially effective program to bolster inbound tourism numbers. in the period of - overseas filipino arrivals represented the second fastest growing sector (up . %) of an inbound tourism market that as a whole actually dropped by . % between (philippine department of tourism, . the overall concept of wow philippines was expected to be statistically significant during and early indications for already indicated a strong return to inbound tourism growth. the overall market for the philippines remained steady during despite the collateral problems of sars and the more pressing problem of terrorism-focused negative travel advisories. the total inbound tourism figures for were . million tourists compared to . million tourists for , representing a drop of . %, considerably less than most other se asian countries. of the philippines major source markets, slight declines in us and japanese tourists were offset by growth from south korea. however, in the philippines suffered drops in arrivals from significant sars-affected source markets: hong kong, taiwan, and singapore. outbound tourism from these three countries was heavily reduced during the period of the sars outbreak period (march-july ) due to entry restrictions imposed by tourism receiving countries including the philippines. the tourism industry in se asia was subjected to an unprecedented degree of volatility during late and the first half of . the bali terrorism attack in october , while disastrous for bali, exerted a powerful ripple effect which impacted most se asian destinations, especially those with substantial muslim populations. the bali bombing placed an unwelcome global spotlight on the perceived and actual threat from islamic organizations on the overall political stability and tourism safety in some se asian nations. the combination of negative media attention and negative government travel advisories from major source markets in the west and japan spurred regional and national responses in se asia. the outbreak of sars in the period of may-june , while largely confined to se china, hong kong, and singapore, was magnified by the media and to some extent by the world health organization as a public health threat, grossly disproportionate to the number of people affected by the disease. on the scale of global epidemic outbreaks, sars was a minnow compared to aids, malaria, cholera, typhoid, and historical manifestations of influenza. the impact of sars in se asia was a severe curtailment of tourism arrivals during the identifiable danger period. the tourism industry response in se asia to sars and terrorism involved an unprecedented degree of regional government and private industry cooperation in recovery marketing programs. the previously moribund asean tourism agreement was rapidly resurrected by the initiative of asean heads of state. pata, iata, and the wto worked closely with the global media and government tourism bodies in se asia to implement a regional marketing recovery program revitalizing tourism it the region. each country in se asia developed and implemented destination-specific marketing and confidence-building programs to restore tourism. the singapore roars campaign was highly organized, centralized, and professional and achieved rapid results. the wow philippines campaign successfully minimized deterioration in tourism during a challenging period for the country. the indonesian government's campaign to restore tourism was hampered by poor leadership, incompetence, a failure to heed professional advice, and a lack of tourism security and safety: from theory to practice national direction. conversely, the balinese regional authorities implemented a successful marketing recovery campaign heavily supported by local and foreign private sector stakeholders. consequently, bali was less dependent on indonesian government support than other regions in the country. the events of late and the first half of demonstrated the vulnerability of the se asian tourism industry to events beyond direct managerial control. sars and terrorism demonstrated the importance of contingency marketing and management practices to optimize recovery from crisis events. the tourism industry's private sector demonstrably and quickly learned from the many crisis events of the early twenty-first century. increasingly, se asian governments with a powerful vested economic interest in maintaining a growing tourism sector have taken the issue of recovery marketing seriously. a minority of se asian countries, especially indonesia, have a long way to go before they are in a position to recover rapidly from tourism crises without a high level of dependence on outside aid. the majority of asean countries at both government and the private sector level are demonstrating a high level of professionalism in their strategic marketing approaches to the protection and recovery of their tourism industries and infrastructure from crisis events. crisis (as applied to this chapter) a situation requiring radical management action in response to events beyond the internal control of the organization necessitating urgent adaptation of marketing and operational practices to restore the confidence of employees, associated enterprises, and consumers in the viability of the destination. restoration alliance the working alliance between all private and public sector segments of the tourism and hospitality industry and destination marketing authorities designed to restore the marketability and security of the tourism industry. the alliance works on both restoring the image and marketability of tourism destinations and regions concurrently to sellers and distributors of tourism product and to consumers. source markets markets that are the main sources from where tourists are attracted to the destination or region. this is usually determined by country of origin and measured by counting the citizenship of tourist arrivals. government travel advisories assessments determined by ministries of foreign governments that focus on the security and safety of destinations. these are designed to inform citizens of the issuing country of the likely threats that citizens of that country may encounter if visiting a given destination. in most instances advisories are graded in accordance with a perceived level of threat. general exemption insurance companies frequently deny cover to insured travelers who incur loss, injury, or death resulting from politically motivated violence. in insurance parlance, denial of such coverage is labeled as "the general exemption." the general exemption is currently undergoing review as a result of consumer pressure. regional marketing in the context of this chapter, regional marketing involves the coordinated promotion and marketing of a group of countries to a commonly targeted source market or set of source markets. pata and asean employed regional marketing of several se asian destinations to specific source markets including china, japan, australia, europe, and the united states with the aim of encouraging tourists to visit more than one of the destinations in a single trip. it also recognized that the crisis indicators that led to the coordinated recovery campaign were common to the region, as opposed to being confined to a single destination. push marketing targeting the sellers, promoters, and suppliers of the tourism product in source markets including wholesalers, travel agents, airlines, hotel chains, and the media. pull marketing marketing to consumers either directly or in cooperation with stakeholders such as wholesalers, the media, airlines, hoteliers, and other principals that sell or have product in the targeted destination. explain the recent upsurge in the significance of government travel advisories as a factor impacting on tourism to se asia and its broader implications for global tourism pata's project phoenix represented a new approach to regional restoration marketing in se asia. assess its success as a strategy and identify the key elements incor in what ways has media coverage impacted the perception of tourism destinations since the development of global media broadcasting through networks such as cnn analyze and compare the effectiveness of the three campaigns examined in this chapter to what extent to you attribute the reconstitution of asean tourism marketing as a reactive measure to tourism crisis or a proactive approach to recovery? how does the marketing recovery campaign in se asia compare to other recovery campaigns in the world, such as the us recovery campaign post-september , turkish recovery after the izmit earthquake, britain post-foot and mouth outbreak, sri lanka post-civil war or others if you were a destination marketer in se asia how would you have approached the management of sars and the bali bombing? are there approaches you would use that would be different from those undertaken in the case studies? references association of south east asian nations the story of the pacific asia travel association restoring tourism destinations in crisis tourism security and safety: from theory to practice terrorism and tourism. managing the consequences of the bali bombings managing a health related crisis: sars in singapore inbound story. strategic intelligence group singapore girds for sars. online asia times flight of the phoenix. pata compass tourism risk management for the asia pacific region. bangkok: world tourism organization (wto) and pata crisis-it won't happen to us director, corporate communications, iata asia pacific vice president of pata key: cord- - yas yqt authors: yoshikawa, minako jen title: dengue and chikungunya virus infection in southeast asia: active governmental intervention in republic of singapore date: - - journal: current topics of infectious diseases in japan and asia doi: . / - - - - _ sha: doc_id: cord_uid: yas yqt this paper discusses countermeasures of republic of singapore towards mosquito-borne infectious diseases, particularly, dengue and chikungunya virus infection to identify an essential factor in controlling emergence of infectious diseases. in spite of expanding areas affected by and upsurge of these diseases in the region, the tropical urban country is known to have sustained an effective vector control, which often resulted in moderate prevalence and/or quick control of domestic outbreaks. this research has adopted an inter-disciplinary review of previous studies combined with field studies: interviewing at the ministry of health, singapore and the national environment agency, singapore; visiting a laboratory and hospitals; and observing on-site vector mosquito surveillance operations conducted by the agency. the findings have pointed out the national vector surveillance and control system implemented by s, followed by improved countermeasures like vector and virus surveillance which have incorporated science and technology especially in the last two decades. the analysis produces an influential role of a government in promoting and supporting public health measures, which have been typically demonstrated through inter-ministry collaboration, public-private cooperation, and community involvement. in light of increasing transnational nature of emerging infectious diseases, singapore’s contribution in the region like sharing its knowledge of and experiences in dengue and chikungunya virus infection is illustrated. the resilient model of singapore’s vector control and governmental action warrants a further study to investigate transferability in other parts of the region. one can find in singapore a government that desires to protect health of the people while preserving economic and trade activities in the ages of globalization. singapore has maintained an impressive track record in responding to emerging and re-emerging infectious diseases (hereinafter expressed as emerging infectious diseases). for example, it was the year of when the country attracted waves of praise as a successful country in handling the outbreak of severe acute respiratory syndrome (sars). also, singapore's resilient vector control management for mosquito-borne infectious diseases is noteworthy. the "energetically sustained" dengue control program is acclaimed as "a model for the rest of the world" [ ] . although a considerable number of studies on its outbreak response, surveillance, prevention, and disease management have been conducted by the medical and science community, others often attribute singapore's outstanding infectious disease control to the small territory and economic affluence alone. medicine and science-oriented studies, too, tend to pay little attention to factors that are not scientifically proven. what seems to be lacking is an inter-disciplinary investigation of emerging infectious disease countermeasures. this paper attempts to elucidate an active role of the singapore government in facilitating and sustaining satisfactory response to emergence of infectious diseases. the government here refers to the governing body consisting of politicians and the public servants engaged in the service of the supreme authority. this paper limits the discussion to singapore's action against dengue fever (df), dengue hemorrhagic fever (dhf)/dengue shock syndrome (dss) (hereinafter abbreviated as dengue infection) and chikungunya viral infectious diseases. we will first review how the young nation, having become an independent state only in , came to establish its national vector surveillance and control system by 's. next, elaborating singapore's measures in the recent decades, we reveal the heavy emphasis placed on the scientific research in public health tools in the country, which has been remarkably evident since 's. finally, we will devote some space to the discussion of singapore's role and capacity in a regional effort to control dengue infection. situated km north of the equator, highly populated singapore is often referred as a tropical city-state. population density was , /km , heterogeneous singapore citizens and permanent residents represented % of . million total population (mid-year estimates, ) [ ] . besides frequent travels of residents, mobility of people in singapore is marked by transnational movements, especially considerable influx of foreign labor and overseas travel. in fact, residents recorded just . % of labor force participation [ ]. about . million tourist arrivals (excluding malaysians arriving by land) show as high as % come from asia, one-half of which are from asean member countries [ ] . being a regional hub of frequent movements of people as well as trades and economy, the congested urban country pays careful attention to mosquito-borne infectious diseases spreading in the region. with constant import potential of viraemic humans, its hot and humid tropical climate of singapore permits another threat: propagation of mosquitoes throughout the year including aedes aegypti and ae. albopictus that serve as vectors of dengue and chikungunya viruses. chikungunya virus (chikv) is a single-stranded rna virus (family togaviridae, genus alphavirus) and is known to be transmitted by the same vector species causing dengue infection. as of march , countries have reported domestic chikv infection and the list includes almost all southeast asian countries including singapore [ ] . section . summerises singapore's response to the first and subsequent domestic outbreaks in . the agent of dengue infection is also a small single-stranded rna virus (family flaviviridae, genus flavivirus). a dengue infection cycle starts when a female aedes mosquito bites an infected human, acquires competence to mediate, and then bites another person(s). there are four serotypes of dengue virus, den- , - , - , and - and infection with one serotype could provide a lifetime protection to the particular serotype. cautions are, therefore, required against the subsequent infection with other serotypes. the world health organization (who) has analyzed factors contributing to the global burden of dengue infection. examples are rapid population growth, migration between rural and urban locations, and transnational travel by infected persons and goods [ , ] . the international health authority often cites that the vector control is the sole preventative tool currently available and maintains that "[d]espite the availability of effective tools to control dengue, efforts to prevent and control dengue have been constrained due to lack of sustained political commitment, inadequate resources and lack of coordinated effort" [ ] . the present study has benefited from inter-disciplinary research of previous studies and fieldworks between september and august . research activities during the field trips to singapore included: document collection; interviews with ministry personnel from the ministry of health (moh), health promotion board under the moh, and the national environment agency (nea) under the ministry of the environment and water resources; visits to the nea's laboratory called environmental health institute (ehi) as well as public and private hospitals; and observing two onsite inspections of the nea. particularly insightful were the larval surveillance and adult trapping operations performed by the south east regional office of the agency. the operations covered private houses, public highrise residential buildings (known locally as hdb flats, figure ), and a construction site of a condominium ( figure ) in september and march [ , ] . in addition, the author attended the inaugural asia-pacific dengue program managers meeting convened by western pacific regional office of the who (wpro) and co-sponsored by the nea in may [ ] . in august , the author visited the regional office of the wpro in manila, the philippines to learn views and activities of the international health authority. result: singapore's resolute efforts to fight against dengue infection known as breakbone fever, df has been prevalent for centuries and dhf first occurred in the philippines in [ ] . the first dhf outbreak struck singapore in , one year after it attained a self-government status ahead of the country's birth as an independent state in . the vector control unit (vcu) was formed in initially under the moh and was later transferred to the ministry of the environment in [ ] . goh kt ( ) elaborated activities of the vcu: it gathered ecological and biological data such as vector distribution and density, location of breeding habitats, and seasonal fluctuations in vector population. chan kl ( ) pointed out that several entomological surveys of slum areas around that time suggested the evidence of huge ae. aegypti inhabitants, supporting a close correlation between dhf and poverty [ ] . evidently, this finding led the young government to address the environmental issue, including replacement of slum houses and cleaning of residential areas. to deal with a challenging task to transform human behavior, the singapore government decided to use law enforcement and health education: the destruction of disease bearing insects act was enacted and the "keep singapore clean and mosquito-free campaign" was designed to motivate the community to participate in the countrywide vector control program in [ ] . in addition to the adult mosquito surveillance began in , a weekly aedes larval routine survey in premises became operational in june . subsequently, the incident rate of dhf dropped; morbidity rate per , was . in [ ] and remained between and for the period from to [ ] . however, optism resulting from low level of incidence might have translated into , cases with deaths in [ ] . the vector surveillance became even more crucial to establish the knowledge of "the normal level" of vector density, which enabled the vcu to calculate a premise index (pi) or a percentage of premises positive for aedes breeding to estimate dengue virus transmission risks. wherever a pi exceeded %, the vcu fogged the area with insecticides to eradicate the adult mosquitoes. as priorities of breeding habitats kept shifting owing to the vector behavioral change, the breeding sites elimination task became difficult in a cat-and-mouse game. to address the issue, the repeated evaluation and feedback system was used in s and s, which became useful to review and amend strategies ( figure ). in addition, the regulatory requirement made dengue infection legally notifiable in under the infectious diseases act of while dhf had been already made administratively notifiable in [ , , ] .while the rest of the southeast asian region experienced epidemics in and , the vector control system contributed to low frequency of dhf in singapore [ ] . singapore benefited from the reduced vectors for a period of almost years after recording cases in . its vulnerabilities to importation of dengue infection, however, existed as long as the disease was endemic in the region [ , ] . by the s, the city-state saw the resurgence of dengue infection. in addition to the expansion and escalation of the diseases in the region, the previous diligent vector control possibly fueled the situation as the low prevalence of the disease generated the large susceptible human populations due to reduced herd immunity [ ] . there was, however, another contributing factor: by then, the labor intensive vector control had been changed to respond to human cases instead of a higher pi in response to a call for efficient usage of public resources [ ] . areas "at risk" may not be sufficiently discovered by case detection [ ] as ooi ee et al. ( ) has illustrated: this shift inevitably overlooked risks that were hidden by subclinical cases [ ] . seeing the dengue infection increase from , cases in to , in , and to , in , the government set up in an educational program and launched volunteer groups. active persuasion of the community began. a political leader's involvement was evident in the following quotation: the best way to protect yourself and your family from dengue fever is to make sure that the mosquitoes do not have a chance to multiply in your homes and neighborhood. unfortunately not enough residents make the special effort necessary to prevent aedes mosquitoes from breeding…residents should therefore come together as a community to get rid of the mosquitoes, and keep the estate free from dengue fever. the above speech was delivered by then deputy prime minister and current prime minister lee hsien loong at the launch of an educational program and volunteer groups in may, [ ] . from this passage, we can infer the political will to solve the problem by influencing the residents to become more responsible and cooperative towards governmental intervention. subsequently, the number of cases declined to , in , in , , in , and , in [ ] . singapore was able to transform human behavior towards aedes mosquito breeding [ ] . however, as transmission outside home premises like construction sites emerged [ ] , the number of cases jumped to , in and , in [ ] . the large outbreak in occurred concurrently with the region-wide epidemic [ ] . by then, singapore was even more congested, experiencing nearly doubled population density from , / km in to , / km in [ ] . replacement of dominant dengue serotypes over the years, "a contributory role" of the rising temperature [ ] as well as cumulative precipitation in years - [ ] had been also documented. laboratory confirmed cases amounted to , comprising , df and dhf; fatalities represented the third largest among all notified infectious diseases in singapore in . several initiatives deployed and countermeasures reinforced in response are detailed in section . . when the city-state achieved lowering the cases significantly in , the who referred singapore as "a good example of a country that has successfully controlled the mosquito population…" [ ] . reported cases of , ( , df and dhf) in represented a decline of % from [ ] and all cases were confirmed by laboratories with one or more tests like anti-dengue igm antibody, enzyme linked immunosorbent assay (elisa), and polymerase chain reactions (pcr) [ ] . the figure included , indigenous, imported, and cases suffered by foreigners of whom the majority is patients having acquired the diseases overseas and sought medical treatment in singapore [ ] . although the territory wide anxiety was heightened in singapore when the weekly reported cases indicated as high as during july - th, , the weekly number in and remained below both the epidemic threshold of weekly cases and the warning level of [ ] . for dengue infection, communicable disease surveillance branch at the moh handles surveillance of human cases while the nea is responsible for environmental surveillance. in response to an alarming upsurge, the moh formed an expert panel in september . local and international experts of the panel reached a conclusion that the regular importation of dengue viruses into singapore was likely to continue "because dengue is a re-emerging disease globally and is endemic in the surrounding regions" [ ] . furthermore, the inter-agency task force was formed around the same time to enhance the communication and coordination among various agencies with the aim to strengthen the countermeasures in the areas of investigation, audit, and infrastructure [ ] . environment heath department of the environmental public health division of the nea is in charge of vector surveillance, control, prevention, and research operations. as many as , residential and , nonresidential premises on average are inspected each month [ ] . devices known as ovitraps are deployed across the city-state; an ovitrap is a black plastic container designed to attract female mosquitoes to lay eggs and then trap the emerging adults within the containers. the weekly checks of the ovitraps enable the nea to detect the presence and types of mosquitoes early and proactively remove mosquito breeding habitats [ ] . the department has compiled examples of common and potential mosquito breeding places by types of premises and sites to draw further attention from residents and visitors [ ] . in situation room at the head office, the nea uses a geographical information system (gis) implemented in for the analysis of the distribution of both vectors and infection cases. in december , the agency reinforced its vector surveillance and control system; about officers were conducting routine ground surveillance across the island especially in dengue-prone areas (e.g. construction sites, compounds of landed housing properties, and schools) for the purpose of detection and removal of breeding sites [ ] . in , the nea carried out inspections of approximately . million premises in addition to over , ground surveys. furthermore, the nea led two intensive source reduction exercises in april-may and july-september [ ] . the singapore authorities make the emergence of infectious diseases in the territory known in a timely manner. as for dengue infection, locations of cases and the results of outbreak investigations are made transparent. the moh also periodically communicates: moh medalert reports outbreaks; moh weekly infectious disease bulletin reveals weekly data; epidemiological news bulletin analyzes quarterly trends and special topics; and communicable diseases surveillance provides annual overviews and comprehensive data. additionally, news and updates of the outbreaks are often issued as press releases. all these materials mentioned above are made available on-line. as for the accuracy of the number of reported cases, the following section will clarify. both residents and visitors often see posters and other warning materials throughout the country especially when dengue cases are on the rise (figure ) . thus, it is reasonable to say that singapore's information is kept widely open to both local and international community. while many southeast asian countries tend to report only the manifested cases based on clinical diagnoses in general, singapore is known to report dengue infection inclusively (df/dhf/dss). thus, the variance in reporting system makes it difficult to compare the reported dengue cases for evaluation among countries in the region. this problem may be partly attributable to underdeveloped costly technology in the region. as for singapore, there is enough evidence to identify dedication of the government to science and technology development, especially following national science and technology plan announced in september . the singapore government prioritized its policy to make singapore "the hub for life-science research in southeast asia" [ ] . the political commitment can be seen as embodied in the grand establishment in : a complex of seven buildings named biopolis houses the biomedical industry including the ehi, the nea's laboratory. singapore regards laboratory-based virus surveillance as an integral part of the dengue countermeasures. it is important since identification of the antigen and four serotypes could produce scientific data that have significant relevance to epidemiological investigation and disease surveillance. in other words, the findings could suggest or predict potential shift of dominant serotype, which would cause large outbreaks. the ehi adopted a new economical method in called the multiplex rt-pcr technique with high throughput capability for the screening of dengue viruses [ ] . the technology can also facilitate rapid and reliable diagnosis to administer proper clinical treatments [ ] even when patients present undifferentiating febrile illnesses. moreover, an ehi researcher revealed faster and greater horizontal and vertical flight ranges of the dengue vector mosquitoes by conducting "mark-release-recapture" studies at three different locations in the city-state [ ] , which supplied useful information for vector control operations. in , researchers in singapore published a diagnostic algo-rithm allowing early diagnosis or differentiation of dengue infection with an accuracy of almost % from other febrile diseases [ ] . it can be said that each achievement is a product of government-driven investments in science for health, which singapore has been active since s. one recent addition was the s$ million grant announced in october ; the government of singapore will make available over five years to researches on dengue infection. the research efforts are expected to focus on the development of evidence-based case management and disease prevention and pursue to fill in gaps between bedside and "bench research" [ , ] . the battle against dengue infection of the nea is constituted of not only the vector control and virus surveillance, but also law enforcement and community involvement. legal compliance of dengue control measures is facilitated through the environmental public health act and the control of vectors and pesticide act. the former consolidates and defines the law pertaining to environmental public health and the latter makes it illegal to breed mosquitoes through the section of prohibition on creating conditions favorable to vectors. examples were (as of february ): s$ fine for the st and s$ for the subsequent offences committed in residential premises; heavier penalties are applied to construction sites as s$ , for the st, s$ , for the nd, followed by court appearance and maximum s$ , and/or six months imprisonment. the agency can ultimately order the construction companies to stop the work. [ ] . community involvement, on the other hand, is encouraged through various social activities and a series of campaigns. in when the author visited singapore for almost two months, an educational community outreach promotion or the indoor " -minute mozzie wipe-out" initiative which had been implemented in was actively seen. the community outreach effort by the agency appeared to ensure that knowledge was translated into practice: for example, it reminded the households to check and remove stagnant water at homes like water in flower vases [ ] . the educational materials prepared by the nea included pamphlets, booklets, posters, and audio-visual items in all four official languages of english, chinese, tamil and malay to reach residents, domestic help workers, and so on. materials addressing construction sites and shipyards showed additional three foreign languages as singapore has abundant influx of foreign labor as has been pointed out earlier. in addition, the standard operating procedures (sops) reveal singapore's action plans for ps, i.e. three sectors of people, private, and public (gov-ernment). the people sector covers grassroots organizations, residential clubs, ngos, and npos while the private sector means private businesses, associations, etc. the public could include government ministries and agencies listed in the singapore government directory but the particular dengue sops make more direct references to the nea in terms of source reduction and ulv/outdoor fogging. the sops have seven steps of action plans depending on the number of cases: , , - , - , - , - , and > cases [ ] . for instance, procedures adhered when two cases of human infection are identified in a particular area: a team of two nea officers gets deployed for vector control tasks; a member of parliament from the particular constituency and a community leader are informed to take actions; the moh warns doctors in the affected area; dengue alert poster/banner at the premises are displayed; grassroots organizations are engaged to speak to residents; grassroots members assist with distribution of dengue prevention pamphlets and alert letters to residents; and so on [ ] . an excess of , volunteers from the ps joined the outdoor "carpet-combing" exercise from september to october , and more than , aedes mosquito breeding and , potential sites were removed [ , ] . about , volunteers sacrificed their weekends to distribute the " -minutes mozzie wipe-out" pamphlets to nearly , homes [ , ] , indicating the community involvement in the governmental initiative. thus, the ps mechanism of human resource mobilization in singapore has proven effective; the national dengue response of the singapore virtually involves the whole nation. the year brought singapore a new challenge as the first domestic outbreak of chikungunya fever arrived in january. impressively, singapore terminated the transmission within days. according to interviews conducted at the moh and the nea in march and may , a collaboration of the clinical network consisting of general practitioners and the reference laboratory, the ehi, had been implemented; an active surveillance on chikungunya fever started as early as in . in fact, blood samples tested negative for dengue virus by pcr were then tested for chikv. the careful and thorough preparation, partly in response to the outbreaks in other countries, may explain why singapore was able to react quickly in january (yoshikawa m.j. et al., manuscript in press). shortly after the first domestic case of chikungunya fever was identified owing to the collaboration, the authorities collected a total of , blood samples within meter radius in the area where the index case worked/resided and discov-ered additional cases [ , ] . as for the vector control, the nea destroyed over , mosquito breeding sites [ ] . however, subsequent domestic outbreaks started in june . interviews at the nea in march and august revealed that the previous control measures were not sufficient to address the new situation. as a phylogenetic analysis of chikv envelope (e ) gene by the ehi revealed, l.c. ng et al. ( ) confirmed that subsequent domestic outbreaks were much more complicated with importation of multiple chikv strains [ ] . furthermore, vector surveillance and control operations proved the new vector competence acquired by additional vector, ae. albopictus [ ] . the first domestic outbreak was mediated by ae. aegypti mosquitoes [ ] . whereas ae. aegypti tend to stay in and around residential premises and buildings, ae. albopictus breed in outdoor environments. thus, lowering the vector population quickly was a real challenge. indeed, the subsequent domestic outbreaks were located in the rural and sub-urban areas of the city-state [ ] . the revised vector control strategy incorporated these scientific findings; the agency increasingly utilized outdoor thermal fogging to kill adult mosquitoes, expanded target area to remove breeding sources, and intensified operations at areas with vegetation. clearly, the city-state benefited from its past and present dengue infection control experiences; the similar governmental intervention was carried out through the inter-ministry collaboration and public-private cooperation during the course of chikungunya fever domestic outbreaks ( global warming and the expansion of affected areas of mosquito-borne infection do not seem to be reversing anytime soon; the northern limit of dengue infection appears moving upward. ae. albopictus in japan raises concern. although its reported cases of dengue and chikungunya virus infection have been all imported for now, df epidemics broke out in the western japan between and [ , , , , ] . approximately % of imported cases during - period were traced to india, indonesia, the philippines, thailand, and malaysia [ ] . as of december , , imported cases of chikungunya fever were recorded in japan arriving from (the patient numbers in parenthesis): sri lanka ( ), india ( ) indonesia ( ), malaysia ( ), and thailand ( ) [ ] . as reiter ( ) claimed a decade ago that singapore was "situated in the world's major region of dengue transmission" [ ] , the city-state is at constant risk, given the significant number of tourist arrivals from the regional countries. in fact, situation in the asean countries deteriorated further in this century [ , ] . with the global expansion of the infected areas, the asia-pacific dengue partnership was set up in march under the wpro and the south-east asia regional office of the who (searo). the who has estimated that . billion populations residing in these two regions are at risk, bearing about % of the global burden of the disease [ , ] . although lower case fatality rates owing to better case management is recently observed in several member states, the disease is spreading not only to more countries but also from urban to rural areas [ ] . dengue infection, therefore, is unlikely to remain just an "urban problem". the wpro and the nea co-hosted the inaugural asia-pacific dengue program managers meeting in singapore in may . the event was attended by member states from the wpro and five from the searo in addition to temporary advisors, partner agencies, and observers [ , ] . the bi-regional initiative can be beneficial for the asean countries to work vis-à-vis the public health threat in the region as they belong to the two separate who regions. during the meeting, singapore presented informative analysis of the historical and current situation of dengue infection and integrated approach on vector control and virus surveillance. several participants praised its unique and outstanding inter-agency dengue task force as having enabled good resource mobilization [ ] . the first asia-pacific dengue workshop was also organized in singapore by the who and co-hosted by the ministry of foreign affairs, singapore and the nea in march . sharing field surveillance technique and laboratory research findings in the week-long capacity building workshop, singapore joined the who in offering expertise on mosquito-borne infectious disease control. in addition, the city-state is said to have provided assistance to cover training and material costs, medical insurance for the participants during the workshop, and accommodation for the entire duration of the workshop [ ] . we recall that community-based approach and program have been emphasized in various global issues of concern in the recent decades, including public health. it is indeed difficult to control infectious diseases without community involvement. however, in light of inherent transnational nature of emerging infectious diseases today, public health professionals are expected to apply effective control measures without seriously disrupting movements of people and goods, coordinate effort regionally and/or globally, and make the use of limited resources. it is necessary to keep in mind that curving mosquito-borne epidemics like dengue infection and chikungunya fever require capacities such as laboratory-based surveillance and territory-wide vector control program as well as regional collaboration. thus, the community-oriented approach is unlikely to accomplish the mission in the absence of respective government involvement. in this respect, as we have examined, singapore has the committed policymakers and the dedicated public servants who strive to sustain and improve infectious disease countermeasures. while there are occasional criticisms towards singapore's strict law enforcement as well as concerns for the dominant party rule, this paper has attempted to deduct an important role of a government in appropriate and successful intervention in emerging infectious diseases of global concern. from what has been seen in singapore's response to dengue and chikungunya domestic outbreaks, we can conclude that the strong governmental intervention of the city-state often manages to achieve support from the community. on the "neglected tropical disease" battlefield of dengue infection, it is inspiring to see the small tropical citystate remain undefeated and laudably accept the continuous challenges from the emerging infectious diseases. however difficult it is to reproduce dedication of the government, some of the country's specific actions can be illuminating subjects for a case study in strategy formation against mosquito-borne infectious diseases, especially in urbanizing areas with rapid population mobility, a phenomenon on the rise in southeast asia. the potential leaves room for further research on applicability of singapore's countermeasures. dengue control in singapore centers for diseases control and prevention. chikungunya distribution and global map world health organization. dengue and dengue haemorrhagic fever report on nea's vector control research area: singapore singapore's dengue heaemorrhagic fever control programme: a case study on the successful control of aedes aegypti and aedes albopictus using mainly environmental measures as a part of integrated vector control. tokyo: southeast asian medical 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singapore cost-effective real-time reverse transcriptase pcr (rt-pcr) to screen for dengue virus followed by rapid single-tube multiplex rt-pcr for serotyping of the virus horizontal and vertical dispersal of dengue vector mosquitoes, aedes aegypti and aedes albopictus decision tree algorithms predict the diagnosis and outcome of dengue fever in the early phase of illness th bms iac meeting announces key achievements in translational & clinical research efforts in singapore dengue control strategy in singapore campaign against dengue impact of 'carpet-combing' vector control operations in terminating the dengue outbreak in singapore singapore's first chikungunya outbreak -surveillance and response clinical and laboratory findings of the chikungunya outbreak in little india entomologic and virologic investiation of chikungunya risk factors for transmission of chikungunya virus infection in singapore dengue vector mosquitoes in japan: the role of aedes albopictus and aedes aegypti in the - dengue epidemics of japanese main islands expansion of the habitation area of aedes albopictus, a dengue fever vector mosquito dengue fever dengue hemorrhagic fever and new findings viral titers in the sera of dengue patients among travelers at the quarantine station of kansai international airport national institute of infectious disease and tuberculosis and infectious diseases control division, ministry of health, labour and welfare, japan. imported dengue and dengue hemorrhagic fever in japan, as of world health organization regional office for the western pacific dengue: guidelines for diagnosis, treatment, prevention and control world health organization regional office for the western pacific this research was supported in-part by grant-in aid for scientific research (kakenhi ) by the japan society for the promotion of science. the author is especially indebted to all the individuals in singapore and at the who for making the research materials available and sparing their precious time for me to interview. key: cord- - kghmzf authors: lai, allen yu-hung; tan, seck l. title: impact of disasters and disaster risk management in singapore: a case study of singapore’s experience in fighting the sars epidemic date: - - journal: resilience and recovery in asian disasters doi: . / - - - - _ sha: doc_id: cord_uid: kghmzf singapore is vulnerable to both natural and man-made disasters alongside its remarkable economic growth. one of the most significant disasters in recent history was the severe acute respiratory syndrome (sars) epidemic in . the sars outbreak was eventually contained through a series of risk mitigating measures introduced by the singapore government. this would not be possible without the engagement and responsiveness of the general public. this chapter begins with a description of singapore’s historical disaster profiles, the policy and legal framework in the all-hazard management approach. we use a case study to highlight the disaster impacts and insights drawn from singapore’s risk management experience with specific references to the sars epidemic. the implications from the sars focus on four areas: staying vigilant at the community level, remaining flexible in a national command structure, the demand for surge capacity, and collaborative governance at regional level. this chapter concludes with a presence of the flexible command structure on both the way and the extent it was utilized. situated in southeast asia yet outside the pacific rim of fire, singapore is fortunate enough to have been spared from major natural disasters such as typhoons, floods, volcanic eruptions, and earthquakes. however, this does not imply that singapore is safe, or immune from being affected by disasters. singapore houses a population of . million, a ranking of the third highest population density in the world. about % of singapore's population resides in high-rise buildings (asian disaster reduction center ) . a major disaster of any sort could inflict mass casualties and extensive destruction to properties in singapore. clearly, like its neighboring countries, singapore is also vulnerable to both natural and man-made disasters alongside its remarkable economic growth. the potential risks may result from its dense population, intricate transportation network, or a transnational communicable disease. moreover, singapore can be affected by the situations in surrounding countries. for example, flooding in thailand and vietnam may affect the price of rice sold in singapore. indeed, singapore in her short history of years has experienced a small number of disasters. chief among these, the severe acute respiratory syndrome (sars) epidemic in was the most devastating. the sars outbreak brought about far-reaching public health and economic consequences for the country as a whole. fortunately, the outbreak was eventually contained through a series of risk mitigating measures introduced by the singapore government and the responsiveness of all singaporeans. it is important to point out that these risk mitigating measures, along with the public's compliance, were swiftly adjusted to address the volatile conditions-such as when more epidemiological cases were uncovered. in this chapter, we introduce singapore's all-hazard management framework as well as the insights drawn from singapore's risk management experience with specific references to the sars epidemic. to achieve our research objective, we utilized a triangulation strategy of various research methodologies. to understand the principles and practices of singapore's approach to disaster risk management, we carry out an historical analysis of official documents obtained from the relevant singapore government agencies as well as international organizations, literature reviews, quantitative analysis of economic impacts, qualitative interviews with key informants (e.g. public health professionals and decision-makers), and email communications with frontline managers from the public sector (e.g. the singapore civil defense force, the communicable disease centre) and non-governmental organizations. the authors also employed the 'cultural insider' approach by participating in epidemic control procedures against sars. in particular, we use the method of case study to illuminate singapore's approach to disaster risk management. the rationale of doing a case study of sars along with singapore's all-hazard approach is that the case study can best showcase the contextual differences, those being political, economic, and social. this case study aims to highlight the lessons drawn from past experiences in a specific context and timeframe, through which we are able to focus more on the nature of the risks, and the processes and the impacts of the disaster risk management and policy intervention. we also examined relevant literature on risk mitigating measures against communicable diseases in order to establish our conclusions. we evaluated oral accounts provided by key health policy decision-makers and experts for valuable insights. this chapter offers empirical evidence on the role of the whole-of-government approach to risk mitigation of the sars epidemic. applying the approach to a case study, our research enriches the vocabulary of risk management, adding to the body of knowledge on disaster management specific to the region of southeast asia. indeed, the dominant perspective in this field holds that the state must be able to exercise brute force and impose its will on the population (lai and tan ) . however, as shown in our paper, this dominant perspective is incomplete as the exercise of authority and power from the government is not necessarily sufficient to contain the transmission of transnational communicable diseases. success in fighting epidemics, as most would agree, is also contingent on a concerted effort of partnership between governmental authorities and the population at large. as discussed in the first section of this volume, community and family ties along with government responses can mitigate disasters. this chapter has four main sections. following this introduction, we provide an overview of singapore's historical disaster profiles. second, we introduce the policy and legal framework, and budgetary allocations for risk mitigation in singapore. third, we detail a case study of singapore's experience in fighting sars, as well as the impact of sars on singapore in its economic, healthcare, and psychosocial aspects. in the fourth section, we discuss the implications for practice and future research in disaster risk management, followed by conclusions. singapore has experienced a small number of disasters since it was founded in . in this section, we briefly provide an historical account of singapore's disaster risk profiles including earthquakes, floods, epidemics, civil emergencies, and haze. singapore has a low risk of earthquakes and tsunamis. geographically, singapore is located in a low seismic-hazard region. however, the high-rise buildings that are built on soft-soil in singapore are still vulnerable to earthquakes from far afield (asian disaster reduction center ) . this is because singapore is at a distance (nearest) of km from the sumatran subduction zone and km away from the sumatra fault both of which have the potential of generating large magnitude earthquakes. this geographic vicinity may produce a resonance like situation within high-rise buildings on soft-soil. recent tremors from the september sumatra offshore earthquake were experienced in buildings located mainly in the central, northern and western parts of singapore. on the front of potential tsunamis, singapore has developed a national tsunami response plan which is a multiagency government effort comprising of an early warning system, tsunami mitigation and emergency response plans, and public education. though singapore does not suffer from flood disasters due to the continuous drainage improvement works by the local authorities, the country has a risk of local flooding in some low-lying parts. the floods take place due to heavy rainfall that aggregates over short periods of time. the worst floods in singapore's history took place on december . the floods claimed seven lives, forced more than , people to be evacuated, and the total damages reached sgd million (tan ) . the swift and sudden floods in were caused by a combination of factors including torrential monsoon rains, drainage problems, and high incoming tides. over the following years, singapore saw a series of flash floods hit various parts of the city-state. for example, for example, - southeast asian floods hit singapore on december as a result of mm rainfall in h. from onwards, singapore has experienced a series of flash floods due to the higher-than-average rainfall. one severe episode occurred on june that flooded shopping malls and basement car parks in its most famous shopping area-orchard road. as per the reported historical disaster data from the cred international disaster database, singapore has suffered only two disaster events caused by epidemics. in , singapore experienced its largest known outbreak of hand-foot-mouth disease (hfmd) which affected more than , young children, causing three deaths. later in , sars hit singapore and it was singapore's most devastating disaster to date. the sars virus infected around , people worldwide and caused around deaths. in singapore, sars infected people, of whom died of this contagious communicable disease. in , novel avian influenza h n struck singapore, which affected , people with deaths. civil emergencies are defined as sudden incidents involving the loss of lives or damage to property on a large scale. they include ( ) civil incidents such as bomb explosions, aircraft hijacks, terrorist hostage-taking, chemical, biological, radiological and explosive (cbre) agents and the release of radioactive materials by warships, and ( ) civil emergencies, for example major fires, structural collapses, air crashes outside the airport boundary, and hazardous material incidents. in singapore, the singapore civil defense force (scdf) is responsible for civil emergencies. since , singapore has experienced several episodes of civil emergencies. for example, the greek tanker spyros explosion at the jurong shipyard in was singapore's worst industrial disaster in terms of lives lost (ministry of labor, singapore ) . in , the six-storey hotel new world collapse was singapore's deadliest civil disaster claiming lives. the collapse was due to structural faults. the scdf, together with other rescue forces, spent days on the whole relief operation. after the collapse, the government introduced more stringent regulations on construction building codes, and the scdf went through a series of upgrades in training and equipment (goh ). singapore experienced its first haze in the period of the end of august to the first week of november as a result of prevailing winds. the haze in , called the southeast asian haze, was caused by slash and burn techniques adopted by farmers in indonesia. the smoke haze carried particulate matter that caused an increase of acute health effects including increased hospital visits due to respiratory distress such as asthma, pulmonary infection, as well as eye and skin irritation. the haze also severely affected visibility in addition to increasing health problems. as a result, singapore's health surveillance showed a % increase in outpatient attendance for haze-related conditions (emmanuel ) . apart from healthcare costs, other costs associated with the haze included short-term tourism and production losses. a study by environmental economists of the southeast asian haze indicated a total of usd$ . million in economic losses in singapore alone. singapore is actively involved in various regional meetings to deal with transboundary smoke haze pollution in order to reduce the risk (singapore institute of international affairs ). the singapore government adopts a cross-ministerial policy framework-a wholeof-government integrated risk management (wog-irm), for disaster risk mitigation and disaster management (asia pacific economic cooperation ). this is a framework that aims to improve the risk awareness of all government agencies and the public, and helps to identify the full range of risks systematically. in addition, the framework identifies cross-agency risks that may have fallen through gaps in the system. this framework also includes medical response systems during emergencies, mass casualty management, risk reduction legislation for fire safety and hazardous materials, police operations, information and media management during crises and public-private partnerships in emergency preparedness. the wog-irm policy frame work in singapore functions in peacetime and in times of crisis. it refers to an approach that all relevant agencies work together in an established framework, with seamless communication and coordination to manage the risk (pereira ) . in peacetime, the home team comprises of four core agencies at central government level. these four agencies are the strategic planning office, the home front crisis ministerial committee (hcmc), the national security coordination secretariat, and the ministry of finance at the policy layer. among them, the strategic planning office provides oversight and guidance as the main platform to steer and review the overall progress of the wog-irm framework. during peacetime, the strategic planning office convenes meetings quarterly for the permanent secretaries from the various ministries across government. in a crisis, the home front crisis management system provides a "ministerial committee" responsible for all crisis situations in singapore. in the wog-irm structure, the hcmc is led by the ministry of home affairs (mha). in peacetime, mha is the principal policy-making governmental body for safety and security in singapore. in the event of a national disaster, the mha leads at the strategic level of incident management. the incident management system in singapore is known as the home front crisis management system (hcms). under the hcms, the scdf is appointed as the incident manager, taking charge of managing the consequences of disasters and civil emergencies. reporting to the hcmc is an executive group known as the home front crisis executive group (hceg), which is chaired by the permanent secretary for mha. the hceg is in charge of planning and managing all types of disasters in singapore. within the operation allayer, there are various functional inter-agency crisis management groups with specific responsibilities, integrated by the various governmental crisis-management units. at the tactical layer, there are the crisis and incident managers who supervise service delivery and coordination. the singapore government holds relevant ministries accountable in accordance to the nature and scope of the disaster. among those ministries and government agencies, the scdf is the major player in risk mitigation and management for civil emergencies. now, let us look into the scdf in more detail. for civil security and civil incidents, the singapore civil defense force (scdf) is singapore's leading operational authority-the incident manager for the management of civil emergencies. the scdf is responsible for leading and coordinating the multi-agency response under the home front crisis management committee. the scdf operates a three-tier command structure, with headquarters (hq) scdf at the apex commanding four land divisions. these divisions are supported by a network of fire stations and fire posts strategically located around the island. the scdf also serves the following pivotal functions. the scdf provides effective -h fire fighting, rescue and emergency ambulance services. the scdf developed the operations civil emergency (ops ce) plan-a national contingency plan. when ops ce is activated, the scdf is vested with the authority to direct all response forces under a unified command structure, thus enabling all required resources to be pooled. however, the wog-irm policy framework only came to existence when singapore encountered sars. the sars epidemic in was an institutional watershed for singapore's approach to risk mitigation and disaster management (pereira ) . prior to the sars epidemic, singapore's executive group mainly focused on crises or disasters that were civil defense in nature. these emergencies were merely conceived to be well managed by a solitary incident manager, supported by other relevant agencies. a specific multi-sectoral governance structure was not considered necessary to handle the crisis. the sars epidemic challenged the prevailing home front crisis management structure as the epidemic transcended just managing civil defense incidents. the policymakers realized the necessity to adopt a comprehensive disaster management framework, an all-hazard approach that includes a mechanism for seamless integration at both the strategic and operational levels among various government agencies. to this end, singapore revamped its home front crisis management framework to produce the current inter-agency structure. the main legislation supporting emergency preparedness and disaster management activities in singapore are the civil defense act of , the fire safety act of , and the civil defense shelter act of . the civil defense act provides the legal framework for, amongst other things, the declaration of a state of emergency and the mobilization and deployment of operationally-ready national service rescuers. provides the legal framework to impose fire safety requirements on commercial and industrial premises, as well as the involvement of the management and owners of such premises in emergency preparedness against fires; and the civil defense shelter act provides the legal framework for buildings to be provided with civil defense shelters for use by persons to take refuge during a state of emergency. to tackle disease outbreak, singapore had earlier promulgated the infectious disease act in . this legislation is jointly administered by the moh and the national environment agency (nea). unlike most governments that make regular national budgetary provision for potential disaster relief and early recovery purposes, the government of singapore makes no annual budgetary allocations for disaster response because the risks of a disaster are low (global facility for disaster reduction and recovery , p. ). however, the singapore government can swiftly activate the budgetary mechanisms or funding lines in the event of a disaster and ensure these lines are sufficiently resourced with adequate financial capacity. to illuminate singapore's approach to disaster management, we now use a case study of singapore's fight against sars to highlight policy learning and lessondrawing in a specific context and timeframe. this case study has three sections. we first introduce the epidemiology of sars in singapore. in the second section, we describe the impact caused by sars epidemics on singapore in the economic, healthcare, and psychosocial aspects. in the third section, we demonstrate singapore's risk mitigating management, and detail the government's risk mitigating measures to contain the epidemic. singapore is a small open economy. external shocks can result in high levels of volatility resonating across the domestic economy. these shocks in turn would bring about higher levels of risk and uncertainty in singapore. at the beginning of , singapore's economic outlook was clouded by the iraq war and its impact on oil prices (attorney-general's chambers ). the unexpected outbreak of sars led to greater uncertainty in the singapore economy. singapore's financial markets were severely affected due to the loss of public confidence and reduced floor trading. the impact of sars on the stock market reflected in the straits times index (sti) (see fig. . ). the market did not react well to the sars epidemic. in the first fortnight of the epidemic, the sti closed down points. even though more cases were reported, the sti climbed progressively up points over the next fortnight, eclipsing the earlier falls. this could be attributed to the strict measures which the singapore government introduced. the sti remained relatively stable over the immediate fortnight as new cases were reported. however, it started a downward plunge over the following fortnight as the number of cases peaked once more. the sti plunged points. however, the resilience of the sti was shown when it climbed back up, surpassing the level reported at the beginning of the sars period. the volatility of the sti demonstrates the vulnerability of a small open economy from exogenous forces-in this case, the sars epidemic. sars was the one single activity which contributed to the volatility of singapore's gross domestic product (gdp) in . the ministry of trade and industry (mti) revised the forecast for singapore's annual gdp growth down from to . %. this forecast was later revised upwards to . %. there were a number of channels by which the sars epidemic affected the economy. the economic impacts will be discussed from the positions of demand and supply shocks. the main economic impact of the sars outbreak was on the demand side, as consumption and the demand for services declined (henderson ) . the economic consequence caused fear and anxiety among singaporeans and potential tourists to singapore. the hardest and most directly hit were the tourism, retail, hospitality and transportrelated industries, for example airline, cruise, hotel, restaurant, travel agent, retail and taxi services, and their auxiliary industries (see fig. . and this had a direct impact on hotel occupancy rates, which declined sharply to % in late april . cancellation or postponement of tourism events increased by about - %. revenues of restaurants dropped by % while revenues of the travel agents decreased by %. sars had an uneven impact on various sectors of the economy. a four-tiered framework to assess the impact on the respective sectors showed that tier industries, such as the tourism and travel-related industries were most severely hit. tier industries account for . % of gdp. the tier industries, such as restaurants, retail and land transport industries were significantly hit, which account for . % of gdp. the next two tiers were less directly affected by the sars outbreak. tier industries include real estate and stock broking, which account for close to % of gdp. the remaining % of the domestic economy in tier includes manufacturing, construction and communications. these industries were not directly impacted by the outbreak of sars. all in all, the estimated decline in gdp directly from sars was %, equaling sgd million. singapore experienced a significant drop in tourist arrivals where visitors usually stay for up to days and transit onto their next destination. the trend for visitor inflow is that visitor inflows fall sharply. this is especially true in the case of singapore, when visitor stays tend to be shorter and the high-end visitors stayed away. as a result, tourism and other related industries were nearly crippled due to a significant reduction in both leisure and business travel. visitors from around the world cancelled or postponed their trips to singapore, causing a drastic decrease of total expenditure from visitors. (see table . ) plummeting visitor arrivals directly impacted hotel occupancy rates, which declined sharply to % in late april (see table . ). the hotel occupancy rate plummeted from to %, compared to the normal level of % or above. the annual averages for hotel occupancy rates were . % in , . % in , and . % in . singapore's national carrier, singapore airlines (sia), faced a record-breaking low passenger capacity of % in april and may . sia cancelled approximately % of its weekly schedules (henderson ) . sia laid off employees, of which were ground staff, as a consequence of a usd million loss in june . the hospitality industry had to resort to cutting budgets, which led to a steep plunge in the number of employed in the service sector. out of a total of , made unemployed, hotels and restaurants went through the biggest cut, that being , employees. the breakdown of total job losses showed % in the service sector, % in construction, and % in manufacturing. additionally, transactions in the retail sector were dropped by %. the private property volume transactions for condominiums and private property price index are also good proxies on the impact of the economy from sars. based on quarterly figures between and , the volume transactions dipped to a low in the first quarter of . also, there was a corresponding decline in the price index. transactions recovered steadily by the third quarter boosted by confidence in market sentiments (see fig. . ) . the sti and private property price index seemed to display fairly similar trends, albeit with some observed lag. note also that there is a lagged effect of consumer's deferred purchases after the outbreak of sars in singapore. demand creates its own supply. therefore, a fall in demand of goods and services is likely to bring about a fall in the supply of such goods and services. also, the loss of consumer and business confidence would reduce the level of aggregate demand. these effects were observed as the manufacturing industry experienced supply chain disruptions as the singaporean economy and employment market continued to weaken. singapore was taken off the who's list of sars affected countries on st may -one of the first countries to be removed from the list. with the "fear-factor" managed, normal daily activities slowly resumed. sars affected industries and sectors started to show signs of recovery towards the end of the second quarter in . a more comprehensive analysis of the economic costs of sars will need to consider the direct impact on consumer spending and indirect repercussions of the shock on trade and investment (asian development bank outlook ). the economic costs from a global disease, such as sars, go beyond the immediate impacts incurred in the affected sectors of disease-inflicted countries. this is not just because the disease spreads quickly across countries through networks related to global travel, but also because any economic shocks to one country spread quickly to other countries through the increased trade and financial linkages associated with globalization. however, just calculating the number of cancelled tourist trips, the declines in retail trade, and some of the factors discussed earlier do not provide a complete picture of the impact of sars. this is because there are close linkages within economies, across sectors, and across economies in both international trade and international capital flows. thus, analyzing the tourism sector alone may not be sufficient in analyzing the overall financial impact of sars. sars inflicted a heavy toll on businesses and immediately impacted severely the viability of business. businesses lost employees for long periods of time due to factors such as illness, the need to care for family members and fear of infection at work, or retrenchment. as the workforce shrunk due to absenteeism, business operations, for example supply chain, flow of goods worldwide and provision of services, were all affected both locally and internationally. in terms of retrenchment, the job prospects of employees in affected companies appeared miserable. a survey performed during the sars period showed that the jobless rate increased more than . %, the highest for the last decade in singapore (ministry of manpower, singapore ) . in absolute numbers, overall employment diminished by , in the second quarter of , the largest quarterly decline since the mid- s recession. unlike previous retrenchment that affected mainly blue-collar labor, sars also affected whitecollar employees too. the implementation of workplace sars control measures added to operational and administrative costs. for example, the policy of temperature taking was implemented at workplaces in the private sector. numerous private establishments installed thermal-scanners in their entrances from day one. however, such precautionary measures were necessary to contain the disease. this helped to restore business confidence and investment potential (a lower level of investments will lead to slower capital growth). but the reduction in an economy's capacity may linger on for a few quarters before it is restored to pre-sars levels. the loss of productive working days from quarantine, and implementation costs incurred to monitor movements of employees contributed to the reduction in the aggregate supply front. some of these economic effects may have worsened the public health situation if strategic planning was not in place. sars reduced levels of service and care in singapore's healthcare system as the system mobilized its medical resources to deal with the sars epidemic. the influx of influenza patients to hospitals and clinics crowded out many other patients with less urgent medical problems for treatment. this particularly affected those seeking elective operations that had to be postponed until the epidemic ended in singapore. sars also severely impacted singapore's healthcare manpower. during the peak of sars from mid-march to early april , there was a shortage of medical and nursing professionals because ( ) the demand for care of influenza patients substantially increased, and ( ) the supply of healthcare manpower decreased as some were also affected by the epidemic. like other business sectors, hospitals, clinics and other public health providers also faced a high staff-absenteeism rate and encountered difficulties in maintaining normal operations. this resulted in a further reduction in the level of service capacity. psychosocial impact from sars was mainly caused by limited medical knowledge of sars when it began its insidious spread in singapore. such uncertainty of contracting a highly contagious disease actually deteriorated the fear of security breaches, and the panic of overexposure (tan ) . responding to the uncertainty of disease transmission, the singapore government instituted many draconian public policies, such as social distancing, quarantine and isolation, as risk mitigating measures. all of these control measures created an instinctive withdrawal from society for the general population. this brought about a behavior which resulted in the public avoiding crowds and public places with human interaction. on march , the moh invoked the infectious disease act (ida) to isolate all those who had been exposed to sars patients. after ida was invoked, on march , schools and non-essential public places were closed. public events were cancelled to prevent close contact in crowds. singaporeans with contact history were asked to stay home for a period of time to prevent transmission. harsh penalties, such as hefty fines of more than usd , or imprisonment, were imposed on those who defied quarantine orders. in a drastic move reminiscent of a police state, closedcircuit cameras were installed in the houses of those ordered to stay home to monitor their compliance with the quarantine order (abc news online ). at the height of sars, , suspected cases were ordered to stay home, all of whom were monitored either by cameras or in less severe cases, by telephone calls. quarantine, regardless of its effectiveness, received strong criticism from the general public during the outbreak of sars due to the invasive nature of that measure (duncanson ) . impact of social distancing remains unclear, but who has recommended such control measures depending on the severity of the epidemic, risk groups affected and epidemiology of transmission (world health organization ). singapore's moh advocated the practice of social distancing during the outbreak of sars. the sole intention of social distancing was to limit physical interactions and close contact in public areas to slow the rate of disease transmission. additionally, social distancing measures in particular have a psychological impact. the practice of social distancing led to a social setback in businesses that suffered economic losses as a result (duncanson ) . the psychological impact of sars is longer lasting. the most immediate and tragic impact was the loss of loved ones. in this section, we detail singapore's command structure, legal framework in fighting sars, as well as risk mitigating measures in economic, healthcare, and psychosocial perspectives. one of the most important lessons the singapore government learned from the sars epidemic was the crucial role played by the bureaucracy in disaster management. the bureaucratic structure in place then was severely inadequate in terms of handling a situation that was both fluid and unprecedented; indeed, fighting sars required more than a medical approach because resources had to be drawn from agencies other than the moh. accordingly, a three-tiered national control structure was created in response to sars-these tiers were individually represented by the inter-ministerial committee (imc), the core executive group (ceg) and the inter-ministry sars operations committee (imoc) (tay and mui ) . the nine-member imc was chaired by the minister of home affairs (mha) and it fulfilled three major functions: ( ) to develop strategic decisions, ( ) to approve these major decisions, and ( ) to implement control measures. notably, the imc also played the role of an interagency coordinator overseeing the activities of other ministries and their subsidiaries. on april ( weeks after the first case of sars was reported), the ceg and a ministerial committee was formed. the ceg was chaired by the permanent secretary of home affairs and consisted of elements from three other ministries: the moh, the ministry of defense (mod) and the ministry of foreign affairs (mfa). in particular, the role of the ceg was to manage the sars epidemic by directing valuable resources to key areas. the imoc, meanwhile, was seminal in carrying out health control measures issued by the imc (see fig. . below). the moh, at the operational layer, formed an operations group responsible for the planning and coordination of health services, and operation in peacetime. during sars, it commanded and controlled all medical resources and served as the main operational linkage between the moh and all the healthcare providers. on march , when the epidemiological nature of sars was still unclear, the moh initiated a sars taskforce to look into the mysterious strain. only days later, after more sars cases were reported and a better epidemiological understanding of the strain was developed, the singapore government swiftly declared sars a notifiable disease under the infectious disease act (ida) (ministry of health, singapore a) . in the case of a broad outbreak, ida made it legally permissible to enforce mandatory health examination and treatment, exchange of medical information and cooperation between healthcare providers and the moh, and the quarantine and isolation of sars patients (infectious disease act ). in particular, the government amended the ida on april requiring all those who had come into contact with sars patients to remain indoors or report immediately to designated medical institutions for quarantine (ministry of health, singapore b) . asa legacy of singapore's british colonial past, the singapore legislature is unique and well-known for passing laws in a swift and efficient manner. the uniqueness in singapore's legal framework allows singapore to tan ( ) swiftly amend the ida during health crises to suit volatile conditions, for instance when more epidemiological cases were uncovered and the virus was better understood. all in all, the ida played an adaptive role in terms of facilitating a swift response to the outbreak of this particular epidemic. on march , the ceg designated the restructured public hospital-tan tock seng hospital (ttsh) as the sars hospital (james et al. ; tan ) . that is, once a suspected sars patient was detected at a local clinic or emergency department, he or she would then be transferred to ttsh immediately for further evaluation and monitoring. the national healthcare system prioritized life-saving resources such as medicine and medical equipment to allocate manpower and protective equipment to the ttsh. to ease the flu-like patient influx into the ttsh, the government diverted non-flu patients away from ttsh so that the sudden surge in the number of flu cases at ttsh did not paralyze its service delivery. the full impact of sars on the economy by and large depended on how quickly sars was contained, as well as the course of the sars outbreak in the region and beyond. to mitigate sars impact on singapore's economy, the government took every precaution and spared no effort to contain the sars outbreak in singapore. two aspects of sars warranted government intervention to mitigate economic impact. first, the information that needs to be collected and disseminated to effectively assess sars displays the characteristics of public good. second, there are negative externalities related to contagious diseases in the sense that they affect third parties in market transactions. public good and negative externalities are typical areas where government action is needed (fan ) . there are three major factors which can explain why some economies are more vulnerable and susceptible to the effect of sars than others (asian development bank outlook ) . these factors are structural issues (e.g. shares of tourism in gdp and the composition of consumer spending), initial consumer sentiments, and government responses. as the research shows, the singapore government implemented a usd million (sgd million in ) sars relief package to reduce the costs for tourism operators and its auxiliary services. on the other hand, an economic relief package worth usd m (sgd m) was created to aid businesses hit by sars. in addition, the government incurred usd$ m (sgd m) in direct operating expenditure related to sars, and committed another usd m (sgd m) development expenditure of hospitals for additional isolation rooms and medical facilities to treat sars and other infectious diseases. the government's economic incentives worked when seeking cooperation of other healthcare providers (such as public hospitals and local clinics) so that they would absorb additional cases of non-flu illnesses. to help sars affected firms tide over the plight and minimize job losses, singapore's national wage council widely consulted the private sector, and recommended sars-struck companies adopt temporary cost-cutting measures to save jobs. the measures adopted by the private sector included the implementation of a shorter working-week, temporary lay-offs and the arrangement for workers to take leave or undergo skills training and upgrading provided by the ministry of manpower and associated agencies. when these measures failed to preserve jobs, the last resort was temporary wage cuts. surveillance and reporting is critical in combating pandemics because it serves to provide early warning and even detection of impending outbreaks. the surveillance process involves looking out for possible virulent strains and disease patterns within a country's borders as well as at major border-crossings (jebara ; ansell et al. ; narain and bhatia ) . when sars first surfaced, the nature of this virus was largely unknown. as a consequence, health authorities worldwide were mostly unable to detect and monitor suspected cases. health authorities in singapore encountered this same problem. but with the aid of who technical advisors, singapore managed to establish in a timely manner identification and reporting procedures. furthermore, the moh also expanded the who's definitions for suspected cases of sars (to include any healthcare workers with fever and/or respiratory symptoms) in order to widen the surveillance net (goh et al. ) . as the pace of sars transmission quickened, the singapore parliament amended the ida on april requiring all suspected sars cases to be reported to the moh within h from the time of diagnosis. although these control measures were laudable, sars also exposed the weaknesses of singapore's fragmented epidemiological surveillance and reporting systems (goh et al. ) . as a major part of lesson-drawing in the post-sars era, a number of novel surveillance measures were introduced to integrate epidemiological data and to identify the emergence of a new virulent strain faster. one of the most notable was the establishment of an infectious disease alert and clinical database system to integrate critical clinical, laboratory and contact tracing information. today, the surveillance system has four major operational components that include community surveillance, laboratory surveillance, veterinary surveillance, external surveillance, and hospital surveillance. to limit the risk of transmission in healthcare institutions once the sars epidemic had broken out, the moh implemented a series of stringent infection-control measures that all healthcare workers (hcws) and visitors to hospitals visitors had to adhere to. the use of personal protective equipment (ppe) was made compulsory. visitors to public hospitals were barred from those areas where transmission and contraction were most likely. the movements of hcws in public hospitals were also heavily proscribed. unfortunately, except for ttsh, these critical measures were not enforced in all healthcare sectors until april , and this oversight resulted in a number of intra-hospital infections (goh et al. ). in addition, the policy of restricting the movements of hcws and visitors to hospitals was taken further. more specifically, their movements between hospitals were now restricted. patient movement between hospitals, meanwhile, was strictly restricted to medical transfers. the number of visitors to hospitals was also limited and their particulars recorded during each visit. it is also important to point out that these somewhat draconian control measures required strong public support and cooperation. indeed, their implementation would not have been successful had these two elements been missing. public education and communication are two indispensable components in health crisis management (reynolds and seeger ; reddy et al. ). communication difficulties are prone to complicate the challenge, especially when there is no established, high-status organization that can act as a hub for information collation and dissemination. therefore, it is necessary to disseminate essential information to the targeted population in a transparent manner. during the sars outbreak, the moh practiced a high degree of transparency when it shared information with the public. indeed, the clear and distinct messages from the moh contributed significantly to lowering the risk of public panic. the moh worked closely with the media to provide regular, timely updates and health advisories. this information was communicated to the public through every possible medium. in addition to the media (e.g. tv and radio), information pamphlets were distributed to every household and the moh website provided constant updates and health advisories to the general public. notably, a government information channel dedicated to providing timely updates was created on the same day- march -when the who issued a global alert. a dedicated tv channel called the sars channel was launched to broadcast information on the symptoms and transmission mechanisms of the virus (james et al. ) . the importance of social responsibility and personal hygiene was a frequent message heard throughout the sars epidemic. as an example, when tan tock seng hospital was designated as the sars hospital at the peak of sars epidemics, the government undertook many efforts in public communication and education to seek cooperation and support from other healthcare providers, such as public hospitals and local clinics, so that they would absorb the additional cases of non-flu illnesses. many organizations displayed prominent signs in front of their building entrances that reminded their staff as well as visitors to be socially responsible. school children were instructed to wash their hands and take their body temperature regularly. the public was told to wear masks and postpone non-essential travel to other countries. the moh advocated the practice of social distancing during the outbreak of sars. the sole intention of social distancing was of course to limit physical interactions and close contact in public areas thereby slowing the rate of transmission. as a result, all pre-school centers, after-school centers, primary and secondary schools, and junior colleges were closed from march to april . school children who had stricken siblings were advised to stay home for at least days. moreover, students who showed flu-like symptoms or had travelled to other affected countries were automatically granted a -day leave of absence and home-based learning program were instituted for those affected. extracurricular activities were also scaled down to minimize social contact. meanwhile, the moh also advised businesses to adopt social distancing measures such as allowing staff to work from home and using split-team arrangements. those who were most at higher risk of developing complications if stricken were moved and removed from frontline work to other areas where they were less likely to contract the virus. as mentioned earlier, the practice of social distancing also drew strong criticisms from those businesses that suffered economic losses as a result. apart from providing economic compensation, measures to mitigate psychosocial impacts are also important. the government's measures of public health control, as mentioned above, drew strong criticisms from businesses and the public during the outbreak of sars due to the invasive nature of those actions. besides these, the economic slowdown affected overall employment and personal income. some households required financial assistance. in response to the public complaints, authorities in singapore provided economic assistance to those individuals and businesses who had been affected by home quarantine orders through a "home quarantine order allowance scheme" (tay and mui ; teo et al. ) . at the same time, the moh worked together with various ministerial authorities to provide essential social services to those affected by the quarantine order. for example, housing was offered to those who were unable to stay in their own homes (because of the presence of family members) during their quarantine, ambulance services were freely provided by the singapore civil defense force to those undergoing quarantine at home to visit their doctors, as well as high-tech communication gadgets such as webcams, for those undergoing quarantine to stay in touch with relatives and friends. impacts on social welfare in large part relate to economic outlook, especially in the area of consumption patterns. all these risk mitigating measures were not only effective in containing the epidemic, but also valid for implications in disaster risk management. in this section, we draw on the lesson-learning from singapore's experience in fighting the sars epidemic, and discuss implications for future practice and research in disaster risk management. the implications are explained in four aspects: staying vigilant at the community level, remaining flexible in a national command structure, demand for surge capacity, and collaborative governance at regional level. it remains questionable that singapore's draconian health control measures may not be applicable or replicable in other countries, for example setting a camera to monitor the public's compliance during home quarantine. the evidence suggests that draconian government measures, such as quarantine and travel restrictions, are less effective than voluntary measures (such as good personal hygiene and voluntarily wearing of respiratory masks), especially over the long term. however, reminding the public to maintain a high level of vigilance and advocate individual social responsibility can be a persuasion tactic by an authority to influence and pressure, but not to force individuals or groups into complicity with a policy. therefore, promoting social responsibility is crucial in terms of slowing the pace of infection through good personal hygiene and respiratory etiquette in all settings. to achieve this goal, public education and risk communication are two indispensable components in health crisis management (reddy et al. ; reynolds and seeger ) . the community must be aware of the nature and scope of disasters. they have to be educated on the importance of emergency preparedness and involvement in exercises, training and physical preparations. at the community level, institutions and capacities are developed and strengthened which in turn systematically contribute to vigilance against potential risks. this is best illustrated in the singapore government's communication strategy to manage public fear and panic during the outbreak of sars (menon and goh ) . throughout the epidemic, the singapore government relentlessly raised the level of vigilance of personal hygiene and awareness of social responsibility. this, in large part, has to rely on public education and risk communication. to effectively disseminate the idea of vigilance across the public, political leaders were seen as doing and initiating a series of countermeasures to reassure the public. by showing the people that government leaders practiced what they preached, the examples served to naturalize and legitimize the public discourse of social responsibility for all singaporean citizens (lai ) . the need to stay vigilant is never overemphasized, but being vigilant does not equate to a panacea that ensures all government agencies work together. to be well prepared for the unexpected, we need a clear and swift national command structure that can flexibly respond to, and even more promptly than in the case of disease transmission, the changing situation. all local agencies responding to an emergency must work within a unified national command structure to coordinate multi-agency efforts in emergency response and management of disasters. on top of facilitating close inter-agency coordination, the strength of this flexible structure is in its ability to ensure a swift response to an epidemic outbreak by implementing risk mitigating measures more effectively and efficiently. structural flexibility involves swift deployment of forces to mitigate the incident at the tactical level, and to provide expert advice at the operational level, in order to minimize damage to lives and property. among other things, the flexibility endemic to this command structure facilitates the building of trust between the state and its people (lai ). this in turn ensures that government measures are quickly accepted by the general public. as shown in this chapter, the moh has been entrusted by the singapore government and pre-designated to be the incident manager for public health emergencies. when a sudden incident involves public health or the loss of lives on a large scale, the moh is responsible for planning, coordinating and implementing an assortment of disease control programs and activities. during the outbreak of sars, the singapore government established a national command and control structure that was able to adapt to rapidly changing circumstances that stemmed from the outbreak. specifically, the moh set up a taskforce within that ministry even when the definition of sars remained unclear. as more sars cases were uncovered and better epidemiological information became available, the government quickly created the inter-ministerial committee (imc) and core executive group (ceg)-both of which were instrumental in the design and implementation of all risk mitigating measures-to coordinate the operation to combat the outbreak (pereira ) . while this overarching governance structure is more or less standard worldwide ('t hart et al. ; laporte ) , the case of singapore is unique in that the city-state was able to overcome bureaucratic inertia and adapt this governance structure. from singapore's experiences during the sars crisis, we have learnt that the strength of a national command structure lies in its flexibility to link relevant ministries on the same platform. these linkages ensure a timely, coordinated response and service delivery. having a flexible structure was not the only reason behind the successful defeat of sars. in singapore's case, we also notice the success of containing an uncertain, high-impact disaster has to rely on surge capacity. in the context of this paper, surge capacity refers to the ability to mobilize resources (such as ppes, vaccines and hcws) to combat the outbreak of a pandemic. singapore's response to sars in illustrates the importance of being able to increase surge capacity swiftly to deal with an infectious disease outbreak. in the asia pacific region, this problem continues to hamper many countries' ability to combat infectious diseases (putthasri et al. ). for many public health organizations in asia, it is a matter of fact that they are unable to deal with pandemics because the resources to do so are simply absent (balkhy ; hanvoravongchai et al. ; lai b; oshitani et al. ) . meanwhile, there are evidences which suggest that surge capacity alone is not the full answer. for example, during the sars outbreak, abundant resources contribute an important but not all-encompassing element in the fight against these pandemics. as it turned out, when different stakeholders brought to the task-at-hand their unique skill sets and resources, they actually complicated the fight due to their lack of synergy. in fact, abundant resources without synergy might even undermine collaborative efforts. therefore, it is essential that the ability to link up various stakeholders must be complemented by some type of synergy between them. such ability can be enhanced through close collaboration. this brings us to the third implication for disaster management: collaborative governance at regional level. the trans-boundary nature of the disasters calls for a planned and coordinated approach towards disaster response for efficient rescue and relief operations lai a) . combating epidemics requires multiple states and government agencies to work together in close (webby and webster ) . therefore, it is clear that collaborative capacity of various stakeholders is central to the fight against transboundary communicable diseases (lai ; lai b; leung and nicoll ; voo and capps ) . while member states that are of advanced economic development typically lead such efforts, the inclusion of other developing countries, non-traditional agencies, and organizations (including non-governmental ones) is necessary and ultimately, inevitable. indeed, major countermeasures such as border control and surveillance are often made possible with the aid of regional collaboration. take the association of southeast asian nations (asean) as an example. asean countries take regional, national and sub-national approaches to disaster risk management ). the asean committee on disaster risk management (acdm) was established in and tasked with the coordination and implementation of regional activities on disaster management. the committee has cooperated with united nations bodies such as the united nations international strategy for disaster reduction (unisdr) and the united nations office for the coordination of humanitarian affairs (unocha). the asean agreement on disaster management and emergency response (aadmer) provides a comprehensive regional framework to strengthen preventive, monitoring and mitigation measures to reduce disaster losses in the region. in recent years, singapore has been active in providing training and education for disaster managers from neighboring countries. singapore has an ongoing exchange program with a number of asia pacific nations and europe. for example, to partner with apec to increase emergency preparedness in the asia-pacific region, singapore's scdf provides shortterm courses on disaster management in the civil defense academy (asia pacific economic cooperation ). the world today is far more inter-connected than ever before. international travel, transnational trade, and cross-border migration have drastically increased as a consequence of globalization. no country is spared from being influenced directly or indirectly by disasters. singapore is no exception. singapore is vulnerable to both natural and man-made disasters alongside its remarkable economic growth. in response, the singapore government adopts an approach of whole-of-government integrated risk management, a concerted, coordinated effort based on a total national response. we have witnessed in the case study singapore's all-hazard management framework with specific references to the sars epidemic. in fighting sars, singapore's health authority was responsive enough to swing into action when they realized that the existing bureaucratic structure was inadequate in terms of facilitating close cooperation between various key government agencies to tackle the health crisis on hand. therefore, a command structure was swiftly established. the presence of a flexible command structure, the way and the extent it was utilized, explains how well an epidemic was successfully contained. flexibility actually enhanced organizational capacities by making organizations more efficient under certain conditions. epidemic control measures such as surveillance, social distancing, and quarantine require widespread support from the general public for them to be effective. singapore's experiences with sars strongly suggest that risk mitigating measures can be effective only when a range of partners and stakeholders (such as government ministries, non-profit organizations, and grass-roots communities) become adequately involved. this is also critical to disaster risk management. whether all of these aspects are transferrable elsewhere needs to be assessed in future research. nonetheless, this unique discipline certainly has helped singapore come out of public health crises on a regular basis. singapore's response to the outbreak of sars offers valuable insights into the kinds approaches needed to combat future pandemics, especially in southeast asia. singapore imposes quarantine to stop sars spreading. abc news managing transboundary crises: identifying the building blocks of an effective response system apec partners with singapore on disaster management hfa implementation review for acdr asian development outlook update accessed adrc country report impact of sars on the economy, singapore government avian influenza: the tip of the iceberg severe acute respiratory syndrome -singapore how singapore avoided who advisory, toronto star impact to lung health of haze from forest fires: the singapore experience sars: economic impacts and 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architecture for network centric operations in unconventional crisis: lessons learnt from singapore's sars experience. california: thesis of naval postgraduate school sars in singapore: surveillance strategies in a globalizing city influenza pandemic and the duties of healthcare professionals are we ready for pandemic influenza who guidelines on the use of vaccines and antivirals during influenza pandemics. geneva: word health organization acknowledgement the authors would like to thank the economic research institute for asean and east asia (eria) to initiate this meaningful research project, and four commentators-professor yasuyuki sawada (tokyo university), professor chan ngaiweng (university sains malaysia), dr. sothea oum (eria), mr. zhou yansheng (scdf) and all participants in eria's two workshops, for their insightful comments for an earlier draft of this chapter. key: cord- -ytal wog authors: henderson, joan c.; ng, alex title: responding to crisis: severe acute respiratory syndrome (sars) and hotels in singapore date: - - journal: nan doi: . /jtr. sha: doc_id: cord_uid: ytal wog the sudden outbreak of severe acute respiratory syndrome (sars) in singapore in was a grave crisis for the tourism industry as a whole and highlights the importance of effectively managing and planning for such occurrences. this study looks at the particular consequences of the infectious virus for the hotel sector and reactions to the challenges posed. further health‐related crises seem inevitable in the modern world and some guidelines for dealing with these are proposed, based on the singapore experience and an existing framework for tourism crisis management. copyright © john wiley & sons, ltd. i n an increasingly uncertain world, almost all organisations connected to the tourism industry face the likelihood of experiencing some form of crisis. however, levels of preparedness and the competence with which difficulties are handled vary and the topic of tourism crisis management is attracting greater attention from both academics and practitioners. this study is concerned with severe acute respiratory syndrome (sars), a new and potentially fatal virus, which affected much of the east asian region during early . it focuses on how the epidemic impacted on singapore's hotel sector and management reactions to it, affording insights into the problems caused by outbreaks of infectious disease at destinations and possible responses. after an opening summary of the literature on tourism and crisis, certain features of sars and the implications of its presence in singapore are outlined. steps taken by hotels are reviewed and the paper concludes by presenting proposals for the management of similar hospitality crises which might lie ahead. findings are derived from a sample survey of singapore's largest hotels, supplemented by interviews with managers, and the analysis also draws on secondary data from published sources. crisis and disaster are prevalent nationally and internationally (blakie et al., ) and commentators maintain that it is no longer a question of whether they will arise, but when and how they will be dealt with (barton, ; kash and darling, ) . faulkner ( ) distinguishes between disasters resulting from exogenous catastrophic change and crises due to organisational problems such as weak management. the conditions are closely related, however, and an outside disaster can evolve into an institutional crisis so that the terms are frequently used interchangeably. tourism has proved itself sensitive to a host of internal and external influences that can disrupt operations (faulkner and russell, ; mckercher, ; nankervis, ) , and fink's ( , p. ) observation that 'any time you're not in a crisis, you are instead in a precrisis, or prodromal mode' would seem especially apt. the industry's exposure to crisis has been acknowledged by researchers, its vulnerability revealed by the wave of adverse events that marked the opening years of the st century and their harmful repercussions. terrorist activity has become a primary concern (pizam, ) , but health scares should not be overlooked and have the capacity to inflict serious damage (travel business analyst, ) . the world health organisation (who) warns of the risks of known and unknown communicable diseases, the progress of which could be accelerated by tourism movements (who, ) . members of the world tourism organisation (wto) have also been called on to formulate tourism health policies incorporating mechanisms for reporting conditions at destinations (wto, (wto, , . the expanding literature on the theme of tourism and crisis includes case studies of good and bad practice, with a consensus that planning for various scenarios and allocating responsibilities in advance could be vital in averting crisis or surviving it and even finding new commercial opportunities to exploit (pottorff and neal, ; roberts, ) . the significance of good communications is highlighted in many accounts, and the media is seen to occupy a central role in the dissemination of information and formation of opinions and images (berno and king, ). nevertheless, not every public or private sector tourism organisation is in possession of a plan (cassedy, ; prideaux, ) and those that do exist are often informal and undocumented, addressing only one particular type of hazard (drabek, ) . neglect of such an important area as crisis management is surprising and an untenable position given contemporary global instability. faulkner's ( ) exploration of the dynamics of a tourism disaster is commonly cited by researchers and he traces the disaster process through a series of stages noted in table . although derived from evaluation of a natural disaster, the theory is agreed to have a broader relevance that permits its applicability to other emergencies (ritchie, ) . the model thus provides a suitable framework for examining the ways in which the disruption created by sars was handled by singapore's hotels. appropriate actions to combat a health-related the coronavirus caused a contagious atypical pneumonia, with a mortality rate of - %, which spread rapidly after its discovery. the epidemic centred on east asia and locations such as china, hong kong, singapore and taiwan were amongst the worst hit. fears of infection by the potentially deadly disease were widespread, aggravated by intense media publicity and speculation about its means of transmission, which is now assumed to be through vapour droplets. there is no vaccine or cure as yet, control depending on the identification and isolation of suspects. air travel was seen as facilitating diffusion of the virus and the who advised aircraft disinfection and health screening of outbound travellers from areas with local transmission in a bid to prevent further contagion (who, ) . given the lack of knowledge and limited understanding of sars, singapore was initially unprepared for and unprotected from the disease. this was imported by three residents returning from hong kong and confirmation of their state in early march , accompanied by a wave of infections, precipitated public health and tourism crises. visitor arrivals fell dramatically for the april to june quarter, reaching a nadir in may when figures were over % lower than the previous year (stb, (stb, , a . tourists from around the globe either cancelled or postponed their trips and passenger traffic at singapore's changi airport halved, several airlines halting flights altogether (the straits times, a). travel warnings were issued by the who, as well as governments overseas, and leisure and business travel both slumped. several companies turned to alternatives of video and teleconferencing and prohibited staff from travelling to countries where sars had been reported (the straits times interactive, ) . many locals also chose to avoid public places, thereby contributing to the decline in leisure spending. the unanswered questions originally surrounding the virus should be stressed and these added to anxieties and complicated decision making, nobody knowing how long the outbreak would last and its ultimate extent. as the epidemic ran its course, the number of those who succumbed dwindled and there was growing confidence that the battle was being won. however, the crisis remained acute until late may when singapore was declared free of local transmission of sars by the who and travel warnings were downgraded. the final death toll was , another patients recovered and thousands had been subject to a rigorous system of home quarantining for individuals having contact with sars sufferers. although the wto announcement was an occasion for celebration, the industry sought to guard against complacency. worries persisted at home and abroad that the virus might return and scientists cautioned that total eradication would be impossible, but the downturn in tourist arrivals was arrested and there were signs of a return to normal flows by the end of the year. nevertheless, sars proved an unprecedented tourism crisis and seriously undermined singapore's reputation as a destination synonymous with safety and security (henderson, ) . hotels in singapore have to be registered by law and there are that are formally gazetted, a status determined by features such as the number of rooms, attached bathrooms and food and beverage outlets (hlb, ) . these are liable for cess duty payments, unlike nongazetted units, which are generally very small establishments. of the total gazetted in , were classed as medium sized ( - rooms), as large ( - rooms) and nine as very large (over rooms); these collectively constituted the sample population. the postal questionnaire survey sought details about the consequences of sars for hotels and their attempts to overcome the problems it brought in its wake, being completed at the close of when recovery was well underway. only nine hotels responded, or . %, but the different sized properties were almost consequences of sars for hotels in singapore equally represented and their guests came from all singapore's principal tourist generating countries with an emphasis on asia. the findings thus represent an industry view of the gravity of the crisis and policies pursued during its lifecycle, although the limitations of such a disappointing response are accepted. singapore tourism board (stb) statistics confirm the severity of the situation for the hotel sector as a whole. the average hotel occupancy rate (aor) for the second quarter of was %, compared with . % for the previous year, and average room rates contracted by . %. industry-wide data correspond to those for the surveyed hotels, which had an average aor in april of . %; this dropped to . % in may, before rising to . % in june. there were some contrasts in the performance of individual hotels and one saw occupancies of only % in june (stb, (stb, , a . the respondent hotels tended to rely on corporate clients, who made up over % of customers. demand from both business and leisure travellers was, however, almost equally eroded by an estimated . % and . % respectively. the greatest decreases were recorded by guests from japan and hong kong, followed by those from australia, america and europe; in comparison, the indonesian, thai and indian markets were perceived to be more robust. on average, the hotels surveyed calculated that they would lose at least one-third of their annual revenues because of sars, two hotels expecting to sacrifice % of earnings for . the singapore hotel association expected revenue losses as a result of cancellations and postponements to be in excess of $ million for all singapore's hotels (sha, ) . expressions of government concern reflected an acute awareness of the havoc being wreaked by sars as it reverberated through the economy and also the direct and indirect value of international tourism to the republic, justifying a degree of official intervention to protect the industry during the depths of the crisis. several assistance programmes were assembled, the most prominent being an s$ million relief package aimed at the tourism and transport industries, which included property tax rebates and bridging loans for small and medium enterprises (smes) facing cash difficulties (the straits times, b). a major portion was allocated for hotels, comprising measures such as a halving of the unskilled foreign worker levy and the waiver of television licence fees (the straits times, c) . the stb, together with the standards, productivity and innovation board, also launched a fixed interest rate financing scheme to help smes gain access to short-term funds (stb, b) . the moves were welcomed by hoteliers, although some felt that the amounts of financial support could have been more generous. the sudden onset of the crisis and its nature cut short any pre-event or prodromal stages, with no chance of evasion and very little time to prepare. the crisis cycle thus commenced almost immediately at the emergency period when the principal worry for hoteliers was shrinking revenues linked to falling occupancy, priority being allocated to cost savings and generating income. with regard to human resources, none of the respondents retrenched permanent staff. however, seven terminated the services of contract workers, salaries were reduced at three hotels and all requested employees to go on unpaid leave. multitasking was another popular option. to minimise other operating costs, six respondents took rooms or floors out of service and one shut down for a major renovation and revamp in the middle of the year. at the same time, the crisis was an opportunity to upgrade skills and six respondents accordingly sent members of their workforce for training, taking advantage of the sars relief tourism training assistance (srtta) programme. this was a component of the government aid package designated for the retraining of employees in approved tourismrelated courses, one objective being to minimise redundancies (stb, c) . in the face of mass cancellations and very few new bookings, hotels were anxious to sustain their day to day business and ensure some cash flow. with many foreign visitors j. c. henderson and a. ng shunning singapore, all respondents turned to residents and devised promotional packages targeted at them. this was considered a temporary arrangement only due to a long standing belief that the domestic market was too small to be commercially viable as geographical factors encourage singaporeans to escape to neighbouring malaysia and indonesia for inexpensive breaks, instead of holidaying in their own very urbanised environment. one respondent described adding value through the offer of extra amenities to local and foreign guests, rather than discounts on room charges. half of the respondents engaged in advertising campaigns and seven stated that they had collaborated with airlines, travel agencies and the stb in assorted schemes to attract more tourists. hotels sought to demonstrate a commitment to exemplary standards of hygiene and cleanliness in an effort to reassure customers and build confidence. the tourism board's cool singapore project aimed to communicate the message that singapore was not dangerous and specific venues were uncontaminated by sars, providing guidance for industry participants on keeping the infection out of their premises. hotels that met the criteria were granted cool awards which they could display to try and convince the public that they were sars-free and sars-ready (stb, d) . most hotels surveyed were quick to be certified 'cool' and also abide by ministry of health (moh) instructions. all hotels procured thermometers and daily temperature-taking of employees was conducted in accordance with moh directives, fever being a key and easily identifiable symptom of sars. the stb itself circulated information and proffered advice on practical matters, which hotels complied with, guests too being asked to complete health declaration forms. all but two of the respondents declared that they had crisis management plans prior to sars, but these were not always strictly relevant and covered either eventualities unconnected to such a disease or were generic in scope. a sars manager was appointed from the existing management team by most hotels to be in charge of liaison with the stb and moh, as well as helping the general manager, with final decisions commonly left to the latter. the above measures were in place throughout the emergency, which prevailed until singapore was removed from the who list of countries with local transmission of sars on may. the who declaration propelled the crisis nearer to recovery, judged by respondents to have begun in july. common indicators of progress were an upturn in room occupancy, revenue and reservations and a slowdown in the decline of tourist arrivals. june therefore might be seen as the intermediate month, during which many aspects of the emergency regimes were maintained. initiatives designed to secure and accelerate recovery were introduced after the who decision when attention shifted to marketing. hotels retained certain procedures they had installed at the height of the crisis, with a gradual relaxation of some of the more stringent precautions such as constant screening for fever. five indicated that they had or would be undertaking more advertising in a bid to increase customer awareness and stimulate demand, and six collaborated with other tourism organisations such as airlines and travel agencies in promotional campaigns. only two hotels carried on actively selling to the singapore market. in terms of product development, half the respondents were seeking to improve the quality of their facilities and seven of them to provide superior customer service. business was deemed to have returned to pre-sars levels by the last quarter of when room occupancies averaged . %. as the recovery advanced and resolution seemed closer, there was time for reflecting on the past and looking ahead. most hotels felt better able to cope with another sars epidemic after having survived the first in which positive attributes such as team spirit, adaptability and professionalism had been fostered. in addition, procedures had been devised and tested that could be reintroduced at short notice should the virus resurface. the handling of sars in singapore does not entirely correspond to theories of crisis man-consequences of sars for hotels in singapore agement as there was little advance warning of the virus or appreciation of its significance. the pre-event and prodromal periods, preceding the emergency, were therefore of very short duration. the delisting of singapore by the who marked the cessation of the emergency and start of recovery, separated by a brief intermedial transition. although the hotels surveyed were in possession of crisis management plans before the onset of sars, discussions indicated that these were not entirely apposite and managers were caught unawares and forced to act instinctively. decision makers initially were largely at the mercy of the epidemic's evolution until later when there were opportunities to take the initiative and seek to direct events. responses ranged from reactive and defensive to proactive and offensive, incorporating collaboration with other agencies within and outside the tourism industry. actions undertaken can be categorised as disease and hygiene controls, cost savings, marketing and lobbying for official aid. these tactics were also evident in hong kong where singapore's hotel crisis was repeated (chien and law, ; pine and mckercher, ) and echo measures of 'marketing, hotel maintenance, human resources and government assistance' implemented in other examples of hospitality crises (israeli and reichel, , p. ) , suggesting a common pattern of response. partial recovery in singapore had been achieved by the end of , but resolution was still incomplete in the opening months of because of the threat of a resurgence of sars and a few isolated cases across asia. these circumstances created anticipation of a second outbreak and round of crisis, leading the industry to assume a pre-event stance of intensified vigilance. foreseen damaging developments in the arena of public health were not confined to sars and encompassed the mutation of a strain of avian influenza, which was erupting across asia into an extremely infectious and deadly human virus (the straits times, ) . although the direst predictions about so-called 'bird flu' had not been realised at the time of writing, the fact that it was hailed immediately as a potential tourism crisis indicates that lessons had been learnt from sars. such learning is a crucial final outcome of crisis and should inform and strengthen strategic planning. the singapore experience of sars offers a perspective on the demands made of the hotel sector when dealing with rampant infectious disease. although suggesting the benefits of being in a state of readiness, the study does raise questions about the wisdom of investing scarce resources in formulating plans tied too closely to specific crises. more common incidents such as fire, power failure and food poisoning are relatively easy to plan for, but the uniqueness of certain situations frustrates advance identification and limits the general value of a narrow response strategy. it could be argued that hotels should avoid being overly prescriptive and maintain a flexible approach, giving some attention to drafting a series of protocols that provide broad guidance on structures and procedures to use in order to accommodate the unpredictable. external forces may also be a major influence on the efficacy of any plans, illustrated in this case by the who and the impact of its decisions. the imposition and continuation of advisories are likely to have undermined certain aspects of attempts to manage the sars tourism crisis, not least marketing activity, by setting the pace of recovery. another striking feature of the virus was that it affected both destinations and source markets, bringing tourism throughout much of the region to a halt. it was consequently beyond the ability of any single business or destination to manage comprehensively and, however competently the singapore industry and authorities reacted to conditions in the republic, they were partly dependent on the manner in which public and private organisations elsewhere dealt with their own crises. individual hotels, alongside other enterprises, were thus relatively powerless within the overall picture of the international crisis and its complicated dynamics. nevertheless, outbreaks of existing or new types of infectious disease might be expected to recur and the risks should not be ignored by hoteliers. a set of guidelines to assist in coping with such a scenario is presented in table , drawing on faulkner's tourism disaster directives. the proposals recommend fully utilising the preliminary pre-crisis stages to prepare for the climax of the crisis when a machinery of systems, processes and personnel can be installed with minimum delay and maximum efficiency. meeting immediate needs gives way to a medium term perspective as the emergency recedes, to be replaced by an intermediate step when normal business operations can begin to be restored. recovery requires marketing and development programmes, as well as government involvement if necessary, and a return to regular modes of operation. resolution is a time for review when formal plans can be revised in the light of the knowledge gained from living through one crisis, enhancing their applicability to any of a similar character that might materialise in the future. the epidemic of sars in was an exceptional crisis for singapore's hotels and an exacting test for its managers, in which advances to near normality were dictated by outside developments and agencies as much as 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management consequences of sars for hotels in singapore key: cord- -qz pffei authors: tay, k; kamarul, t; lok, wy; mansor, m; li, x; wong, j; saw, a title: covid- in singapore and malaysia: rising to the challenges of orthopaedic practice in an evolving pandemic date: - - journal: malays orthop j doi: nan sha: doc_id: cord_uid: qz pffei with the increasing number of covid- cases and related deaths worldwide, we decided to share the development of this condition in singapore and malaysia. first few cases were diagnosed in the two countries at the end of january , and the numbers have surged to thousands by end of march . we will focus on strategies adopted by the government and also the orthopaedic community of the two countries up till the beginning of april . we hope that by sharing of relevant information and knowledge on how we are managing the covid- condition, we can help other communities, and health care workers to more effectively overcome this pandemic. on st dec , the world health organization (who) china office was informed of a type of respiratory infection in the city of wuhan which was noted to be different from previously known coronavirus infections that causes sars (sars-cov) and mers (mers-cov) . this novel virus (sars-ncov) was later re-named severe acute respiratory syndrome coronavirus two (sars-cov- ), and the genomic sequence was published on th january . with the development of the reverse transcription polymerase chain reaction (rt-pcr) test kit to detect the presence of sars-cov- , confirmation of the disease (covid- ) can be made . within the following weeks, new cases were detected in thailand, south korea, and japan, and their epidemiological patterns started to indicate that human to human transmission is possible , . considering the mortality and morbidity risk of the national population, the chinese government decided to implement lockdown of the province of hubei on rd january , one day before the spring festival celebration where millions of people were expected to travel across the whole country . on th january , with new confirmed cases in united states, europe, middle east and australia, who declared the condition to be a public health emergency of international concern (pheic) . by means of early confirmation of new cases, stringent contact tracing, social distancing and travel restrictions, the number of new covid cases seems to have plateaued in south korea and japan, and even reduced in china in the month of march. however, with more than , cases from countries reported globally, who declared the status of pandemic on th march . singapore, a city state in southeast asia with a highly robust travel network within the region and east asia, rapidly became the epicentre of the covid- epidemic in late january to early february, with several countries imposing travel restrictions to singapore . the index imported covid- case was diagnosed in singapore on rd january . highly pro-active measures were immediately taken in a coordinated multiministry taskforce set up by the singapore government in close cooperation with the country's healthcare services to try to contain the impact of the epidemic . in spite of this, spikes were still observed which can be broadly described as ) imported cases from mainland china, ) local clusters, and ) imported cases from returnees from other parts of the world (fig. ) . in spite of a rigorous protocol for contact tracing, there remains a slight uptick in unlinked cases diagnosed locally , . on th january , three chinese nationals touring malaysia were diagnosed to have covid- . thermal scanners were installed on all entries to the country, and on th january the government identified hospitals to handle investigations and treatment of covid- patients , . on th january, a committee coordinated by the national disaster management agency (nadma) in collaboration with few other ministries was formed to organise a the return of malaysian nationals from hubei, china. up till end of february, most of the confirmed cases in malaysia were foreigners who had contacted the disease before they enter the country . a second cluster of cases that was associated with a religious gathering in petaling jaya emerged in early march . on th march, the prime minister announced two-week period of movement controlled order (mco) that involved closing of international borders, shutdown of non-essential businesses, prohibition of traveling and public gatherings . however, confirmed number of cases surged to more than in the month of march (fig. ) , and roughly half of the cases were associated with the second cluster . mco was later extended to th april . the singapore national centre for infectious diseases handles the majority of covid- cases in the country while isolation facilities with capabilities for intensive care are also created in all public hospitals. as the workload increased, recovering covid- patients are also housed in private hospital facilities within mount elizabeth hospital and gleneagles hospital. across the whole malaysia, the ministry of health has identified hospitals to serve as covid- admitting hospitals, and the remaining hospitals including the health centres as screening centres . with close to ten-fold increase of total number of confirmed cases in the month of march (from to more than , ), all these hospitals have been procuring essential material including testing kits, personal protection equipment (ppe), medicines and ventilators . although the orthopaedic surgery specialty may not be directly involved in the care of covid- patients with predominantly respiratory problems, we are actively participating in various aspects of the preparation. beyond significant disruptions to daily supplies and manpower resources due to the traditionally high inter-dependence of malaysia and singapore, the sudden surge in healthcare resources diverted to the current pandemic, which looks increasingly to be protracted, is also challenging effective services for elective and chronic conditions in terms of: sudden reduction in inpatient beds and resources: • potential risk for healthcare transmission • overwhelming of the healthcare infrastructure leading to an inability to deal with other important health issues • lack of trained manpower in the event of staff morbidity and mortality from covid- • affected healthcare staff morale in preparation for a potentially drawn out fight against a pandemic, a robust comprehensive plan was crafted in order to maintain continuity of care for all surgical disciplines including orthopaedic surgery. workflows were created and refined through a series of in-situ simulations . these encompassed coordination of staff, movement of surgical equipment, infection prevention practices and decontamination following the procedure. orthopaedic teams performing surgeries would have to outline all the equipment they would require during such surgeries to facilitate the move of the necessary equipment to this stand-alone facility. this would require forward planning, and examples of orthopaedic cases requiring this workflow would be debridement for necrotising fasciitis in a suspect covid- case . the simulations were performed by anaesthesia and surgical teams, using various scenarios with different surgical disciplines. these aided in refining such workflows and identifying possible problems, such as inadequacies in coordination and communication, environment limitations, unsatisfactory equipment set-up, and unfamiliarity with protective equipment and infection control measures. to address these, an anaesthetist would be appointed during every case to oversee and ensure that essential steps which might have compromised patient and staff safety were not missed . based on the principle of complete segregation and in accordance to "disease outbreak response system condition" (dorson) orange directive to prevent potential cross contamination between healthcare workers, the operating theatre (ot) team was segregated into two separate sub-groups; two teams to deal with acute trauma cases and one team for urgent spine surgeries. this allowed the department to continue service provision for orthopaedic cases in singapore while adhering to strict infection control measures. for the general trauma ot teams, each team comprised of a complete subset of sub-specialty surgeons from tumour surgery, arthroplasty, foot and ankle surgery and pelvic and acetabular specialist . each team had sufficient expertise to handle complex cases that required specific skillsets. the spine team focused on operating on patients that required urgent decompression or restoration of spine stability. the trauma ots and spine ot ran during office hours. the ot location was chosen to be at least two theatres apart to further ensure physical distancing and to prevent cross contamination the surgical management of covid- was carried out in malaysia according to the th edition ministry of health guidelines for covid- management which was released on th of march . a special core of covid- orthopaedic team with at least one specialist, two medical officers and two staff nurses were identified to standby for all suspected covid- patients, and should be optimally trained in managing covid- patients including handling the ppe, sample taking and packaging. the most fully equipped, dedicated ots for covid- patients /person under investigation (pui) were immediately made available. the ot chosen ideally is one with negative air pressure or one that will minimise ot contamination, staff exposure and nearest to the entry point. the non-covid operation theatres were further divided into emergency and semi-emergency ot. all electives cases were being postponed indefinitely. surgical management of emergencies such as fractures, dislocations, tumours and infections might still be undertaken and surgeons must adhere to the recommendations of the surgical and orthopaedic association regarding this. the emergency and semi-emergency cases were required to be tested for covid- . even if they were tested negative, the non-covid cases would still be handled by health care workers (hcw) in full personalised protective equipment (ppe). this is to protect the hcw against "false negative cases" , , (fig. ) . ward/in-patient management team encompassed not only the management of patients directly managed under orthopaedic surgery, but also for inpatient referrals made by other specialties. the ward group was segregated into two main groups that of a "clean ward", meant for patients without any infections or open wounds, and a "dirty ward". the former had patients with spine conditions or closed fractures; there were no elective surgeries during this period; however, patients pending discharges after elective surgeries were kept in this ward. the latter ward was for patients with musculoskeletal infections, and the staff here were also the designated teams to round patients admitted to wards outside of these two wards ("overflow" wards), or suspected or confirmed covid- cases. this was to ensure that should a team be inadvertently exposed to a suspected or confirmed case, rapid contact tracing and isolation of relevant staff could be performed. each ward was also divided up by bed numbers into individual sectors. the sectors were covered by teams comprising consultants/associate consultants, registrars, and medical and house officers. this afforded a degree of geographic separation amongst doctors, and also ensured continuity of care with the same team of doctors covering an assigned number of patients. across the two wards, surgeons from varying subspecialties were present, mirroring the admixture of surgeons in the operating theatre. in the lead up to the segregation, the department ensured that patients fit for discharge were either discharged home or transferred to community hospitals to reduce the likelihood of exposure to covid- of existing inpatients, to free up beds for admission of suspect covid- cases and ensure manageable workload. plans were laid down for discharge planning and management of ongoing medical issues were handed to the teams designated to cover relevant ward sectors. the ward group command team met on a regular basis to be updated regularly discuss standard operating procedures (sops) perform pre-surgical audits, and discuss any critically ill, febrile or potential covid- patients. the highest attention was paid to sops designed towards the management of potential or confirmed covid- cases. these guided the doctors on the identification of potential cases in consult with the department of infectious diseases, and minimise the number of staff potentially exposed for adequate patient care. malaysia, the management of covid orthopaedic ward or inpatient is based on the moh guidelines for the management of covid- patients. the covid- patients /pui were nursed in the infectious disease ward, unless patients required intensive or specialised orthopaedic attention. these patient will be nursed in an individual room or isolation room in the orthopaedic ward. the limited negative pressure rooms were reserved for those confirmed to be infected. just like in singapore, patients fit for discharge were either discharged home or transferred to other public or private hospitals to reduce the likelihood of exposure to covid- of existing inpatients and to free up beds for admission of suspected covid- cases. each surgical unit is recommended to have their own management pathways based on their own logistics and resources. the usually heavy outpatient clinic poses potential challenges in terms of potential disease clusters and inadvertent lapses due to work overload. actions were taken to maintain a reasonable workload and minimise staff and patient contacts by: • cutting down non-essential workload such as patients on long term follow-up or conservative management • limiting ourselves to urgent care such as trauma, infection, acute spine emergencies and tumour referrals • allowing for off-site prescription top-ups, extension of medical leave and correspondences for whatever indications as the outpatient services can be exposed to patients from various sources, a strict screening protocol in accordance to existing singapore ministry of health guidelines covering travel histories, contact histories, and coryzal symptoms were taken before admittance to the outpatient clinic. cases deemed at-risk were seen if required for urgent conditions. these patients were immediately isolated, and consults and any outpatient procedures performed in full personal protective equipment (ppe). at-risk patients with non-urgent conditions had appointments deferred for three weeks as a safety precaution. malaysia, face to face patient consultations appointments carry significant risk due to the covid- pandemic, with the increasing incidence of community spread of the disease. in order to restrict face to face consultations, only the walk-in urgent cases are seen in the clinic. patients will be strictly screened as above and triage. at the clinic, social distancing is practised at all times. non-essential consultations such as for patients on stable long term follow-up and non-urgent cases will be minimised by offering them with longer duration of off-site prescriptions, offering telephone consultations and internet consultations where possible. clinic nurses and support staff will contact patient listed for follow up to offer them alternative follow up dates, and this would include postponement of scheduled blood or imaging investigations. medical record office of the hospitals will facilitate easy access to digital or online medical records for the clinicians to evaluate the condition of selected patients to ensure those requiring early attention especially the orthopaedic oncology patients will not be neglected. consultation via online facilities was also available for new patient referrals, so that a management plan can be partially implemented for patients seeking an opinion and treatment. to cater for the surge in inpatient beds required for treating acute covid- patients requiring hospitalisation, institutions in singapore developed central command teams which reviewed overall healthcare resources available on a weekly basis. the majority of elective surgeries were postponed, with allowances for urgent surgeries such as tumour, infective cases, acute and delayed trauma and spine surgeries with deteriorating neurological status. inpatient beds were also created in community hospital facilities that are within close proximity of the surgical teams to cater for these surgeries . when the government of malaysia announced the mco on th march , all the admitting hospitals postponed their semi-elective orthopaedic procedures and cut down semi-elective / trauma cases. facilities for managing emergency cases like open fractures and polytrauma is maintained, but patients would be referred to other government hospitals once the conditions have been stabilised. some private hospitals have also offered to share their services in managing trauma patients with discounted overall fee that is comparable to government hospitals. with the reduced road traffic and presence of enforcement officers along all major highways, we did not anticipate many road traffic accidents during this period. under no circumstances should a staff enter the operating theatre without properly applied ppe. . intubation of patient is considered an aerosol generating procedure (agp) and standard contact and airborne procedure protocols need to be adhered to strictly . . surgeons should not be in the operating theatre for intubation unless concurrent management of bleeding etc. requires their presence. . regional anaesthesia should be preferred over general anaesthesia whenever possible. . strict haemostasis. . liberal use of suction. . electrocautery at low settings. . protection of the health care workers, surgeons, anaesthetists and all supporting staffs must not be compromised at all time and their needs, physical and mental health and well-being must not be overlooked or ignored. able to share their slides via screen share and interact with respective students. students were also able to log in from their home location to adhere to social distancing guidelines. by using well established video conferencing tools which could be freely downloaded by students, it was easy to launch the elearning modules. in addition, the audio and visuals were of good quality with minimal lag. . small group discussion were held between each clinical group and their tutors on a daily basis using zoom© platform. . additional teaching materials such as case based scenarios were uploaded on a shared learning platform so that students could continue to "clerk" patients as they would in the ward. . live streaming of surgical procedures allowed students to have a close up view in the safety of their homes. surgeons also gave live commentary to enhance their learning value. . formative and summative assessments (eg: mini-cex and logbooks) were submitted online for respective tutors to evaluate. since singapore escalated to dorscon orange in february , all medical students were barred from clinical postings to reduce the risk of exposure and infection. with such short notice, medical educationists had to adapt quickly to modify the clinical curriculum without significantly impacting students' learning. in order to do so, we harnessed the powers of technology to bring the entire clinical curriculum online (fig. ) . whilst clinical posting and actual patient interaction cannot be replaced by e-learning, in extenuating circumstances such as the current covid- situation, online learning has proven to be effective and well received by both students and tutors. importantly, this can avert an unnecessary delay in our medical students' progression. similarly, undergraduate medical education in public and private medical schools in malaysia have been temporarily modified to adopt online mainly teaching through webinars and videoconferencing. the impact would be worse for students who are preparing for upcoming final professional examination especially for institutions where clinical performance is an essential component for this evaluation. for postgraduate masters orthopaedic training, rotation posting in the six teaching universities will remain static during the cmo period in malaysia. all general orthopaedic and subspecialty courses, short-term fellowship postings in neighbouring countries, inter-hospital exchange postings, and department meetings have been temporarily cancelled. following a recent meeting of the malaysian medical deans' council, the national orthopaedic specialty committee (osc) part- examination which was supposed to be held end of april was postponed to november . it is not advisable to request the candidates for the examination to travel, and nearly impossible to convince patients to volunteer as clinical case models for the clinical components of the examination. in addition, several regional and international conferences scheduled to be organised in the two countries for the next few months have also been postponed, and this includes the asean orthopaedic association congress in kuala lumpur . the covid- pandemic is panning out to be a protracted situation. by practicing strict inter-team segregation both in actual working space and during rest times, we are able to ensure that only one team will be affected should any doctor be involved in a suspected or confirmed covid- case. ensuring staff safety is of paramount importance. a list of the appropriate ppe is drawn up and included in all staff briefings. stocks of appropriate ppe are made available at all settings and readily accessible to clinical staff in the course of their daily duties for handling suspect cases. training should be performed for mask-fitting and ensure staff comply with appropriate methods of donning themselves with the full ppe, especially in handling suspect or confirmed cases. communication is continuously maintained between the inpatient/ward, operating theatre and outpatient teams. to achieve proper hand over of cases and continuity of care, a pair of doctors comprising of one specialist and one trainee from the operating theatre team is appointed as the point-ofcontact (poc) to liaise with colleagues manning the ward using confidential communication tools such as tigertext. similarly, the doctors in the clinic group communicate any concerns or instructions to the ward group for any patients admitted from clinic, and the ward group reciprocated for any patients requiring attention to specific concerns during outpatient reviews on discharge. at all times, suspected covid- cases are highlighted, so that every transition between the clinic, ward and operating theatre is carefully managed to minimise exposure to staff. the command team has also looked into issues of maintaining cohesion and morale amongst the junior staff, to avoid staff burn out. working arrangements are made such that there is a degree of redundancy in the system, such that doctors have adequate rest days during the weekend. seniors maintain vigilance to look for signs of any stress in junior staff, particularly when it comes to exposure to potential covid- cases. in the local context this is needed, as junior doctors sometimes feel reticent to share any issues of stress or burn out, for fear of "letting their peers down". from the early stages of the covid- epidemic in wuhan, china, who has initiated research and development in diagnostics, vaccines and therapeutics for this infection. although the natural history of the condition is still far from clear, there are many pertinent questions that need to be answered urgently . in our search for treatment, cure and prevention for covid- , we have to rely on well-designed clinical trials . one example would be the large multi-national solidarity trial that is designed to test the effectiveness of four groups of drugs that have the potential to be used for covid- . preventive measure like development of an effective vaccine would probably be months if not years away . although the field of research may not be directly related to orthopaedic service, as a component of the medical profession, it is important for us to support and participate in these researches . a survey of orthopaedic surgeons in wuhan who were diagnosed with covid- is a good example of how we can contribute towards better understanding of this condition . having a shared border between singapore and malaysia entails potential challenges after lifting of the mco with resumption of human traffic across the borders. though it entails some risk of cross border transmission, effective precautions would include: • enforcing the stay home notice (shn) or movement control order (mco) to reduce nonessential travelling of the public. • rigorous screening and self-monitoring measures • appropriate social distancing continuous data sharing and joint policy-making processes between medical personnel from both countries. this follows on a joint covid- taskforce between malaysia and singapore already in place . the covid- pandemic has caught many countries off-guard though regions previously exposed to the sars-cov outbreak are somewhat better prepared. with more than million population over a relatively small geographical region, south east asia will have to be better prepared for public health emergencies of this nature table i . various medical specialties should utilise all available channels of communication to share our experience, learn from each other, and join force with our partners from other parts of the world to overcome this challenge. we hope that through this sharing of information between orthopaedic communities in this region, we can generate more interest among our medical fraternity to collaborate and join forces to overcome this pandemic. who statement regarding cluster of pneumonia cases in wuhan, china world health organization. coronavirus disease (covid- ) technical guidance: laboratory testing for -ncov in humans [internet]. geneva: world health organization united nations office for the coordination of humanitarian affairs a familial cluster of pneumonia associated with the novel coronavirus indicating person-to-person transmission: a study of a family cluster wuhan lockdown 'unprecedented', shows commitment to contain virus: who representative in china director-general's opening remarks at the media briefing on covid- - world health organization. who announces covid- outbreak a pandemic coronavirus: which countries have imposed travel restrictions singapore confirms first case of wuhan virus. cna [internet world health organization. coronavirus disease (covid- ) situation dashboard. geneva: world health 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transmission: a systematic review malaysia: the ministry of health malaysia michigan surgery recommendations updated consensus statement: safe airway society principles of airway management and tracheal intubation specific to the covid- adult patient group minimally invasive surgery and the novel coronavirus outbreak: lessons learned in china and italy novel coronavirus and orthopaedic surgery: early experiences from singapore the challenges of "continuing medical education" in a pandemic era th asean orthopaedic association annual congress : announcing new dates orthopaedic association novel coronavirus ( -ncov) situation report - . geneva: world health organization sars-cov- and covid- : the most important research questions who launches global megatrial of the four most promising coronavirus treatments singapore scientists study genes to fast-track covid- vaccine. the straits times the orthopaedic forum survey of covid- disease among orthopaedic surgeons in wuhan, people's republic of china singapore and malaysia to form joint working committee on coronavirus we would like to express our appreciation to dr joyce koh suang bee and dr howe tet sen from singapore general hospital, and dr gracie ong siok yan from university malaya medical centre for their assistance in the preparation and editing of this manuscript. we would like to dedicate the article to dr lukman shebubakar from jakarta, who passed away on th april due to covid- infection. his contribution towards medical service and orthopaedic training in indonesia ands this region will always be remembered. key: cord- - wkes nk authors: goggin, gerard title: covid- apps in singapore and australia: reimagining healthy nations with digital technology date: - - journal: nan doi: . / x sha: doc_id: cord_uid: wkes nk widely and intensively used digital technologies have been an important feature of international responses to the covid- pandemic. one especially interesting class of such technologies are dedicated contact and tracing apps collecting proximity data via the bluetooth technology. in this article, i consider the development, deployment and imagined uses of apps in two countries: singapore, a pioneer in the field, with its tracetogether app, and australia, a country that adapted singapore’s app, devising its own covidsafe, as key to its national public health strategy early in the crisis. what is especially interesting about these cases is the privacy concerns the apps raised, and how these are dealt with in each country, also the ways in which each nation reimagines its immediate social future and health approach via such an app. a striking feature of the covid- pandemic has been the use of and appeal to digital technologies -fusing together what these technologies might offer in terms of efficacious communication and public health responses to help individuals and communities cope and contain the pandemic, on the one hand, as well as extending resources for social practices, expression, making sense, persisting with and reconfiguring rituals, and conjuring with the profound affective dimensions wrought by illness, death, loss, fear and isolation, on the other. in the pandemic, digital technologies have been used across societies, in a way that harked back to earlier ideas from the s of social life being nigh wholly dependent on life in 'cyberspace', and 'virtual communities'. with widespread access to and ownership and use of internet, mobile phones, social media, data, artificial intelligence (ai) and associated technologies already deeply, if very unequally, distributed globally, especially in middle-and high-income countries, the inception of the pandemic saw extended reliance on digital technologies -where terms of digital inclusion allowed for it. in a number of countries, governments also took the opportunity to issue calls to the acceleration of digitalisation, especially across groups and demographics where digital inclusion and take-up had been low, due to infrastructure, literacy and education, information and affordability. one stand-out area in this regard was apps. apps have been around since the s and s; however, it was the 'smartphone moment' of the launch of the apple iphone in , and subsequent development of the apps for apple mobile operating system devices (ios) and launch of its apps store, that kicked off the process by which apps became an integral part of everyday life for billions of users (goggin, ; miller and matyivenko, ; morris and murray, ) . from until the present day, technology companies around the world have offered their own apps and apps store, first with the 'app store' wars of - featuring many of the handset vendors that were household names in the worlds of g and g mobiles such as nokia and blackberry. competition was much more suggestion in china, evidenced by the many chinese app stores that dominate its huge market, and are significant distribution points for many users and communities internationally -especially given digital technologies being at the centre china's external trade, finance and soft power 'going out' (keane and wu, ) . thus, apps are key to what has been recently called 'infrastructural imaginaries' (nielson and pedersen, ; see also anand et al., ; athique and baulch, ; mansell, ) . so it is no surprise that apps formed a key part of the infrastructures woven into the pandemic, but also a specific, highly visible and 'normalized' response (hoffman, ) , in the form of dedicated apps -especially for tracing people and their 'contacts'. apps were used for many significant purposes during the pandemic. existing popular apps such as whatsapp were used in some countries to send official government messages and distribute crucial public health information. the data sets generated by smartphones, computers, apps and people's use of them, such as that data collected by apple and google, were used by public health officials, researchers and journalists to map population or district-level activity and movement, leading to the very interesting charts, graphs and visualisations in news and current affairs reports and features seeking to map and analyse the spread of covid and its impact on social and economic activity. apps allied with machine learning and ai were also used by medical researchers and clinicians to assist in the diagnosis of covid, by asking millions of users to track and enter their symptoms, diary-like, to offer a way of pinpointing when someone might have become positive. among the many varieties of covid-dedicated apps were apps devoted to the purpose of tracking people and their potential contacts, in case they contracted the virus. so many countries developed apps for tracking and contact tracing, with so many prototypes in development and implemented, that mit launched a contact tracing app database (https://www.scl.org/ news/ -the-mit-contact-tracing-app-database), based on key questions from american civil liberties union (aclu) white paper (aclu, ), to provide an authoritative reference point for those seeking to find their way through the claims and counter-claims of effectiveness. apple and google joined forces to amend their policies and create a joint protocol to make it easier for countries to use such data for contact tracing via apps (michael and abbas, ) . a full treatment of covid contact tracing apps is outside the scope of this article (see, for instance, cattuto et al., ; hoffman, ; vinuesa et al., ) . instead i focus on two especially interesting cases that offer us early insights into the socio-technical dynamics at play in such apps and the pandemic itself. these are singapore's tracetogether app and australia's covidsafe app. asian countries were often referred to for their decisive and often authoritative responses to the pandemic. however, it was singapore that attracted considerable early notice for its pioneering role in developing a particular kind of covid contact tracing app -that captured the imagination of many other countries. singapore was a pioneer in the development of covid bluetooth app in the form of its tracetogether app. what was less publicised was that, shortly after launch of tracetogether, singapore changed tack. this modification of the app deployment and promotion, and place in the overall public health strategy, was less evident outside the city-state. instead, singapore's tracetogether app became a stand-out model for other countries, rather than the various other apps being implemented around the world such as those developed by the united states, south korea, china, india or israel (babones, ) . australia comes into the picture because it is australia who first and most systematically sought to build on the tracetogether model, including its privacy safeguards, with its own covidsafe app. in the capstone analysis of their series of timely interventions into the privacy debates on the introduction of australia's covidsafe, leading privacy scholars graham greenleaf and katherine kemp ( ) note, 'australia's experiment is further advanced than most [countries] that are attempting to build a system based on voluntary uptake, protected by legislation (abstract, para ). the australian government sought to deploy covidsafe as a centrepiece of its effort to re-open australian society after the national and state lockdowns occasioned by the 'first wave' of infections from march to may . where public concern regarding and discussion of privacy issues was clearly presented but publicly muted in singapore, in australia there was furious debate. to explore the emergence, dynamics and implications of these two covid apps, i will proceed as follows. first, i introduce and discuss singapore's tracetogether, its development and first phase of take-up and deployment. second, i turn to australia's covidsafe and consider its fast journey from incubation and policy idea to the touchstone to warrant the country's re-opening, a veritable 'national service' (as prime minister morrison couched it). third, i return to singapore, to discuss the rebooting of tracetogether, after nearly months of tepid take-up, as that country's leadership sought to reassure its population that conditions were safe to re-open social life. finally, i offer concluding remarks about covid apps, social and technological imaginaries and digital media, as the nation state returns (flew et al., ) , and seek to gauge and exert its brittle powers, in a still deeply interconnected world. to great fanfare, a dedicated contact tracing app was unfurled as a breakthrough in monitoring outbreaks of covid- at the population level. while many teams around the world produced similar versions, the singapore government rolled out the first such app -called 'tracetogether'. tracetogether is an open source app based on bluetooth, using the 'bluetrace' protocol devised by a singapore government team led by the govtech agency -who have a track record of developing new kinds of open government apps, such as the parking.sg app. in a interview, for instance, janil puthucheary ( ), minister-in-charge of govtech, discussed how the 'govtech guys, as a result of having to do the code for the service . . . are having to . . . hack policy'. puthucheary explained, 'you have to be able to codify the policy', however that 'some of our governmental processes and regulations result in extremely inelegant code' (puthucheary, : ′ ″, ′ ″) . tracetogether was made available for adoption elsewhere via github. it is a combination of centralised contact tracing and follow-up (undertaken by government health authorities) and 'decentralised contact logging'. the user downloads the app and activates bluetooth on her device. the app can then detect another device in its vicinity, exchanging proximity information. to do so, the app uses information generated by the bluetooth relative signal strength indicator (rssi) readings that occur between devices over time to estimate proximity and duration of an encounter between users (team tracetogether, c). if a person fell ill with covid- , they could grant the ministry of health access to gather their tracetogether bluetooth proximity data -to assist in contacting people who had close contact with the infected app user. for their part, the developers emphasised their view that tracetogether would 'complement contact tracing, and is not a substitute for professional judgement and human involvement in contact tracing' (team tracetogether, d) . interestingly, they also underscored that the 'hybrid model' of decentralised and centralised approach is what they feel 'works for singapore' and that they 'built it specifically for singapore' (team tracetogether, b) . released on march by the ministry of health and govtech (baharudin and wong, ) , tracetogether received over half a million downloads in its first hours. a month later, the singapore government claimed the app had achieved a % adoption rate -some . million users, of an overall estimated population of . million users (team tracetogether, a). upon launch in singapore, there was relatively little public discussion of the privacy implications of tracetogether in mainstream media and fora -although there was considerable disquiet, criticism and debate evident in blogs, social media and elsewhere. for the most part, this is due to the structure and dynamics of singaporean society, and its political arrangements, public policy traditions and strong systems of social control and clear support for or alternatively discouragement and sanctioning of different kinds of expression and voicessomething well established in the scholarly literature (chua, ; george, george, , lee, lee, , , especially via various studies published in media international australia (most recently, lee and lee, ) . in recent years, the singapore government, following the dampened level of votes received by governing people's action party (pap), that has ruled since the , in the election, and a more sceptical populace (barr, ; zhang, ) , it has sought to extend consultation and formal 'listening' mechanisms to provide additional opportunities for citizens' voices. furthermore, while there has been increased discussion of privacy with the rise of digital technologies and unprecedented expansion of data generation, collection and use, the legal and regulatory framework is relatively weak in relation to privacy rights taken-for-granted in many jurisdictions (chesterman, (chesterman, , , even in the wake of the european general data protection directive (gdpr). however, as we shall see, such debate did build over some months, as tracetogether evolved. what is also important to note is that the singaporean government clearly acknowledged the strength of attitudes and importance of privacy and data protection concerns, and sought to anticipate debates by building in some level of privacy protection. the vision of tracetogether is that proximity data gathering is 'done in a peer-to-peer, decentralised fashion, to preserve privacy', and that it relies upon a 'trusted public health authority, committed to driving adoption' (team tracetogether, c). the developers and government emphasised that the privacy safeguards in the tracetogether app are in effect an effort of the longstanding ideal of 'privacy-by-design' (hustinx, ) . the government emphasised that the information was stored on a user's phone for days, and then deleted -and user's phone numbers are not exchanged, no geolocation data, personal identification data are not exchanged, so, as minister puthucheary noted, 'the engineering has preserved the privacy of the users from each other'-calling the app 'fairly elegant', in the way it 'preserves a fair degree of privacy' (ng, ; see also govtech, ). almost immediately the app did receive notice and discussion internationally, as one of a growing number of examples of covid- contact tracings apps raising privacy concerns (hu, ) . meanwhile in singapore, tracetogether downloads flatlined. this occasioned international deliberation, such as an article in the wall street journal entitled 'singapore built a coronavirus app, but it hasn't worked so far' (lin and chong, ) . the stalled downloads of tracetogether brought into view the conversations about privacy concerns, and whether this was a factor in user's lack of motivation to download the app. another reason advanced was that the app posed challenges for battery draining, due to the need to keep phones on. this was a view put by the ceo of singapore's investment or sovereign wealth company temasek holdings, madame ho ching who has a reputation as a prolific commentator on public affairs by dint of her regular controversial facebook posts (ho is also the wife of prime minister lee hsien loong) in a facebook post of may on the problems with tracetogether (ho, a) . whether by design or dawning acceptance, the government eased back its public communication and encouragement for citizens and other residents alike to download and use tracetogether. instead, it encouraged businesses, organisations, government offices and other entities to use a range of techniques to gather information about people's movements -especially when they visited or spend significant time in public places. check-in was principally done via scanning of a national identity card or employment or work permit id card, or via an app called safeentry. based on scanning of qr codes specific to each location, the safeentry app, and the policy it supported, was comprehensively promoted by government. this contrasted with tracetogether, which was only lightly promoted by the singaporean government, with the major campaign at the outset of its launch. presumably, on a small island -city-state, with strong civil service corps, existing id systems (singpass), and tightly managed immigrant and foreign worker id and records, and digital government and technology capabilities, this evolving contact tracing system did not need to premised on an app such as tracetogether, which presumably government was happy to allow to 'fail fast', given the bugs it faced. despite the effectively prototypical status of tracetogether, one of the first jurisdictions to adopt the technology was australia. prime minister scott morrison referred to such an app as a key requirement in australia's ability make its transition out of lockdown (prime minister et al., ) . in a radio interview with national talk show host alan jones, morrison's language is instructive, because it imagines technology, especially automated technology, as taking the vagaries and morally dubious qualities of human agency out of the picture: '[w]e need to get an automatic industrial level tracing of the coronavirus . . . now, we've been working on this automatic process through an app that can ensure that we can know where the contacts were over that infection period and we can move very quickly to lock that down' (morrison, a: para ) . this kicked off a heated debate about privacy implications, leading a high-profile member of his own coalition government, rural parliamentarian barnaby joyce to declare that he would not be downloading the app -countered by many other public figures who promised to do so. despite the widespread criticism and concern, there was also significant support with some million downloads in the first day of its release, topping the million mark in early may (koslowski, ) , then . million by june (meixner, ) . these figures raise various concerns, such as whether those who download the app used or continued to use it. also what the rate of downloads were in different parts of the nation (slonim, ) . let alone whether the covidsafe app was playing a role in helping to trace contacts and find positive cases of the virus (preiss and dexter, ) . for the prime minister, the covidsafe app was a rhetorical centrepiece of his policy initiative to vouchsafe a loosening of restrictions and begin to repair the economic damage the virus caused: the chief medical officer's advice is we need the covidsafe app as part of the plan to save lives and save livelihoods. the more people who download this important public health app, the safer they and their family will be, the safer their community will be and the sooner we can safely lift restrictions and get back to business and do the things we love. (prime minister et al., : para ) while he drew attention to the voluntary, consent-based nature of the app, morrison also sought to exert maximal symbolic pressure by framing adoption in patriotic terms, likening it to national service in wartime (and also not ruling out making it mandatory) (gredley, ) : i'll be calling on australians to do it as a matter of national service. in the same way people used to buy war bonds, back in the war times, you know, to come together to support the effort . . . if you download this app you'll be helping save someone's life. (morrison, b: sec : ) on may , morrison announced that australia had earned an 'early mark', with restrictions being lifted in a week. in doing so, he spoke of the download numbers being a 'critical element' in deciding to what extent the easing would occur: 'mr morrison said not installing the app was like going into the "blazing sun" without wearing sunscreen' (armstrong and minear, ) . various commentators and researchers expressed their views on how to promote downloading and take-up of the app. in the australian financial review, a piece by technology editor paul smith, entitled 'think like a founder', reported, 'entrepreneurs and health technology experts have urged the government to adopt all the tricks of the start-up trade to get more australians downloading the covidsafe contact tracing app' (smith, ) . the australian chief scientist through his rapid research information forum commissioned a brief on motivators for use of the covidsafe app, supported by the australian academy of humanities, with professor genevieve bell as lead author, and various leading media, communications and humanities researchers among the contributing authors (bell et al., (disclosure: i was a peer reviewer of this brief)). the brief suggested that 'illustrating that covidsafe works as intended may assist decision-making for those yet to download the app' (bell et al., : ) . it also concluded that the stories we will tell about australian responses to, and uses of, covidsafe will matter too. the voices of trusted figures, community leaders, healthcare workers and citizens will likewise inform the adoption, and continued use of, covidsafe. (bell et al., : ) many of these 'stories' clustered about the public perceptions and debate about the privacy, data and surveillances implications of the covidsafe app (bell et al., ) , driven by long-standing sensitivities and attitudes of australians concerning privacy. stretching back to the infamous and ill-fated australia card proposal of , citizens' privacy concerns had been more recently exacerbated by the federal government's poor handling of the ramp-up of its national e-health records registration system, myhealth, which switched from an 'opt-in' to 'opt-out' basis in (komesaroff and kerridge, ; goggin et al., ) . with much at stake in terms of public health concerns at a critical juncture of the covid pandemic, the australian government emphasised that it was keen to adopt a 'consent-based' model, hence its interest in adapting the singapore tracetogether app. the government sought a formal privacy impact statement from a leading law firm -which it published, with a detailed response from the department of health ( b; maddocks, ) . this privacy impact documentation put important details of the workings of the covidsafe application, and the production, storage and handling, of resulting user data on the public record. in response, the government emphasised that participation would be voluntary (department of health, a); however the privacy impact statement noted the potential for third-parties such as workplaces or businesses put pressure on or require people to use the app (maddocks, ) . deleting the app would also delete the data stored on a user's device, but not data in the national data store (however, the government guaranteed that all data held would be deleted at the end of the pandemic). the government was at pains to reassure the public on the secure hosting of the covidsafe data store, undertaken by amazon web services (aws). their guarantees related to the data privacy and security obligations applying to aws, but also to any prospect that such data might be requested and commandeered by the us government (given aws is headquartered in the united states, and subject to their laws). over some weeks a furious debate ensued, and the australian government proposed legislation to address the key concerns. this safeguard took the form of the privacy amendment (public health contact information) act . the bill quickly passed through the house of representatives and the senate and received assent on may . the act creates several serious offences dealing with covid app data, including 'non-permitted, use, or disclosure', 'uploading covid app data without consent', 'retaining or disclosing uploaded data outside australia', 'decrypting encrypted covid app data' and 'requiring participation in relation to covidsafe' (privacy amendment, : ). 'covid app data' is defined as 'data relating to a person . . . collected or generated . . . through the operation of covidsafe' and is either 'registration data' or 'is stored, or has been stored . . . on a communication device' (s. d ( ) (a-b), privacy amendment, : - ). while the bill was passed containing significant safeguards, it contained serious flaws. as summarised by greenleaf and kemp, these included key information upon which the law was based and would operate was not made available to the public, including advices to the minister upon which he relied to make the earlier determination, and, crucially, the agreements between the commonwealth and states and territories regarding the operation of the covidsafe app, and collection and sharing of app data; lack of public assessment of the law by the federal and states and territories privacy commissioners; and only the source code for the covidsafe app was released, not the code for the national covidsafe data store (i.e. the server-side of the system, where security and privacy issues often manifest) (greenleaf and kemp, ) . in addition, greenleaf and kemp critique the narrow focus of the privacy act amendment on 'covid app data', suggesting instead that what is being created is an information system they dub the 'covidsafe system' (greenleaf and kemp, ) . as well as the specific defects of the new law, then, the major issue it raises is precisely the one feared by many experts and members of the public alike: that the app-based contact tracing represented by covidsafe, and other apps around the world, represent a deepening of technologies of surveillance in social life. while such apps and measures in which they are embedded are justified as exigent public health measures crucial in the emergency conditions of a pandemic, there is wellfounded fears that this increase in surveillance will not be automatically or easily rolled back once countries feel the threat of covid is ended or at least contained. as australian debates over covidsafe privacy subsided, there was a slow return to tracetogether emerging in singapore as the country's leadership gingerly considered how to effect its re-opening from its -month circuit breaker. a task all the more urgent, given the ruling party's dwindling time to call a national election. singapore's was regarded an international model of wise and swift response with its handling of its 'first wave' of infections. however, in the second week of march , singapore tightened its measures, enacting a general shutdown and stay-at-home policy that it dubbed a 'circuit breaker'. initially the circuit breaker was announced to last for month, but with the rising tide of positive cases in the crowded migrant worker dormitories, the government quickly extended for a second month. a disturbing feature of singapore's data gathering and public reporting and communication during this period was the distinction clearly drawn and maintained in the daily bulletins between; cases in the migrant worker dormitories; and 'community cases' (these community cases were in turn divided between figures on singapore citizens, permanent residents (prs), migrant workers on work permits and workers on employment passes) (han, ; palma, ) . the migrant workers were quarantined in the dormitories, with many then moved to across other repurposed facilities. and the numbers of cases were similarly quarantined, in a communicative-epistemological manner, to emphasise that the 'real' community spread remained low (usually below cases in the 'community'). those numbered among the community included citizens and prs initially, but subsequently, foreign pass holders who do not reside in dormitories but lived among the regular population, became part of these statistics once the dormitory cases started subsiding. ahead of the planned end to the circuit breaker on june, the government made some mention of tracetogether at various times in its public communications. however, its main focus remained racking movement and individuals' location via check-in at the public places and business still open, such as convenience stores and shopping centres, or in taxis and ride-hailing services, especially via the safeentry app discussed above. as the re-opening loomed, there was increasing discussion in government, and in parliament, on measures that would need to be implemented to contain and reduce the number of infections via contacts with migrant workers, especially once they were allowed to more regularly leave the dormitories, where they had been quarantined during the circuit-breaker period, and so circulate in the 'community'. the government announced a new app, sgworkpass, to 'show which migrant workers can leave their dormitories for work' . workers will 'get a "green status" on the app to indicate that their employer has been granted approval to resume operations, and that the dorm they stay in has been cleared' . otherwise, the app will show red to indicate they 'cannot go out for work' . this is reminiscent of the chinese app, also adopted by india, which uses qrs, to show a user's status as green (when they may enter offices, restaurants, malls or parks), or yellow (at risk) or red (strict quarantine) (hu, ; india today, ) . at this stage, tracetogether returned -this time, as a central feature of the strategy. the government had been at pains to keep tracetogether opt-in, with foreign minister vivian balakrishnan, also minister-in-charge of the smart nation initiative, providing reassurance that the app would remain voluntary 'as long as possible' (balakrishnan, ) . in early june, balakrishnan noted the problems with tracetogether, including the technical issues with the app not running properly on apple. as a result, he let it be known that singaporean government was developing a 'portable wearable device' that will achieve the same end, that if it worked could be 'distributed to everyone in singapore': 'i believe this will be more inclusive, and it will ensure that all of us will be protected' (balakrishnan, ) . the government emphasised that there would no 'gps chip' on the device, nor any internet connectivity. even then, the tracetogether token would need to be physically handed to the health ministry for uploading of the data, if a user tested positive for covid- (yu, ) . the government's keenness to be seen to address privacy was doubtless fuelled by a public backlash against the token. as policy researcher and commentator carol soon, from the institute of policy studies, noted, 'within a short span of three days, a petition against the development of the device attracted about , signatories' (soon, ) . concerns of singaporeans regarding data privacy were addressed in a report authored by her colleagues, which found attitudes vary according to the technology involved, illustrated by the finding that nearly in respondents supported use of cctv to monitor people's movements during the covid 'circuit breaker period', but less than % were comfortable with having their mobile phone data tracked for contact tracing without their consent (tay, ) . to address such deep-seated concerns, soon suggested the need for singapore to urgently 'achieve a working compromise between personal data and public good', establishing principles and considering measures such as formation of a citizen's panel for public deliberation (soon, ) . regardless, the first batch of , tracetogether tokens were distributed to seniors shortly on the eve of the july general election -with officials from the smart nation and digital government group (sndgg) suggesting they were settling in for a long haul, saying the government will 'continue to generate more awareness about the token among our prioritised population' (sndgg officials quoted in yip, ). at the time of writing, the pandemic rages globally, and the career of covid- contact tracing apps is still unfolding -with little evidence as yet of their efficacy. however, there are already clear grounds for concerns. the strange thing about the australian embrace of bluetooth-based covid tracing apps is how strongly it figured, for a time at least, as instrumental to the country's public health response. various commentators noted the irony that at the point covidsafe was being pushed upon the public, australia was at a positive inflection point in terms of infections. as greenleaf and kemp note, this set the bar because other measures had already appeared to be successful in greatly abridging the spread of the virus (greenleaf and kemp, : ) . the other obvious thing is that where apps did play a role in diminishing infection rates, these were not: ( ) bluetooth-based tracing apps, ( ) and the apps used were integrated into a wider system of cross-referencing and marshalling personal identification and contact information and database systems (greenleaf and kemp, ). yet the australian government, for a short time at least, was very keen on the app as a symbolic game-changer in its public health approach to the pandemic -showing that it was taking charge. rather like british health secretary, matt hancock some weeks later, when he promoted the english app-based test-and-trace system, telling the public 'it is your civic duty': do it for the people you love. do it for the community. do it for the nhs and do it for all the frontline workers . . . you'll have the knowledge that when the call came you did your bit, at a time when it really mattered. (hancock quoted in bosley and stewart, ) in july , there was an outbreak of covid- cases that saw a lockdown re-imposed, and fuelled national concerns. at the time victorian chief medical officer brett sutton said the 'app has not added a close contact' that authorities had not already discovered via traditional contact tracing (borys, ) . federal health minister greg hunt advised that at least contacts nationally had been identified via the covidsafe app (borys, ) . for her part, nsw's chief health officer kerry chant, the state next in line for a potential resurgence of cases described the app as 'one of the tools', but not a 'major feature' in contact tracing (borys, ) . in his parsing of the app's effectiveness, australian deputy chief medical officer, dr nick coatsworth, suggested that because of movement restriction, people had not been circulating, so the 'app hasn't identified those cases', and that as 'numbers go up then the app can come into its own' (coatsworth, ) . with the groundswell for mask use in mind, coatsworth ( ) cleverly sought to link the two, suggesting 'if you are a supporter of mask use, you must also be based on the modelling, a supporter of downloading and activating the app' (here he refers to the study by sax institute, see currie et al., ) . for its part, singapore took a less dramatic, more considered approach, especially in the first phase as it developed and launched its tracetogether app. singaporean leaders and health officials were also preoccupied with promoting the app to gain the maximum take-up and adherence. yet, for reasons not entirely clear as yet, singapore was reluctant to push the adoption of the app to the extent that australia did -an interesting situation given earlier critiques of singapore technocratic approach to health care, in particular (barr, ) . as well as the privacy concerns that emerged in the second phase of the tracetogether token initiative, it may be that singaporean actors thought the app was promising but not the main game. this would be because of the already well entrenched systems of requiring and using personal data, through an extensive infrastructure of technologies (including the cctvs that featured in the ips report), without the kind of concomitant privacy rights and practices that would be expected in some other jurisdictions such as australia. the task of enlisting and normalising singaporeans participation in these aspects of its surveillance-extensive 'smart nation' policies, over cumulative implementation of technology is taken to be essential, but it is increasingly fraught (lee, ) . in the first months of pandemic response, then, the central element was singapore's established singpass and other systems of identification cards and passes, which could be used in coordination with video recordings, and the wealth of digital data available from urban transportation systems, stored valued and transit cards, ride-hailing accounts and so on. as well as also as the citizen and netizen sousveillance and activism that saw recordings of potential miscreants breaching the regulations circulated online. in addition in the early weeks of the pandemic, identifying details of people's residential locations, down to building numbers, were published in daily updates from ministry of health, and reprinted in media outlets. such measures point to the differences in privacy laws and protections in singapore, as compared to australia. whereas australian privacy act dates back to , singapore only enacted its first comprehensive law in , the personal data protection act. at the time, legal scholar simon chesterman suggested that singaporean had taken a 'pragmatic approach', potentially striking a balance between european and us approaches: in singapore, at least, reform is not being driven by the desire to defend the rights of data subjects; rather, it is based primarily on economic considerations, as well as the desire to position singapore as a leader in the region for data storage and processing. (chesterman, : ) . the singapore laws and approach to privacy and data protection have not substantially changed since (chesterman, ; ong, ). yet clearly citizens do have concerns -as the public response to the tracetogether token suggest. from a broader perspective, the return of tracetogether to the fore of the singaporean government's strategy, especially to assist with the re-opening process after its 'circuit breaker', is very interesting indeed in the context of the country's digitally underpinned governmentality (ho, ; lee, lee, , willems and graham, ) . this is worth being in mind in interpreting the election, in which the government received some strong criticism by opposition candidates for its poor handling of the pandemic, especially concerning the continuing high number of cases in migrant worker dormitories. the pap was returned to government, still with a 'super majority', of seats out of the available . however, it was chastened by its share of the vote being reduced to . % (from its . % share in the election) -and an unprecedented seats won by the opposition workers' party (loh, ) . in the aftermath, the government has signalled its willingness on listening to electorate concerns, especially those of young voters (yong, ) . all in all, in both these case studies, we see that the variations of the covid- contact tracing apps, and the technical, social, policy and design dynamics of these, offer rich food for thought when it comes to understanding apps. health information is an area of considerable sensitivity for most people. trust is key, and with the widespread diffusion of mobile communication there has been considerable work on how to design and implement systems that can support cooperative and sustainable sharing of information between people and authorities to map the spread of infectious diseases (lwin et al., ) . however, it is now evident that the task of assembling appropriate social and cultural understandings of people's lives and identities, their data selves (lupton, ) , the intricacies of technologies, the enmeshing of privacy expectations in design, and the construction of suitable legal, policy and governance arrangements, is challenging. in the covid- pandemic, many countries across the world have had recourse to apps, as flexible agents with capacity to encode, materialise, represent and integrate such requirements, including some contradictory ones, and imagine and forge majoritarian supported social action. it is difficult not to see the turn to tracing apps as a pivotal moment in the expansion and entrenchment of surveillance technology in digital societies, of which singapore in particular has been a leading example (lee, ) -but is also playing out in contests and debates in many countries especially in europe and asia. how this ultimately turns out, and with what benefits for health, as well as legacies for democratic freedoms and daily life, we must wait and see. american civil liberties union (aclu) ( ) aclu white paper -principles for technology-assisted contact trading the promise of infrastructure coronavirus: australia set to start easing covid- restrictions, donald trump's plan to punish china countries rolling out coronavirus tracking apps show why they can't work coronavirus: singapore develops smartphone app for efficient contact tracing. straits times skype interview with annelise nielson, sky news australia. transcript, may. available at singapore: the limits of a technocratic approach to health care ordinary singapore: the decline of singapore exceptionalism what motivates people to download and continue to use the covidsafe app? 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media release how does tracetogether measure distance and duration of contact? what thresholds constitute close contact? media release team tracetogether ( d) what is blue trace? media release available at a socio-technical framework for digital contact tracing the imagination of singapore's smart nation as digital infrastructure: rendering (digital work) invisible. east asian science yip wy ( ) coronavirus: , seniors get first batch of tracetogether tokens. straits times ge : signs of young voters' crucial role in election outcome singapore looks to ease privacy fears with 'no internet' wearable device. zd net social media and elections in singapore: comparing my thanks to two reviewers for helpful suggestions. thanks also to rosemary curtis for her proofing of this article. the author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article. the author(s) received no financial support for the research, authorship and/or publication of this article. https://orcid.org/ - - - key: cord- -cywjp jh authors: chin, wei chien benny; bouffanais, roland title: spatial super-spreaders and super-susceptibles in human movement networks date: - - journal: nan doi: nan sha: doc_id: cord_uid: cywjp jh as lockdowns and stay-at-home orders start to be lifted across the globe, governments are struggling to establish effective and practical guidelines to reopen their economies. in dense urban environments with people returning to work and public transportation resuming full capacity, enforcing strict social distancing measures will be extremely challenging, if not practically impossible. governments are thus paying close attention to particular locations that may become the next cluster of disease spreading. indeed, certain places, like some people, can be"super-spreaders."is a bustling train station in a central business district more or less susceptible and vulnerable as compared to teeming bus interchanges in the suburbs? here, we propose a quantitative and systematic framework to identify spatial super-spreaders and the novel concept of super-susceptibles, i.e. respectively, places most likely to contribute to disease spread or to people contracting it. our proposed data-analytic framework is based on the daily-aggregated ridership data of public transport in singapore. by constructing the directed and weighted human movement networks and integrating human flow intensity with two neighborhood diversity metrics, we are able to pinpoint super-spreader and super-susceptible locations. our results reveal that most super-spreaders are also super-susceptibles and that counterintuitively, busy peripheral bus interchanges are riskier places than crowded central train stations. our analysis is based on data from singapore, but can be readily adapted and extended for any other major urban center. it therefore serves as a useful framework for devising targeted and cost-effective preventive measures for urban planning and epidemiological preparedness. the ongoing outbreak of the infectious coronavirus disease (covid- , also known as ncov- and caused by the pathogen sars-cov- ) is progressing worldwide with a reported number of cases surpassing million as of april , . the pathology of covid- and its global spread remain a critical challenge to all worldwide , . as of this writing, no approved treatment for covid- has been identified and a vaccine is expected to be months to months away from being widely available. based on our current medical knowledge, covid- is more infectious than the severe acute respiratory syndrome (sars is caused by sars-cov- ) , , and with the main transmission pathway being through respiratory droplets, with infected patients experiencing an incubation period of maximum days (possibly longer in some reported cases) before exhibiting a set of flu-like symptoms , . the asymptomatic latent period of covid- and its highly contagious nature have made the spread of covid- extremely difficult to control and prevent . the outbreak of covid- started in december in the city of wuhan, hubei province of china. following the domestic outbreak in mainland china, the disease started spreading worldwide in january (or even as early as december ), leading to a declaration of public health emergency of international concern (pheic) by the world health organization (who) . until this declaration of pheic, a total of , cases were confirmed, in which only were cases outside china . in february , covid- continued spreading internationally, primarily in east and southeast asia, as well as some european countries having extensive air-travel routes to wuhan and china. the first wave of international spreading took place during the critical period of the chinese new year holiday, during which china experiences the largest human migration every year . countries that were first hit by this outbreak include thailand, japan, singapore, south korea, france, germany and the united kingdom . those imported cases have quickly turned into local transmissions in most of these countries. in march , as the outbreak reached an exponential growth in italy, spain, france, and germany, the epicenter of covid- moved to europe , which became the second wave of this outbreak and international pandemic. that second wave triggered a near-complete lockdown in most of the largest european countries. the purpose of these country-level or city-level lockdowns was to introduce and enforce strict social distancing measures, that were hoped to bring a fast reduction in the spread of imported and local community transmissions. the central assumption behind these drastic public-health measures was that restricting human movement is key to controlling the spread of covid- in communities, between cities and countries. 'physical distancing' has been coined as a better term to super-susceptible, it would require particular attention since it would pose the risk of simultaneously being a hotbed of infection and disease spreader. identifying these places would therefore be critical in the fight with infectious diseases such as in this article, we report a study aimed at systematically identifying the spatial super-spreaders and spatial super-susceptibles in the spatial human network of the city-state of the republic of singapore. the particular choice of singapore stems from it having: ( ) been hit early in the first wave of infection directly from wuhan and with a systematic tracking and mapping of infected people , ( ) one of the highest population densities in southeast asia, ( ) a dense and highly interconnected human mobility and transportation networks , , and ( ) detailed and reliable data for the construction of spatial networks . as mentioned earlier, a spatial super-spreader is a locus with a high outflow of people-i.e. a place where a lot of people are originated from and those people are moving to a high variety of places. in the same vein, a spatial super-susceptible is a destination for a large number of individuals originating from different places. hence, this work proposes a systematic data-centric framework enabling the identification of spatial locations, which should be targeted by public health agencies in the event of an epidemic such as covid- . with these critical places identified, policy makers would then be able to implement cost-effective targeted responses with prevention and intervention measures directly connected to the level of vulnerability of a given location. this section is divided into three parts: descriptions of (a) the study area, (b) the flow data, and (c) the metrics and indexes. this study focuses on the public transportation flow network in singapore. the city-state primarily occupies an island located in southeast asia with a total surface area of about . km . as of , the total population of singapore is about . million people (with a population density of about , . per km ), in which . % are residents (citizens and permanent residents) and . % are non-residents (foreigners with long-term passes). according to the general household survey , about . % students and . % working person relies on bus or rail transport services to travel to schools or work places, thereby making public transportation the primary mode of transportation in singapore. as a result, the density of people using the public transports during the morning and evening peaks are high, and the distance between people at the stations and vehicles is short. hence, a direct consequence of the high population density combined with a high rate of people using public transportation is that physical distancing is extremely challenging if not impossible during regular operations. this issue is a serious concern when facing the spreading of a highly contagious disease such as covid- . to analyze the data, we consider the administrative subzone level spatial boundaries (from the singapore master plan ) as the analysis unit. the residential population density (from the general household survey ) are shown in fig. . there are five regions (central, west, north, north east, and east), with planning areas, and subzones . some of the subzones contain no residential population (white areas), which include airports and airbases (e.g. changi airport in the east region) and industrial parks or ports (e.g. jurong island and bukom at the south of the west region, and simpang north and south at the north region). although these places lack residential population, they are the workplaces (destinations) of a large number of individuals. the darker color areas indicate the home for a large number of people; in other words, a large number of journeys starting from and ending at these locations. we used the origin-destination (od) ridership data of bus and train to generate the public transport flow networks. the od ridership data is systematically collected by the singapore land transport authority (lta is a government statutory board under the ministry of transport) through api calls . in this study, we used the ridership from november to january . in terms of temporal resolution, the od ridership data provides hourly passenger flows between each pair of bus stops or train stations (including mass rapid transit and light rail transit). the raw data are then aggregated into weekdays (a total of days in november , days in december and days in january ) or weekends ( days in both november and december and days in january). as the raw data records the flow between od pairs of bus stops or train stations, we spatially aggregate the data into flows between subzones, according to the bus stop or train station locations. a total of subzones (out of a total of ) contained at least one bus stop or one train station. these subzones then form the nodes ( nodes) of the weighted direct network, with flows between nodes corresponding to the weight of directed edges. a total of , edges were found, with a vast majority ( , edges or %) being edges across subzones, and less than % (exactly edges) were within-subzone flows (i.e. corresponding to self-loops from the network perspective). given that very limited number of such intra-subzone flows, they were ignored in this study. to carry out this study, we introduce two indexes, namely the spreader index (spi) and the susceptible index (sui) to search for the spatial super-spreaders (ssp) and spatial super-susceptibles (sss). both indexes sui and spi are quantitatively determined and calculated using two key elements: ( ) the local strength of human in-and outflows, and ( ) the diversity of their respective neighborhoods . the local strength of in-and outflows for a given location is the number of people coming to or leaving from the location, i.e. respectively the weighted in-degree and weighted out-degree of the corresponding node. the neighborhood diversity is captured and quantified by two types of concepts: ( ) the diversity of zones and ( ) the diversity of coreness. the diversity of zones , refers to people that are coming from different parts of the city. as for the diversity of coreness , , it refers to people either coming from the core or from the periphery of the country. more details about what constitutes core and periphery is given in step below. we applied this analysis framework to the singapore public transport flow network, and identified the ssp and sss using the sui and spi indexes. the population flow patterns are expected to be different for weekdays and weekends. thus, the flow data were separated into weekday and weekend ones. the calculation flow of the spatial spreader and spatial susceptible indexes is detailed in fig. . the first part consists in aggregating the bus and train od flow data to subzones as mentioned earlier. that top layer provides the main data for the calculation, i.e. two weighted and directed networks: weekday and weekend flow networks. these networks are subsequently used to compute three network characteristic measurements, including degree centrality (step ), community detection (step ), and k-shell decomposition (step ), which are described in full details in the following subsections. the degree centrality is used as a proxy for the intensity of the local out-and inflows, whereas the community detection and k-shell decomposition results enable the computation of neighborhood diversity, including zone-entropy and coreness-entropy as introduced below. finally, in the last step (step ), the three network characteristics are used to calculate the sui and spi. step : degree centrality the degree centrality in this study includes both the non-weighted and weighted in-and out-degrees. the non-weighted and weighted versions of the degree centrality represent different concepts in terms of network characteristics. the non-weighted in-degree and out-degree are the number of links (or edges) that are pointed to and from a subzone, respectively. this non-weighted degree centrality measures the number of relationships that a particular subzone has. as for the weighted in-degree and out-degree, they correspond to the summation of incoming/outgoing flows for a given subzone, respectively. this weighted version of degree centrality indicates the total strength of a node in terms of gathering flows or spreading flows without accounting for the actual number of (incoming or outgoing) edges. in this study, the weighted degree centrality is used to represent the local intensity of nodes for the calculation of the sui and spi. the weighted degree centrality is scaled within the unit interval. on the other hand, both non-weighted and weighted degree centralities are used in the weighted k-shell decomposition analysis performed as step . this study uses a community detection method (mapequation algorithm ) to identify the zones from the flow network, instead of using the administrative spatial boundaries (i.e. the boundaries of planning areas and regions as defined by the singapore government in its master plan ) that were designed and selected for governance and political purposes. the communities from this flow network analysis capture both the strength and direction of flows, which reflect the spatial activity of people derived from their daily commuting/mobility behaviors . as the community distribution is identified for weekday and weekend networks, similarly the distribution should be differentiated between weekdays and weekends. mapequation is used to identify the communities in the flow networks . this algorithm considers the direction and weight of edges to identify the strongly connected nodes in a directed and weighted network. this particular algorithm is different from modularity-based community detection methods since mapequation's calculation concept emphasizes the strength of flows in community, i.e. higher flow intensities within a community than between communities (flows cycling within communities). mapequation captures the effect of direction while ensuring large amount of flows are kept within the community. moreover, the communities obtained with mapequation are used as the zones that contain strong human flows cycle, which is quantified with the concept of zone-entropy. note that to maintain the spatial continuous properties of the community, we integrate a distance decay effect in the flow intensity calculation (see eq. ( )) before running mapequation: where f(o, d) is the number of people moving from the origin subzone o to the destination subzone d, distance(o, d) is the distance between the two subzones, and f (o, d) is the actual flow intensity incorporating the distance decay effect. first, we run the mapequation algorithm on the two networks (weekdays & weekends), and identify the zone (set of communities z = {z , z , ..., z max } with z j = {n| ∀ n belongs to community j}) in which each subzone (node) belongs to. then, for each subzone, the incoming/outgoing neighbors' zones are retrieved from the results together with the weights of incoming/outgoing edges (w( j, i) or w(i, j)). the neighbors' zone information and flow weights are used to calculate the normalized entropy (h zone neigh (i)) using eqs. ( )-( ). the entropy is normalized using the total number of zones in the network to enable a comparison between nodes. note that the zone-entropy value ranges between and as a consequence of this step : coreness-entropy the k-shell decomposition is a method to label the coreness (k-shell levels) of nodes in a network based on the connectivity structure . because the edges of the flow networks were weighted, we use the weighted k-shell decomposition , which is an extended version that consider both the number of links (degree) and the weights of links while labeling coreness. the coreness of a location indicates the position of the location in the range from periphery (low k-shell levels) to core (high k-shell levels). in a population flow network, the core locations indicate the common origins or destinations for a large number of passengers. in this study, we first run the weighed k-shell decomposition using the non-weighted and weighted in-/out-degree (from step ) to calculate the in/out-k-shell levels for each subzone. then, the k-shell levels are grouped into core (in-/out-core) or periphery (in/out-non-core) using the median value as a cutoff. finally, for each node, its incoming/outgoing neighbors' core/non-core information is integrated with the flow weights to calculate the so-called coreness-entropy (h core neigh (i)) as defined in eqs. ( )-( ). the entropy is normalized using the total number of coreness levels (binary levels here, i.e. c = {core, periphery}), to facilitate the comparison of the results between nodes. note that the coreness-entropy value ranges between and after this normalization. step : spatial spreader & susceptible indexes the spatial spreader index (spi) and spatial susceptible index (sui) are base on the general concepts of the framework proposed by fu et al. . however, the exact indices are largely modified to account for the specificities of our study. specifically, the spi and sui calculations are based on a geometric average of three key network metrics. the spi (see eq. ( )) is the geometric average of the local normalized weighted out-degree (nwoutdegree(i)), the zone-entropy of outgoing neighbors (h zone outneigh (i)), and the out-coreness-entropy of the outgoing neighbors (h core outneigh (i)). to understand this particular definition, one may for instance consider the case for which a node's spi is high: this node has a high volume of outgoing flows (high local intensity), half of the flows are directed to the core area and the other half to the non-core area (periphery); these flows are equally divided into different zones (high out-neighbors' zone-entropy). in other words, a high spi subzone has a large number of travelers originating from there, and these individuals are on their way to both core and periphery places, which are located in various zones. therefore, with such a high spi index value, the disease spreading would be facilitated within a short period of time. the flow intensity and diversity measurements are all normalized in the unit interval, and consequently the geometric average also varies between zero and one. the spatial susceptible index sui (see eq. ( )) is constructed in a completely similar way as the spi, with the exception that we are considering all incoming components as opposed to outgoing ones in the spi: e.g. local normalized weighted in-degree (nwindegree(i)), the zone-entropy of incoming neighbors (h zone inneigh (i)), and the in-coreness-entropy of incoming neighbors (h core inneigh (i)). again, the concept associated with the sui is better understood when considering a subzone with large incoming flows: half of the flows are coming from the core area and the other half from the non-core area, and these flows are equally coming from different zones. in other words, this subzone is a destination for a large number of travelers originating from various zones and their origins of movement contain both core and periphery areas. therefore, a high sui subzone is / expected to be a place where travelers would be more vulnerable and sensitive to being infected. like the spi, the sui varies in the unit interval. the spatial distribution of the non-weighted/weighted in-degree and out-degree for weekdays are shown in fig . it appears that the patterns for the non-weighted and weighted in-degrees (top row) are similar to those of their out-degree counterparts (bottom row). this points to the fact that inflows and outflows are fairly balanced, which is expected for daily aggregated data associated with steady human movements. for the non-weighted degree measurements (left column), the high in-and out-degree subzones appear to be mainly concentrated at the east, north east and central regions, whereas the west and north have a higher number of lower degree subzones. these results are correlated with the distribution of human density in singapore, namely high to very high in the east, north east and central regions, and lower in the west and north of the island. for weighted degree measurements (right column), the east region has higher degree subzones; the number of high degree subzones drop in the central region; north, north east, and west regions have relatively more higher degree subzones when compared with their non-weighted counterparts. (d) ) refers to the out-degree. the townships are separated into four groups using the %, % and % percentile as breaks, thereby giving the "low", "mid-low", "mid-high" and "high" intensities. the distribution of the non-weighted measurements for weekends are essentially the same as the results for weekdays. figure displays the differences in weighted in-and out-degree between weekdays and weekends. most subzones are in the lightest green or purple colors, thereby indicating that their degree measurements are only very slightly larger than each other (the differences are less than . times). these subzones have a similar number of people using public transportation during weekdays and weekends. only a few subzones are in dark colors indicating larger changes as compared to weekdays. these subzones reveal a notably different usage of public transportation at these locations between weekdays and weekends; the changes of usage for weekdays are twice larger than weekends (dark purple), or the other way round (dark green). figure . differences of weighted in-and out-degree between weekdays and weekends. subzones in green indicate weekends have higher degree, whereas subzones in purple indicate weekdays having higher degrees. the color range from light to dark following the scale of higher degree. as discussed in the materials and methods section, a critical component of our network analysis is based on community detection. figure shows the spatial distribution of communities for both weekdays and weekends. the mapequation algorithm with the provided data reveals different communities for both weekday flow network and weekend flow network. most communities are spatially continuous as the flow data is integrated with the inverse of the distance. however, some exceptions exist in both weekday and weekend communities (e.g. weekday and weekend community # ). the spatially-continuous patterns are expected given the spatial embedding of our networks and it indicates, as expected, that interactions between closer subzones are effectively stronger. on the other hand, the few spatially-split communities appear to be the by-product of a strong flow of human movement between two spatially-distant locations with sparser spaces between them. although weekday communities and weekend ones are different-some are split and others have different boundariesoverall, they show some notable similarities (e.g. weekday community # and weekend community # ). this observation can be attributed to two particular features of singapore: ( ) given the limited available land, singapore has a dense and compact urban landscape with a high level of mixed-use areas, be them residential, industrial and/or commercial, ( ) a non-negligible fraction of the working population is active on saturdays, which creates a high flow of travelers with the same commuting patterns as during weekdays. for instance, in the western region, weekday communities # and # are extremely similar with weekend communities # and # . these particular communities are fairly large with a heavy mixed-use of residential and industrial areas, where people have similar daily activities within a week. the north east region (ner) contains three similar communities during weekdays and weekends (community # (upper part), # , and part of # during weekdays, and the similar patterns of # (upper part), # , and # during weekends). the north region (nr) is split into multiple communities (community # (lower part), # , # , # , # , # during weekdays, and # (lower part), # , # , # , # during weekends). the identified communities # , # , # , # , # , # during weekdays, and communities # , # , # , # , # during weekends are similar and fit well with the central region (cr), which is the central business district of singapore. the community detection results show that the boundaries of human activity can be changed between weekdays and weekends. community # in weekends appears to be an area resulting from the merger of communities # , # and part of # during weekdays. this indicates that the area has stronger human movement interactions during weekends than weekdays, probably because the area is mostly residential with few shopping places providing daily needs products and necessities. in summary, the human movement boundaries are not fixed to a static pattern, and it is usually smaller than the shape of the known regional/administrative boundaries. the spatial distribution of the core area is shown in fig. . as detailed in the materials and methods section, the calculation of coreness is separated into two parts for each network, one of which uses the (weighted or unweighted) in-degree, and the other the (weighted or unweighted) out-degree. hence, two sets of coreness results (outgoing core area and incoming core area) are obtained for each network. some areas are identified as core in both incoming and outgoing directions (red subzones in fig. ), some are core for either incoming (pink subzones in fig. ) or outgoing (purple subzones in fig. ) but not both. however, the vast majority of areas are core ones from both the incoming and outgoing flows perspective. these red areas happen to have a notable overlap with residential areas with a high population density, thereby indicating that places where people live would always have high incoming and outgoing flow: a core area of human movement and commuting. the calculation of spreader and susceptible indexes require access to the local normalized in-degree and out-degree centrality, as well as the incoming and outgoing neighborhood zone-entropy (eqs. ( )-( )) and coreness-entropy (eqs. ( )- ( )). note that these three key indicators (local weighted degree, zone-entropy and coreness-entropy) are in the unit interval, i.e. with variations between zero and one. figure shows the local out-and in-degree (left column), the outgoing and incoming neighborhood zone-entropy (central column) and coreness-entropy (right column) of the weekday (first two rows) and weekend (bottom two rows) flow networks. the spatial distribution shows notable differences between centrality, zone-entropy and coreness-entropy. figure . distribution of core/non-core areas from the weighted k-shell decomposition. the coreness in (a) refers to weekday flow data, while in (b) it is for weekend flow data. red-colored areas are for subzones identified as both incoming and outgoing core areas, purple-colored areas refer to solely outgoing core subzones, and pink-colored subzones highlight solely incoming core subzones. in addition, high levels of local weighted out-and in-degree are mostly concentrated in the east, north east, and central regions. as for the zone-entropy, these high levels are primarily located in the north and central regions, while high levels of coreness-entropy are mostly found in subzones in the north region. essentially, most of the subzones have high levels of one, two or even three of these key indicators. however, only subzones with high levels of all three indicators are ssp or sss. the distribution of the spreader index (spi) and susceptible index (sui) of each subzone for weekdays and weekends are shown in fig. . all four distributions suggest a similar poisson-like type of distribution, with a mean value between . and . (solid vertical lines). the fact that these mean values are very close for both indexes on weekdays and weekends is in line with our previous comment related to an expected balance between incoming and outgoing flows of human movement. however, for our analysis the locations of interest are those that are outliers corresponding to large spi and/or sui values. using the interquartile range (iqr) method, the outliers are identified as the subzones located above the q + . fig. as a reference level (dotted vertical lines) . the subzones that lay between q and q + . × iqr are categorized as secondary-spreaders or secondary-susceptibles. this analysis reveals that a non-negligible number of locations exhibit large spi and/or sui values, thereby contributing to our identification process of spatial super spreaders and spatial super susceptibles. the spatial distributions of super-spreaders (ssp) and super-susceptible (sss) is shown in fig. for weekdays and in fig. for weekends. for weekday flow movement (see fig. ), subzones are identified as ssp (red-colored zones in fig. (a)) corresponding to spi ≥ q + . × iqr; subzones are identified as sss (red-colored zones in fig. (b)) corresponding to sui ≥ q + . × iqr. it is worth noting that subzones overlap in both figures, thereby corresponding to both spatial super-spreaders and super-susceptibles (subzones a) to i) in both figures, shown as red-colored subzones with a purple border). this indicates that most of the subzones with the highest spi values would also have the highest sui values, and vice versa. in fig. (a) , all identified ssp are also identified as sss. in fig. (b) , two subzones-j) khatib, and k) tampines east-are identified as sss only, with a lower spi (q ≤ spi < q + . × iqr). the weekend distributions exhibit slightly different patterns. there are subzones identified as ssp on weekends, with of them also being identified as ssp on weekdays (subzones a) to h) in fig. (a) ); none of which are less than q in the previous figure. similarly, all weekend sss are either super-or secondary-susceptibles on weekdays, and vice versa. a total of sss are found with the weekend human movement network ( fig. (b) ); of them (subzones a) to i)) are also weekend ssp; of which overlap with those of the weekday sss results, the other two subzones-j) boulevard, and k) bukit batok central-are promoted from weekday secondary-susceptibles subzones (pink subzones in fig. (b) ). this result further confirms that the spi and sui are not dramatically different between weekdays and weekends. there are eight subzones (a) to i) except h) in fig. , and a) to h) in fig. central), and three at the north region (sembawang central, woodlands regional centre and yishun west) are identified as both ssp and sss (in red) in both weekdays and weekends. during weekdays, most of the identified ssp or sss areas belong to the regional core that contained a higher density of human activity. the eight ssp and sss can be separated into two types. the first type consists of five subzones (a), c), e), f), and i) in fig. ), which contain high population density; the second type consists of the other three subzones (b) jurong gateway, d) maritime square, and h) woodlands regional centre in fig. ) associated with a lower population density. the subzones in the first type are typical residential area, where the intensity of human activity are high due to the extensive need to travel out during the day time and travel back in the evening. on the other hand, the subzones in the second type are regional hubs of public transportation, which naturally attract a large population flows. public transport facilities along with numerous commercial buildings (shopping centers). one counter-intuitive observation can be made from fig. and fig. : the cbd contains less ssp and sss as one could expect. the cbd of singapore is located at the southern central part of the central region. high intensity of human activity exists within the cbd area. as shown in fig. , most of the subzones in the cbd have either a low weighted degree or a low neighborhood coreness-entropy. the low weighted degree probably finds its origin in the smallness of the area itself, which limits the catchment of incoming and outgoing flows. as for the low coreness-entropy, we trace it to the fact that a majority of the people are circulating within the cbd, which are mainly composed by the core area (fig. ). this result indicates that the cbd workplaces are less influential in terms of quickly spreading the disease to the rest of the city/island, but a contagious disease would quickly spread inside the cbd area as a consequence of its strong internal flows. in summary, the key influential areas are clearly identified as being the regional transport hubs, which connect the residential areas with the rest of the country. the concept of super-spreader was originally introduced in the field of social network analysis to identify the most influential persons or nodes within a given social network. these persons could be opinion leaders, trend setters, public figures within a group of people , . furthermore, this concept of super-spreader individual has been borrowed by epidemiologists to identify and study the abnormally high spreading activity of a small group of individuals , in large populations during an epidemic outbreak. while previous studies focused on the identification of super-spreaders within a social network-nodes are individuals and edges represent the existence of interactions between two persons (binary edge)-this study focused instead on spatial networks of population flow with nodes representing physical locations and weighted/directed edges representing flows of human movement. this study sought to extend the concept of super-spreader to spatial interaction networks, with the objective of identifying possible spatial super-spreader locations-a set of locations that have the most influential effects in terms of disease spreading. the concept and calculation method were also reversed to uncover another group of critical locations: the most vulnerable places defined as super-susceptibles. our results based on large-scale data analytics show that most of the ssp are also sss. this is reasonable and somehow expected given the nature of the daily population flow network. specifically, since we are considering daily-aggregated data, the number of people who are leaving from a place can be expected to be of the same order as the number of people who are going to this place, i.e. we are in the presence of balanced commuting flows and the larger the outgoing flow intensity, the larger the incoming flow intensity. based on the results, the places with intense flows have higher potential to be both ssp and sss, and this is captured by the directed nature of the networks and the incorporation of the weighted in-degree or out-degree in our calculations. it is worth noting that our results are in good agreement with previous studies based on the k-shell decomposition method: the core nodes of a social group tend to be, in general, the most influential ones , . besides the local incoming and outgoing flow intensities, this study also considers two critical neighborhood diversities of these networks: the zone-entropy and coreness-entropy. the diversity of neighborhood is especially important while identifying multiple super-spreaders from a network , . the zone-entropy is used to measure if the outgoing flows are directed towards more zones within the city-state. for instance, if the outgoing flows from a given place are converging to one zone only, this place can only affect one of the zones among all throughout singapore, thus its influential power is clearly weak. conversely, if human movement originating from one place flows to many zones across the country, its influential power is relatively high. in addition, coreness-entropy captures the diversity of flows to or from core or periphery areas. if the flows are all directed towards one of the periphery or core, its influential power is somehow limited to this particular type of areas. conversely, if human movement flows to both core and periphery areas, this clearly indicates that whenever an outbreak happens at this place, it could quickly affect and spread to both core and periphery areas. these two diversity metrics complement one another and are combined in the calculation framework for differentiating places with high density of flows into strong and weak influential places (see materials & methods). this study enables us to establish a list of subzones, which have a strong capability in terms of diseases spreading, as well as a list of subzones, which are more vulnerable in terms of being a place of high risk of contagion. in summary, the identified subzones are found to be mainly in the core area of residential and transportation hubs. these places have high population density and activity, such as transportation hubs or community hubs. therefore, these places should be targeted by public health agencies, with higher resource allocations and disease monitoring aimed at prevention and intervention purposes. for example, public health agencies could consider these locations while planning to setup body temperature checkpoints, or to provide personal hygiene toolkits, or also setting up advertisements related to appropriate behaviors to counteract the ongoing epidemics. moreover, since these locations are more vulnerable and more influential, they should get more attention while setting up differentiated policies such as the temporary closure of some businesses or restrictions on large-scale human activities as opposed to a blanket lockdown across the country. the proposed network analysis framework rests upon the integration of the local flow intensity with neighborhood diversity measures-zone and coreness-to assess the effective spreading ability of particular locations. from the theoretical perspective, the proposed framework considers weighted and directed interactions between nodes (places) to identify super-spreaders and super-susceptibles. from the practical perspective, this study presents a quantitative and systematic framework to identify the key influential and vulnerable locations based on public transport flow data usually available by most transportation agencies in metropolitan areas. it is worth noting that there are several limitations to this study. first, our analysis is limited to human flow associated with the use of public transportation, which is high in places like singapore or other continental european cities but could be much lower in other urban areas with far less developed public transportation networks, such as in the united states for instance. in addition, our data only includes ridership of buses and trains and misses out on other important means of public transportation, including taxis, private-for-hire automobiles (cars, motorcycles, shuttle buses or vans), and active transportation (by walking, bicycle, skateboard, scooter, personal mobility devices, etc.). some of the subzones currently do not have bus stops or train stations. however, as mentioned previously, public transportation by bus and train in singapore is fairly high-more than % of daily commuting-thereby confirming the importance of the obtained results, as being representative of key human movement patterns. second, singapore is an island country with its northern national border connected to malaysia through two land checkpoints. unfortunately, these cross-border flows are not included in this study. many workers and students commute daily between singapore and the state of johor in malaysia. there are some dedicated bus services directly connecting stations in johor bahru, malaysia and various places across singapore, including woodlands at the north region, jurong east at the west region, and bugis at the central region, etc. since these data were ignored, the in/out-flows of these places in singapore are certainly underestimated. third, inter-mode trip transfers and bus transfers are not captured in the dataset used to carry out our study. trip transfers between mass rapid transit (mrt) lines are captured from the tap-in and tap-out records, i.e. passengers changing lines at some interchanges. but the od data for buses only records the direct flow between bus stops, i.e. the records present only the tap-in and tap-out bus information, the records of the exchange of bus services are not shown/captured in the data. on the other hand, the data about changing from bus to train and vice versa is also unfortunately not available. therefore, we can only capture direct bus services and this naturally limits the movement of travelers to the existing direct bus/train services. fourth, the short-time scale dynamics throughout a day is ignored. indeed, we considered daily-aggregated data. however, a higher temporal resolution could be considered (say on an hourly basis), which could reveal different patterns of ssp and sss. the temporal evolution of the sui and spi indexes would be the topic of a future study. in summary, we have developed for the first time a framework allowing the identification of spatial super-spreader and super-susceptible locations. we believe that our results and analysis could be extended in two key directions. first, our analysis would benefit from being complemented by working with epidemiologists specialized in simulations of disease spreading through human contact networks. this would integrate our results with differential spreading across more or less vulnerable places. specifically, the dynamic patterns of disease propagation could be observed from the simulation models, and thus the effects of the ssp and sss could be quantified in terms of its actual contamination rate in the population. second, the geography, demography, and social-economic of the spatial super-spreaders and super-susceptibles could be accounted for and included in our analysis using some statistical models, to identify the potential social and physical environmental factors that made these locations super-receivers and super-susceptibles. in conclusion, it is well known that dealing with the reopening of economies and cities after a blanket lockdown requires a finely calibrated approach from governments. although, here we used the singapore public transport flow data to build these networks as a case study, similar analyses can readily be carried out using the exact same process in order to uncover the ssp and sss in any large urban center. our data-driven methodology, analysis and results offer an effective way of devising targeted and localized preventive measures when lifting stay-at-home orders. such targeted measures for vulnerable locations are also critical in order to optimize government resources in the face of economic decline. the datasets-generated from the singapore lta database -used for this study are available from the following spa-tial_spreader_susceptible_data repository: https://github.com/wcchin/spatial_spreader_susceptible_ data. coronavirus disease (covid- ) situation report genomic characterisation and epidemiology of novel coronavirus: implications for virus origins and receptor binding clinical features of patients infected with novel coronavirus in wuhan epidemiological and clinical 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communities confirmed imported case of novel coronavirus infection in singapore; multi-ministry taskforce ramps up precautionary measures transportation and territorial development in the singapore extended metropolitan region republic of singapore. passenger volume by origin destination bus stops & passenger volume by origin destination train stations general household survey master plan subzone boundary (no sea the map equation. the eur a k -shell decomposition method for weighted networks a model of internet topology using k-shell decomposition a computer movie simulating urban growth in the detroit region searching for superspreaders of information in real-world social media the effect of superspreading on epidemic outbreak size distributions this research was supported by an sutd grant (cities sector: pie-sgp-ctrs- ). w.c.b.c. conceived and conducted the experiment and the data analysis. w.c.b.c. and r.b. analyzed the results and wrote the manuscript. all authors reviewed the manuscript. to include, in this order: accession codes (where applicable); competing interests the authors declare no competing interests.the corresponding author is responsible for submitting a competing interests statement on behalf of all authors of the paper. this statement must be included in the submitted article file. key: cord- -xlz hm authors: koh, vanessa; lim, al; tan, jill j. title: the singaporean state and community care in the time of corona date: - - journal: city soc (wash) doi: . /ciso. sha: doc_id: cord_uid: xlz hm nan in the early days of the coronavirus outbreak, various health experts praised singapore's response to the virus. on february , , the straits times-singapore's national newspaper-reported that four epidemiologists at harvard university had praised singapore as "a gold standard of nearperfect detection." less than a month later, minister for foreign affairs vivian balakrishnan noted in an interview that this pandemic is "an acid test of every single country's quality of healthcare, standard of governance, and social capital… if any one of these tripods is weak, it will be exposed quite unmercifully." he would later be proven correct, but not in the way he likely intended. by early april, singapore saw a huge surge in covid- cases, as many migrant workers who have built the city-state's infrastructure tested positive. the prime minister subsequently announced the imposition of a "circuit-breaker" (simply put, a lockdown), and the media narrative quickly turned to an examination of the dense and poor living conditions foreign workers have endured as singapore transformed from a model of effective governance to a cautionary tale. technocrats often boast that singapore not only has a competent state that can deliver solutions in times of crisis, but also a socially compliant population that responds to state policies. this trust in government was especially visible during the earlier months of the pandemic (quah ) . one of us has been conducting (now interrupted) fieldwork in singapore since early february, and witnessed various statements that reinforced the notion that a competent government would surely provide a way out of a public health crisis. for example, one singaporean acquaintance suggested that there was no need to worry too much about the virus because the government had learned important lessons from sars years ago. "they have policies in place to ensure we're prepared for an outbreak like this. we are checking temperatures as people enter buildings and doing vigorous contract tracing. there is a whatsapp group to convey factual information to the public to combat fake news so they will know not to panic. it's paternalistic but do you trust people to be prudent or stupid? i tend to go with the latter." a whatsapp message sent by the government to the public advising against panic buying. image credit: vanessa koh the framework of political governance in singapore is largely a technocratic one that operates on the belief that foreign-educated elites will deploy knowledge, logical reasoning, and technical expertise to govern in ways that transcend ideology and partisanship. under such a configuration, the implicit social contract is a negotiated settlement in which people cede substantial amounts of authority to the technocratic governing elite in exchange for persistent delivery on technical (and economic) solutions to a series of challenges. despite bouts of panic buying of groceries every time the prime minister announced that he would address the nation-in anxious anticipation that the government might decide to lock the country down-there was a prevailing sense of security in the state for two months, as shopping malls and public transit remained crowded and everyone clung onto the hope of some semblance of normalcy. as news first broke about the struggles in italy, singaporeans largely remained confident. it was easy to explain the italian healthcare system as being overwhelmed due to their perceived slowness in implementing strict social distancing measures, or to see the system as weakened by punishing austerity measures over the years. by contrast, singaporeans took relative comfort in having a robust healthcare system and a proactive government. certainly, these points are not to be dismissed wholesale. we are not suggesting that there is no validity to certain technocratic policies. contact tracing, for example, has and likely will continue to be useful as the state slowly reopens. every person in singapore is entitled to free testing and citizens and long-term residents will not have to pay out of pocket for treatment. however, we caution against an unshakable faith in a system that promulgates a narrow and elitist definition of care that excludes vulnerable subsets of the city-state's population. at the time of writing (may , ), there are over , confirmed cases of in singapore, and these are differentiated by citizenship or employment status. foreign work permit holders in dormitories account for , ( %) of the , cases. "community cases" (a term most commonly associated with singaporean citizens and permanent residents; excluding imported cases) comprise , cases, which is less than % of the national total. the disparity of these numbers- % of cases from foreign dormitory residents and % of cases from the community-and separate reportage illustrate that there are two realities in singapore: one for those who live in dormitories and another for the rest of the singaporean population. the everyday realities also correspond to this bifurcation. singaporeans that returned from overseas were housed in -star hotels for their -day quarantine period, whereas many work permit holders were forced to stay indoors in crowded dormitories, where often, to men have to occupy one single room. demanded an apology." this reply has been over-sensationalized, but it is evidence of the state's lack of reflexivity and sensitivity during a moment of intense public scrutiny and stress. it would baffle anyone to think that a migrant worker, at risk of being deported, could confront an mp to demand an apology. the workers already face immense debt on top of psychological tolls from being away from family and worrying if the virus will prevent them from sending money home to their families. these worries have driven workers to attempt to speak the language of the state in order to get redress for wages they may not have yet received or ex gratia payments that are often magnitudes smaller than what they are entitled to. they are far too anxious and intelligent to demand an apology. however, situating minister teo's comments within the context of the rest of the speech is essential. her response reads: ms. anthea ong asked about an apology. we interact very closely with the workers themselves, on a very regular basis at the dormitories, and even outside the dormitories whenever i'll ask teams, you know, follow up on their requests and feedback. i think what they're focused on is how we can help them to handle this present situation, not fall sick, and if they fall sick, help take care of them, how to look after their wages being paid, how to ensure that they can send money home (emphasis added). the latter three factors are, in fact, the needs that the migrants have learned to articulate. they are also important according to numerous ngos that have worked with them in the past years, such as healthserve, twc , home, migrant workers centre, and singapore migrant friends. these economic factors capture why they have come to singapore in the first place. on labor day, nmp ong also posted a message on facebook that addressed the workers directly. she writes: "the world sees you now, you are no longer invisible -we must and will do right by you." the use of the word "now" suggests that this is a recent change that emerged as a consequence of scrutiny due to the coronavirus. yet even as ministers are acknowledging the state's responsibility towards the workers, there remains a hesitance in reflecting on the structural conditions that led to the outbreak at the dormitories. when pressed about the living conditions at the dormitories in a recent interview with cnbc, the minister for national development and co-chair of the coronavirus task force lawrence wong cited the provision of recreational facilities and convenient access to amenities as proof of improved conditions over the years. he suggested that the crux of the problem is that "these dormitories are designed for communal living, where the workers eat together, they live together, and they cook together." he went on to say that despite the best efforts at putting in place precautions and safeguards, such as reminding the dormitory operators that "these non-essential communal activities have to be ceased at the start of the outbreak, the lesson we've learned from this experience is that with this unprecedented pandemic, the safeguards were not sufficient and the design of dormitories have to change." by insisting that the way forward is to redesign these places of residence, the state is reducing what is indeed a sociopolitical problem-the second-class treatment that migrant workers endure-to a solely technocratic one that can be solved by a mere architectural makeover. communal activities such as eating and cooking together are not extraordinary even during a global pandemic; those of us who do not live in dormitories engage in these activities with the people who are a part of our respective households. persisting with an anti-politics machine (ferguson ) that views caregiving only as a technocratic project and disregards the social injustices of a political system will only hinder efforts to flatten the curve and prepare for future pandemics. it is useful to distinguish how the state is administering care from how individuals and ngos are doing so. we refer to the distinction felicity aulino makes between care-as-maintenance and care-as-concern in her recent work on the anthropology of care. aulino observes that contemporary usage of the english word "care" may contribute to the tendency to assume a correspondence between particular internal states, such as feeling affection or being concerned ("care about"), and the acts of best providing for another ("to care for") (aulino : ) . aulino cautions against such conflation, which may place an inordinate value on emotional concern in acts of providing for others while obscuring other important facets of care. instead, in her ethnographic work on caregiving practices, aulino focuses on the physical and pragmatic work of maintenance. in the case of care practices in the time of covid- , we examine where state and community approaches fall between the poles of care-as-concern and care-as-maintenance. in isolation, each form of care is often insufficient, but a robust vision of care draws from both concern and maintenance. care-as-maintenance, which is largely understood as the concern of the state, hinges on and plays out in the administering of technocratic care. for instance, in the area of expanding healthcare, technocratic solutions to the upsurge in numbers of people with covid- who need treatment have included conversions of large community facilities into treatment facilities, like when singapore expo was converted into a hospital. administering care-as-maintenance also notably encompasses the state's ability to delegate maintenance to non-state actors, such as private subcontractors who employ and oversee the dormitories of short-term migrant laborers. critiques of care-as-maintenance indict the state's subhumanization of migrant laborers who are often treated as if they need to be "maintained" in order to continue fulfilling their roles. care-as-concern, meanwhile, is evident in the language of care used by ngos and the upswell of community action and civic activism around addressing the plight of migrant laborers. support coalition advocated for seeing the "human aspects" over only "seeing [migrant support] as a humanitarian relief operation" or an intellectual discussion focused solely on policy. in the same conversation, michael cheah, the executive director of healthserve, noted that more care must be paid to workers' breaking points: the stresses of work and life, and loneliness as they navigate distance away from families for whom they must provide. the language of care of ngos and community advocates does not always stress emotional care over practical mediation. notably, calls for empathy have been channeled through allaying the immediate physical needs and logistical anxieties of those unable to advocate for themselves. this closes the gap between calls for care-as-concern and competent care-for-maintenance and includes requests for an increase of ngo oversight to provide better care. other responses by aid organizations, however, have foregrounded personal narratives and private messages between migrant workers and volunteers as testimony in order to emphasize the humanity and plight of migrant workers. such centering of individuals' lives and testimonies is ostensibly a sign of pushback against the sense that singapore's response to covid- neglects to take into account migrant workers' welfare in terms of both policy and statistics. yet the language and means of such outreach measures potentially fall prey to instrumentalizing individual's lives and stories, even if it is in service of raising awareness and drawing attention towards perceived needs and gaps. care-as-concern, when directed at maximizing human pathos, must thus be cautioned against in this unmitigated form on grounds of relational ethics and efficacy. following aulino, and contra some of the rhetoric of aid organizations, we take seriously care-as-maintenance as a valid approach to care in the time of covid- , and note that competence on the part of state actors and policy-makers has little to do with sentiment or "concern" per se in terms of daily problem-solving and an overall moral orientation. rather than adding to existing critiques of the state's lack of care-as-concern, we focus instead on the structural issue of singapore's policies around migrant labor in singapore that now renders present techniques of care-as-maintenance as insufficient. pure care-as-maintenance fails because it renders workers simply as a cost-benefit input-output equation. since the mid- s, singapore has relied on a merry-go-round of migrant nationalitiesinitially, thai and malay, then indonesian and chinese, and now south asian-to service its economy and dependence on cheap labor, while absconding from social responsibility. anthropologists and geographers have documented the asymmetrical power dynamic between state elites and migrant workers who realize the aspirations of the state (constable ; elsheshtawy ; kitiarsa ; yeoh ). singapore's economic model has relied on factor accumulation to deliver its gdp growth at the expense of productivity increase, primarily through labor market policies reliant on large inputs of a cheap, transient pool of unskilled labor (fong and lim ). the model has not changed, perhaps due to growth fetishism or preferring the most convenient route to growth, in spite of evidence of diminishing returns and socio-spatial constraints in singapore (pang and lim : , ) . instead of focusing on improving the workers' skills and quality of life, the government is more interested in depressing their wages to ensure higher capital gains through the input-output framework. for instance, it is not difficult to deport a worker back to their home country and it is also easier to hire a worker from overseas than to hire one who is already in singapore due to kickbacks. sociologist chua beng huat ( ) identifies this as an issue of the ruling party being wary of setting a precedent that would allow migrant workers to make a set of claims and thereby officially designate the state to be the primary caretakers of these workers. that the migrants are not citizens and are classed as "low-skilled" work permit holders place them under a series of legal and practical restrictions, even extending to their reproductive capacities (constable ) . there is also a tunneling effect in their everyday lives, where they experience a limited daily time-space based on a state-mandated policy to limit their mix/interaction between the migrant and host population (collins : ) . even before the outbreak, migrant workers were not allowed to use the same toilet as singaporeans. read together, the "othering" of the migrants, their designation as "inputs" into an economic model to propel singapore to international acclaim, and singapore's trend of utilizing different nationalities of cheap labor point to an urgent need to treat workers with dignity. where public critique has focused on insufficient care-as-concern of the state, we might also look at systemic reasons as to why its techniques of care-as-maintenance are falling short. the enforced disposability of "unskilled" migrant foreign workers from the singaporean state's purview and their inability to gain citizenship based on the work permits they hold is magnified and complicated by a global pandemic when it comes to the matter of yet-fulfilled labor contracts. with employers and agents still owed work and processing fees by migrants who are now quarantined due to being perceived risks to the singaporean public instead of working, and migrants who are unable to return home because of contracts and the need to send remittances back, the recourse of repatriation after the term of employment is no longer the built-in easy option for the state. on the one hand, risk, contagion, and common precarity have complicated the disposability of migrant laborers in terms of their repatriation; on the other, by hothousing migrants in conditions which all but guarantee contraction of covid- , their disposability in singaporean society has never been more obvious. while community advocates and aid organizations stress care-as-concern as necessary affective responses, we must also question why care-as-maintenance has failed this segment of singapore's population. to recognize and care for people as fully human entails not only the recognition of their narratives but the structures under which their basic maintenance of life is and has been troubled. in the aforementioned roundtable with various ngo leaders, some also shared that the media's overemphasis on cramped dormitories is secondary to long-standing issues such the lack of timely payments by employers. of-the-moment responses in the time of covid- may, therefore, fail to highlight areas of provision most needed for migrants in singapore, beyond perceived insufficiencies in both care-as-concern and care-as-maintenance frameworks. practices of care must also be considered alongside its temporalities -how long will care-as-concern last, considering modes of attention based on -hour news cycles and the episodic nature of processing a pandemic? we suggest that the issue at hand is not that the state does not care, but that it relies on an outmoded form of care. care-as-concern as an affective and communal response to the crisis has been rightly advocated for across the board. care-as-maintenance can also be a serious crisis response, but its apparent insufficiencies must be read within a larger context of structural inequalities that dispossess short-term migrant laborers in singapore, rather than simply a lack of accompanying care-as-concern. in sum, the singaporean experience with covid- illustrates how we need to rethink what an ethics of community care constitutes. that the state draws a distinction between migrant worker cases and local "community" spread points to the ways in which "community" is limited to citizens, long-term residents, and skilled migrants ("expats") who inhabit the homes that "lowerskilled" migrant workers have built. care is not just about the application of technocratic policy, but it also entails a concerted effort to reverse historical trends of othering "lower-skilled" nationalities and treating them as inputs into an economic growth model. we echo former nmp sadisavan's ( ) statement that the government's stellar academic and professional credentials cannot replace the need to consult its citizens because of the complexity of contemporary issues. this is especially vital in light of global sentiments of xenophobia that have emerged during the pandemic. in singapore, issues of brownface and the recent facebook post by member of parliament yaacob ibrahim, which expressed his happiness about how the virus had cleared out a space where foreign workers congregate, suggest that what many label as the "silent majority" might have entrenched racist views that have, up until this point, been simply left unsaid. what we can learn from the handling of singapore's covid- situation is that inclusion entails not just access to information, but also recognition within legislative information in terms of statistics, recommendations, and narratives by the state and its media. beyond human interest pieces on the plight of migrants in singapore, what must be remembered of this moment is how existing policies have endangered the vulnerable in singapore for there to be a semblance of movement towards the possibility of inclusive care. rituals of care for the elderly in northern thailand: merit, morality, and the everyday of long-term care we the citizens : black swans & sacred cows transnational mobilities and urban spatialities: notes from the asia-pacific maid to order in hong kong: stories of migrant workers tales of two cities: legislating pregnancy and marriage among foreign domestic workers in singapore and hong kong transitory sites: mapping dubai's 'forgotten' urban spaces the anti-politics machine: "development the "bare life labour, productivity, and singapore's development model singapore's policy response to covid- we the citizens : black swans & sacred cows bifurcated labour: the unequal incorporation of transmigrants in singapore key: cord- -qz msrl authors: wilder-smith, annelies; goh, kee tai; paton, nicholas i title: experience of severe acute respiratory syndrome in singapore: importation of cases, and defense strategies at the airport date: - - journal: j travel med doi: . / . . sha: doc_id: cord_uid: qz msrl background: the importation of sars was responsible for the outbreaks in singapore, hong kong, vietnam and canada at a time when this new disease had not been identified. we report the incidence and impact of cases of sars imported to singapore between february and may , and describe national measures to prevent further importation. methods: information on imported cases of sars and measures taken at entry points to singapore was retrieved from the ministry of health and the civil aviation authority of singapore. results: of the imported cases, which all occurred before screening measures were implemented at the airport, only the first resulted in extensive secondary transmission. of , air passengers screened after measures were implemented, were sent to a designated hospital for further sars screening; none was diagnosed as having sars. conclusions: the sars outbreak in singapore can be traced to the first imported case. the absence of transmission from the other imported cases was probably a result of relatively prompt identification and isolation of cases, together with a low potential for transmission. new imported sars cases therefore need not lead to major outbreaks if systems are in place to identify and isolate them early. screening at entry points is costly, has a low yield and is not sufficient in itself, but may be justified in light of the major economic, social and international impact which even a single imported sars case may have. on march , the world health organization (who) issued a global alert on severe acute respiratory disease (sars), a new emerging respiratory illness associated with significant morbidity and mortality. international travel was responsible for the rapid intercontinental spread of this disease, and by may sars had affected countries with a total number of , cases. the large outbreaks in hong kong, toronto, singapore and vietnam were initiated by cases that were imported before this new disease had been identified and before appropriate measures had been put in place to prevent transmission. [ ] [ ] [ ] there remains a concern that, even with such measures, prevention of transmission from imported sars cases may be difficult for countries that receive many international travelers from areas badly affected by sars. singapore has one of the busiest airports in southeast asia, and has numerous arrivals each day from countries in the region affected by sars. the country is therefore potentially vulnerable to importation of sars cases that may initiate new outbreaks. we report the incidence of imported cases of sars to singapore and its impact on the national sars outbreak. we also describe the national response in preventing further importation of sars. information was retrieved from the singapore ministry of health on cases of imported sars from the day on which the first cases of sars arrived in singapore ( february) until may , when singapore was declared sars-free by the who. these cases were verified against hospital records. the who definition for probable sars was used. information on measures taken at the national airport (changi airport), seaports and road entry points to reduce the importation of further cases was obtained from the civil aviation authority of singapore (caas) and from the websites of the ministry of health, singapore (http://www.moh.gov.sq/sars/news/chronology.html; accessed june). seven imported cases were notified to the ministry of health between march and may . one was excluded as imported sars after review of the case notes: the subsequent clinical impression during the course of disease was not that of sars, and convalescent sars serologies remained negative. of the persons who imported sars (confirmed by serology and/or sars coronavirus polymerase chain reaction (pcr)) to singapore, all were residents of singapore and had visited hong kong (plus guangdong in cases and beijing in case). cases and traveled together to hong kong at the end of february , and stayed on the th floor of hotel m.they are likely to have been infected by a sars patient (a chinese doctor from guangdong) who stayed on the same floor of hotel m on and february and transmitted the disease to guests, including a canadian and a hong kong person, who in turn sparked off major epidemics in their respective countries. , upon return to singapore on february, they developed fever, and a few days later a dry cough, and were admitted on march to two different hospitals in singapore and isolated days later. the first case in singapore admitted to tan tock seng hospital infected close contacts ( health care workers, and relatives or friends). these in turn infected people (all health care workers, patients and relatives), who then contributed to the current epidemic in singapore.isolation and infection control for these patients was instituted on march, hospital-wide infection control was enforced on march, and tan tock seng hospital became the sars designated hospital on march. case was unrelated to the first cases, but had been a guest at hotel m in hong kong during the same period, and returned on february. she developed a fever on february, was admitted to tan tock seng hospital on march, and was isolated the next day. cases and were a mother ( years) and son ( years) who had returned on march from visiting relatives in guangdong and hong kong. they developed symptoms within days after arrival in singapore, and were admitted and placed in isolation on and march respectively. the father and other son who had traveled with them were not infected. case was a -year-old designer who had been on a business trip to hong kong and beijing and developed high fever and a cough while in beijing. she consulted two doctors in beijing, but the diagnosis of sars was not made at that time. she became very unwell and breathless on her return flight from beijing to singapore on march, but no precautions were taken on the airplane,as her diagnosis was not known.immediately after arrival, her mother took her in a taxi to tan tock seng hospital,where she was isolated in the intensive care unit. she developed acute respiratory distress syndrome and multiorgan failure, and died days later. both the mother and the taxi driver were quarantined,but neither developed sars. the ministry of health was able to contact of the passengers, as well as all crew members, and they were put under home quarantine order and active surveillance for days; none developed sars. three of the six imported cases developed symptoms of sars only after arrival in singapore, whereas three had symptoms on the return flight to singapore (cases and , fever only, case , fever, cough, and shortness of breath). the first two were admitted to a hospital at a mean of days after onset of symptoms, and placed in isolation days later. cases to had symptoms of sars in singapore for a mean of . days, and all were immediately placed in isolation after hospital admission (except case : after day). cases and were therefore without infection control measures for days, and cases to for a mean of . days. only case resulted in secondary transmission. no health care workers and no other contacts were infected by cases to . the table summarizes the six imported cases. to prevent further importation of sars, the following measures were taken at the airports, seaports and road entry points into singapore. from march , health alert notices were issued to air passengers arriving from affected areas. on march, visual screening was instituted for all passengers arriving from sars-affected areas, and this was replaced by temperature screening a few days later. passengers who appeared to be unwell or had a temperature of > . °c were sent by a special ambulance to a single hospital that had been nominated to perform sars screening. from april onwards, passengers arriving from sars-affected countries were asked to complete health declaration cards. the information required included not only recent travel and contact history and symptoms suggestive of sars, but also addresses in singapore and flight seats, to facilitate contact tracing. on april, thermal scanners were installed at changi airport and the road entry points to check the temperatures of all departing and arriving passengers. temperature checks were introduced to all of singapore's ferry terminals on april. sars screening was progressively extended to all arriving flights from april onwards. after implementation of these screening methods, no further importation of patients with sars occurred ( march until may). in total, , air passengers were screened between march and may , and of those, were sent to tan tock seng hospital for further sars screening and observation, but none was diagnosed as having sars. the figure depicts the time of arrival of imported sars in singapore and measures taken. our findings illustrate that not every imported case of sars results in new disease clusters: only one of the six persons who imported sars transmitted the disease in singapore. the sars epidemic in singapore can be traced to this single person, who imported sars before the who alert on march at a time when the disease was not widely recognized. , the experience with sars in singapore is therefore analogous to that in hong kong, vietnam and canada, where the first imported cases were associated with a large number of health-care-associated infections. , by may,the national epidemic had resulted in a total of cases with probable sars, with the large majority being directly or indirectly (secondary, tertiary, etc.) linked to this first imported case. the absence of community transmission associated with the sars cases imported after appropriate public health measures were taken in singapore is probably a result of relatively prompt identification and isolation together with a low potential for transmission (i.e. they were not superspreaders , ) , whereas the absence of nosocomial transmission is probably due to the immediate isolation and enhanced infection control measures. singapore introduced a large number of measures to prevent further importation of sars, at considerable cost and inconvenience. our experience shows that no cases of sars were identified by these measures. this is most likely due to a combination of factors, such as travel advisories which resulted in reduced travel to and from sars-affected areas, implementation of effective predeparture screening at airports in sars-hit countries, and a rapid decline in new cases worldwide since may . three of the six imported sars cases developed symptoms only after arrival in singapore, and would thus have been missed on airport screening. therefore, screening measures at entry points are not sufficient in themselves. health education for incoming passengers on recognition of sars symptoms and advice to seek prompt consultation if symptoms develop therefore remain important additional public health measures. active surveillance of all passengers on flights with a sars patient on board was only instituted from march , when the infectious disease act was invoked in singapore, and no in-flight transmission was documented. for the imported cases early in the epidemic, no active surveillance of passengers and crew was possible, but systems were in place in singapore for detection of sars, and no cases were linked to any of these flights. our findings raise the hope that new imported sars cases need not lead to major outbreaks if systems are in place to identify and isolate them efficiently. screening at entry points is costly and troublesome, has a low yield, and is not sufficient in itself. however, the medical, economic, social and international impact of one single imported sars case, as shown by the singapore experience, more than outweighs the costs of such measures and would justify them. outbreak of severe acute respiratory syndrome -worldwide a major outbreak of severe acute respiratory syndrome in hong kong identification of severe acute respiratory syndrome in canada severe acute respiratory syndrome (sars) in singapore: clinical features of index patient and initial contacts severe acute respiratory syndrome: imported cases of severe acute respiratory syndrome to singapore had impact on national epidemic outbreak of severe acute respiratory syndrome in hong kong special administrative region: case report severe acute respiratory syndrome -singapore transmission dynamics and control of severe acute respiratory syndrome transmission dynamics of the etiological agent of sars in hong kong: impact of public health interventions the authors had no financial or other conflicts of interest to disclose. key: cord- -gk cow k authors: glasser, john w.; hupert, nathaniel; mccauley, mary m.; hatchett, richard title: modeling and public health emergency responses: lessons from sars date: - - journal: epidemics doi: . /j.epidem. . . sha: doc_id: cord_uid: gk cow k modelers published thoughtful articles after the sars crisis, but had limited if any real-time impact on the global response and may even have inadvertently contributed to a lingering misunderstanding of the means by which the epidemic was controlled. the impact of any intervention depends on its efficiency as well as efficacy, and efficient isolation of infected individuals before they become symptomatic is difficult to imagine. nonetheless, in exploring the possible impact of quarantine, the product of efficiency and efficacy was varied over the entire unit interval. another mistake was repeatedly fitting otherwise appropriate gamma distributions to times to event regardless of whether they were stationary or not, particularly onset-isolation intervals whose progressive reduction evidently contributed to sars control. by virtue of their unknown biology, newly-emerging diseases are more challenging than familiar human scourges. influenza, for example, recurs annually and has been modeled more thoroughly than any other infectious disease. moreover, models were integrated into preparedness exercises, during which working relationships were established that bore fruit during the a/h n pandemic. to provide the most accurate and timely advice possible, especially about the possible impact of measures designed to control diseases caused by novel human pathogens, we must appreciate the value and difficulty of policy-oriented modeling. effective communication of insights gleaned from modeling sars will help to ensure that policymakers involve modelers in future outbreaks of newly-emerging infectious diseases. accordingly, we illustrate the increasingly timely care-seeking by which, together with increasingly accurate diagnoses and effective isolation, sars was controlled via heuristic arguments and descriptive analyses of familiar observations. in the summer of , at a field station high in the canadian rockies, a handful of public health physicians met with a larger number of infectious disease modelers to discuss the intersection of modeling and public health policymaking. this workshop arose from the observation that, while the infectious disease modeling community is comparatively small, it is contributing increasingly to the development of policy to address foreseeable public health problems. until recently, however, our role in shaping actual responses to infectious disease outbreaks had been more limited. modelers published thoughtful articles after the severe acute respiratory syndrome (sars) crisis (e.g., anderson et al. ), but had limited, if any, real-time impact on the global response. the reason arguably is that we did not provide what health policymakers needed, reliable projections of the impact of alternative actions. by overestimating the potential of managing contacts versus cases, moreover, we may even have inadvertently contributed to a lingering misunderstanding of means by which this epidemic was controlled that will affect their future responses to newly-emerging infectious diseases. among its many uses, modeling can improve our understanding of actual pasts, as well as make predictions about hypothetical futures. in this spirit, we share reflections on our collective contribution to policymaking during the sars epidemic that grew out of discussions at this retreat. while all participants shared a common goalincreasing the utility of modeling to public health decision makersthis essay is not their consensus about the best means of attaining that goal. neither is it a thorough review of the sars modeling literature. most of us also supported policymaking during the more recent influenza pandemic, but sars was so much more challenging that our earlier experience more fully exemplifies the value and difficulty of policy-oriented modeling. when sars emerged, us health policy decision-makers had only just begun involving modelers in their deliberations, convening working groups on smallpox and anthrax modeling in and , respectively. and sars was a new human disease. while the causal agent was identified quickly, experience with diseases caused by other coronaviruses was much less informative than the previous h n and intervening pandemics and annual influenza were during . by virtue of their experience with influenza, moreover, modelers were invited to contribute to preparedness exercises during which relationships were forged that bore fruit during the actual pandemic. the confidence in modeling that our assistance in preparing for and responding to this foreseeable crisis engendered may extend to routine public health policymaking. during unforeseen crises, however, the utility of modeling depends not only on more accurate and timely insights than we provided during the global response to sars, but more effective communication. as observations are most familiar to policymakers, here we endeavor to support heuristic arguments about the contribution of various public health measures to sars outbreak control by descriptive analyses of salient observations. public health officials may have multiple mitigation options to consider in the face of emerging threats. during the influenza pandemic, for example, there were various pharmaceutical (vaccine, antiviral medications) and nonpharmaceutical (closing schools, staying home, or wearing masks) options. because the efficacy of existing pharmaceuticals against newly-emerging infectious diseases generally is unknown, authorities cannot rely on them. they can, however, promulgate guidelines for managing patients or their contacts, and modelers should be able to inform their decisions. early sars models demonstrated the theoretical impact of isolation before symptom onset on disease transmission (e.g., lipsitch et al. ; fig. ) , and thus the potential benefit of interventions such as contact tracing and quarantine. because the impact of any intervention depends not only on its efficacy, but on the proportion of targets reached, knowledgeable public health practitioners might have cautioned against overestimating the ease of identifying asymptomatic people in whom pathogens were replicating. where published observations permit assessment, only about % of infected contacts of sars patients (i.e., susceptible people associating with infectious ones intimately enough for infection) were in fact isolated before symptom onset. in singapore, for example, only of the people ultimately diagnosed as probable cases (tan ) and in taiwan only of (hsieh et al. ) had been quarantined. other contacts were identified in singapore, but evidently their perceived risk did not warrant movement restriction. could infected contacts have been identified more efficiently? in beijing, , close contacts of , probable cases were quarantined over the course of the epidemic (pang et al. ). analysis of a subset of those individuals with good records (covering , contacts of patients from districts) revealed a range in the probability of diagnosed illness among quarantined individuals from % to . %, depending on their relationship to the patient. transmission was relatively high among spouses, other relatives, friends, and other household members, and low among co-workers, schoolmates, and healthcare workers. separately, ou et al. ( ) studied geographically representative precincts throughout haidian district, where , contacts of patients were quarantined. the probability of infection among a subset of quarantined people ranged from % to . %, also depending on the nature of their contact with patients. consistent with the findings of pang et al. ( ) , caring for ill household members imposed the greatest risk, followed by visiting and residing in the same household. in sharp contrast to the situation in hong kong, where a faulty sewage system at the amoy gardens apartment complex may have facilitated fecal-oral transmission (hong kong doh, ) , no risk was associated with sharing an apartment building or workplace. in singapore, . % of cases were infected in healthcare institutions (overall, . % were healthcare workers, . % friends or visitors, and % other patients), . % at home, and . % in the community or workplace (goh et al. ) . when infectious people infect less than one susceptible person on average, epidemics wane. interventions to reduce the average number of secondary infections (typically denoted ℜ) most expeditiously are preferable, provided all else (including, e.g., compliance and cost) is equal. the impact of such interventions depends crucially on pathogen life cycles and host contact patterns. thus, in some environments, with some infectious agents, certain interventions may reduce disease transmission, whereas in other environments, or with other agents, the same interventions may not, despite being applied with equal diligence. as will be apparent, the natural history of sars readily explains why encouraging people with compatible prodromal symptoms to seek care (and ensuring that clinicians and hospital infection control personnel had the wherewithal to diagnose and isolate them effectively) was only marginally less effective than quarantine. because infected people are more easily identified when symptomatic, the greater efficiency of this intervention more than compensated for any deficit in its efficacy. one can assess the potential impact of any intervention on a transmissible disease by calculating its effect on the reproduction number. the naming of this quantity reflects its demographic origin (heesterbeek ) , but infectious disease modelers focus instead on the average number of effective contacts while infectious, where effective means sufficiently intimate for infection of susceptible individuals; the consensus for sars is roughly (world health organization, ). because ℜ = ℜ ( − p), where ℜ is the basic reproduction number and p is the product of any intervention's efficiency and efficacy, we solve for the ℜ at which ℜ = , below which threshold outbreaks subside. with the aforementioned % efficiency observed in singapore and taiwan, and assuming % efficacy (i.e., quarantined people infected no one), evidently quarantine could not control any disease whose ℜ n . . thus, while implementing this measure may have communicated authorities' concern about the situationpossibly increasing compliance with recommended hand washing, mask wearing, and social distancing practicesevidently quarantine per se contributed little to sars control. because contact management can be socially disruptive, potential costs and benefits must be weighed realistically. identifying only probable cases among , contacts restricted to their homes in singapore and among , telephoned daily (tan ) imposed significant (if unquantified) costs, apparently for minimal gains. we have dates of symptom onset and isolation for clinically diagnosed cases in singapore, but do not know which had been quarantined or telephoned daily, so cannot determine if identified contacts were isolated any more quickly than others, as tan's ( ) juxtaposition of weekly proportions of probable cases who had been identified as contacts and mean onset-isolation intervals suggests. similarly, in taiwan, only probable cases were identified by quarantining , contacts and none by quarantining , travelers from sars-affected areas (hsieh et al. ). we do not know how many probable cases were quarantined in beijing, but the ratio of contacts to patients reported by pang et al. ( ) was ; in taiwan, this factor was ( including travelers), and in singapore, it was ( including those telephoned). tailoring activities to specific risk groupsthose defined by ou, pang, and their co-workers, for examplecould mitigate the social cost. in beijing, quarantine was most appropriate for people who cared for ill household members. being instructed to quickly seek medical care should any symptom that might herald sars develop, however, was appropriate even for contacts with lower risk exposures. in singapore, paradoxically, those telephoned actually were at much greater risk ( / , ) than those quarantined ( / , ). case management also can be problematic. in taiwan, for example, the incidence of laboratory-confirmed influenza was elevated among young adults hospitalized during , with the excess presumably suspected of having sars. the proportion of suspect cases not reclassified as probablean overestimate absent consistent laboratory analyseswas nonetheless modest, relative to misclassification of uninfected people as contacts (in singapore, e.g., - / , n . % were misclassified), and most patients benefit from medical care. if not by contact management, how was sars controlled? available evidence suggests that the reduction in time from symptom onset to clinical presentation and diagnosis during the course of this outbreak, together with increasingly effective isolation and other infection-control procedures, contributed most to containment. this hypothesis also can be explored mathematically. because ℜ is the sum (while infectious) of products of contact rates and probabilities of transmission on contact, either or both of which may vary with time since infection or symptom onset, in principle estimating the impact of isolating infected people at any time is straightforward. if we make the simplifying assumptions that probabilities of transmission on contact reflect infectiousness, which is proportional to viral load (successive logarithms of which can, in turn, be represented via a continuous statistical distribution), and that contact rates do not change substantially during illnesses, we can determine from the appropriate cumulative distribution function when isolation would have prevented ℜ − infections. such an estimate can be derived from analyses of samples collected during the sars epidemic. in the most exhaustive of several quantitative rt-pcr studies to date, he et al. ( ) analyzed serological samples, throat washes, and fecal samples from sars patients to determine viral loads at successive times after symptom onset. as the causal agent was transmitted primarily via respiratory secretions (except possibly among residents of the amoy gardens apartment complex), it seems prudent to base our estimate on results from the throat washes. given the assumptions outlined above, together with a gamma distribution, these results suggest that for a disease with ℜ = , isolation that was % effective in blocking transmission could prevent ℜ − infections (and thus lead to epidemic control) if implemented up to . days after symptom onset, on average (fig. ) . the operational requirements can be calculated for any efficacy. for example, isolation that was only % effective should suffice to effect disease containment if implemented up to . days after symptom onset under the given assumptions, and so on. analyses of the earlier studies of peiris et al. ( ) and cheng et al. ( ) yield similar results. that said, we must emphasize that these simple calculations are intended to be heuristic. if contact rates declined sharply after symptom onset, for example, the time available for isolation would be overestimated. day et al. ( ) , fraser et al. ( ) and lloyd-smith et al. ( ) have developed frameworks for evaluating such questions more rigorously in future outbreaks of newly-emerging infectious diseases. figs. and illustrate daily mean intervals between symptom onset and diagnosis and proportions diagnosed within days of symptom onset (i.e., during the largely noninfectious prodrome), respectively, by onset date in singapore and taiwan. the remarkable similarity of these observations in societies valuing different aspects of human nature suggests a common behavioral mechanism for the control progressively attained globally (wallinga and teunis ): as patients were not very infectious until acutely ill, evidently sars was controlled by their earlier and probably progressively more effective isolation after symptom onset (feng et al. , table ), phenomena that authorities facilitated mainly (recall that only of probable cases in singapore and / in taiwan were traced) via effective health communications (menon ) with healthcare providers as well as the general population (chen et al. ) . others have noted that these times to event were not stationary (e.g., anderson et al. ) , which precludes fitting the otherwise appropriate gamma distribution , even by epoch (leung et al. ) . it is safe to assume that shortening intervals between the onset of clinical symptoms and isolation of patients with communicable diseases will reduce their effective infectious periods and thus the extent of onward transmission. could modelers have demonstrated that timely isolationnot quarantinewas the key to controlling sars early enough to have influenced the public health response to this crisis (especially in light of the amoy gardens event, which may have biased responsible officials towards more aggressive interventions)? feng et al. ( ) demonstrate that the ratios of infection rates during the prodrome and acute phases fitted to the first days and all hospital admissions are similar, answering this question affirmatively. but could we have convinced health authorities to allocate more resources to encouraging peopleespecially those who might have been exposed to someone subsequently diagnosedto seek medical care upon experiencing symptoms that might herald sars, and to aiding clinicians in diagnosing, and infection control personnel in isolating patients? also, looking ahead, as participants in the canadian workshop endeavored to do, what lessons from sars might increase the utility of modeling the next time that a new infectious disease emerges? evaluating models is difficult, especially in the throes of public health emergencies, but the disparate predicted and realized impacts of quarantine during the sars epidemic reinforce the importance of such evaluations and the care with which they must be performed. even the best modeling is limited by inaccurate or incomplete information. and during health crises, humanitarian needs trump record-keeping. nonetheless, to ensure that interventions are modeled realistically, epidemiologists must scrutinize all available information lest observations that seem invaluable in hindsight be underappreciated or even overlooked. for example, lipsitch et al. ( ; fig. d ) observed that the mean number of secondary infections per case in singapore climbed dramatically when time from onset to isolation exceeded four days. to our knowledge, however, the implication of this observation vis-à-vis the potential impact of case versus contact management has not heretofore been articulated. nonetheless, the inference that infected people were not particularly infectious until acutely ill was subsequently substantiated by the isolation of the sars coronavirus and assessment of viral loads and shedding as functions of time from symptom onset. shortening the period between such observations and deductions will ensure that timely public health decisions are based on credible science in future. once models have been evaluated and any deficiencies remedied, pertinent analytical or simulation results must be translated into actionable information for policy makers. mathematicians may be convinced by the relative magnitude of partial derivatives of control reproduction numbers with respect to alternative parameters, but to have any impact whatsoever on decision making, such results must be expressed in the language of public health practice and with reference to readily available (or quickly improvisable) interventions. until recently, few modelers had been intimately involved in emergency response or policy development, so facilitators with practical experience in these areas, who understood the potential of modeling in elucidating the relevant issues, were indispensable. recent experiences may have narrowed the gap between the health and mathematical sciences, but field observations or results of natural experiments still carry more weight among most public health practitioners. modeling may guide or support observational studies. while the impact of closing schools and cancelling large public gatherings during future influenza pandemics was predicted by modeling (ferguson et al. , germann et al. , it may have been more persuasively communicated by analyses of actions taken by state and local policymakers in cities throughout the united states during the pandemic (hatchett et al. ) . by their own account, the epidemiologists who performed the latter study would not have known what patterns to seek in historical records without the guidance provided by modeling. but do the apparently beneficial effects of historical school closures reliably translate into similar contemporary effects, given secular changes in family and workforce structure? even if contacts among schoolchildren could be reduced, any possible benefit might be offset by increased contacts between children and adults, some elderly (e.g., grandparents caring for children so that parents could continue working). and elderly people are more likely to die of complications. similarly, at a time when elected officials were deeply concerned about the threatened reintroduction of smallpox by terrorists and some modelers were arguing for the resumption of universal vaccination (e.g., kaplan et al. ) , most public health officials were persuaded that contact tracing, vaccination, and surveillance of contacts would suffice (as they had during the era of eradication) by observations indicating little pre-symptomatic transmission (eichner and dietz ) and substantial residual immunity among previously vaccinated members of the population (eichner ) . in fact, biological inaccuracies in early models (compared by ferguson et al. ) caused some policymakers with firsthand knowledge of smallpox to eschew modeling. from a policy perspective, therefore, modeling can serve many functions. besides making qualitative predictions, models can also serve as tools or instruments with which to explore the nature of problems iteratively. feng et al. ( ) , for example, have embedded analytical results from a generic model of a respiratory disease transmitted by close contact, but about which little else is known, in software that permits end users to explore a variety of possible responses. with such a modeling environment, one can evaluate control efforts for sars, deduce the more general results of day et al. ( ) and fraser et al. ( ) , and possibly even guide official responses during future emergences of new human diseases. models should not serve as the sole basis for policy decisions, but they are at least capable of illustrating the consequences of alternatives, including inaction, in a manner readily appreciable by policy makers. while it certainly is easier to publish modeling studies in periodicals catering to mathematicians, the people whose decisions modelers hope to inform are more likely to read medical or general science journals. a dominant theme in the modeling literature about vaccine-preventable diseases, for example, is that everyone need not be vaccinated to control transmission. indeed, to protect those who cannot receive live vaccines or who respond poorly, if at all (e.g., elderly people), it is essential to vaccinate those who might otherwise infect them. thus, while endeavoring to "stockpile enough [smallpox] vaccine for every man, woman, and child" (thompson ) may have reassured an electorate whose homeland had recently been violated, it also may have generated an expectation that will haunt us in future (when, e.g., production problems lead to shortages of influenza vaccine). clearly, in this era of evidence-based medicine, a bridge between the two worlds must be forged to get all relevant information (even if model-based) to those charged with applying it through the expenditure of taxpayer dollars. public health officials must decide how to deploy available resources most advantageously. modelers can contribute to their decision making by exploring the impact of alternative scenarios. lest results be misleading, however, models must be faithful to available information, including expert opinion. knowledgeable public health practitioners might have cautioned against overestimating the potential impact of managing contacts of sars patients, and interpreted observations suggesting that infected people were not particularly infectious until acutely ill as an indication for managing cases instead. in retrospect, we might encourage policymakers to interpret the progressive shortening of intervals between symptom onset and isolation characterizing most if not all sars outbreaks as tangible evidence of the potential of effective health communications, which could be invaluable in future crises. absent such observations, conveying complex and occasionally nonintuitive results supporting policy decisions to public health and medical professionals is challenging. lay audiences are even more difficult. by virtue of age variation in vaccine efficacy, for example, modelers know that people at risk of influenza complications may be better protected by vaccinating those who might otherwise infect them than by being vaccinated themselves (bansal et al. ) . but do health policymakers? nonetheless, where infectious diseases are concerned, citizens likely will act in ways they perceive as congruent with their own survival or self-interest, and that of 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ying-hen hsieh. the information about influenza hospitalizations cited in the text was provided by jen-hsiang chuang. several of us served on the hhs working groups that d.a. henderson convened in and under the aegis of the council on public health preparedness, during which we learned among other things to appreciate experienced public health practitioners, who make invaluable modeling teammates. we are grateful to him and to larry anderson, beth bell, and elliott churchill for reviewing earlier drafts of this manuscript. of course, we are responsible for any residual errors. key: cord- -mfz q authors: kim, hye kyung; ahn, jisoo; atkinson, lucy; kahlor, lee ann title: effects of covid- misinformation on information seeking, avoidance, and processing: a multicountry comparative study date: - - journal: sci commun doi: . / sha: doc_id: cord_uid: mfz q we examined the implications of exposure to misinformation about covid- in the united states, south korea, and singapore in the early stages of the global pandemic. the online survey results showed that misinformation exposure reduced information insufficiency, which subsequently led to greater information avoidance and heuristic processing, as well as less systematic processing of covid- information. indirect effects differ by country and were stronger in the u.s. sample than in the singapore sample. this study highlights negative consequences of misinformation during a global pandemic and addresses possible cultural and situational differences in how people interpret and respond to misinformation. the pandemic caused by the coronavirus disease (hereafter referred to as poses unprecedented threats to global human well-being. because of the high uncertainty associated with the novelty of covid- , many people rely on online health information to learn more about how to protect themselves and their families from the imminent health threat (bento et al., ; garfin et al., ; hernández-garcía & giménez-júlvez, ) . while its prevention and treatment require practices based on scientific evidence, there are myriad sources of incorrect information circulating on the internet about what prevents and cures covid- . this is critical because relying on such misinformation can bring about detrimental health outcomes by encouraging people to engage in ineffective-even harmful-remedies. for example, nearly people have been killed by ingesting methanol based on harmful treatment recommendations that spread across social media in iran (associated press, ) . in south korea, churchgoers were infected with covid- after church leaders sprayed saltwater into their mouths out of a misguided belief that the water would help prevent the spread of covid- ; the spray bottle became contaminated with the virus in the process and spread infection (park, ) . in the united states, rumors spread on social and national media that ingesting bleach might help kill the virus; research suggests that this misinformation contributed to individuals "engaging in non-recommended high-risk practices with the intent of preventing sars-cov- transmission, such as washing food products with bleach, applying household cleaning or disinfectant products to bare skin, and intentionally inhaling or ingesting these products" (gharpure et al., , p. ) . accordingly, the world health organization (who; ) has declared an "infodemic" related to covid- and actively sought to rectify the crisis levels of misinformation spreading online. despite the proliferation of online misinformation, the internet is an important source of information during a disease pandemic as it can be an efficient and expeditious channel for providing necessary information and for correcting misinformation. indeed, risk communication scholars have emphasized the importance of providing timely information in risk contexts to help aid decision making, especially when there is considerable uncertainty about the most effective course of action in a given situation (edgar et al., ; yang, aloe, & feeley, ) . therefore, scholars must find ways to better understand how the power of the internet to misinform is affecting its ability to inform. one important, still unanswered question is whether exposure to misinformation serves to motivate or deter subsequent information seeking, and/or changes the way encountered information is processed. prior theorizing on risk communication has often focused on immediate outcomes of information exposure; yet there is a lack of understanding about the subsequent information management that follows exposure to risk information (so et al., ) . the current study addresses these important gaps in the extant literature in its examination of exposure to misinformation on this study builds on previous research by offering two main contributions. first, guided by the risk information seeking and processing (risp) model (griffin et al., ) , we posit that a reduction in the perceived need for additional information (or information insufficiency) is an important mechanism that underlies adverse consequences of misinformation exposure on subsequent information seeking and processing. given that prior research has often focused on the spread of misinformation (guess et al., ; valenzuela et al., ) , addressing the implications of that spread on information seeking and processing helps to enrich our understanding of misinformation effects. second, this current study examines whether the effects of misinformation exposure are universal across cultures or specific to certain cultural contexts. studies on information seeking and processing have been conducted predominantly in western contexts, and cross-cultural studies, especially studies that involve multiple countries, are lacking in the extant literature. for theory building and refinement, it is important to examine the validity of a theoretical prediction across different cultural contexts and populations. misinformation is defined as objectively incorrect information that is not supported by scientific evidence and expert opinion (nyhan & reifler, ) . while misinformation can persist for a long time without contradiction (kata, ) , for scientific issues, what is true or false can be altered with newly emerging evidence and consensus among experts (vraga & bode, ) . researchers also differentiate misinformation from misperception and disinformation: misperception is holding a belief that is incorrect or false (southwell et al., ) , whereas disinformation is driven by the intention to deceive (wardle, ) . while misinformation is inadvertently false, its propagation or sharing can subsequently be either deliberative or accidental (southwell et al., ) . there is ample evidence on the pervasiveness of misinformation in the context of infectious disease outbreaks. for example, a study on the zika virus found that half of the top news stories were based on misinformation or rumors, and those stories were times more likely to be shared on social media than stories based on facts (sommariva et al., ) . studies on covid- similarly found that misinformation was more frequently tweeted than science-based evidence or public health recommendations (bridgman et al., ; pulido et al., ) . researchers have addressed the potential consequences of misinformation that could undermine the adoption of preventive measures (bridgman et al., ; dixon & clarke, ; tan et al., ) , which could exacerbate the spread of the epidemic. researchers have also suggested that exposure to misinformation can trigger individuals' additional information seeking to verify the information that they suspect to be false (tandoc et al., ) . for example, when individuals cannot verify information on social media based on their own judgment and knowledge, they seek out information from their social circle and other sources to authenticate (tandoc et al., ) . researchers, however, also point out that the motivation for subsequent information seeking may not always be related to accuracy (southwell, ) . as thorson ( ) addressed, misinformation exposure actually may prevent individuals from seeking new information and instead may trigger motivated processing to protect their preexisting attitudes or beliefs. such selective information exposure and motivated reasoning make it difficult to rectify misinformation once false beliefs are deeply held (bode & vraga, ; jerit & barabas, ) . as porter and wood ( ) argued, however, individuals can simultaneously pursue the accuracy on factual matters as well as the goals that serve their pre-extant beliefs. in the context of a novel disease pandemic, it is also important to consider the uncertainty regarding what is true and false about the disease and its prevention, given that the expert consensus and "best available evidence" are subject to change (vraga & bode, , p. ) . such information uncertainty may as well have implications on the public's information behaviors. in a recent study, perceived exposure to covid- misinformation was positively associated with seeking more information and complying with health advisories (hameleers et al., ) . because perceived misinformation exposure takes into account individuals' judgment on the veracity of information, its implications may differ from exposure to misinformation that is based on actual state of scientific evidence (vraga & bode, ) . we thus take the latter conceptualization in the current study to understand the effects of misinformation exposure. guided by the risp model (griffin et al., ) , the current study examines whether and how exposure to misinformation about covid- prevention motivates or deters effortful seeking and processing of relevant information. the risp model is one of the most comprehensive models that seeks to understand social psychological motivators of seeking and processing risk information (yang, aloe, & feeley, ). in the model, various concepts drawn from the theory of planned behavior (ajzen, ) and other works are depicted as having an indirect impact on information seeking and processing through the model's central concept of information insufficiency. however, the risp model does not theorize individuals' prior exposure to risk information within the model, despite the possible implications of prior exposure on information seeking and processing. in risk contexts, information seeking and processing are driven by the motivation to reduce uncertainty. information insufficiency refers to one's subjective assessment of the gap between their perceived current knowledge about a risk and what they feels is sufficient knowledge for adequately coping with the risk (sufficiency threshold). information insufficiency is at the heart of the risp model because uncertainty reduction occurs only when individuals are sufficiently motivated to engage in the tasks needed to achieve the desired judgmental confidence (eagly & chaiken, ) . while little is known about how exposure to misinformation influences individuals' perceived (needed) knowledge, misinformation on covid- can potentially make individuals feel overwhelmed with different and inconsistent recommendations on what prevents and cures the disease (pentina & tarafdar, ) . in turn, this sense of being overloaded with information may manifest as having sufficient information on a given issue (i.e., a lower information insufficiency). indeed, pentina and tarafdar ( ) have argued that the amount and variety of unverified information circulating online can make individuals feel overloaded with information, given individuals' limited capacity to process. researchers have also suggested that the ambiguity, low quality, and novelty of information can trigger the feeling of overload as these attributes make it more difficult for individuals to process information (keller & staelin, ; schneider, ) . thus, we posit our first hypothesis on information insufficiency as follows: hypothesis (h ): exposure to misinformation will be negatively associated with information insufficiency. the risp model theorizes information insufficiency as the primary component that predicts subsequent information seeking and avoidance as well as how the information will be processed. information seeking is defined as a volitional process of acquiring desired information from relevant sources, whereas information avoidance refers to deliberately shunning or delaying the acquisition of available information. we treated information seeking and avoidance as two orthogonal constructs, instead of the opposites on a continuum, as they can coexist under some circumstances that involve uncertainty (yang & kahlor, ) . informed by the heuristic-systematic model (eagly & chaiken, ) , the risp model posits a dual system of information processing. the dual system includes one that requires more effortful and deeper processing (systematic processing) and another that involves more superficial processing and poses fewer cognitive demands on individuals (heuristic processing). griffin et al. ( ) predicted that the drive to overcome information insufficiency motivates individuals to seek more riskrelated information and to systematically process the information, while making it less likely for them to heuristically process. some empirical work has supported the insufficiency principle in this role (griffin et al., ; kahlor, ) , while a meta-analysis of the risp model found limited evidence (yang, aloe, & feeley, ) . the conflicting evidence points to the possibility of information insufficiency serving as a mediator between misinformation exposure and information seeking and processing. prior exposure also may have direct associations with information seeking and processing. past information exposure and related attitudes have been related to other information behaviors, including information avoidance and information sharing (kahlor et al., ; yang & kahlor, ; yang, kahlor, & griffin, ) . furthermore, a study by kalichman et al. ( ) suggested a positive relationship between exposure to misinformation about aids/hiv and information avoidance behaviors. thus, we posit the following direct and indirect effects of misinformation exposure on information seeking and avoidance, as well as systematic and heuristic processing. hypothesis (h ): exposure to misinformation will be associated with (a) reduced information seeking, (b) increased information avoidance, (c) reduced systematic processing, and (d) increased heuristic processing. hypothesis (h ): informational insufficiency will mediate the effect of misinformation on (a) information seeking, (b) information avoidance, (c) systematic processing and (d) heuristic processing. the risp model also addresses several psychosocial factors that predict information insufficiency. the most powerful predictor of risk information seeking to emerge from the risp research is informational subjective norms, that is, perceived pressure from others to engage in a given information behavior (kahlor, ; yang, aloe, & feeley, ) . these norms also constitute an important predictor of information insufficiency (kahlor, ; yang, aloe, & feeley, ) . another important risp concept is risk perception, which comprises subjective probability and perceived severity of harm and is the most commonly examined cognitive component of how individuals assess a given risk (yang, aloe, & feeley, ). the risp model also takes into account affective responses to risk, such as anxiety and fear, which serve as important heuristic cues in making risk decisions (finucane et al., ) . affective responses, which result from risk perceptions, increase an individual's desire for information (griffin et al., ; so et al., ; yang & kahlor, ) . one interesting question is whether misinformation exposure influences these psychosocial factors, which would subsequently affect information insufficiency as well as information seeking and processing. there are two different possibilities. if misinformation exposure increases perceived risk, affective response to risk, and informational subjective norms, then this also would increase information insufficiency, thus counterbalancing the negative implications of misinformation hypothesized in h . in contrast, if misinformation decreases these psychosocial factors, this would further explain h . to examine these possibilities, we pose the following research question: what is the role of risk perception, affective response, and informational subjective norms in the relationship between misinformation exposure and information insufficiency? there is limited understanding of why certain individuals or societies are more or less vulnerable to misinformation (wang et al., ) . researchers suggest that older adults (mitchell et al., ) , those with lower cognitive ability (de keersmaecker & roets, ), and those who are less educated (kalichman et al., ) are more likely to be misinformed than those who are younger, have higher cognitive ability, or are more educated. prior research also points to ideological asymmetries in sharing and believing misinformation. the research suggests that people who prioritize conformity and tradition (i.e., conservatives) also tend to emphasize uncertainty reduction, and thus exaggerate within-group consensus and maintenance of homogenous social relationships, both of which contribute to the spread of misinformation (jost et al., ) . beyond these individual-level characteristics, we lack data comparing the relative susceptibility to misinformation between populations and societies based on cultural differences. research on cultural differences suggests that uncertainty avoidance, which refers to the "extent to which the members of a culture feel threatened by uncertain or unknown situations" (hofstede, , p. ) , is a cultural dimension related to anxiety, security needs, and rule orientation. high-uncertainty avoidance cultures tend to be less tolerant about ambiguity and diversity than low-uncertainty avoidance cultures. because misinformation on covid- prevention is characterized by scientific uncertainty, we suggest that cultural differences in uncertainty avoidance may moderate the effect of misinformation exposure on information seeking and processing. moreover, cultural differences in uncertainty avoidance also may change the relative strength of the relationship between information insufficiency and information seeking and processing. that is, those in high-uncertainty avoidance cultures may be more likely to act on their information insufficiency to seek out and effortfully process relevant information in order to reduce their uncertainty, than those in low-uncertainty avoidance cultures. consistent with this prediction, in the context of climate change, one crosscultural study based on the risp model found the information insufficiencyinformation seeking intention association to be stronger in the u.s. sample (a relatively higher uncertainty avoidance culture) compared to the china sample (a low-uncertainty avoidance culture; yang, kahlor, & li, ) . given the conceptual importance of information insufficiency in the risp model, we extend prior work by comparing the relative strength of the effect of information insufficiency between the u.s. sample and two other countries, one with a higher uncertainty avoidance culture (south korea, index score = ) and the other with a lower uncertainty avoidance culture (singapore, index score = ) compared to the united states (index score = ; hofstede, ; hofstede et al., ) . research question (rq ): do the direct and indirect effects of misinformation exposure on information seeking, avoidance, and processing differ between the united states and south korea or singapore? an online survey was conducted in the early stages of the covid- pandemic in three countries, the united states (march - , ), south korea (february -march , ) and singapore (february -march , ). panel members were recruited from online panel companies: global research in south korea (n = , ) and qualtrics in singapore (n = , ) and the united states (n = ). we employed quota sampling in terms of age, gender, and ethnicity to match with the national profile of singapore, south korea, and the united states. the survey took about minutes to complete and was administered in english in singapore and united states and in korean in south korea. the english survey questionnaire was translated into korean by two bilingual researchers. for the combined samples, respondents ranged in age from to (m = . , sd = . ) and consisted of . % females. the median educational attainment was "some college or an associate's ( -year) degree." the majority of the singapore sample was ethnic chinese ( . %), followed by . % malay. in the u.s. sample, . % self-identified as white and . % identified as black or african american. south korea is a monoethnic country. table presents the sample profile and descriptive statistics by country. information seeking and avoidance. information seeking was measured by five items derived from j.-n. kim et al. ( ) and j.-n. kim and grunig ( ) . sample items, on a -point likert-type scale ( = strongly disagree, = strongly agree), included "i regularly check to see if there is any new information about this problem" and "i spend a lot of time learning about this issue" (m = . , sd = . , α = . ). information avoidance was measured by five items adapted from howell and shepperd ( ) and miles et al. ( ) . on the same likert-type scale, items included "i don't want any more information about covid- " and "i avoid learning about covid- " (m = . , sd = . , α = . ). systematic and heuristic processing. systematic processing was assessed by three items derived from yang et al. ( ) and yang et al. ( ) . on a -point scale ( = not at all, = very much), sample items included "after i encounter information about covid- , i stop and think about it" and "for me to understand about covid- , the more viewpoints i get the better" (m = . , sd = . , α = . ). heuristic processing was assessed by three items from yang et al. ( ) and kahlor et al. ( ) . using the same -point scale, items included, for example, "when i come across information about covid- , i focus on only a few key points" (m = . , sd = . , α = . ). although cronbach's alphas for these scales are relatively weak, they are comparable to the one used by yang et al. ( ) , who suggest that these processing scales are still under development and thus have room for improvement (also see deng & chan, , as yang et al., , reported omega rather than alpha). information insufficiency. to calculate information insufficiency, we separately assessed perceived current knowledge and sufficiency threshold (griffin et al., ; yang et al., ) . to assess perceived current knowledge, participants rated to what extent they currently know about covid- on a scale of (knowing nothing) to (knowing everything; m = . , sd = . ). for sufficiency threshold, participants estimated how much knowledge they would need in order to deal adequately with the risk of covid- on a scale of (need to know nothing) to (need to know everything you could possibly know; m = . , sd = . ). we employed the analysis of partial variance (cohen & cohen, ) to compute information insufficiency (m = . , sd = . ) that contains the residual variance of information threshold accounting for the variance of perceived current knowledge (rosenthal, ) . this approach helps to address the limitations of using a raw difference score (e.g., sensitive to floor and ceiling effects) and the regressed change approach (e.g., the inflated explained variance in information insufficiency). exposure to covid- information. exposure to misinformation was assessed with five claims on covid- prevention measures that were identified as false at the time of data collection (who, ): (a) gargling with mouthwash, (b) eating garlic, (c) avoiding pets, (d) vaccination against pneumonia, and (e) regularly rinsing the nose with saline. on a -point scale ( = not at all, = a lot of times), participants reported how often they had heard that each of the five claims from eight different information sources (e.g., news app or website, social media app or website, medical or health websites, television and radio news; tan et al., ) . cronbach's α for the exposure scales across the five claims ranged from . to . , and items were averaged to create composite scores. the composite scores were further averaged into an index of exposure to misinformation (m = . , sd = . , α = . ). for comparison purpose, we also examined exposure to general covid- information without specifying the information content. on a -point scale ( = never, = very often), participants reported how often they learned about covid- using different information sources (rains, ; e.g., websites or social networking site [sns] of governmental health agencies, print or online newspapers, sns of newspapers, individual sns, television). responses were averaged into a score of exposure to general covid- information (m = . , sd = . , α = . ). exposure to misinformation and exposure to general covid- information were moderately correlated (r = . , p < . ). risk perception. two components of risk perception were assessed: perceived susceptibility and severity. to assess perceived susceptibility (brewer et al., ) , participants estimated their chances of contracting covid- in several weeks if they do not take any preventive actions on a given slider between % and % at % intervals (m = . , sd = . ). on a -point likert-type scale ( = strongly disagree, = strongly agree), we used three items derived from weinstein ( ) to measure perceived severity (e.g., "i think that covid- is a very dangerous disease"; m = . , sd = . , α = . ). based on convention (griffin et al., ; weinstein, ) , we multiplied perceived susceptibility and severity to create an index of risk perception (m = . , sd = . ). affective responses. we assessed negative affective responses experienced during the covid- pandemic such fear, anger, sadness, and anxiety derived from prior work (yang, ; yang et al., ) . these emotions have been reported to be frequently experienced in crises and pandemic situations (jin et al., ; h. k. kim & niederdeppe, ) . on a -point scale ( = not at all, = very much), participants rated their feelings toward the covid- situation on the following emotions themed under fear (afraid, fearful, scared), anger (angry, mad, irritated), sadness (sad, downhearted, unhappy), and anxiety (anxious, worried, concerned). responses were averaged to create a scale of affective responses (m = . , sd = . , α = . ). informational subjective norms. derived from yang and kahlor ( ) , we used four items asking participants' perception of other's expectations about their seeking covid- -related information on a -point scale ( = not at all, = very much; e.g., "most people who are important to me think that i should seek information about covid- "). responses were averaged to create a scale of informational subjective norms (m = . , sd = . , α = . ). to examine our hypotheses and research questions (summarized in figure ), we used hierarchical ordinary least squares regression, which allowed us to enter variables in separate blocks to test the incremental assessment of r in each step as well as the relative effects of variables while accounting for those entered together or in earlier steps (cohen et al., ) . all the analyses controlled for demographic factors (i.e., age, gender, education, country), having a respiratory disease in the past few weeks (yes/no), and presence of local cases of covid- in the subject's city (yes/no). multicollinearity tests showed tolerance values above zero and variance inflation factor values below the conventional cutoff value of for all variables entered in the models (cohen et al., ) . we entered exposure to misinformation and general information on covid- in the first block along with other control factors (testing h and h ), and risp model components (risk perception, affective response, informational subjective norms, and information insufficiency) in the second block. addressing h and rq , we tested a serial mediation model (model ) with process macro (hayes, ) to investigate the indirect effects of misinformation on information seeking, avoidance, and processing, separately mediated through risk perception, affective responses, and information subjective norms, as well as serially via information insufficiency. addressing rq , the conditional indirect effects via information insufficiency by country were analyzed with process macro model . the u.s. sample served as a reference group given its middle position in regard to the level of uncertainty avoidance (hofstede, ) . we estimated confidence intervals (cis) with , bootstrap samples. we hypothesized that exposure to misinformation would be negatively associated with information insufficiency (h ). as shown in table , h was supported. information insufficiency was negatively correlated with misinformation exposure (β = - . , p < . ) and positively with general information on covid- (β = . , p < . ). risk perception (β = . ), affective response (β = . ), and information subjective norms (β = . ) were also positively associated with information insufficiency (all p < . ). we also predicted that exposure to misinformation would be negatively associated with information seeking and systematic processing, and positively associated with information avoidance and heuristic processing (h a-d). as shown in table , h a was not supported, as misinformation was positively associated with information seeking (β = . , p = . ). however, h b and h d were supported, as misinformation was positively associated with information avoidance (β = . , p < . ) and with heuristic processing (β = . , p < . ). as predicted, h c also was supported, as systematic processing was negatively associated with misinformation exposure (β = − . , p = . ). at step , controlling for other risp components, information insufficiency was negatively associated with information avoidance (β = − . , p < . ) and heuristic processing (β = − . , p = . ), whereas it was positively associated with systematic processing (β = . , p < . ). no association was found with information seeking (β = . , p = . ). we predicted indirect effects of misinformation on information seeking, avoidance, and processing via informational insufficiency (h ). in light of the predictions of the risp model, we also included risk perception, affective responses, and informational subjective norms in a serial mediation model using process macro (model ; finally, we sought to explore whether the direct and indirect effects of misinformation are further moderated by country (rq ). we used process macro (model ; table ) to examine the moderated mediation via information insufficiency by country (u.s. sample served as a reference group) on information seeking, avoidance, and processing. figure presents the effects of misinformation exposure by country, and figure presents the effects of information insufficiency by country. in a model predicting information seeking, the direct effect of misinformation differed between singapore and united states (p = . ; south korea-united states comparison, p = . ) such that it was significant only in the singapore sample (Β = . , p = . ; Β us = −. , p = . ; Β kr = . , p = . ). in contrast, the effect of information insufficiency on information seeking was significant only in the us sample (Β = . , p = . ), which was significantly different from that of the singapore sample (p < . ; Β sg = −. , p = . ) but not from the south korea sample (p = . ; Β kr = . , p = . ). the conditional indirect effect was significant only in the us sample ( % ci [−. , −. ]) and this effect statistically differed only from the singapore sample (index of moderated mediation = . , ci [. , . ]). in predicting information avoidance, the direct effect of misinformation was significant across all three countries (Β us = . , Β sg = . , Β kr = . , all p < . ), but the effect size significantly differed only between the u.s. and south korea samples (p = . ; united states-singapore comparison, p = . ). the effect of information insufficiency on information avoidance was significant in the u.s. and south korea samples (Β us = −. , Β kr = −. , all p < . ) but not in the singapore sample (Β sg = −. , p = . ); thus, only the contrast between the united states and singapore was significant (p = . ). the conditional indirect effect was significant only in the u.s. ( % ci [. , . ]) and south korea samples (ci [. , . ]); there was a significant moderated mediation for the united states-singapore contrast (index = −. , ci [−. , −. ]). as for systematic processing, the direct effect of misinformation was significant only for the u.s. sample (Β us = −. , p < . ; Β sg = −. , p = . ; Β kr = −. , p = . ), and it contrasted significantly with the effect in the singapore sample (p = . ) but not the south korea sample (p = . ). the effect of information insufficiency did not differ by country (united states-south korea comparison, p = . ; united states-singapore comparison, p = . ) and all conditional indirect effects were significant on systematic processing regardless of country ( % ci in predicting heuristic processing, the direct effect of misinformation was significant across all countries (Β us = . , Β sg = . , Β kr = . , all p < . ), while the effect size being stronger in the u.s. sample than in the singapore (p = . ) or south korea samples (p = . ). the effect of information insufficiency was significant only in the u.s. sample (Β us = −. , p < . ; Β sg = −. , p = . ; Β kr = −. , p = . ), and its coefficient was significantly different from that of the singapore (p = . ) and south korea samples (p = . ). accordingly, the conditional indirect effect was significant only in the u.s. sample ( % ci [. , . ]) and the moderated mediation was significant for both united states-singapore ( the covid- pandemic represents one of the biggest challenges to global human well-being to date. an epidemic of misinformation makes this formidable challenge even more so by impeding people from getting correct information on how to prevent and curb the spread of the disease. based on a multicountry survey conducted in the early stages of the global pandemic, this study documents that exposure to misinformation demotivates individuals from seeking out and thoughtfully processing information on covid- . our intercountry comparisons suggest, however, that the influence of misinformation exposure may not be equivalent across different populations and cultures. thus, we provide important insights for theory building, as well as for the mitigation of misinformation effects across populations as they all face a common goal-to prevent and curb the spread of disease. this study found that exposure to misinformation was negatively associated with information insufficiency. that is, when people encounter misinformation, they perceived less informational need for adequately preventing and treating covid- . it is noteworthy that exposure to misinformation reduced both sufficiency threshold and current knowledge, when these variables were analyzed separately. yet the decrease in sufficiency threshold was greater than that of current knowledge, which resulted in lower information insufficiency. unlike the association of misinformation, exposure to general information was positively associated with information insufficiency. this suggests that the influence of misinformation is distinguished from that of general information on covid- . in the early stages of a novel disease pandemic, exposure to general information on the unknown risk at hand may make individuals realize that they need more information, whereas the opposite is true for misinformation. information insufficiency served as a significant mediator of the relationship between misinformation exposure and information avoidance, systematic processing, and heuristic processing. that is, when individuals perceived that they know enough about covid- as a result of misinformation exposure, they were more likely to avoid information and heuristically process (rather than systematically process) relevant information. this counters the findings from a study that assessed perceived misinformation exposure (hameleers et al., ) . as vraga and bode ( ) addressed, the public may have different perceptions than what is agreed upon among experts (e.g., who) on misinformation, thus having differential implications on information behaviors. on the other hand, when other mediators suggested in the risp model are taken into account, the total indirect effects were not significant on these information outcomes. notably, affective response and informational subjective norms, both of which could be triggered by exposure to misinformation, appear to counterbalance the mediating role of information insufficiency. while information insufficiency was not directly linked to information seeking, misinformation exposure was indirectly associated with information seeking when mediated by affective response and informational subjective norms. across all three countries, exposure to misinformation had a significant direct association with information avoidance and heuristic processing. this relationship was stronger in the south korea sample for information avoidance (vs. united states) and in the u.s. sample for heuristic processing (vs. south korea and singapore). it is also noteworthy that exposure to misinformation had a direct relationship with information seeking only in the singapore sample, and with systematic processing only in the u.s. sample. these results suggest that exposure to misinformation may have different implications on information seeking or processing depending on culture or population. that is, misinformation exposure may have more implications on how americans process information, whereas for south koreans or singaporeans it will be reflected in their information seeking or avoidance. these may reflect cultural differences in how people manage uncertainties or contextual factors such as partisanship and information sources. in particular, the stronger relationship between misinformation and information avoidance in the south korea sample (vs. united states) may reflect the high-uncertainty avoidance culture of south korea (hofstede et al., ) . in light of the direct positive association with both seeking and avoidance in the singapore sample, singaporeans may be uniquely motivated to deal with misinformation having ambivalent responses toward such information. interestingly, only in the u.s. sample, information insufficiency served as a constant predictor across all information outcomes. in the south korea sample, information insufficiency was significantly associated only with information avoidance and systematic processing. in the singapore sample, only systematic processing was associated with information insufficiency. similar to our findings, yang, kahlor, and li ( ) also found a stronger relationship between information insufficiency and information seeking intention in the u.s. sample than the china sample. collectively, western populations may be more likely to be influenced by epistemic motivation than eastern populations, regardless of uncertainty avoidance tendencies. instead, cultural differences in perceptions of personal control or ability to seek, process, and retain information may be closely related to the differential effects of information insufficiency. alternatively, given that the risp model was developed in the western context, the model and its measurements may better reflect westerners' seeking and processing tendencies. future work should examine these possibilities in cross-cultural contexts. this study has several limitations to note. first, the sample sizes were not balanced among the three countries examined and these countries were differently affected by covid- at the time when the surveys were conducted. while we controlled for risk characteristics and relevant experience, it was not possible to account for all contextual factors that could confound the results. nonetheless, we believe that it is imperative to document public sentiment and responses during an actual pandemic, and thus this work could have unique value in studying misinformation effects. second, this study cannot confirm causal orderings proposed in the conceptual model due to the cross-sectional nature of the data. future work should consider employing a longitudinal or experimental design to support causal statements about the proposed relationships here. last, while there are multiple types of covid- -related misinformation circulating on the internet, we focused on five false claims relevant to the prevention of covid- that reflect the state of scientific evidence at the time of data collection. it would be beneficial for future studies to investigate additional types of misinformation to better understand misinformation effects. despite these limitations, this study makes important contributions to the extant literature on misinformation and information seeking and processing. first, this is the first study that examined implications of misinformation exposure on information seeking and processing. because information seeking and processing constitute important components in managing uncertainty and risk situations (griffin et al., ) , understanding the mechanisms of how misinformation affects these informational behaviors offers crucial insights into human tendencies under uncertainty. second, this is one of just a few studies to make comparisons across multiple countries that are simultaneously affected by a common risk in studying information seeking and processing. studies in these areas have often focused on one cultural, mostly western, context, and intercultural comparisons have been scarce. comparing the relative predictive utility of a theoretical framework across different cultural contexts and populations is important for theory development. on the practical front, critical assessment of information as well as active seeking of quality information are crucial for mitigating the false beliefs that could be formed based on misinformation. given that misinformation demotivates individuals from these important information activities during a disease pandemic, it is necessary to minimize exposure to such incorrect information and to deliver evidence-based health advisories. to this end, risk communicators and government authorities should continuously monitor and clarify emerging misinformation on various online platforms to prevent the public's misperception and engagement in fake remedies or scientifically unproven measures. in light of the counterbalancing role of informational subjective norm we found, it would be beneficial to emphasize the social expectation on keeping up with health advisories to minimize the adverse effects of misinformation exposure. in dealing with global pandemics, like covid- , it would be essential for international and local health agencies to take into account differences in culture in communicating risk. for example, compared to lowuncertainty avoidance cultures (e.g., singapore, sweden), high-uncertainty avoidance cultures (e.g., south korea, japan, germany) may be less tolerant about information uncertainty (misinformation) as well as changes in health advisories, which are inevitable in most pandemic situations. in high-uncertainty avoidance culture, clear and consistent risk communications as well as implementation of formal governing structures (e.g., laws) could be particularly beneficial for mitigating uncertainty. the author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. the author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: this work was supported by the ministry of education of the republic of korea, the national research foundation of korea (nrf- s a a ), and singapore ministry of education academic research fund tier . hye kyung kim https://orcid.org/ - - - x notes . during data collection, local cases of covid- increased from , to , in the united states (out of . million total population), from to , in south korea (out of . million), and from to in singapore (out of . million). . in keeping with cohen and cohen ( ) , we used perceived knowledge to predict sufficiency threshold, and noted the unstandardized regression slope (Β). then, information insufficiency was computed by subtracting perceived knowledge * Β from sufficiency threshold. . in march , who removed avoiding pets and gargling with mouthwash from myth busters in response to the emerging evidence on these measures. there is no evidence that pets have infected humans with covid- , but an infected dog was found in hong kong. as well, there is no proof that gargling prevents respiratory infections caused by covid- , but health experts note that there is little downside in gargling. the theory of planned behavior evidence from internet search data shows information-seeking responses to news of local covid- cases in related news, that was wrong: the correction of misinformation through related stories functionality in social media risk perceptions and their relation to risk behavior the causes and 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mediating roles of health information seeking spreading the (fake) news: exploring health messages on social media and the implications for health professionals using a case study social networks and popular understanding of science and health: sharing disparities misinformation among mass audiences as a focus for inquiry exposure to health (mis)information: lagged effects on young adults' health behaviors and potential pathways audiences' acts of authentication in the age of fake news: a conceptual framework belief echoes: the persistent effects of corrected misinformation the paradox of participation versus misinformation: social media, political engagement, and the spread of misinformation defining misinformation and understanding its bounded nature: using expertise and evidence for describing misinformation systematic literature review on the spread of health-related misinformation on social media fake news. it's complicated perceived probability, perceived severity, and health-protective behavior coronavirus disease (covid- ) advice for the public: myth busters altruism during ebola: risk perception, issue salience, cultural cognition, and information processing risk information seeking and processing model: a meta-analysis fearful conservatives, angry liberals: information processing related to the presidential election and climate change what, me worry? the role of affect in information seeking and avoidance i share, therefore i am: a us−china comparison of college students' motivations to share information about climate change a united states-china comparison of risk information-seeking intentions from information processing to behavioral intentions: exploring cancer patients' motivations for clinical trial enrollment hye kyung kim (phd, cornell university) is an assistant professor in the wee kim wee school of communication and information at nanyang technological university in singapore. her research applies communication and social psychological theories to understand the processing and effects of communicative interactions in health and risk. her research ultimately seeks to develop theory-driven communication strategies that improve persuasion.jisoo ahn (phd, the university of texas at austin) is a research professor at health and new media research institute at hallym university. her research studies health and environmental and disaster communication and seeks effective ways to deliver information to the public by using interactive media technologies. austin. her research looks at communication in the context of sustainability and the environment. she focuses on the ways message components in environmental communication campaigns influence environmental attitudes, beliefs, and behaviors.lee ann kahlor (phd, university of wisconsin-madison) is an associate professor at stan richards school of advertising & public relations in the university of texas at austin. her primary research interest is in health and environmental risk communication with an emphasis on information seeking, avoiding, and sharing. key: cord- - nvrt y authors: tan, boon fei; loong tuan, jeffrey kit; yap, swee peng; ho, shaun zhirui; chek wang, michael lian title: personal view: managing the covid- pandemic as a national radiation oncology centre in singapore date: - - journal: clin oncol (r coll radiol) doi: . /j.clon. . . sha: doc_id: cord_uid: nvrt y abstract covid- , caused by severe acute respiratory syndrome coronavirus (sars-cov- ), was declared a global pandemic in march . it has impacted the world medically, financially, politically and socially, with countries such as china and italy adopting a full lockdown of their cities to mitigate the transmission. the current mortality rate is . %, with people infected worldwide. the disease is reminiscent of sars in , from which the healthcare system of singapore has garnered many lessons and applied them in the current climate. as a result of the high transmissibility of the virus, hospitals in singapore have reduced clinic loads and elective treatments to halt propagation of the virus and also to allow redistribution of healthcare workforce to the frontline. cancer patients, who are often immunocompromised, are at risk of contracting the disease and becoming seriously ill. at the same time, delaying treatment such as radiotherapy in cancer patients can be detrimental. here, we describe our experience as a large radiation oncology department in singapore, including the challenges we encountered and how we managed our patient flow. on january , singapore reported its first imported case of the novel coronavirus infection, officially named covid- , [aq ]which was later declared a global pandemic by the world health organization (who) [ ] . the causative virus, severe acute respiratory syndrome coronavirus (sars-cov- ), was thought to have originated from a seafood market selling wildlife in wuhan, hubei province, china. since its emergence in december , it has infected people across countries, with a fatality rate of . % [ ] . as it is highly infective, many countries have adopted measures to curb its transmission, including a full lockdown of large cities. healthcare systems across the globe are currently facing immense strain, having to manage the rapidly increasing numbers of unwell covid- patients while continuing with emergency and essential medical care to those not infected. for cancer patients, the situation has been particularly challenging, as they are at higher risk of contracting the disease and becoming seriously ill [ ] , but at the same time, cancer treatment for most of these patients could not be deferred for too long. the sars epidemic caused by the sars-cov virus in remains a fresh memory for many healthcare workers in singapore. it infected more than people across countries and claimed almost lives [ ] . in singapore, people were infected, % of whom were healthcare workers [ ] . having suffered from a strain on the healthcare system at that time, singapore responded by building the national centre for infectious disease and enhanced emergency protocols for disease outbreaks to better equip itself for future epidemics, such as the middle east respiratory syndrome (mers) and h n , which followed on in the last decade. as covid- shares similar features to sars, the experience provided important lessons in handling the covid- outbreak. at the hospital level, all visitors' temperatures were checked and health declaration forms completed at each hospital's entrances. any suspected cases were quickly isolated for further assessment. within our radiation oncology department, the workforce was split into two teams. patient-fronting staff were required to wear n masks at all times. within the cancer centre, instead of running simultaneous single subspecialty oncology clinics, it was restructured so that different subspecialties were housed in one clinic area to prevent the quarantine of an entire subspecialty team in the event one member becomes infected. despite being one of the earliest and worst hit countries at the onset of the covid- pandemic, the swift response, stringent guidelines and open communication with the public meant that we were able to slow down the rise in cases. this prevented the healthcare system from being overwhelmed and bought us time to further ramp up the healthcare infrastructure and redistribute medical manpower to meet the increase in demand. here, we detail our response to the national threat as a national radiation oncology centre. our workflow integrated government protocols, who recommendations and position statements from oncology associations [ ] . the division of radiation oncology is a clinical division of the national cancer centre singapore (nccs), the largest comprehensive cancer treatment and research facility in singapore. it is affiliated with the largest hospital in the nation, the singapore general hospital (sgh). besides radiation oncology, nccs also houses the outpatient services for other clinical divisions, including medical oncology, surgical oncology, oncologic imaging and palliative medicine. the division serves about % of the country's population who require radiotherapy, treating about - patients per day, including inpatients from sgh and other hospitals within the healthcare cluster. there are, in total, nine linear accelerators. the set-up of the division is unique to the country. it consists of two treatment sites: b in the basement of the main sgh building and b in the basement of nccs. each site is supported by separate ancillary services, mould rooms and computed tomography simulators. they are also each managed by a separate workforce consisting of radiation therapists, medical dosimetrists, physicists and nurses, while radiation oncology doctors cross-cover both sites. radiation oncologists also service outpatient clinics and multidisciplinary tumour board meetings in other hospitals of the cluster, such as the kk women's and children's hospital (kkwch) and changi general hospital (cgh). before the first confirmed covid- case in singapore, a multi-agency task force was set up to manage the impending crisis. in the hospital setting, a disease outbreak taskforce was set up to coordinate the development and implementation of protocols and kept everyone updated with regards to the rapidly evolving situation. table summarises the national and departmental response to the covid- pandemic. table here we have continued to treat inpatients from our affiliated hospitals that do not have inhouse radiation therapy services. of note are paediatric cases from kkwch, which treats most of the paediatric cancer patients in singapore. anaesthesia for these patients is provided by a dedicated anaesthetic team from kkwch assigned to our sgh site. figure depicts the pathway of patients after the hospital entrance's triage. should any patient who is quarantined for days due to close contact with confirmed covid- cases or those with a stay home notice (shn) due to recent entry from abroad as of march require radiotherapy, it will be conducted in a highly controlled manner with close collaboration with the ministry of health. quarantined patients will have to be specially transported by dedicated ambulances accompanied by quarantine officers. shn patients will have to attend via private transport. they will be treated at nccs and scheduled as the last case of the day, after all patients have left the premises. only the bare minimum assigned staff will be allowed to be present and they must ensure full personal protective equipment (ppe) is worn. these patients will have to enter the building through dedicated pathways into an isolation waiting room. upon completing the treatment, the isolation and treatment rooms will undergo terminal cleaning. ppe will be disposed of in biohazard bins within the room. for those who are yet to start treatment, we will defer non-urgent cases until their period of quarantine or shn is over. at the time of writing, there are people currently quarantined in singapore [ ] . we foresee the need to prepare for a surge of both quarantined and shn cases as more singaporeans are returning from the increasing list of countries with high infection rates. there are certain challenges unique to the radiation oncology division. first, many cancer patients have symptoms due to their tumour, treatment side-effects or their immunosuppressed state, including cough, fever, fatigue and shortness of breath [ ] . these are also symptoms of covid- . hence, symptomatic patients irrespective of travel or contact history would have to be assessed at the fever clinic and a proportion tested to rule out covid- , resulting in a delay in radiotherapy treatment. where possible, alternative therapies are sought, for example optimising medical treatment for palliative cases. second, in line with the department's protocol to reduce patient flow through the hospital, consultants needed to look through their patient lists to ensure only the most stable patients have their appointments postponed. in our satellite gynaecological and breast cancer clinics at kkwch and cgh, this issue was mitigated by engaging our surgical colleagues to review recently treated patients. patients who needed to be seen more urgently were given appointments at nccs instead. we were also more likely to postpone a patient's appointment if they were reviewed by another specialty doctor recently and were deemed well. telemedicine for remote consultation is being considered in the event of a prolongation of this global pandemic. third, although it is possible to defer any untreated non-urgent cases, deferring radiotherapy in category patients (patients with rapidly proliferating tumours) can be detrimental. on a regular basis, the division treats a proportion of patients with hypofractionated regimens, such as in adjuvant radiotherapy in breast cancer patients, the chhip protocol in prostate cancer and single gy for palliative cases. during this pandemic, the division aims to increase the use of validated hypofractionated regimens where possible to reduce the amount of daily hospital attendance, thereby decreasing exposure to possible infection. as of april , singapore had confirmed cases, of whom have fully recovered and there have been six deaths [ ] . there is now a second wave of imported cases from regions outside of china. although not as deadly as sars, covid- proves to be a respectable foe due to its highly transmissible capabilities. we may have a long way to go before life returns to normalcy. time waits for no man and for many of our cancer patients delays in treatment could result in detrimental effects, including death. hence, we need to tailor our services accordingly to ensure that we do not compromise the safety of our cancer patients but also ensure they receive their treatment in a timely manner. we hope our experience will provide other institutions with some guidance on tackling the current pandemic. check and log temperature twice daily on database *as of march . †as of march . ‡as of april . §visitors must declare any recent travel history and/or symptoms (including fever, shortness of breath, cough) and/or contact with positive cases or clusters, papr, powered air-purifying respirator; ppe, personal protective equipment. novel coronavirus ( -ncov) situation report - , world health organization covid- ) outbreak situation, world health organization cancer patients in sars-cov- infection: a nationwide analysis in china severe acute respiratory syndrome (sars) world health organization. weekly epidemiological record covid- ) for clinical oncology press release, more cases discharged; more cases of covid- infection confirmed clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan, china updates on covid- (coronavirus disease ) local situation. ministry of health singapore the authors declare no conflicts of interest.author query aq is the change to the text ok? ☑ the authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.☐the authors declare the following financial interests/personal relationships which may be considered as potential competing interests: key: cord- -duukt wh authors: chew, nicholas w.s.; lee, grace k.h.; tan, benjamin y.q.; jing, mingxue; goh, yihui; ngiam, nicholas j.h.; yeo, leonard l.l.; ahmad, aftab; ahmed khan, faheem; napolean shanmugam, ganesh; sharma, arvind k.; komalkumar, r.n.; meenakshi, p.v.; shah, kenam; patel, bhargesh; chan, bernard p.l.; sunny, sibi; chandra, bharatendu; ong, jonathan j.y.; paliwal, prakash r.; wong, lily y.h.; sagayanathan, renarebecca; chen, jin tao; ying ng, alison ying; teoh, hock luen; tsivgoulis, georgios; ho, cyrus s.; ho, roger c.; sharma, vijay k. title: a multinational, multicentre study on the psychological outcomes and associated physical symptoms amongst healthcare workers during covid- outbreak date: - - journal: brain behav immun doi: . /j.bbi. . . sha: doc_id: cord_uid: duukt wh objective: since the declaration of the coronavirus (covid- ) outbreak as pandemic, there are reports on the increased prevalence of physical symptoms observed in the general population. we investigated the association between psychological outcomes and physical symptoms among healthcare workers. methods: healthcare workers from major hospitals, involved in the care for covid- patients, in singapore and india were invited to participate in a study by performing a self-administered questionnaire within the period of february to april , . healthcare workers included doctors, nurses, allied healthcare workers, administrators, clerical staff and maintenance workers. this questionnaire collected information on demographics, medical history, symptom prevalence in the past month, depression anxiety stress scales (dass- ) and the impact of events scale-revised (ies-r) instrument. the prevalence of physical symptoms displayed by healthcare workers and the associations between physical symptoms and psychological outcomes of depression, anxiety, stress, and post-traumatic stress disorder (ptsd) were evaluated. results: out of the healthcare workers who participated in the survey, ( . %) screened positive for moderate to very-severe depression, ( . %) for moderate to extremely-severe anxiety, ( . %) for moderate to extremely-severe stress, and ( . %) for moderate to severe levels of psychological distress. the commonest reported symptom was headache ( . %), with a large number of participants ( . %) reporting more than four symptoms. participants who had experienced symptoms in the preceding month were more likely to be older, have pre-existing comorbidities and a positive screen for depression, anxiety, stress, and ptsd. after adjusting for age, gender and comorbidities, it was found that depression (or . , % ci . – . , p = . ), anxiety (or . , % ci . – . , p = . ), stress (or . , % ci . – . , p = . ), and ptsd (or . , % ci . – . , p = . ) remained significantly associated with the presence of physical symptoms experienced in the preceding month. linear regression revealed that the presence of physical symptoms was associated with higher mean scores in the ies-r, dass anxiety, stress and depression subscales. conclusions: our study demonstrates a significant association between the prevalence of physical symptoms and psychological outcomes among healthcare workers during the covid- outbreak. we postulate that this association may be bi-directional, and that timely psychological interventions for healthcare workers with physical symptoms should be considered once an infection has been excluded. on december , , the china office of world health organization (who) was notified regarding some cases of pneumonia of unknown etiology in wuhan city of hubei province. it was subsequently termed coronavirus disease (covid- ) by the who. the rapid global spread of the disease led to the declaration of covid- as a pandemic on march , (organization, ) . being a global hub with high international traffic, singapore observed an increasing spread of covid- . accordingly, the disease outbreak response system condition (dorscon) alert level was escalated to orange on february , , which indicates that the outbreak is deemed to have moderate to high public health impact, necessitating additional measures like quarantine and temperature screening to minimize risk of further virus transmission in the community (s k. singapore raises cornavirus outbreak alert to orange: what does it mean., ; sk ca-l, ). similarly, being a densely populated country, the indian authorities imposed a lockdown on march , , which involved barring of all public transport and prohibiting opening of public spaces (the times of india, ). between february to april , , singapore reported slightly over confirmed covid- cases with deaths, while india has reported > , confirmed cases with > deaths (the times of india, ; ministry of health singapore, ). much uncertainty revolved around the nature of spread of covid- , its severity, associated mortality and the availability of essential resources like facial masks, hand sanitizers and digital thermometers. widespread fear of imposed quarantine and lockdown measures led to the unusual displays of panic in the form of frenzied buying of goods by the general public observed in many countries (coronavirus: hong kong shoppers snap up rice and noodles as fears over outbreak mount., ; 'it's pandemonium': virus panic-buying hits los angeles., ; t a. coronavirus: politicians, supermarkets urge calm amid panic-buying of groceries, ). infectious disease outbreaks are known to have psychological impact on healthcare workers as well as the general population. a notable example would be the psychological sequelae observed during the severe acute respiratory syndrome (sars) outbreak in (mcalonan et al., ministry of health s, ) . studies on the sars outbreak revealed that healthcare workers experienced acute stress reactions (tam et al., ; grace et al., ) . in addition to the specific physical manifestations of various diseases, some symptoms may arise due to the psychological sequelae of these infection outbreaks. such psychosomatic symptoms have been reported with increased prevalence during and after the outbreaks, such as the sars and ebola virus (lam et al., ; lee et al., ; marco et al., ; tucker, xxxx; xiang et al., ) . the commonly reported symptoms range from more specific symptoms like pain (lam et al., ) to non-specific ones like fatigue, weakness and lethargy (leow et al., ) . in some cases, symptoms not perceived to be directly related to a particular infectious disease may be reported. for instance, some survivors of sars outbreak developed chronic extra-pulmonary symptoms during outpatient clinical follow-up (leow et al., ) . it is important to understand the prevalence and patterns of such somatic manifestations since they can lead to undesirable overcrowding of hospital emergency departments (farr, ; abelson, ) , causing additional workload to the already constrained healthcare systems. we investigate the association between various physical symptoms and psychological distress amongst healthcare workers in singapore and india during the current covid- outbreak. from february to april , , we recruited healthcare workers from major tertiary healthcare institutions in singapore and india. during the study period, the healthcare institutions were actively involved in the care of covid- patients. study participants included doctors, nurses, allied healthcare workers (pharmacists, physiotherapists, occupational therapists), technicians, administrators, clerical staff and maintenance workers. written informed consent was obtained from all participants and the study was approved by the institutional review board, in accordance to the principles in the declaration of helsinki. the study questionnaire, written in english, comprised five main components-demographic characteristics, medical history, symptom prevalence in the previous month, depression anxiety stress scales (dass- ) and the impact of events scale-revised (ies-r) instruments. baseline demographic characteristics such as gender, age, ethnicity, marital status, occupation and past medical history were recorded. participants had to indicate if they experienced any of the listed physical symptoms, general or respiratory-related symptoms, during the previous month and rated the severity of the reported symptoms (supplementary material ). the study questionnaire was adopted from our previous study related to the psychological impact on healthcare workers in singapore during the covid- outbreak (tay et al., ) . depression, anxiety and stress were assessed using dass- (lp, ls, ), which is a validated screening instrument for use among patients and general populations. it is a self-reported -item system developed by the university of new south wales, australia, which provides independent measures of depression, stress and anxiety with recommended severity thresholds for the depression, stress and anxiety subscales. the scores for each of the three components were calculated by summing up the scores for the relevant items, and multiplying by two to calculate the final score. cut-off scores of > , > and > represent a positive screen of depression, anxiety and stress, respectively. on the dass- depression subscales, scores of - were deemed as "mild", - as "moderate", - as "severe", and - as "extremely severe" depression. the dass- anxiety subscale score was assessed as "mild" ( - ), "moderate" ( - ), "severe" ( - ), and extremely severe" ( - ). the dass- stress subscale score was divided into "mild" ( - ), "moderate" ( - ), "severe" ( - ), and "extremely severe" stress ( - ) (tay et al., ) . the psychological distress of the outbreak was assessed using the ies-r , (weiss, ) , which is a validated -item self-report that measures the subjective distress caused by traumatic events. it has subscales (intrusion, avoidance and hyperarousal), which are closely affiliated with post-traumatic stress disorder (ptsd) symptoms. participants were asked to rate the level of distress for each component during the previous seven days of their interview. the total ies-r score was graded for severity from normal ( - ), mild ( - ), moderate ( - ), and severe psychological impact (> ). a cut-off score of was used to define ptsd of a clinical concern (creamer et al., ; weiss, ) . both dass- and ies-r have been validated for use in a recent chinese study investigating the psychological impact of covid- on the general population (wang et al., a; ho et al., ) . we evaluated the prevalence of physical symptoms reported by the healthcare workers during previous one month before the survey administration period. additionally, we investigated the association between the presence of various physical symptoms and psychological outcomes, namely the dass- score and ies-r score. categorical variables are expressed as absolute values (percentage) and continuous variables were expressed as mean value ± (standard deviation). student's t-test was used to examine the association between continuous variables and pearson's chi-square test (or fisher's exact test, where appropriate) was used to evaluate categorical variables. multivariable logistic regression was used to adjust for the effect of confounders when appropriate to determine independent associations of binary outcomes. linear regression was employed to evaluate for associations between baseline characteristics, risk status, physical symptoms and the mean scores for dass- and ies-r components. a p-value of < . was deemed significant for this study. all statistical analyses were performed using ibm spss statistics for windows, version . . armonk, ny. of the invited healthcare workers from the major hospitals in singapore and india, ( . %) agreed to participate in this study. of which, respondents were from singapore and from india. majority ( , . %) were female and the median age was (interquartile range: - ) years (table ) . most ( . %) of the participants were indian, followed by chinese ( . %) and malay ( . %) ethnicity. being a relatively younger study population, . % of the participants were unmarried. two hundred and five ( . %) participants had pre-existing comorbidities, migraine ( . %) being the most prevalent followed by eczema ( . %) and asthma ( . %). nurses comprised . % of the study population, followed by physicians ( . %) and allied healthcare professionals ( . %) ( table ) . the commonest reported symptoms were headache ( , . %), throat pain ( , . %), anxiety ( , . %), lethargy ( , . %), and insomnia ( , . %) (fig. ) . while ( . %) respondents did not report any symptom within the preceding -month of the survey administration date, ( . %) reported one symptom, ( . %) reported two, ( . %) reported three, and ( . %) reported more than four symptoms. importantly, the symptoms were generally mild in severity. using our predefined cut-offs for the dass- scoring system to screen for depression, anxiety and stress, we found anxiety in ( . %), depression in ( . %) and stress in ( . %) study participants. there was no difference in psychological outcomes between study participants from the two countries (table ). the overall mean dass- depression subscale score was . (sd . ). of the healthcare workers who screened positive for depression, % of them ( ) were scored as moderate to very severe depression. the overall mean dass- anxiety subscale score was . (sd . ) . of the patients who screened positive for anxiety, . % of them ( ) showed moderate to very severe anxiety. in terms of the dass- stress subscale, the overall mean score was . (sd . ). stress was moderateto-severe in of the participants ( . %) who screened positive for it (fig. ) . healthcare workers rated their levels of psychological distress according to the ies-r during the preceding days. the mean total ies-r score was . (sd . ) while the means (sd) for ies-r subsets for intrusion, avoidance and hyperarousal were . ( . ), . ( . ) . ( . ), respectively. of note, ( . %) of the study cohort screened positive for clinical concern of ptsd, of which demonstrated moderate to severe levels of psychological distress. the group which displayed presence of symptoms in the preceding month had less female participants compared to the group without symptoms (odds ratio (or) . , % confidence interval (ci) . - . , p = . ). on the other hand, participants with physical symptoms were more likely to have pre-existing comorbidities (or . , % ci . - . , p < . ) and older in age (mean difference . , % ci . - . , p = . ). in terms of study outcomes, those with physical symptoms were more likely to have a positive screening for depression (or . , % ci . - . , p < . ), anxiety (or . , % ci . - . , p < . ), stress (or . , % ci . - . , p = . ), and ptsd (or . , % ci . - . , p = . ) ( table ) . in the multivariable logistic regression model, after adjustment for table baseline characteristics of study participants (n = ) . (table ) . linear regression revealed that the presence of physical symptoms was associated with higher mean scores in the ies-r, dass- anxiety, stress and depression subscales. this association was present across the three respiratory-related symptoms (sore throat, breathlessness and cough) as well as constitutional symptoms like lethargy, myalgia, poor appetite. however, there was no statistical significance between the association of coryza and psychological distress (table ) . this multinational, multicenter study found significant association between adverse psychological outcomes and physical symptoms displayed by healthcare workers during the current covid- pandemic. our findings mirror the trend in recent studies on the psychological impact of the covid- epidemic among the general population in china during its initial stages (wang et al., a; li et al., ; kang et al., ) . we have previously reported that the psychological impact (specifically anxiety) of covid- was more common among nonmedically trained healthcare workers when compared to the medically trained personnel (tay et al., ) . symptoms of covid- infection are wide-ranging, and may be non-specific and similar to other viral infections (guan et al., ) . therefore, when healthcare workers develop any such symptoms, they often faced the dilemma of whether to apply for medical leave of absence, or to continue working alongside their over-worked colleagues categorical variables displayed as n (%). during this critical period. even though healthcare workers are entitled to take paid sick leave for a given number of days, little is known about the employment risks posed, especially to the low-paid non-medically trained healthcare contract workers in the event of a prolonged absence. psychological distress levels may also be exacerbated by the fear of being a carrier of the virus, causing transmission amongst fellow healthcare workers and their own families if they choose to continue to work. the fear of transmission is especially high due to the reports of asymptomatic transmission of covid- , including high transmission rates amongst healthcare workers during in china where as many as healthcare workers contracted the infection and of them succumbed (adams and walls, ) . such prevailing and overwhelming thoughts in the current pandemic atmosphere often have adverse psychological sequelae and may lead to various somatic symptoms (joob and wiwanitkit, ) . moderate to severe psychological symptoms were reported amongst the general population in a recent chinese study during the covid- outbreak (wang et al., a; wang et al., b) . this is in sharp contrast to a low prevalence of moderate to severe psychological impact in our study ( . % compared to % reported in the chinese study). furthermore, compared to the chinese study population, our cohort had lower prevalence rates of moderate to severe depression ( . % versus . %), anxiety ( . % versus . %) and stress levels ( . % versus . %). however, despite our lower prevalence rates of emotional distress, our study population displayed higher prevalence rates of physical symptoms such as headache ( . % versus . %) and sore throat ( . % versus . %) when compared to the chinese cohort. the true association of physical symptoms and psychological stress is indeed challenging to determine, especially in the current climate where the active infection needs to be urgently excluded in every suspected case before giving much importance to the 'non-specific' symptoms. nevertheless, somatic symptoms may be more prevalent during periods of stress and these are hypothesized to represent a way of communicating emotions (basant et al., ) . we hypothesize that the increased prevalence of self-reported physical symptoms is likely to have been contributed by the psychological impact of the outbreak. another possible contributing factor could be the social stigma associated with mental health issues, which may have resulted in individuals having a higher tendency to express their psychological distress via physical symptoms instead (yl, ) . headache was the most commonly reported symptom in this study. a recent study on headache associated with personal protective equipment (ppe) among healthcare workers during the covid- pandemic demonstrated that % of respondents reported ppe associated headaches, with a pre-existing primary headache diagnosis reported as an independent predictor for ppe associated headaches (ong et al., ) . similarly, migraine was the most commonly reported comorbidity in our study. hence, the common presenting complaint of headache may be related to the increased adverse psychological impact or an exacerbation of their pre-existing condition. notably in prior studies, fatigue was the most commonly reported symptom among sars survivors in both healthcare workers and the general public. (lam et al., ) interestingly, even in our study, lethargy was one of the most commonly reported symptom amongst healthcare workers. in a previous study from hong kong, lam et al demonstrated that the prevalence of chronic fatigue was significantly higher among sars survivors which persisted through the acute phase of infection till one month after the disease outbreak (lam et al., ) . interestingly, healthcare workers infected by sars were more likely to give up their employment, and the occupational risks faced by the healthcare workers during an epidemic may potentially lead to psychiatric morbidity, physical symptoms such as fatigue, and eventually burnout. although fatigue and headache may be vague and often unsubstantiated, it is crucial not to neglect such physical symptoms as they may be a reflection of underlying psychological distress (lam et al., ) . the association of psychological distress and physical symptoms is table linear regression of physical symptoms in the past one month associated with the psychological impact of the covid- outbreak (n = ) . * p-value < . ; ** p-value < . . n.w.s. chew, et al. brain, behavior, and immunity xxx (xxxx) xxx-xxx poorly understood. in addition to the fear of transmitting the infection to colleagues and family members coupled with the dilemma of applying for sick leave in an already strained healthcare sector, many healthcare workers develop burnout and may experience a sense of intense fear, stigmatization and ostracism when displaying physical symptoms suggestive of the virus infection, which often leads to negative psychological pain (nezlek et al., ; troyer et al., ) . this phenomenon has already been described in the studies during the current covid- outbreak (wang et al., a) as well as previous ebola crisis (matua and van der, ) . we postulate a bi-directional complex relationship between psychological distress and physical symptoms, where an inadvertent psychological distress exacerbates physical symptoms and vice versa (fig. ) . accordingly, the physical symptoms related to high levels of arousal in a stressful environment of a disease outbreak may lead to over-reporting of cardiovascular, respiratory, neurological or gastrointestinal symptoms (mcfarlane et al., ) . furthermore, a known stressor may precipitate or worsen specific physical symptoms. for example, a previous study has reported increased prevalence of respiratory symptoms seen in fire-fighters suffering from ptsd as a result of the psychological stress of smoke inhalation (mcfarlane et al., ) . we believe that various symptoms of throat pain, cough and myalgia during the current covid- outbreak may be over-represented as a result of the psychological stress, and further exacerbated by the presence of various comorbidities (mcfarlane et al., ) . this observation is also commonly evident in patients with depression, with the somatization of back pain and headache (von knorring et al., ) . this is in line with our finding of the significant association of the presence of comorbidities and physical symptoms amongst healthcare workers. targeted multidisciplinary interventions are needed to support healthcare workers by addressing both the psychological manifestations and physical symptoms. all efforts should be made to offer psychological support and interventions once an acute infection has been excluded. dedicated counselling may be arranged to allay their fear of transmitting the infection to their family members (wang et al., a) as well as to boost the confidence and morale of our healthcare workers. given that this is a multinational, multicentre study, with similar prevalence of psychological outcomes in both countries, the observed psychological and physical symptoms findings are more likely generalizable. however, our study has its limitations. firstly, the crosssectional nature of the study does not allow interpretation for causality. whilst we found a strong association between presence of physical symptoms and prevalence of psychological distress, we are unable to conclude that psychological distress had resulted in the manifestation of these physical symptoms. secondly, we did not assess if study participants had taken medical leave of absence, or if they sought the testing for covid- during the manifestation of physical symptoms. thirdly, owing to the stringent hospital infection control protocols to minimize contact between healthcare workers, the questionnaire had to be selfadministered and information provided on symptoms was not verified by a medical professional. fourthly, we did not record socioeconomic status and education level, which could have influenced our results. we intend to re-evaluate our study participants if the current covid- outbreak escalates further in the region, as well as after it subsides to obtain much reliable explanations about the association of psychological sequelae and various physical symptoms. this study describes an expansive range of physical symptoms experience by healthcare workers during the ongoing covid- outbreak. there is a significant association between the prevalence of physical symptoms and psychological distress, which is probably bi-directional. we recommend the provision for timely psychological support and interventions for healthcare workers who present with physical symptoms once an infection has been excluded. visualization, writing. the authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. disclosures vks is the current recipient of senior clinician scientist award from national medical research council, ministry of health, singapore. other authors have no financial disclosures. doctors and patients turn to telemedicine in the coronavirus outbreak supporting the health care workforce during the covid- global epidemic revision notes in psychiatry, rd. united states of america 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population in china the impact of event scale: revised. in: cross-cultural assessment of psychological trauma and ptsd timely mental health care for the novel coronavirus outbreak is urgently needed application of mental illness stigma theory to chinese societies: synthesis and new directions no funding reported. supplementary data to this article can be found online at https:// doi.org/ . /j.bbi. . . . key: cord- - cc r authors: laurie lau, yiu chung title: cybercrime in cloud: risks and responses in hong kong, singapore date: - - journal: the cloud security ecosystem doi: . /b - - - - . - sha: doc_id: cord_uid: cc r the popularity and commercialization of the “internetwork” began in the late s through the interconnection of computer networks using special gateways or routers to transfer packets of electronic data. as with many things in life, internetwork technology has had both positive and negative effects on society, and asia has been no exception. one of the negative effects has been a surge in internet crime. according to a report released by the gartner consulting group, in smart phone sales exceeded regular phone sales for the first time, with million smart phones sold, representing % of the global mobile phone total and an increase of % from . the popularity and technology of the mobile internetwork, especially the smart mobile phone web, has changed the internetwork landscape through the concept of cloud computing. cloud computing is distributed computing over a network, using a program or application that can run on many connected computers and in different locations around the globe simultaneously at a reduced cost. this distributed cloud computing presents law enforcement authorities with the unique challenge of policing internet crime. cloud computing relies on sharing resources to achieve coherence, and in doing so creates economies of scale for converged infrastructures and shared services. accordingly, one problem facing the authorities is the presence of trans- and multijurisdictional crimes. in this chapter, i explore this topic in the contexts of hong kong and singapore, as both are key players on the international stage, especially in relation to international finance and information technology. in both locations, infrastructure works to maintain global financial center status. the remainder of this chapter is organized as follows. a brief overview of the development of cloud computing is followed by an examination of cybercrime risks in the cloud. then, i review how the authorities in hong kong and singapore respond to cybercrime risks and explore the current government policies on cloud computing, particularly in fighting cybercrime. although the term "cloud computing" has already been used elsewhere in this publication, for ease of understanding, in this chapter i follow the model used by quick et al. in their book, cloud storage forensics. basically, cloud computing comprises three models: cloud iaas: this provides clients with access to storage space, bandwidth, and other fundamental computing services. it effectively expands the computing capability of the customer, allowing them to run their own software and applications using the cloud infrastructure; cloud paas: this allows the customer to gain access to the computer platform or operating systems of the cloud instances (e.g. windows and linux) and an underlying database so that they can create or acquire applications; cloud saas: this allows clients of the csp to utilize software and applications running on the cloud infrastructure. the applications are accessed via remote computers and mobile devices using the appropriate cloud interface software. the consumer's device acts like a portal to the software and data stored in the cloud. however, describing cloud computing crime in simple terms has been a challenge ever since the early days of the internetwork revolution. a variety of terms are used when explaining the criminality associated with the popularity and commercialization of information communication technology (ict), including "new technology crime," "online crime," "cybercrime," and "internet crime." these terms tend to be used interchangeably, which makes it difficult to provide universal definitions. ict is constantly evolving along with the associated criminality, including cloud computing crime. in addition, certain types of online activities considered to be "internet" or "cloud computing" crime in some countries are not considered as such in others. for example, in most western common law countries, if a female posts topless beach holiday "selfies" on facebook via a smart mobile phone to share among friends, the act would be considered a harmless private activity. in many muslim countries, and certainly those in the middle east, however, the act would be considered a criminal offense; the woman would be subject to criminal prosecution in court and the act would be punishable by public lashing. both polity and invested interests are at play, and the novelty of the "risk" or "threat" posed by new forms of technology-associated crimes can be used to support a larger share of government funding. cloud computing crime has become a broad term that embraces all forms of digital crime such as television and film piracy and location-based smart mobile phone crime. the growth and development of cloud computing crime has largely been a consequence of the expansion of cloud computing environments capable of facilitating criminality. thus, for the purposes of this chapter, "cloud computing crime" is any criminality committed with the aid of recognized cloud computing models, including the smart mobile phone operation system model. in recent years, places such as hong kong, singapore, and other parts of asia have witnessed noticeable growth in cloud computing. the popularity of smaller mobile computing devices such as smart phones, which have resulted from advancements in internet technologies, has been combined with the nature of cloud computing, which provides faster, easier access to files in remote locations, to allow users to access and update files on the move. although cloud computing technologies offer efficiency in terms of users' hardware requirements and access barriers, they also create challenges for both law enforcement authorities and individuals alike. one such issue is the policing of computer-related crime, which involves gathering evidence from, storing data in, the cloud, and then prosecuting the perpetrator. scholars have drawn attention to some of these issues, but the socio-legal perspective treated here has not received much attention in the literature to date. policing priority is typically set by country or place individually according to their needs. factors affecting policing include the economy, legal traditions, police structure and organization, cultural factors, and political structure. the protection of these factors and their perceived importance is different in each jurisdiction and under each government in power, and thus policing varies accordingly. this phenomenon is also true for policing the internetwork, as the development and level of information technology (it) access and infrastructures differ in different parts of the world. for instance, in accordance with the united nation international telecommunication union (unitu) report on the digital divide in , it disparities in terms of access to information and communication technology are pronounced between the developed western economies such as those of america, canada, and western european countries (this group includes a few advanced economies in asia such as those of japan, south korea, singapore, and hong kong), and the lessdeveloped economies such as those of northern africa, latin america, pacific ocean islands, and some parts of south eastern asia. the level of policing for the internetwork is also different, as each country prompts different government perceptions of its level of technology risk or economic threat. these perceptions are largely dependent on the level of technology each country relies on to generate wealth, and sometimes on how much a given government sees technology as a threat to its political structure and systems. thus, technology policing is prioritized differently from country to country. however, the same unitu report stressed that the digital divide had closed significantly between developed and developing nations, particularly in south east asia and numerous african countries due to the increase in portable devices such as smart phones and the decrease in their cost. as international telecommunication union (itu) director brahima sanou said: the surge in numbers of mobile-broadband subscriptions in developing countries has brought the internet to a multitude of new users. despite the downward trend, prices remain relatively high in many low-income countries. for mobile broadband to replicate the mobile-cellular miracle and bring more people from developing countries online, g network coverage has to be extended and prices have to go down even further. . . . mobile-cellular subscriptions registered continuous double-digit growth in developing country markets, for a global total of six billion mobile subscriptions by end . . . noting that china and india each account for around one billion subscriptions. mobile broadband continues to be the ict service displaying the sharpest growth rates. over the past year, growth in mobilebroadband services continued at per cent globally and per cent in developing countries. there are now twice as many mobile-broadband subscriptions as fixedbroadband subscriptions worldwide. the increased ownership of smart phones in these countries has not only narrowed the gap between them and traditional fixed-location devices such as desktop computers, but also shifted the information and communication technology landscape. the technique of virtualization in cloud computing has created an economy of scale, such that services are only provided when there is consumer demand. this allows service providers to reduce their materials and service costs. on one hand, almost all smart phone devices now allow users to constantly connect with the internetwork on the go; anytime, anywhere. on the other hand, to enhance the user's smart mobile phone experience, service providers must design their services based on users' needs. this can result in compromised safe-guards and security, which in turn create opportunities for criminal activity, and authorities have yet to catch up to these technologies, especially when perpetrators can be located overseas or in different police jurisdictions. the increase in mobile smart phone use has also been rapid and significant in singapore and hong kong. to put it in perspective, according to the nielsen smart phone report in , both hong kong and singapore were ranked at the top for smart phone penetration rate in the asia pacific region, with more than % of their populations owning smart mobile phones. as sagar phadke, director of nielsen's telecom and technology practice in southeast asia, north asia, and the pacific said: the growth in connected device ownership across asia pacific has been staggering in recent years. while this growth is expected to begin levelling out, consumers' use of connected devices will continue to evolve and expand, presenting vast opportunities for organisations to engage with consumers on an almost ubiquitous platform. it is becoming more critical than ever for companies to develop sophisticated mobile strategies designed to leverage changing connected device behaviours and develop ongoing consumer engagement. there has been an ample and growing opportunity for smart phone commerce in fields such as mobile banking, games and videos, and advertising in the asia pacific region, particularly in hong kong and singapore. however, the rapid increase in smart phone use and penetration has greatly increased the potential for corresponding growth in smart mobile phone crime. for example, according to a kpmg international report on cybercrime, cybercriminals are moving beyond desktop computers to target smart mobile phones and other mobile devices. the report stated that in the previous years, digital crimes specifically targeting mobile devices had risen %. although the actual level of smart mobile phone crime is not known, and what is known is probably just the tip of the iceberg, the potential for problems is sobering. what follows are examples of smart phone crime in hong kong and singapore. in hong kong, a local chinese newspaper reported that during the world cup, the hong kong police noticed that betting on illegal football matches through mobile phone apps increased. mobile apps have also been used to sell counterfeit goods in hong kong. in a joint operation between customs and excise and the police in april in the tsim sha tsui area, people were arrested and items of suspected counterfeit goods valued at hk$ , were seized. in july , a similar operation was mounted by the hong kong authorities and people ( of whom were younger than ) were arrested and goods valued at about hk $ , were seized. according to hong kong authorities, in the first months of the number of people arrested who are younger than has risen by % compared to the same period in . in these cases, most of the young offenders participated in the sale of suspected counterfeit goods on internet platforms via mobile phones, through auction sites or social networks, during their leisure time. other types of crime have been committed using smart mobile phones. in january , according to paul gordon, sai kung divisional commander, thieves used surveillance cameras to monitor their targets instead of doing their own reconnaissance: a device will be fixed outside a house and linked to their [smart]-mobile phones, to monitor when it is left unattended. then they will take the chance to break in. the device was low-tech and could be bought cheaply in the sham shui po electronics market. but it was the first time police had seen it used in this kind of crime. in singapore, for example, according to a report released by websynergies, there have been a million singaporean cybercrime victims. the report estimated a total of us$ billion lost through cybercrime over the period of a year. smart mobile phones have become the tool of choice for cybercriminals in singapore, as viruses can migrate from personal computers (pcs) to mobile devices. the incidence of related petty crimes such as smart phone snatching has also risen. in another example from singapore, channel news asia interviewed an inspector of the singapore police. during the live interview, conducted on april , , the inspector described a smart mobile phone crime case involving a woman in her late s who was an accountant by profession. she allegedly befriended a male who claimed to be a pilot for singapore airline. they met and chatted on whatsapp through their smart phones for some time, and ultimately agreed to meet face-to-face in a café near the singapore international airport. the supposed pilot told the woman that he had been in a hurry to get out of his flat and had forgotten to bring enough euros with him. he asked the woman if she would transfer singapore dollars to a certain bank account under his name, so that when he landed in germany the next day he could withdraw the cash from an atm. he promised to repay her in a week's time, when he returned. the woman agreed and transferred the money via her smart phone. for some time, she did not hear from the man and could not contact him on whatsapp. after months she reported him to the police. the man was eventually arrested wearing a pilot's uniform near the international airport, in a sting operation mounted by the police after a few more women fell victim to his scam and reported him. we only know about these cloud computing-enabled smart mobile phone crimes because they were in the public domain, but the true level of such crime remains unclear. the lack of reports on cloud computing crime is probably related to the fact that cloud computing is a relatively new concept for law enforcement authorities. the term was only coined in the late s. victims of cloud computing crime might not even realize their status as such, or they may choose not to report it, as the police are sometimes unable to recognize it as such and instead record it as traditional street crime. even when the police recognize and record an event as cloud computing crime, they may have difficulty following up, especially if the servers and data involved are located overseas or in multiple jurisdictions. as quick et al. explain, "the key component of cloud computing is multi-tenancy capability, which is referred to as a shared pool of resources . . . individual files may be distributed across multiple disks and storage systems across multiple jurisdictions." securing and preserving a chain of evidence for prosecution in court involves significant police resources, and even if the culprit is deported to face justice, the case may not pass the prosecution's test of public interest and the perpetrator could escape justice. key factors shaping "response": hong kong, singapore . hong kong hong kong, founded by the british for trade purposes, was a british colony for over years before it was restored to the people's republic of china (prc) on july , . as an entrepot and capitalist enclave without natural resources, hong kong's economy has largely been dependent on international and interregional trade. in the intermittent period between the s and the early s, hong kong was labeled a sweat-shop for the world's light manufactured goods, but with the open-door policy introduced by communist china in , hong kong industrialization came to an abrupt end in the early s. almost all of the manufacturing factories were moved northward across the border to shenzhen city or beyond in mainland china, due to cheaper wages and land. by this time, hong kong was beginning to establish itself as a financial center and professional services hub, largely serving the booming mainland china economy supported by the open-door policy and the growth of the asian economy. by the beginning of the twenty-first century, hong kong had become well established as the fourth largest global financial and banking center in the region. over % of hong kong's gross domestic product (gdp) is generated from nonmanufacturing-related industries, including banking, financial and professional services, and retail. see quick et al. ( , p. ) . entrepot is a term use to describe a place where merchandise can be imported and exported without paying duties or tax, therefore the profit is being maximize. without other industries to generate wealth for hong kong, what is left is its status as an international financial center and its professional service-based industry, both of which are highly dependent on modern ict to operate from, protect, and maintain the integrity of hong kong's ict infrastructure. to its advantage, culturally, hong kong has been very receptive to newer technologies. the rapid adoption rate of smart mobile phones is one example. this is partially due to the fact that most new technology is manufactured in asia, and thus the closest source of production is relatively cheap to purchase. hong kong's per capita income is also relatively high (at us$ , in ), and that wealth and purchasing power means the general population can afford to buy newly marketed technology rapidly, and as such they have become increasingly technologically savvy. for example, hong kong was one of only a few places on the globe to launch apple's iphone in august . hong kong's political structure reflects its legacy as a british colony. characterized as a semiauthoritarian city state, hong kong did not become a democracy after its return to the prc in . although there is currently an ongoing debate in hong kong over the democratic election (supposedly one man, one vote) of the chief executive of the hong kong government special administrative region in , things remain uncertain because beijing is wary about democracy in hong kong out of a fear that it might become a base for subversion to undermine the communist party rule in mainland china. hong kong's governmental decision making is semiauthoritarian and top-down in nature, and the selection of the chief executive (formerly governor) is tightly controlled from beijing. only members of a select committee are allowed to vote in the chief executive election, and a great majority of them are pro-beijing merchants and professionals. the first chief executive was a well-known shipping tycoon, and the man who currently holds the office is also a well-known professional-turnedmerchant. the hong kong executive councilors (the executive branch of government policy decision-making body, who act as a cabinet to the government) are largely appointed from a pool of merchants and professionals. government policy does not answer to the public, and the general population does not vote the government into power. policy answers only to hong kong's tycoons the small number of select committee members and the political master in beijing. ultimately, government policy's priority is to protect and reflect the interests of the ruling elite and their supporters, rather than those of the general public, because the latter does not vote. since hong kong's reintegration with china in , there have been fears that some of the former's core values are being threatened, such as the erosion of rule of law due to the ways in which things are done in mainland china (corruption, nepotism, gangsterism, and the use of power and connections to avoid the law). some events have been cause for concern in hong kong. for example, beijing interpreted the basic law (the mini constitutional law of hong kong) in the late s and early s, but the major clash between beijing and hong kong over the rule of law occurred in , when beijing instructed hong kong's government to introduce article into the basic law to regulate subversion. article is similar to the national security laws in many western countries, but the very idea of such a law was new to postcolonial hong kong, and given the chinese communist party and the chinese government's track record, it sent chills down the spines of many in hong kong. the legislative process for article triggered a mass public outcry, with over half a million people protesting in the streets against the legislation. eventually, hong kong's government put the national security bill on hold indefinitely, temporarily shielding the rule of law in hong kong from being "mainlandized." however, the "mainlandization" of hong kong has accelerated, especially since , after a series of crises including the asian financial crisis in and the avian flu and severe acute respiratory syndrome outbreaks. these crises prompted hong kong to actively seek help from the mainland and push for greater economic integration. the closer economic partnership arrangement between mainland china and hong kong is a case in point. politically, it is in beijing's interest to help hong kong, as it would be seen as a failure for beijing if hong kong failed only a few years after reintegration. these factors have helped to accelerate the pace of hong kong's integration with the mainland, both politically and economically. hong kong's police force, as an arm of the government established in the early s, is directly funded by the government. the commissioner of police is appointed by and answers directly to the chief executive. the police force as a whole is directly accountable to the government officials at the security bureau. the commissioner of police, government officials, and the chief executive can be called before the legislative council to explain their decisions on issues relating to policing, but because hong kong is not a democratic society, the priorities for policing in hong kong are not set by election manifesto. thus, policing priorities are more likely to reflect the interests of the officials at the highest level of government than those of the general public. as a former british colony, hong kong is founded on common law. the main piece of legislation on computer-related crime is the computer crimes ordinance of . according to a report released by the hong kong interdepartment working group on computer-related crime, the computer crimes ordinance was instituted by amending existing laws and creating some new offenses to broaden the coverage of the extant legislation. hong kong's computer-related crime legislation is sufficiently flexible to cover both the physical and the virtual worlds. like hong kong, singapore was also part of the british empire. however, unlike hong kong, singapore gained independence from malaysia in the late s as a fully sovereign nation. singapore's economy is also different from that of hong kong. it comprises manufacturing (including hi-tech manufacturing and r&d), biotechnology, pharmaceuticals, electronics, technology and telecommunications, import and export, oil refinery, shipping and transport (south east asian hub), financial and banking services and professional services, and retail. almost % of singapore's export trades are interregional: malaysia ( . %), hong kong ( . %), mainland china ( . %), indonesia ( . %), and japan ( . %). hence, singapore economy is diverse. as an independent nation, singapore's clear advantage over hong kong is that she does not answer to a political master and is free to decide her own economic policy. one benefit of this is singapore's technological policy. from early on in its independence, singapore's government has exploited technology as leverage for economic development. as a result, singapore's economy has improved by adopting technology as its bedrock to upgrade industries across the economy. meanwhile, singapore's government has directly nurtured new technology-based industries, especially in the economy's indigenous sectors such as it, biotechnology, microelectronics, robotics and artificial intelligence, lasers/optics, and communications technology. the establishment of infocomm development authority (ida) of singapore is a case in point. as connie carter put it: few can doubt that singapore is a successful example of a growth-oriented, interventionist, capitalist state . . . for four decades the singapore government resolutely promoted economic development by: providing free market access to certain things; establishing and maintaining efficient infrastructure; orchestrating and investing in key export-led sectors of the economy; disciplining and educating the work force; and creating an ideology and delivering social justice and tangible benefits that secure the acquiescence of the people to the activities of the state and its elite bureaucrats. singapore's technological economy policy not only directly rewards indigenous sectors for innovation and high-tech adoption, but singaporean society at large also benefits from this technology-focused economy policy by being receptive to newer technology and becoming early adopters of high-tech products. the high penetration rate of the latest smart mobile phone is such an example. unlike hong kong, singapore is not dependent on a single industry to generate wealth. despite being capitalist and unlike hong kong, whose government is not directly involved in the economy, the singaporean government is deeply involved in the economy. in singapore, the domestic economy is largely dominated by two sovereign wealth funds: temasek holdings and gic private limited (formerly known as government of singapore investment corporation, gic). they are used to manage the country's reserves. initially, the state's role was oriented more toward managing industries for economic development, but in recent decades the objectives of singapore's sovereign wealth funds have shifted to a commercial basis. as a result, in recent years, government-linked corporations (glcs) have played an increasingly substantial role in singapore's domestic economy. the top six singapore-listed glcs account for about % of total capitalization of the singapore exchange. these fully and partially state-owned enterprises operate on a commercial basis and are granted no competitive advantage over privately owned enterprises. state ownership is prominent in strategic sectors of the economy, including telecommunications, media, public transportation, defense, ports, airport operations and banking, shipping, airlines, infrastructure, and real estate. for example, ida is the singaporean government's invisible hand-a statutory board of the singapore government under the ministry of communications and information. it was formed in when the government merged the national computer board and telecommunication authority of singapore to facilitate the convergence of it and telephony. with an annual budget of more than s$ million, the ida is responsible for the development and growth of the infocomm sector in singapore, and it functions as the country's infocomm industry champion, the national infocomm master planner and developer, and the government chief information officer. the ida's most recent project has been intelligent nation , a -year master plan. singapore is aiming to be the first nation in asia to be considered an it-related "smart nation." in , singapore has achieved a number of top benchmarks, including having the most digitized government (with % of government services online and in the cloud and more that % of singapore's information technology and communication (itc) in the cloud) and being the most networked country in the world (with % of the school-age population reporting access to a computer at home and % of households reporting access to broadband). like hong kong, singapore is also very receptive to newer technology, and its population is technologically savvy. the british broadcasting corporation (bbc) has profiled singapore as ". . . a hi-tech, wealthy city-state in south-east asia." singapore's per capita income is also relatively high (at us$ , in ). with this kind of wealth and purchasing power, the latest technological products are easily afforded by the general population. however, unlike hong kong, singapore is recognized by its government as a multiracial society with different ethnicities (chinese is the majority at almost %, with the rest of the population comprising those of malay and indian heritage). singapore's government has managed its society carefully, through social engineering of ethnicity and by providing subsidy housing (today over % of the population is housed through the government housing scheme) and socially engineering education, particularly that with an english language base. this has transformed singapore from a society once characterized by sharp contrast between ethnic groups who spoke different dialects and were separated by a large wealth gap into an affluent, english-speaking, middle-class industrialized metropolis. this has made singapore culturally different from many of its neighbors in south east asia, with the former being more in tune with technological development around the world because english is the common language used in commerce and in top scientific publications. thus, singapore has had an easy time acquiring newer technological knowledge and upgrading their skills. in theory, unlike hong kong, singapore is a democratic nation state with a parliament based on the westminster model. the government is voted into office via a one man-one vote election process. every years there are free and fair elections. the majority party or coalition gets to choose the prime minister, who then selects his/her cabinet of ministers. however, in practice, there is a similarity between hong kong and singapore. as vadaketh explains, "singapore has been governed as an authoritarian state. one party, the people action party (pap), dominates parliament." democracy in singapore, however, is "singapore style" or "asian democracy" whereby political power is in the hands of few singaporean elites. this "elite governance" or, more importantly the pap, has been active since for almost years. decision making is largely a top-down process because there is little-tono opposition in the parliament. as low said, "the pap government has viewed the economy and society as machines," and since pap came to power, its legitimacy has largely been gained through a strategy of social pacification and the institution of repression and redistribution. however, in recent years the pap suffered a setback in the popularity vote at the general election, only receiving . %, which was down % from the general election in . pap is facing the call for legitimacy in the government. nonetheless, with more than % of the popular vote, pap is still firmly in power. policymaking is largely pursuing economic growth, and anything else is a secondary consideration for the pap government, as they believe that economic growth would benefit most segments of society. like hong kong, singapore was a british colony, and thus it has a common law tradition and a court system similar to that of hong kong, with a court of appeals at the top (equivalent to the court of final appeal in hong kong, since july , ), then the high court and the subordinate courts such as district, magistrates', etc. however, the foundation of singapore's penal code is different from that of hong kong's, as the former was taken from india's penal code in its exact entirety and gradually developed a local flavor. another difference is the syariah court, which hong kong does not possess. one of the important first local pieces of legislation was the criminal procedure ordinance of , which was subsequently revised in . over time, various criminal laws were enacted. one of the most relevant to it was the computer misuse act, amended in . although singapore's computer misuse act followed the english act, one noteworthy difference from the hong kong computer crime ordinance is that the offense created by the singapore act has extraterritorial effects, as chan and phang explain: provided either the accused person was in singapore at the time or if the computer, program or data was in singapore at the time. this is in recognition of the widespread reliance on computer technology all over the world and its vulnerability to manipulation either from within our shores or abroad. as a former british colony, singapore's criminal justice system is a punitive regime with no jury at court trial and punishment based on hard labor. the prison system is designed to be as degrading as possible, and public caning is not a rare punishment for wrongdoers. although singapore's prison system has been reformed in recent years with the introduction of concepts such as restorative justice, rehabilitation, education and training, the police, courts, and other regulatory agencies still take a hard line on crimes by "nipping them the bud" as a deterrent to others. according to the bitglass cloud adoption report published in august , over % of businesses are still hesitant to transfer their data to the cloud due to security risk concerns that are largely about the cloud core architect of leveraging on virtualization. for example, dropbox for android smart phones uses cloud technology, and each time see chan and phang ( , p. ) . the singapore syariah court was established in by the government as an institution in settling disputes between divorcing muslim couple and related matters, such as maintenance, mut'ahconsolatory gift payable to the ex-wife upon divorce, custody care control and access to children, and matrimonial property (see syariah court singapore). chan and phang ( , p. ) . see bitglass, . data are delivered over the internetwork through different telecommunication channels, the data are virtualized, leaving the user unaware of which servers are involved or which host is delivering and its location, because the cloud only delivers a minimum volume of data stored for any given client. businesses that worry about data integrity and that fear losing their sensitive data have questioned whether their data are protected from outsiders and from other tenants sharing the same cloud data center. small business is especially vulnerable to this, as australian institute of criminology research in (hutchings et al., ) shows that small business is vulnerable to side channel attack or cross-guest virtual machine breaches, because in cloud, resources are shared with different tenants at the same cloud data center. as a result, tenants might crossing the shared virtual machine segment and accessing the data of other tenants using shared physical resources. more importantly, the same research has identified that small business is more vulnerable because they operate in highly financially constrained environment when compared with larger "global multinational" business, yet they are induced by the promise of cloud computing to save on their ict overhead. as hutchings et al. said "however, in adopting cloud computing, it is this distinct operating environment that also renders small businesses vulnerable to criminal and security threats [once attack happened some small businesses might not able to recover from it and the business could possibly come to abruptly end]." nevertheless, nearly % of the businesses in hong kong and in singapore are regarded as small businesses employing less than people. interestingly, users also wonder whether the data are protected from the cloud provider. cloud computing is largely modeled on the demand for access to a shared pool of configurable computing resources such as networks, servers, storage, applications, and services. all such resource sharing is to ensure fast provision and saving on costs. for example, us researchers were able to hack into gmail accounts with a % success rate by exploiting a weakness in smart mobile phone memory. the same research also found that once a smart mobile phone memory has been exploited, there is a great risk of collateral damage to other mobile apps on the same smart phone. as zhiyun qian said: the assumption has always been that these apps can't interfere with [each] other easily, but such assumption was wrong, one app can in fact significantly impact another and result in harmful consequences for the user. although in theory hong kong and singapore are exposed to similar risks and threats in the cloud, their level of readiness depends on how they perceive risk, as each individual jurisdiction interprets and responds to risk differently according to their unique policing needs. for example, hong kong would react strongly if its economy was threatened, particularly banking, financial, and professional services, because see hutchings et al. ( , p. ) . hutchings et al. ( , p. ) . see bbc news ( ). they represent the only industries by which wealth is generated. hong kong's reputation as an international financial center is dependent on the integrity of its ict. thus, the hong kong police keep a watchful eye on the it infrastructure to maintain foreign investor confident in hong kong, which creates employment and facilitates the payment of government taxes. furthermore, as a part of china since , hong kong must consider internal national politics, such as the growing threat of the separatist terrorism group from the xinjiang region. in nevertheless, the current setup of tcd, with limited manpower and as a division within the ccb, is not able to meet the challenges of the increasingly sophisticated technology crimes and cyber security threats, not to mention the constant support provided by tcd to other formations of the police in various cases, such as death inquest and locating missing persons. today, hong kong has one of the highest concentrations of wi-fi hotspots in the world, and % of households are able to access to broadband services. with a high mobile phone penetration rate of % which is expected to grow further, individuals, corporates, and critical infrastructure are prone to technology crimes and cyber security threats. subsequently, a more dedicated police formation "organization and structure" is needed to tackle the fast growing technology crime trend, including smart mobile phone crime: . . . to tackle the fast growing technology crime trend have become one of the operational priorities of the hkpf. given the rapid advancement in information technology and the transnational nature of technology crime, there is a pressing need to strengthen the overall capability of the hkpf in combating technology crime and cyber security incidents. hong kong's police have carefully explained their strategies to the legislative councilors, to take effect once the new technology crime bureau is established in early : dedicated attention and strategic planning to tackle the fast growing technology crime trend have become one of the operational priorities of the hkpf. given the rapid advancement in information technology and the transnational nature of technology crime, there is a pressing need to strengthen the overall capability of the hkpf in combating technology crime and cyber security incidents. with the establishment of a new bureau dedicated to the prevention and detection of technology crime and protection of cyber security, the hkpf's capability in combating technology crime and handling cyber security incidents will be greatly enhanced through the formulation of long-term objectives and strategies and expanded and dedicated efforts in the following areasi) detecting syndicated and highly sophisticated technology crimes and conducting proactive intelligence-led investigation; providing assistance to critical infrastructure in conducting timely cyber threat audits and analysis in preventing and detecting cyber attacks against them; ii) enhancing incident response capability to major cyber security incidents or massive cyber attacks; iii) strengthening thematic researches on cyber crime trend and mode of operation, vulnerabilities of computer systems and development of malware; iv) strengthening partnership with local stakeholders and overseas law enforcement agencies in information exchange and sharing of best practices to counter prevalent technology crime and cyber threats; and v) developing new training programmes on cyber security and technology crimes. hong kong's government recognizes the need to upgrade the police and equip them to face the ever-evolving technological landscape, with its ubiquitous mobile electronic devices such as smart mobile phones and tablets. furthermore, after being reintegrated with china for more than years, hong kong is far closer to china than ever before, economically and politically. the threat of terrorism from inside mainland china and especially from the xinjiang region has increased, and this terrorist group is known to be quite it savvy, often using social media to disseminate information and communicate with like-minded group members around the globe. they were said to have downloaded a video clip onto their smart mobile phones via the cloud and then watched it before carrying out their bombing attack inside mainland china. therefore, the hong kong government must consider this type of threat. the increase in muslim militant extremists represents an interregional, if not a global threat, and such militants are also known to use the electronic highway and smart mobile phones to carry out attacks and spreading ideological campaign material among themselves and other affiliated groups in asia. like hong kong, singapore is an important international financial center, yet its economy is more diverse, with a mixture of industries such as manufacturing, ibid., p. . oil refinery, shipping, and biotechnology. singapore is a democratic and a sovereign state with self-determination, even though its democratic process is regarded as a "controlled" democracy because the pap has been in power since the first day of independence from malaysia more than years ago, with little or no opposition in parliament. on august , , in a singapore national day speech broadcast live on channel news asia, prime minister lee hsien leong said, "keep singapore special in asia" by transforming it into "a smart nation." he introduced the singapore smart nation plan and provided detailed examples of a brand new housing community to be built in jurong lake district. the community will feature sensor boxes connected to fiber-optic lines deployed across the community and, eventually the entire country, at street lights, or bus stops. the sensor boxes can be designed to detect air pollutants, heavy rainfall, or traffic jams, or to report how full rubbish bins are, paired with cameras that can detect litter and remind litterbugs to pick up their trash. singapore has already laid the groundwork for the smart nation plan. for example, fiber internet is available to most households in the country, with super-fast gbps service costing as little as us$ per month. one of the key features of the proposed smart cities is the use of sensor boxes to set up wireless hotspots for a heterogeneous network, allowing smart phones and mobile devices to switch seamlessly between mobile data and wi-fi. singapore has also set aside spectrum to create new super wi-fi networks with greater range and coverage but a lower power requirement compared to standard wi-fi. the network will also be used to transmit smart nation data via the cloud. singapore is controlled from the top-down; it is an authoritarian society. the government is trying to harness the power of technology to increase the economy's productivity and efficiency. therefore, if the pap responds and wants to increase the resources provided to the singapore police to further increase their ability to fight the growing threat of technology-related crime, doing so will be relatively easier than it would be in many other democratic societies in western developed economies. singaporean voters may not necessarily agree with the pap's decisions regarding finite public resources being transferred from other more pressing social needs, as when they voted to form the government. however, the pap's manifesto may not mention anything about resources being earmarked for fighting technology-related crime, rather they may prefer to say that they will tackle traditional street crime and other forms of crime important to singaporean voters. even if both hong kong and singapore have the resources to respond to the potential risk of surging smart mobile phone crime, cloud computing-related crime is relatively new, and what worked in the past for less mobile devices such as personal computers may not work for the constant connectivity inherent in mobile devices. in the cloud, the configuration is usually a many-to-many network. to maximize the computing efficiency, virtualization is adopted, and thus data storage is located in host machine severs located in a many different places or countries. as gray explains: cloud technology offers wonderful potential for users in terms of convenience, ease of obtaining updates etc. however, it presents significant legal challenges. our laws, largely based on notions of territoriality, struggle to respond to technology in which lines on maps are largely irrelevant therefore, providing the financial resources is an important first step for law enforcement agencies to build up their policing capabilities in the cloud. other important elements are also required, such as knowledge of the cloud and the skills to find and collect electronic evidence in a live flow of data on a distribution network in the cloud, especially in a virtual machine. for example, in cloud data environments, it is often not possible to access the physical media that stores a customer's data, because cloud data are likely to be stored overseas and outside the investigating officer's jurisdiction. as hooper et al. noted: even if the data is stored within jurisdiction, data distribution technologies [in cloud] may split a user's data across a number (potentially thousands) of storage devices within the cloud computing environment. leas would need to rely upon the cloud technology and the cloud service provider to gain access to the data that is stored by a customer and this can introduce issues with chain-ofcustody best practices. another problem facing the investigating officer is the preservation of the cloud data evidence. the integrity of the data is important, so potential data evidence cannot be modified. however, when exporting cloud data evidence for examination by the investigating officer, there is a high chance of modification, as hooper et al. explain: preserved (to ensure that the potential evidence is not modified) function which many cloud computing environments do not currently support. consequently, this could result in accidental modification of data as it is exported from the cloud computing environment for lea [law enforcement agency] use or intentional destruction of data by the suspect. once the lea has secured access to the cloud computing data, the format of the data is still not guaranteed and most of the prevalent digital forensic analysis tools have not yet been updated to decode the major cloud computing data export formats. while many iaas data exports will likely mimic the data format that is currently supported as virtual machines, saas instances are more likely to use proprietary data formats and as such are unlikely to be supported by current tools finally, even if the police in singapore and hong kong do increase their policing capabilities in smart mobile phone and cloud-related crime, the legal limitations gray ( , p. ). see hooper et al. ( , p. ). ibid. remain a key factor in whether the perpetrator faces justice for the crime they have committed. even though singapore has enacted an extraterritorial law, because each country has enacted their own law according to their own socio-politic, socio-economic, cultural and legal traditions, and regulatory regimes, policing priorities differ by jurisdiction. there has been good progress on harmonizing the laws in recent years (interpol / mutual legal assistant, council of europe convention on cybercrime, etc.), but the task remains problematic due to jurisdictional issues. both hong kong and singapore will have trouble bringing an overseas perpetrator from their country of domicile to face justice for committing a cloud computing crime in hong kong or singapore. in short, it is clear from this chapter that lots of catching up need to be done for hong kong and singapore in order to beef-up their policing capability on cloud. at the domestic level, both governments in hong kong and in singapore must provide sufficient financial support to the policing agencies to enable them to fight the emerging crime such as cloud and smart mobile phone crimes. fighting technology-related crimes is an "arms race" which needs both money and human resources. more importantly, the government must provide training opportunities and education (including general public education to increase public awareness on emerging technologies crimes like cloud and smart mobile phone crimes and learning to cooperate with the private sector or businesses to reduce crime) for the law enforcement officers to upgrade their skills and knowledge on cloud which eventually help increase the success rate in bringing the perpetrator to face justice and punish them in court-as a deterrent to others not to commit the same offense. however, at the international level, it seems there is little that hong kong and singapore can do to alter the current situation, except to participate actively within the international bodies and convention on technology-related crime, and to learn from other jurisdictions around the world on what they are doing and, at the same time, tap into latest information on cloud computing crime to get a head start in fighting the emerging technology-related crime for themselves in the region. gmail smartphone app hacked by researchers eyes on the prize: law and economic development in singapore the development of criminal law and criminal justice cloud computing and its implications for cybercrime investigations in australia cloud computing for small business: criminal and security threats and prevention measures cyber crime-a growing challenge for governments legislative council panel on security creation of a permanent chief superintendent of police post of the cyber security and technology crime bureau technological policy and national competitiveness what went wrong for the pap in lockup or lose it, residents warned. south china morning post newspaper united nation international telecommunication union report information service department, hong kong sar government midnight world cup favours illegal bookmakers drawing new blood singapore: wealth, power and the culture of control key: cord- - s acr m authors: poh ng, lisa fong title: the virus that changed my world date: - - journal: plos biol doi: . /journal.pbio. sha: doc_id: cord_uid: s acr m personal account of a young virologist working in singapore at the height of the sars pandemic w hen i first read this little poem in the lancet in january (heikkinen and jarvinen ) , it elicited little more than a bemused chortle. there are few who would deny the paradox that for all the medical advances providing cures for multitudinous diseases afflicting the human condition, there remains a large hole in the understanding of and treatment for the common cold. we know that it is caused mainly by rhinoviruses and coronaviruses, but that's about it. having worked on coronaviruses for my doctoral thesis, i knew some of the many open questions. a few months later, however, our ignorance concerning these viruses took on an urgent relevance when an exploding viral pandemic in southern china, hong kong, vietnam, canada, and singapore left the scientific community stunned. in march , nobody was prepared for the onslaught of sars (severe acute respiratory syndrome)-we knew nothing about the causative agent for the disease and had no idea how to treat it. in singapore, the sars outbreak constituted the most challenging medical crisis in decades. doctors, scientists, government officials, educators, and even businessmen scrambled to contain the epidemic. schools were closed and children were ordered to stay at home. business organizations granted their employees medical leave, and many offices shut down temporarily. the bustling commerce and social scene in the country all but ground to a halt as people were afraid to gather in crowded places. even some churches were closed and sunday masses cancelled; those that remained opened required the congregation to don protective masks at all times. travelling on public buses and trains suddenly became an exercise in not merely avoiding the rush-hour crowds, but in avoiding any crowds at all. trendy shopping centres, cafes, and restaurants, once vaunted for packing in the throngs, became places to be avoided as the forbidding belief quickly spread that crowded places were hotspots for the transmission of sars. at changi airport, all in-and outbound passengers from singapore were "temperature-printed" (that is, they were asked to walk through scanners that picked up body temperatures above . ˚c) in order to curb the export and import of sars. with close to medical workers dressed in camouflage fatigues, gloves, and surgical masks stationed at the gateways to the country and ambulances ready to whisk away anyone who was sick or showed questionable signs of infection, the international press labelled the copyright: © lisa fong poh ng. this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. normally bustling airport a "combat zone." despite the rampant fear of sars and the frantic measures to contain it, not everyone complied with the rules and regulations. schools required that students declare the countries and places they had visited over the weekend or during the mid-semester holidays, but there were parents who told their children to conceal questionable information for fear of having to quarantine them at home. violation of quarantine orders by a few prompted the singapore government to threaten fines and jail sentences for those who failed to comply. cameras were installed in homes to ensure that people put under quarantine stayed indoors, and those who refused had electronic tags strapped around their wrists. such drastic measuresprompting the international herald tribute to refer to singapore as "a country with a reputation for dramatic approaches to public policy" (bradsher )-may have been greeted with defiance and frustration at first, but the vast majority of the population got quickly behind the approach. there was to be no letting up on the vigilance and precaution. not when it came to sars. in the three months that singapore was labelled as a "sars country" by the world health organization (who), over cases of sars were reported, and people died. these figures were devastating for singapore, which had not witnessed an epidemic of such proportions since the s, when polio was a major problem. referring to the high standards of medical care and the societal measures put in place, dr david mansoor of who said that if not even singapore could contain the outbreak, it was going to be very hard for other countries to prevent sars from spreading (chua i was to be part of the diagnostic team, and work began almost immediately. although we were under a great deal of pressure and stress, there was also a certain level of excitement in the face of a real-life crisis situation. the early days were the toughest, as we had very little information and were more or less groping in the dark. long, exhausting hours took over our lives, and on many occasions i felt discouraged and frustrated when the experiments did not yield anticipated results. however, there was no time to be despondent and ponder the vicissitudes of life as more and more people-friends among them-were struck down by the disease. all of us felt the need to work even harder, as we knew we could not afford to fail. the key goal was to uncover the complete sequence of the virus. at the end of april, researchers at the michael smith genome sciences centre in vancouver, british columbia, canada, and at the national microbiology laboratory in winnipeg, manitoba, canada, were the first to obtain the full sequence of sars-cov. in the following week, the sequencing team at gis, led by dr ruan yijun, obtained five different complete sequences (designated "sin") and compared these with the isolates from canada (tor ), hong kong (cuhk-w and hku ), hanoi (urbani), guangzhou (gz ), and beijing (bj , bj , bj , and bj ). dr ruan's team identified sequence variations among the isolates, and common variant sequences at four loci defined two distinct genotypes of the sars virus, whose signatures could be used to trace the sources of infection. shortly after this achievement, gis entered into a collaboration, through exploit technologies (the commercial arm of a*star), with roche diagnostics gmbh to develop a reliable diagnostic kit for sars. the gis team, which involved prof ren, dr martin hibberd, and myself, aimed to develop a clinically reliable polymerase chain reaction (pcr) assay for the sars sequence based on roche's lightcycler system. a one-step reverse transcription pcr (rt-pcr) assay was developed for specific and highly sensitive detection of sars-cov rna from clinical samples. multiple teleconferences were doi: . /journal.pbio. .g new premises of the genome institute of singapore at the biopolis (photograph by daniel lum, corporate communications, genome institute of singapore.) held with our collaborator, dr thomas emrich from roche diagnostics penzberg, to work out technical details before the optimal conditions were obtained. after two months of work, the kit performed to our satisfaction and became available commercially. collaborating with roche not only made a big difference to my ideas and my few experiments, but it was also a truly enriching experience to work with some of the world's experts in clinical diagnostics. from my earlier work, i had a good understanding of coronaviruses and their functional gene products, as my previous projects involved the study of the proteolytic processing of viral products. data obtained from this work were significant for further understanding of coronavirus replication and pathogenesis, but never had i imagined that i would be able to use this knowledge in designing the sars-cov diagnostic kit with roche. beginning in may, the sars pandemic started to retreat, and by the end of july, the who declared the end of the outbreak. the vigilance, however, is expected to continue for some time, as who authorities have warned of a possible return of sars during the winter months in the northern hemisphere. in singapore, temperature monitoring is still in place in many organizations, and as i was writing this article, news broke that another sars case had been discovered here. however, this time round, the authorities and the people are technically, academically, and emotionally much better prepared for the challenge. the months working on sars opened my mind, as it did my heart, about the importance of research and of keeping our faith and motivation even in the toughest times. interacting with some of the best minds in the field strengthened my commitment to a scientific vocation. but even more importantly, it reminded me of the true reasons for and potential of cold-eyed, back-breaking scientific exploration. i feel truly privileged to have been part of the unfolding of a small medical revolution.  hong kong moving modestly on sars. international herald tribune available at www.iht.com/articles/ .html via the internet sars puts singapore under the microscope. the straits times april. available at straitstimes.asia .com.sg/ columnist/ , key: cord- -fh b n authors: au yong, phui s.; chen, xuanxuan title: reducing droplet spread during airway manipulation: lessons from the covid- pandemic in singapore date: - - journal: br j anaesth doi: . /j.bja. . . sha: doc_id: cord_uid: fh b n nan reducing droplet spread during airway manipulation: lessons from the covid- pandemic in singapore phui s. au yong* and xuanxuan chen singapore *corresponding author. e-mail: angie.au.yong.p.s@singhealth.com.sg keywords: airway management; covid- ; extubation; infection control; intubation; operating room; prevention editordcoronavirus disease (covid- ) was declared a pandemic by the world health organization on march , because of its rapid worldwide spread. in the operating theatre (ot), anaesthetists are taking precautions for every patient to minimise perioperative viral transmission as infected patients can be asymptomatic. airway manipulation poses a high risk of viral transmission to humans within close contact because of the proximity of the respiratory secretions that can aerosolise from coughing and gagging. supplementary fig from chan and colleagues shows the dispersion of respiratory particles: the dispersion distance of exhaled air can range from to mm, and from coughing bouts after intubation up to mm. the singapore general hospital instituted guidelines for airborne and contact precautions, including (i) environmental, reducing staff during airway manipulation, regular disinfection and sterilisation, sufficient air exchange time; and (ii) personal protective equipment (ppe). we identified a potential shortcoming in that none of these measures reduced the production and spread of respiratory secretions, which contain the bulk of the viral burden. decontamination of the ot depends on adequate cleaning of ot equipment and reduction of viral load by high-frequency air changes. there is a long period between intubation and extubation, in which respiratory droplets remain on surfaces before cleaning. we describe some practical innovations that anaesthetists can consider integrating into their workflow. these innovations are not meant to replace ppe, but aim to reduce the cumulative risk of perioperative viral transmission to all the personnel in the ot. in countries where doctors are advised to reuse ppe because of shortages, these may afford an extra degree of protection. supplementary figs and were taken from a simulation run for proof of concept. all volunteers gave their consent. the appropriate ppe for intubation was not worn in this simulation to conserve supplies. the main aim of constructing a tent or screen is that, if the patient coughs/gags during intubation, secretions will land under the sheet. making the tent involves combining two transparent plastic bags into a single bag large enough to be draped over the patient's head to chest. two drip stands are used to hold the tent up. a videolaryngoscope and tracheal tube can be passed under the plastic tent for intubation. the c-mac ® (karl storz endoscopy (uk) ltd) videolaryngoscope is shown because it has an external screen outside the tent that would provide a clear laryngoscopy view. the tent is disposed and the drip stands wiped down. alternatively, supplementary fig shows the use of a large plastic screen for intubation. the same plastic sheet is draped over the patient's head and chest after inducing unconsciousness, and taped down at the sides to minimise leak. intubation is performed with the aid of the mcgrath™ (medtronic, usa) videolaryngoscope because of ease of cleaning compared with the c-mac ® . the plastic sheet can be left in the same position for the duration of the operation. if the patient needs to be in a lateral or beach chair position, the sheet is shifted correspondingly over the face. the advantage of the tent is its low cost, easy availability, and disposability. it allows room for manoeuvring the tube and is tall enough to allow a bougie in. the length of the tent is sufficient to fall past the patient's pillow so that there is no contact between the intubating personnel and the patient. this protective tent can be modified for use in icus during suctioning, bronchoscopy, and other aerosol-generating procedures. the screen is similar to the tent and provides a tighter seal. we suggest leaving adequate holes at the sides and the head end for the airway team to access the patient. there are reports of using acrylic boxes with preformed armholes for intubation. , however, that requires time and cost for manufacturing and delivery before it is available. the armholes, being of fixed shape and size, limit dexterity in manipulating the tracheal tube, especially in difficult airways. the bottom panel of the box is left open, which runs the risk of the assistant standing there being exposed to aerosolised respiratory secretions. supplementary fig shows use of a plastic screen for extubation. a small hole is cut distally to allow the ventilator tubing to pass through. if the patient coughs, secretions will land on the plastic sheet. a potential window of infection exists when the tracheal tube is removed with secretions at the cuff before it is thrown into the bin. we suggest for the tracheal tube to be wrapped with a plastic bag and immediately disposed. supplementary fig shows the two holes at the sides of a hudson mask (teleflex, usa) being taped up using a transparent dressing. the hudson mask is placed over the patient's face following intubation, and the tracheal tube passes under the hudson mask. at extubation, the hudson mask is connected to oxygen, and a suction catheter is passed under the hudson mask into the patient's mouth. once the patient is ready for extubation, the tracheal tube and the suction catheter are removed from under the mask and discarded immediately. should the patient cough post-extubation, secretions are contained within the mask. the patient can then be transferred out of the ot with the hudson mask for oxygen supplementation. in summary, these low-cost, accessible, and disposable methods can reduce contamination by respiratory secretions at the source. they may add another layer of protection from perioperative viral transmission during outbreaks of highly infectious diseases, such as covid- , especially in the context of acute shortages of ppe. statement-on-the-second-meeting-of-the-international-health-regulations-( )-emergency-committee-regarding-the-outbreak-of-novel-coronavirus-( -ncov presymptomatic transmission of sars-cov dsingapore air, surface environmental, and personal protective equipment contamination by severe acute respiratory syndrome coronavirus (sars-cov- ) from a symptomatic patient exhaled air dispersion during bag-mask ventilation and sputum suctioningdimplications for infection control iium doctor tweaks idea of aerosol boxes, urges engineers to make them in covid- treatment to assist frontliners barrier enclosure during endotracheal intubation the authors would like to thank david hui (department of medicine and therapeutics, the chinese university of hong kong, hong kong) for use of figure from his article. further thanks to sengkang general hospital, singapore for use of their ot, huiyi tan (department of anaesthesiology, sengkang general hospital, singapore) for being a participating investigator, and shariq ali khan (division of anaesthesiology, singapore general hospital, singapore) for his advice. the authors declare no conflicts of interest. supplementary data to this article can be found online at https://doi.org/ . /j.bja. . . . key: cord- -zb ih dl authors: chongsuvivatwong, virasakdi; phua, kai hong; yap, mui teng; pocock, nicola s; hashim, jamal h; chhem, rethy; wilopo, siswanto agus; lopez, alan d title: health and health-care systems in southeast asia: diversity and transitions date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: zb ih dl southeast asia is a region of enormous social, economic, and political diversity, both across and within countries, shaped by its history, geography, and position as a major crossroad of trade and the movement of goods and services. these factors have not only contributed to the disparate health status of the region's diverse populations, but also to the diverse nature of its health systems, which are at varying stages of evolution. rapid but inequitable socioeconomic development, coupled with differing rates of demographic and epidemiological transitions, have accentuated health disparities and posed great public health challenges for national health systems, particularly the control of emerging infectious diseases and the rise of non-communicable diseases within ageing populations. while novel forms of health care are evolving in the region, such as corporatised public health-care systems (government owned, but operating according to corporate principles and with private-sector participation) and financing mechanisms to achieve universal coverage, there are key lessons for health reforms and decentralisation. new challenges have emerged with rising trade in health services, migration of the health workforce, and medical tourism. juxtaposed between the emerging giant economies of china and india, countries of the region are attempting to forge a common regional identity, despite their diversity, to seek mutually acceptable and effective solutions to key regional health challenges. in this first paper in the lancet series on health in southeast asia, we present an overview of key demographic and epidemiological changes in the region, explore challenges facing health systems, and draw attention to the potential for regional collaboration in health. southeast asia consists of the ten independent countries located along the continental arcs and off shore archipelagos of asia-brunei, singapore, malaysia, thailand, the philippines, indonesia, vietnam, laos, cambodia, and myanmar (burma) (fi gure )-collectively known as the association of southeast asian nations (asean). the region contains more than half a billion people spread over highly diverse countries, from economic powerhouses like singapore to poorer economies such as laos, cambodia, • the diversity of geography and history, including social, cultural, and economic diff erences, have contributed to highly divergent health status and health systems across and within countries of southeast asia. • demographic transition is taking place at among the fastest rates compared with other regions of the world, whether in terms of fertility reductions, population ageing, and rural-to-urban migration. rapid epidemiological transition is also occurring, with the disease burden shifting from infectious to chronic diseases. • rapid urbanisation, population movement, and highdensity living raise concerns about newly emerging infectious diseases, but these outbreaks have stimulated regional cooperation in information exchange and improvement in disease surveillance systems. • southeast asia's peculiar geology contributes to it being the most disaster-prone region in the world, more susceptible to natural and man-made disasters aff ecting health, including earthquakes, typhoons, fl oods, and environmental pollution. climate change along with rapid economic development could exacerbate the spread of emerging infectious diseases. (continues on next column) (continued from previous column) • health systems in the region are a dynamic mix of public and private delivery and fi nancing, with new organisational forms such as corporatised public hospitals, and innovative service delivery responding to competitive private health-care markets and growing medical tourism. • the health-care systems are highly diverse, ranging from dominant tax-based fi nancing to social insurance and high out-of-pocket payments across the region. there is a greater push for universal coverage of the population, but more needs to be done to ensure access to health services for the poor. • private health expenditure is increasing relative to government expenditure, where new forms of fi nancing include user charges, improved targeting of subsidies, and greater cost recovery. health-care fi nancing could be further restructured in response to future demographic shifts in age-dependency, as in introduction of medical savings and social insurance for long-term care. • there is potential for greater public-private participation with economic growth through asean integration and further regional health collaboration, despite the current division of the region under two who regional offi ces. and myanmar (table) . [ ] [ ] [ ] [ ] [ ] [ ] [ ] by comparison with india and china, southeast asia is less visible in global politics and economics. the same is also true of global health. in the fi rst paper in this lancet series on health in southeast asia, we analyse the key demographic and epidemiological transitions of the region to delineate the challenges facing health systems and to emphasise potential for regional collaboration in health. this regional overview sets the scene for more detailed discussion of specifi c health issues presented in the fi ve subsequent reports in this series, profi ling maternal and child health, infectious diseases, non-communicable diseases, health workforce challenges, and health-care fi nancing reforms. southeast asia contains about million people, or % of the world's population, with indonesia having the largest population (and fourth largest in the world) and brunei the smallest (see table) . nearly half ( %) of the region's population live in urban areas, which is less than the world average, but there is much variation between countries, from % in cambodia to % in singapore. the region's average population density of people per km² also masks substantial intercountry and in some instances intracountry diff erences. population densities range from a low of people per km² in laos to a high of per km² in singapore. population densities in southeast asia's only two megacities, jakarta and manila, are much higher, at more than people per km². although their population sizes are similar (around million), the greater sprawl of manila and jakarta make them less densely populated (ranked th and th in the world) than mumbai and delhi (ranked st and th, respectively). the next largest city in southeast asia, bangkok, is ranked th. although urbanisation is expected to continue to rise in the region, urban slum populations seem to be less deprived than they are elsewhere, with about a quarter living in extreme shelter deprivation (defi ned by un habitat as a slum household lacking three or more of the following conditions: access to water, access to sanitation, access to secure tenure, a durable housing structure, and suffi cient living space). , although life expectancy in all countries in the region has improved, there have been signifi cant variations in the rate of progress. most countries have enjoyed continuous rises in life expectancy since the s, and these are converging. in some cases (myanmar, cambodia) political regimes and history of confl ict have aff ected progress, as has hiv in thailand (fi gure ). where life expectancy gains have slowed, this trend has been mainly attributable to slow progress in reduction of adult mortality. there has been little progress towards reduction of intercountry diff erence in life expectancy during the past years, with the gap remaining at around years. as elsewhere, decreased fertility has been the main factor contributing to ageing of the populations in these countries. the speed and timing of fertility reduction has varied widely across the region (webappendix p ). singapore had the earliest and sharpest reduction-the total fertility rate fell from more than six children per woman in to · in the mid- s, and since , it has ranked among countries with ultra-low fertility (table). thailand's fertility decrease mirrors that of singapore, although beginning somewhat later; it is currently the only other country in the region with we used quantitative and qualitative data from academic and grey literature to review the health situation in southeast asia. search terms used were "health", "health statistics", "health systems", "socio-economic development", and "southeast asia". data were gathered after a call for information from regional experts on selected subthemes related to health (geography, history, demography, epidemiology, and health systems rapid socioeconomic development and strong family planning programmes are likely to have driven this reduction. interestingly, this statement was true for indonesia, but less so for brunei and malaysia, although all three countries share a common dominant religion, islam. malaysia adopted a pronatalist policy in the late s under the then prime minister mahathir mohammad. catholicism has been a major contributing factor to the slow uptake of family planning programmes in the philippines, alongside the persistence of cultural norms that support large family sizes. the high fertility rates recorded in cambodia and laos are related to low educational levels, as refl ected in their low proportion of enrolment in secondary school- - % compared with - % elsewhere in the region (including % in vietnam). according to cleland, although literacy confers cognitive abilities to use contraception, the social and psychological skills conferred by higher education probably enable people to "translate the desire to postpone or limit childbearing into contraceptive practice… [and] they are also more likely to use allopathic health services for a range of needs including ante-and natal-care, child immunization and curative care [that lead to better child survival]". economic and demographic developments have prompted the movement of people across the region, mainly for short-term employment, but also for settlement. rapid economic growth and the slowing of domestic population and labour force growth due to fertility reduction have prompted countries such as singapore to open its doors to in-migration of foreigners at all skill levels for employment, with the option of permanent settlement for the highly skilled. the philippines, indonesia, and vietnam are major labour-exporters, whereas malaysia and thailand both receive and send nationals abroad. besides this internal labour market, countries in southeast asia also send and receive migrants from outside the region. since the s, however, destinations within asia have replaced labour migration to countries such as the usa and to the middle east. there is signifi cant undocumented or illegal migration as well as movement of displaced people in the region. , these groups are particularly vulnerable since "[u]ndocumented migrants are disproportionately more exposed to health risks due to inadequate working conditions and irregular movements, but are unlikely to seek medical attention because of their status, and are also often left out of assistance programmes in times of disasters and emergencies". population age structures of countries in the region vary widely as a result of past diff erences in fertility, mortality, and migration trends (fi gure ). these trends are in turn aff ected by economic, social, cultural, and political developments. singapore and thailand have among the fastest ageing populations in the world, with the proportion of elderly residents projected to double from % to % in and years, respectively-shorter than the years expected for japan - because of more rapid fertility reduction in these two countries. with increasing longevity, the pace of increase in numbers of the oldest old, aged years and older, in southeast asia is projected to exceed that of east asia over the period - . the other major factor contributing to population ageing has been the decrease in mortality. figure shows estimated trends in risk of child death (ie, between birth and age years) in countries of the region during the past four decades. child survival has improved substantially in all countries, but particularly in indonesia, vietnam, thailand, malaysia, brunei, and singapore, where the risk of child death is now typically less than about · %, compared with - % in the s. measured by the risk of dying between ages and years, regional diversity in levels of adult mortality is even greater than for child mortality (fi gure ). typically, the risk of dying at these ages for men is - %, and is higher ( %) in cambodia, laos, and myanmar ( - %), and signifi cantly lower in singapore, where the level is similar to those in australia and japan ( - %). this regional diversity in risk of adult death is similar for women, but with rates typically - % less than those for men. increasing longevity is a result of diminishing burden from communicable, maternal, and perinatal diseases (group diseases; webappendix p ), whereas countries with aged populations have a higher burden of noncommunicable diseases (group diseases). interestingly, mortality rates from these two groups of diseases, as well as from injuries, are correlated. countries with high mortality rates from communicable diseases also have high death rates from chronic diseases (webappendix p ). deaths from communicable diseases are still prominent in cambodia, myanmar, and laos. injuries are an important cause of death in all countries, but less so in singapore and brunei. few countries in the region have complete cause of death data systems to inform health policy and planning, and of those that do only singapore has reliable cause of death certifi cation and coding. although not representative of present health conditions in neighbouring countries, understanding of how leading causes of death have changed in singapore during the past years or so can provide important insights into what other countries of the region could expect to achieve, provided there is a similarly strong public health commitment to disease control and injury prevention. figure summarises trends in selected causes of death for both sexes in singapore since . in the early stages of transition, striking reductions in infectious diseases such as tuberculosis were achieved, off set by increases in non-communicable diseases including cardiovascular diseases and cancers, as well as injuries. although deaths due to road traffi c accidents have subsequently decreased and cardiovascular diseases seem to have reached a plateau, breast cancer has continued to rise. except for stomach and cervical cancer, mortality from all other cancers is still rising (data not shown). these data illustrate the success of singapore in reducing mortality from the diseases of poverty, as well as the eff ects of inadequate chronic disease control programmes, although there is evidence of some success in control of lifestyle-related diseases in recent years. as other countries in the region succeed in bringing communicable diseases under control, the importance of injury prevention and chronic disease control programmes will become increasingly pressing. the region as a whole does not have reliable longitudinal data for disease trends. however, evidence from studies of disease prevalence shows a strong inverse association with national wealth, which can be largely attributed to the social determinants of health, including the provision of more effi cient health systems with greater population coverage. the fi gure provided on p of the webappendix shows the relation between prevalence of tuberculosis and per head income (log-log scale). the regression equation (not shown) suggests that a doubling of per head income is associated with a reduction in tuberculosis prevalence of %. for diabetes mellitus prevalence, countries can be roughly divided into three groups that are positively correlated with income, although the eff ect tapers off at higher levels of per head income, (webappendix p ), possibly because of more eff ective disease control programmes with greater coverage. hiv was introduced into the region in the s. transmission peaked in the early s in thailand, followed by myanmar and cambodia. hiv/aids has been a major cause of death in some countries of the region (eg, thailand), although its spread has been partly controlled by the promotion of condom use. in the early s, more eff ective antiviral therapies emerged, followed by the introduction of compulsory licensing. although universal access to treatment has been attempted, patient compliance and losses to follow-up care are still prevalent. , aids mortality in southeast asia has stabilised since the mid- s, although prevalence remains high in myanmar, laos, and cambodia. the environment continues to be an important contributing factor to disease and mortality in the developing world, including countries in southeast asia, accounting for up to a quarter of all deaths. regular monsoons and typhoons occur in southeast asia. the el niño and la niña phenomena also intensify the annual variation of the hot and wet climate, leading to droughts, fl oods, and the occurrence of infectious diseases such as malaria and cholera. countries in the northern part of the region such as the philippines and vietnam are badly aff ected by seasonal typhoons that have increased in intensity over time. the philippines and indonesia are located on the pacifi c ring of fire, a zone of earthquakes and volcanoes where around % of the world's earthquakes occur. southeast asia is one of the most disaster-prone regions in the world; the indian ocean earthquake off the coast of sumatra in caused a devastating tsunami in aceh, indonesia, and countries on the fringe of the indian ocean, one of the worst natural disasters ever recorded. uncontrolled forest fi res raged in the indonesian states of kalimantan and sumatra in . the severity of the fi res was also closely linked to the occurrence of the el niño southern oscillation, which has historically brought severe drought conditions to southeast asia, creating conditions ripe for fi res. in , the severity and extent of haze pollution was unprecedented, aff ecting some million people across the region. the health-related cost of the haze was estimated to be us$ million. the health eff ects of the haze in southeast asia have been well documented. , an increase in concentration of particulate matter with diameter μm or less from μg/m³ to μg/m³ was signifi cantly associated with increases of % in upper respiratory tract illness, % in asthma, and % in rhinitis from public outpatient care facilities in singapore. time-series analyses in people admitted to hospital in kuching, malaysia, showed that signifi cant fi re-related increases occurred in respiratory hospital admissions for chronic obstructive pulmonary disease and asthma. survival analyses suggested that people older than years who had been previously admitted to hospital for cardio respiratory and respiratory diseases were signifi cantly more likely to be readmitted during the haze episode. climate change could exacerbate the spread of emerging infectious diseases in the region, especially vector-borne diseases linked to rises in temperature and rainfall. southeast asia has been identifi ed as a region that could be vulnerable to eff ects of climate change on health, because of large rainfall variability linked to the el niño and la niña oscillation, with attendant consequences for health systems. southeast asia's rich history and recent industrialisation and globalisation have raised new challenges for the region's health systems. modern medical technology is available in the world market but at costs higher than most of the region's population can aff ord. many traditional health practices persist alongside the use of new medical technologies and pharmaceutical products, presenting regulatory problems in terms of safety and quality. with increasing educational levels, ageing populations, and growing consciousness of human rights in the recently developing democratic environment, the demand for better care is increasing. health systems in the region face more serious adjustment problems than ever before. health services have become an important industry, with a mix of public and private non-profi t and for-profi t actors, along with the growth of trade and medical tourism. the provision, fi nancing, and regulatory functions of the public sector have to adapt accordingly to these transformations. the need to restructure healthcare delivery and fi nancing systems becomes crucial to balance new demand and supply equilibriums. , countries in southeast asia and their health system reforms can thus be categorised according to the stages of development of their health-care systems. a typology of common issues, challenges, and priorities are generated for the diverse mix of health systems of southeast asia at diff erent stages of socioeconomic development (see webappendix pp - ). the pressures placed on national health-care systems by the recent demographic and epidemiological transitions that we have described are amplifi ed by the growing demands of an increasingly educated and affl uent population for high quality health care and the supply of the latest medical technology. before the east asian fi nancial crisis in - and the recent global economic recession, an expanding middle class in the urban populations of the larger cities pushed their demand for high quality care into a booming private sector. as a result, market forces have turned many aspects of health care into a new industry in countries such as singapore, malaysia, and thailand, contributing to labour-force distortions for the production and distribution of health workers both within and across countries. the s began with the opening up of socialist states and rapid growth among market economies in the region. while they were each fi nding ways to reform their health systems, the asian fi nancial crisis in - posed more challenges for countries of the region. the depreciation of local currencies resulted in increased costs of imported drugs and other essential supplies, at the same time as access to basic health care was reduced for the most vulnerable population groups. however, reported spikes in suicides and mental illnesses in the other aff ected east asian economies such as south korea, taiwan, and hong kong were not as signifi cant in southeast asia. following the lessons learnt from the past fi nancial crisis, most countries have strengthened their social protection mechanisms and essential health services. there is a greater push among countries to increase universal coverage of basic health services, especially to vulnerable and disadvantaged populations. , throughout the region, many innovative pro-poor fi nancing schemes were implemented, such as the health card and -baht schemes in thailand, the health fund for the poor in vietnam, health equity funds in cambodia and laos, and, even in affl uent singapore, the medifund, a meanstested hospital fees subsidy scheme for indigent patients. so far, the health-care systems with dominant tax funding are fairly stable, in view of the strong role of governments and eff ective controls by health agencies to overcome inequity problems. however, crucial issues involve rising costs, future sustainability of centralised tax-fi nanced systems, effi ciency and quality of the public services, and higher public expectations. in both malaysia and singapore, the health-care systems are changing from government-dominated health services towards greater private-sector involvement. attempts to privatise public hospitals have been controversial, thus resulting in many hybrid forms of corporatised entities that continue to be controlled or subsidised by governments. [ ] [ ] [ ] [ ] some of the most innovative and advanced forms of publicprivate mix in health services have developed within the region, for example the restructuring or corporatisation of public hospitals in singapore from as early as and the later swadana (self-fi nancing) hospitals in indonesia. with the anticipated rise in the ageing population and future problems of intergenerational funding through pay-as-you-go mechanisms, there are experiments with new health-care fi nancing such as compulsory medical savings and social insurance for long term care. [ ] [ ] [ ] some countries such as the philippines, vietnam, and indonesia have radically decentralised their health-care systems with the devolution of health services to local governments, a restructuring that has aff ected aspects of systems performance and equity even though the impetus for cardiovascular diseases excluding rhd breast cancer tuberculosis road traffic accidents decentralisation was mainly political. consequently, to ensure increased fi nancial coverage and aff ordability, many governments have passed laws to establish national health insurance systems and mandated universal coverage, although implementation is problematic. with existing policies of decentralisation and liberalisation, equity issues and poor infrastructure will continue to challenge the development of the health sector. , the severe acute respiratory syndrome (sars) epidemic has emphasised the need to strengthen regional health collaboration. this cooper ation has occurred via two channels-direct bilateral collaboration by individual countries (ministries of health and foreign aff airs) and those under the aegis of asean. the mekong basin disease surveillance project is an example of successful health cooperation. it was established under the collective agreement of each ministry of health of member states of the greater mekong subregion to share important public health information. the emergence of infl uenza a h n and h n outbreaks has led to common eff orts to strengthen epidemiological surveillance and stockpiling of antiviral drugs. enthusiasm for regional economic collaboration continues to grow, evident from the explicit goal of the asean free trade area to increase the region's competitive advantage as a production base geared towards the world market. asean leaders have identifi ed health care as a priority sector for region-wide integration. from an economic perspective, opening of health-care markets promises substantial economic gains. at the same time, however, this process could also intensify existing challenges in promotion of equitable access to health care within countries. it could also lead to undesirable outcomes whereby only the better-off will receive benefi ts from the liberalisation of trade policy in health. health and trade policy can and do appear to contradict each other. tobacco use is the major preventable cause of non-communicable disease and death among the populations of asean countries. all asean members except indonesia have embraced the framework convention on tobacco control (fctc) and all countries endorse some form of tobacco control policy. however, most of these states are, to varying degrees, still involved in investment in or promotion of the tobacco industry, often using the justifi cation of poverty alleviation. there are clear contradictions inherent in the state seeking to prevent tobacco use in the interests of health, while actively promoting tobacco for the economic benefi t of its population, resulting in both substantial and symbolic harm to eff orts to implement the fctc. for example, tobacco production is legitimised; rational policy principles are violated, and direct cooperation between the state and multinational tobacco corporations is made possible by modifi cation of control policies. tobacco exports within asean also threaten the group's health solidarity. divestiture of state ownership of capital in tobacco corporations and a much stronger commitment by states to control the use and promotion of tobacco are urgently required in asean countries. issues of intellectual property rights surrounding products such as essential pharmaceutical drugs as public health goods are also of concern to countries. thailand started compulsory drug licensing in . indonesia has called for the urgent development of a new system for virus access and a fair and equitable sharing of the benefi ts arising from the use of the infl uenza virus in research (now commonly referred to as viral sovereignty). additionally, indonesia has pressed for the development of medical products to replace the existing patent system in global health governance. with globalisation, ensuring of accessible health services for citizens is no longer the sole responsibility of the state; health care in southeast asia is fast becoming an industry in the world market. the private sectors in singapore, thailand, and malaysia have capitalised on their comparative advantage to promote medical tourism and travel, combining health services for wealthy foreigners with recreational packages to boost consumption of such health services. patients from elsewhere, including the developed countries, are choosing to travel for medical treatment, which is perceived to be high quality and value for money. because of poor local economic conditions, the philippines had a policy to export human resources for health to the world and to richer countries in the region as an income-generating mechanism. although the fi nancial returns from this strategy seem substantial, equity issues have surfaced concerning the negative eff ects of international trade in health services and workforce migration on national health systems, especially in widening disparities in the rural-urban or public-private mix. regional collaboration in standards of data collection and health systems analysis is hampered by who's division of the asean region into two areas under separate regional offi ces: the south-east asia regional offi ce, encompassing indonesia, myanmar, and thailand, and the western pacifi c regional offi ce, consisting of the remaining countries. potential benefi ts from enhanced who regional cooperation include improved health surveillance, information-sharing, and health systems strengthening in all asean countries. southeast asia is a region characterised by much diversity, including public health challenges. social, political, and economic development during the past few decades has facilitated substantial health gains in some countries, and smaller changes in others. the geology of the region, making it highly susceptible to earthquakes and resultant tsunamis, along with seasonal typhoons and fl oods, further increases health risks to the population from natural disasters and longterm eff ects of climate change. public policy in these countries cannot ignore such risks to health, which could have important social and economic consequences. regional cooperation around disaster preparedness and in the surveillance of and health systems response to disease outbreaks has obvious advantages as a public health strategy. concomi tantly, all countries in the region are faced with large or looming chronic disease epidemics. even in the poorest populations of the region, non-communicable diseases already kill more people than do communicable, maternal, and perinatal conditions combined, with many of these deaths occurring before old age. greatly strengthened health promotion and disease prevention strategies are an urgent priority if the impressive health gains of the past few decades in most countries of the region are to be replicated. further growth and integration of the asean region should include as a priority enhanced regional cooperation in the health sector to share knowledge and rationalise health systems operations, leading to further public health gains for the region's diverse populations. all authors contributed to data collection, interpretation, writing, and revision of the report. we declare that we have no confl icts of interest. population division of the department of economic and social aff airs of the un secretariat maternal, neonatal, and child health in southeast asia: towards greater collaboration emerging infectious diseases in southeast asia: regional challenges to control the rise of chronic non-communicable diseases in southeast asia: time for action human resources for health in southeast asia: shortages, distributional 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and access to vaccines and other benefi ts this paper is part of a series funded by the china medical board, rockefeller foundation, and atlantic philanthropies. key: cord- -ds jv ek authors: tambyah, paul a title: severe acute respiratory syndrome from the trenches, at a singapore university hospital date: - - journal: the lancet infectious diseases doi: . /s - ( ) - sha: doc_id: cord_uid: ds jv ek summary the epidemiology and virology of severe acute respiratory syndrome (sars) have been written about many times and several guidelines on the infection control and public health measures believed necessary to control the spread of the virus have been published. however, there have been few reports of the problems that infectious disease clinicians encounter when dealing with the protean manifestations of this pathogen. this is a qualitative account of some of the issues faced by an infectious disease physician when identifying and treating patients with sars as well as protecting other healthcare workers and patients, including: identification of the chain of contagion, early recognition of the disease in the absence of a reliable and rapid diagnostic test, appropriate use of personal protective equipment, and the use of isolation to prevent super-spreading events. many issues need to be addressed if clinicians are to be able to manage the virus should it reappear. the epidemiology and virology of severe acute respiratory syndrome (sars) have been written about many times and several guidelines on the infection control and public health measures believed necessary to control the spread of the virus have been published. however, there have been few reports of the problems that infectious disease clinicians encounter when dealing with the protean manifestations of this pathogen. this is a qualitative account of some of the issues faced by an infectious disease physician when identifying and treating patients with sars as well as protecting other healthcare workers and patients, including: identification of the chain of contagion, early recognition of the disease in the absence of a reliable and rapid diagnostic test, appropriate use of personal protective equipment, and the use of isolation to prevent super-spreading events. many issues need to be addressed if clinicians are to be able to manage the virus should it reappear. the severe acute respiratory syndrome (sars) coronavirus is a novel pathogen that emerged in southern china at the end of and because of a single event in a hotel in hong kong one night in february , spread to three continents. who issued an unprecedented global alert; by the end of the epidemic, more than people had been infected with sars, of whom died, and the economies of several east and southeast asian countries were damaged. there have been many publications and scholarly reviews on the origin, pathophysiology, virology, , clinical features, and epidemiology of the virus. however, there are few detailed accounts of the practical issues faced by clinicians in dealing with a novel, lethal, emerging, nosocomial pathogen. this paper describes the experience of a busy infectious disease clinician at a large teaching hospital in singapore during the sars outbreak. on march , , a year old woman who reported having fever, chills, productive cough, and diarrhoea for days came to the national university hospital (nuh), singapore; her past medical history included hypertension only. the previous day, the ministry of health in singapore had declared tan tock seng hospital (ttsh), where the first cluster of sars infections happened, as the national sars hospital. all patients who met the who criteria for sars were to be transferred to ttsh for isolation and treatment. in the week before she presented to nuh, our patient visited a friend with hepatitis at ttsh and then travelled to east malaysia. she had no direct contact with patients with sars at ttsh and the only sars affected country she had been to was singapore. on examination she was febrile to º c, tachypnoeic, tachycardiac, and had bilateral infiltrates on chest radiography (figure a). initial pathology analyses were: a white blood cell count of · ϫ /l (polymorphs %, lymphocyte %), haemoglobin · g/l, platelet count of ϫ /l, urea · mmol/l, creatinine mol/l, and lactate dehydrogenase iu/l. this patient was admitted to an isolation ward with a diagnosis of community-acquired pneumonia. she was not transferred to ttsh as a suspect sars case because there had not been any direct contact with patients with sars and because of her leucocytosis, which was not thought to be a feature of sars. even now she would be excluded from singapore's "post-epidemic sars surveillance", which mandates the absence of leucocytosis. she was treated with levofloxacin and ceftriaxone, but because she continued to deteriorate, her treatment was changed to ceftazidime and later imipenem. she was transferred to the medical intensive care unit where she was intubated and mechanically ventilated. a bronchoalveolar lavage was done on march , and cultures were negative for bacteria, fungi, respiratory viruses, and mycobacteria. despite inotropic support, haemofiltration, and intense ventilatory support with high frequency oscillatory ventilation, she died days after her admission (figure b). later it became known that two patients who were being nursed in the same ward as, two rooms from, the friend our patient visited at ttsh had undiagnosed sars. at postmortem examination our patient was confirmed to have sars by a dot-blot immunoassay using a viral lysate in an analysis of a serum sample that was taken from her days after admission. days after the bronchoscopy was done, the intensivist, who wore a n mask, gloves, and a gown during the procedure, developed fever, chills, and myalgia and was admitted directly to ttsh. the intensivist progressed to acute respiratory distress syndrome (ards), and had mechanical ventilation, but survived. the son of our patient was also admitted to ttsh with a diagnosis of sars. the polytechnic where he was studying was closed for days while contact tracing was done for all students and those with closest contact with him were placed on a restrictive home quarantine order; none had sars. careful temperature surveillance and a serological study showed that nobody at the nuh intensive care unit or isolation ward was infected with sars. the global dissemination of the sars virus, including that of our patient, can be traced to a hotel in hong kong on february , . a physician from guangdong province in china who eventually died from sars stayed on the ninth floor of the hotel; when other people staying on the ninth floor returned to vietnam, the usa, canada, hong kong, ireland, and singapore they started epidemics in these countries. [ ] [ ] [ ] [ ] it is striking that despite extensive global air travel from hong kong and southern china, both clinical and molecular epidemiological evidence suggest that the entire worldwide epidemic of sars outside of southern china can be traced back to that single event. four women from singapore stayed on the ninth floor that night, three of them returned to singapore and developed pneumonia in the next week. for reasons that are unclear, only one of these women was associated with transmission of the sars virus. hsu and coauthors have reported the clinical features of the index case and her contacts at ttsh. one of eight doctors and nine of nurses who were caring for this person developed sars; one of patients in the same ward as this person and nine of friends and family that visited her became infected. when combined with the other "imported" cases of sars in singapore, these rates of exposure and infection are comparable to those in beijing, china. in beijing, quarantine of family member or healthcare worker contacts yielded cases-an overall attack rate of · %. in a beijing hospital study, infection rates were highest in nursing assistants ( · %) compared with nurses ( · %) and doctors ( · %), possibly the result of differences in contact with patients with sars. these infection rates are lower than have been reported for airborne viruses, suggesting that contact transmissionthrough direct contact with infected patients, or their large particle respiratory droplets, or environmental surfaces-is more likely to lead to sars than airborne transmission in most situations. this suggestion perhaps should lead to re-examination of an infection-control strategy that involves respiratory protection and environmental control of ventilation in hospital facilities. there are situations in which airborne transmission is thought to have resulted from the use of aerosol generating procedures. during days without isolation, a single patient who received nebulised bronchodilator therapy four times a day at the prince of wales hospital in hong kong became the source patient for other patients, although, the role of nebulised bronchodilator therapy in that outbreak has been challenged. when our patient was incubating sars, she had been on a short holiday by aeroplane. there is no evidence of transmission during her two flights, but this raises the issue of travel advisories. whereas many countries as well as who issued widespread travel advisories, a dispassionate analysis of patients infected with sars who travelled on aeroplanes showed that, with one exception, sars was rarely transmitted on aeroplanes. a single flight was associated with the transmission of sars to passengers (confirmed in a laboratory in cases), some of who were seated at a distance from the source patient and did not meet who criteria for close contact. another flight carrying four symptomatic individuals was not associated with transmission of sars and only one of passengers had any symptoms. the singapore experience as reported by wilder-smith and co-authors is also instructive. seven aeroplanes carrying nine passengers with sars, four of who had symptoms, arrived in singapore. only one of passengers and crew were infected. this was in spite of one of the symptomatic individuals being a so-called "super-spreader" and another being so critically ill that she had to be intubated and mechanically ventilated shortly after arriving in singapore. beijing authorities screened · million aeroplane passengers for fever, detecting febrile individuals, ten of whom developed sars. travel advisories had a devastating effect on the economies of the affected countries, but their role in controlling the epidemic is not clear. it is possible that the original purpose of the travel advisories was to prevent the virus from crossing borders but most countries did not implement such intense screening at land borders and by the time the advisories were issued, sars had already spread to three continents. the impact of a belated travel advisory on the city of toronto was considerable and has been debated at length. thankfully, with the recent cases of sars in southern china and beijing, travel has not been restricted. perhaps for a virus that was largely nosocomially transmitted in canada, singapore, and vietnam, travel advisories should have advised only against travel to hospitals in affected countries. one of the problems with the management of sars was the non-specific nature of the illness. sars was not recognised in our patient because of a dependence on the case definitions of who. these excellent case definitions were designed for epidemiological investigation but had limited utility for clinicians managing cases presenting to busy hospital emergency departments. the who criteria required a temperature of greater than º c, cough or respiratory symptoms, and direct contact-defined as having cared for, lived with, or had close contact with the respiratory secretions or bodily fluids of a patient with suspect or probable sars-none of which applied to our patient. the problem with our patient and with many others in singapore is that the epidemiology was not initially apparent. rainer and co-authors reported that the who sars criteria is % sensitive for predicting which of the patients presenting to a busy emergency department during the sars epidemic had sars. in our hospital, we found that use of the who criteria as a clinical screening tool gave a sensitivity of %, specificity of %, positive predictive value of %, and negative predictive value of %. data now emerging on the initial presentations of sars , , suggest that fever and myalgia are more prominent initial symptoms and that respiratory symptoms manifest only later in the illness. unfortunately, these symptoms are so non-specific that few hospitals anywhere in the world could afford to isolate all patients with fever and malaise. consequently, sars-affected countries such as singapore had to modify the who definitions to suit local conditions; there was a loss in sensitivity as greater specificity was achieved. on march , it was decided that ttsh would be the only hospital in singapore to treat patients with sars. management of all potential cases of sars at one hospital was introduced to allow the rest of the healthcare system to function normally. the impact on ttsh and other hospitals was considerable; patients were rapidly discharged from ttsh to clear beds for the admission of patients with suspected sars, and other hospitals had to carry the load from diverted patients. unfortunately, many of the patients transferred to other hospitals were incubating the sars virus through casual contact with patients with sars in the same ward or in common areas such as radiology suites. these patients went on to start epidemics in four of the other five major public hospitals in singapore. for future outbreaks, we have learnt that all patients in the wards of infected patients are potentially incubating the virus and should be isolated rather than moved to other hospitals. this was practised in september when an inpatient at the singapore general hospital (sgh) was found to have (a laboratory-associated case of) sars. our patient was "atypical" because she did not have an obvious contact history at the time of presentation. she also had an elevated white blood cell count, thought to indicate "typical" rather than "atypical" pneumonia, which was the initial description of sars. other such cases and subsequent nosocomial transmission led all the other hospitals in singapore to adopt very broad screening policies. without a validated, rapid, diagnostic test, we had to isolate and monitor patients who did not meet the who criteria for sars, and thus would not be eligible for assessment at ttsh, but still were of concern for the admitting physicians. at nuh, we started with one isolation ward but by the peak of the epidemic, we had five isolation wards; large inpatient areas were converted and at nuh these occupied the entire private wing of the hospital. extractor fans were placed in the rooms to generate a negative pressure relative to the corridor and nurses station, and the fans were exhausted to the exterior-a forested area. patients who did not meet the who criteria for sars and thus could not be transferred to ttsh were isolated; of these patients had sars. isolation was an enormously costly process and it is doubtful that such a strategy is sustainable. an increased risk of adverse events has been associated with isolation, and this was experienced during sars. although practices varied across the countries that had an outbreak of sars, , it is still unclear whether the designation of a sars hospital is an effective method of controlling the spread of the virus. personal protective equipment (ppe) was key to the public face of sars infection control. the mask became ubiquitous in hospitals and in many public places in singapore and other sars affected countries. in singapore, , , as in taiwan, some healthcare workers were infected with sars despite wearing full ppe-gloves, gown, and n mask. the intensivist involved in the case described at the start of this article wore full ppe but became infected during a bronchoscopy. it was speculated that the n mask fitted the intensivist poorly, and this led to a crusade to test the fit of the mask on all workers, regardless of the paucity of evidence to support fit testing in extensive studies of the prevention of nosocomial tuberculosis. , in two retrospective studies of sars in hong kong and canada, researchers have investigated the use of masks in the protection of healthcare workers. although both studies found that surgical masks as well as n masks were protective, they were limited by small numbers and a possible recall bias. early in the epidemic hospital administrators at nuh declared that masks would be available for anyone who wanted to use them, which was very reassuring to healthcare workers. in addition to the primary benefit of reducing infections, the psychological effect of the masks was beneficial. by the end of march, with the head of the hospital's intensive care unit infected with sars and atypical presentations of sars, the decision was made to mandate the use of full ppe by all staff in the intensive care unit. the use of powered air purifying respirators for all aerosol generating procedures, including bronchoscopy and intubation, was introduced; these were also used in canadian intensive care units and are thought to have been protective. the use of nebulisers was also discouraged and metered dose inhalers (with spacers as appropriate) were more widely used. by the second week of april an increased number of atypical cases of sars were being detected in older patients, who had comorbidities or chronic steroid therapy without fever, and ppe was mandated for all patient contact. even though patients with sars passed through our hospital for an average of · days (range - days) before transfer to ttsh, excluding the intensivist described above and five healthcare workers infected during a "superspreading event", none of the staff in our hospital were infected. whereas the universal use of ppe protected staff, an undiagnosed sars patient, with no recorded fever, was the source of infection for two other patients in the emergency department and for the visitor to the adjacent bed. our visitor restriction policy began with patients being limited to one visitor and was revised to no visitors when it became clear that we could not provide ppe for large numbers of visitors. the costs of ppe were huge; weeks into the epidemic, the total cost for ppe was at least us$ . as in other settings, the widespread use of ppe seemed effective in controlling the spread of sars in our hospital but at an immense cost. again, the challenge will be to find a sustainable approach in the event of a larger recurrence of sars. the clinical features of sars have been described in a range of studies. , , cases identified at our hospital , were similar to those reported elsewhere except that because we were not a designated sars hospital, we tended to get patients with atypical presentations. fever was almost universal; those on steroid therapy did not have a fever and fever tended not to present initially, especially in elderly patients. myalgia, upper respiratory symptoms, and diarrhoea were also notable clinical features. most laboratory tests were unhelpful, although many patients had lymphopenia, which can also be detected in a range of viral infections. the vast majority of patients with sars in singapore were managed at the designated sars hospital. one-sixth of patients developed respiratory distress and were intubated and mechanically ventilated. lew and colleagues have described the intensive care unit experience in singapore and it is remarkably similar to that experienced in toronto. readers are referred to the review of peiris and colleagues for a detailed discussion of the therapeutics of sars. although ribavirin was initially used in a number of cases, this was stopped when in vitro data showed a lack of efficacy. others have used ritonavir/lopinavir. steroids were also used in many patients, especially when it became clear that the viral load of patients declines as patients become worse, suggesting an immunopathogenesis. this suggestion was confirmed by autopsy studies of patients who died from sars and had large numbers of inflammatory cells in sections of lung tissue. however, as with any other patient with ards, steroid therapy was associated with a number of adverse effects. to date, there is no consensus on the best treatment for sars. pcr in respiratory specimens has been used to detect the sars coronavirus. it is necessary to obtain good specimens for diagnosis of respiratory pathogens but because most patients with sars have non-productive coughs, it has been a challenge to obtain deep secretions. clinicians are unwilling to be put at risk of infection by trying to obtain deep respiratory secretions with procedures such as saline nebulisation or bronchoscopy that are associated with transmission to healthcare workers wearing ppe. , however, it is difficult for laboratory staff to work with scanty specimens. a number of serological assays , , are available but are not sensitive until late in the course of the illness, by which time either numerous individuals will have been infected or countless others needlessly isolated. in some patients in singapore, serological assays did not turn positive until week or of the illness. thus, the currently available tests have considerable specificity but limited utility in the rapid diagnosis of patients presenting with the non-specific symptoms of early sars. the unusual features of the sars epidemic in singapore included super-spreading events; these were demonstrated by "shoe leather" epidemiology of contact tracing and quarantine of contacts long before the molecular evidence personal view sars in singapore was available. it has been shown that the most patients with sars in singapore did not infect another person, even from the early days of the outbreak before the institution of drastic quarantine laws or strict isolation procedures. strikingly similar data are available from vietnam and china. however, a small number of super-spreading events were responsible for the infection of - people. a super-spreading event that happened at nuh is illustrative. a -year-old vegetable seller with a history of hypertension and ischaemic heart disease was admitted with shortness of breath. he had no fever, was found to be in atrial fibrillation, and was admitted to a general medical ward with a diagnosis of heart failure. he did not meet sars criteria for transfer to ttsh or for isolation in our hospital. despite treatment for heart failure, he deteriorated and had to be intubated and mechanically ventilated; he became the source of infection for an entire shift of nurses and the doctor who had administered high flow oxygen therapy to him while wearing a well-fitting n respirator. he was transferred to ttsh when his brother was identified as the source of an even larger cluster of infections at sgh. he died of sars and the infection of several of his work colleagues led to the closure of singapore's largest wholesale vegetable market and devastation of the local fresh cuisine industry. home quarantine orders were issued for more than people working in the market, none of whom were later found to be infected with sars. in singapore, as with most other things, enforcement is approached very seriously and cameras can be placed in the home to ensure compliance with quarantine. an individual was publicly prosecuted and jailed for breaking quarantine. the social stigma attached to quarantine was considerable; before the installation of cameras, i was officially quarantined and it was not a pleasant experience. it is not known whether quarantine was necessary, , , or whether strict isolation and early case finding would have been a better use of resources. in singapore and elsewhere, isolation has been shown to be highly effective in reducing the number of secondary cases associated with individuals with sars. lipsitch and colleagues showed that as the singapore epidemic progressed, the time to isolation decreased and the corresponding number of secondary cases decreased, with the notable exception of the sgh cluster. in any future epidemic we should be able to isolate and detect cases early and may not have to resort to draconian quarantine rules. alternatively, a careful system of outpatient follow-up and clinical or serosurveillance, as we did with our first case, might be more practical. individuals arriving in taiwan from sars affected countries were quarantined for days and only one person ( . % of the total) developed laboratory confirmed sars. the cluster of infections at sgh that were started by our patient's brother, also reported by chow and colleagues, were similar to that in our hospital-an alternative diagnosis could explain the patients' clinical presentation. a patient with a documented escheria coli renal abscess and nosocomial pneumonia that responded to carbapenem therapy was also incubating the sars coronavirus. this patient became the source of infection for healthcare workers, other patients, and eight visitors including our patient. dual diagnoses are problematic for the management of patients with suspected sars. what should be the patient management protocol? do we isolate all patients who were in the same ward as patients with sars, even if they did not have direct contact with the infected patients? do we isolate these patients for the duration of their hospital stay in spite of normal chest radiographs and alternative explanations for their fevers? it is clear that we urgently need a rapid diagnostic test. the current diagnostic tests have severe limitations in clinical practice. , in singapore hospitals, some measures used to control the epidemic initially were continued for a year. staff continued recording their temperatures twice daily even though the infected staff in our hospital were detected by contact tracing of infected patients, not temperature screening. ppe use is still mandated in emergency departments and isolation areas at the time of writing, although we have not had a single case of sars in our hospital since the end of april . the september laboratory acquired sars case was a setback to our sars containment plans. it is hard to evaluate the effect of the draconian measures that were put in place (figure ). the epidemic was already in decline when the no visitor policy was instigated in our hospital; the policy was partly in recognition of our inability to protect visitors from contracting sars in the hospital. it is unlikely that a randomised trial could be done to show the measures necessary to prevent the spread of sars, should there be an outbreak in the future. we did a seroepidemiological study of healthcare workers at nuh, to understand the risk factors for infection and to determine if there were any asymptomatic carriers of the infection. while all six clinical cases of sars were found to be seropositive, we found two additional healthcare workers with mild symptoms, including fever that resolved within days, no changes on serial chest radiographs, and evidence of sars on two separate serological assays that were done in two separate, blinded, offsite laboratories. this study confirms the findings of other investigators who found few if any asymptomatic seroconverters in hong kong. , this finding is interesting given the observation that handlers of civet cats in the wild animal markets of guandong had serological evidence of sars but no clinical disease. although this finding has been cited as evidence for the civet cat as the source of the virus but i look forward to emerging data to help to identify the origin of the virus. sars patients have a pneumonia; typically, it does not present with any respiratory symptoms but with the non-specific symptoms of fever and malaise , , that are seen in a huge proportion of any general practice. the virus can be detected by sophisticated laboratory tests but only after a period of time, during which many people have either been infected or unnecessarily isolated. a broad triage policy can detect most, but not all, patients with sars during an epidemic and any patient that is not identified can start a major epidemic. , there are some treatment possibilities for sars and some indications of which patients are likely to spread the disease. ppe is effective most of the time, but some of the time additional protection is needed. , importantly, this virus is here to stay and much remains unknown about it. a reliable, rapid, diagnostic test and some 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isolation and characterisation of viruses related to the sars coronavirus from animals in southern china key: cord- -n ywei t authors: keck, frédéric title: avian preparedness: simulations of bird diseases and reverse scenarios of extinction in hong kong, taiwan, and singapore date: - - journal: j r anthropol inst doi: . / - . sha: doc_id: cord_uid: n ywei t this article describes relations between humans, animals, artefacts, and pathogens in simulations of disasters, taking bird diseases in three chinese sentinel posts as ethnographic cases. drawing on distinctions between simulation, ritual, and play, it shows that the engagement of actors in the imaginary of simulations, which they describe as ‘realism’, reflectively reverses the oppositions between humans and nonhumans, active and passive, fiction and reality that shape ordinary life. borrowing from the anthropology of hunting societies, it argues that simulations of bird diseases, considered as signs of future species extinction, rely on cynegetic techniques of power, in which humans and animals symmetrically shift perspectives, and not only on pastoralist techniques, in which humans are above the population they monitor and sometimes sacrifice. of action, simulations can be described as ritual performances displaying relations between humans and nonhumans in extraordinary settings. this article starts from observed simulations of an avian influenza pandemic in china. influenza viruses emerging from birds have been considered as potentially causing future pandemics, because birds (particularly waterfowl in south china) have been identified as the reservoir in which flu viruses mutate before spreading successfully between humans (shortridge & stuart-harris ) . among other techniques such as early warning systems and stockpiling vaccines, preparing for the next pandemics therefore involves simulating the transmission of pathogens from birds to humans (caduff ; lakoff ) . arguing that a human pandemic is a symmetrical threat to the extinction of a bird species, i then consider another bird disease for which chinese experts organize simulations: botulism. this disease, which doesn't affect humans, is considered a potential disaster for black-faced spoonbills because it kills migratory birds when they concentrate in wetlands on their flyways (wilson : ) . bringing together simulations of avian influenza and botulism, this article questions the ethnography of simulation from the perspective of animal studies. how does preparedness transform relations between humans and birds? what does it mean to include birds, and more generally animals, in exercises simulating coming disasters? how does the description of animals as victims of disasters transform them into actors of simulations (keck & ticktin ) ? i will show that animals become, in a paradoxical way, 'passive actors' when they carry the signs of diseases that can potentially affect humans. techniques of preparedness have been included in the set of tools for global health initiatives, either in humanitarian actions or in biosecurity interventions, which have shaped contemporary affects and anticipations of the future (adams, murphy & clarke ; lakoff ) . global health has been extended to animals and the environmentan approach called 'one world, one health' -thus requiring an interspecies approach towards the ethical issues involved (hinchliffe ) . one of the most debated questions in the anthropology of pandemic preparedness is the adequacy of the notion of sacrifice to describe how some populations are separated from others and killed or left to die for the sake of public health. in exercises of triage, some patients are prioritized over others through the framework of urgency (nguyen ; redfield ) . in the management of human populations, migrant workers are considered as a threat by educated experts using viral connectivity as a metaphor of modernity (macphail ; mason ) . in the management of zoonotic pathogens, the notion of sacrifice seems even more obvious, since animals are massively killed to eradicate the reservoir of emerging infectious diseases; and in the management of wild animals, some individuals are sacrificed to protect the species (van dooren ). other descriptions, however, have been proposed of the entangled relations between animals and humans in the 'hotspots' or 'sentinel devices' where emerging pathogens connect them in productive ways (brown & kelly ; fearnley ; keck & lakoff ; lezaun & porter ; lowe ) . while sacrifice separates some living beings from others to eradicate pathogens, sentinels instantiate relations between living beings through the anticipation of future pathogens. simulations of bird diseases shift perspectives between humans and animals through the use of fiction. to support this argument, i rely on the anthropology of hunting societies, by contrast with pastoral societies. while public health relies on pastoral techniques of power combining sacrifice and surveillance to contain the threats coming from outside in a population (foucault ) , the 'one world, one health' approach uses techniques from birdwatchers and wildlife managers to monitor data about changing relations between humans and animals. whereas pastoral techniques are asymmetrical, relying on the pastor's superior gaze over the flock manifested by sacrifice, cynegetic techniques are symmetrical, as hunters and prey constantly change perspectives when displayed in rituals (chamayou ) . most analyses of simulation have placed it in a genealogy starting with the cold war, using notions of ritual, performance, and play (davis ; galison ; gusterson ; lakoff ; masco ) . but they don't take the perspective of animals because they consider simulations as pastoral techniques of biopower, therefore bypassing what the anthropology of hunting societies shows about ritual action. in this article, i define a cynegetic practice of simulation that is always mixed with forms of planning, combining two different forms of anticipation. i call 'avian preparedness' this mix of cynegetic becoming-animal and pastoralist care for populations initiated by microbiologists, considered both as 'virus hunters' (perrey ) and as 'microbe farmers' (caduff : ) . to analyse simulations of bird diseases, i combine the notion of reverse scenario (schull ) with the notion of reflexive ritual. pandemic or extinction scenarios, i argue, connect humans and animals in realistic ways to play on the imagination of what could happen if a pathogen emerges. using animal reservoirs as mirrors in which anxieties about pandemics are reflected, humans exchange their perspectives with animals in an imagined future where their relations are reversed. simulations can thus be situated in an anthropological space between play and ritual. roberte hamayon ( : ) has called 'simulation' the way shamans in mongolian hunting societies imitate the movements of animals in a ritualized setting to prepare for the uncertainties of hunting. in an article entitled 'dissimulation and simulation as forms of religious reflexivity' , michael houseman proposes to move away from a definition of ritual as a collective action based on a shared secret to study 'the emergent properties of ritual simulation generally ' ( : ) . he draws on two cases taken from hunting societies of central africa, one in which male novices are symbolically killed and the other in which a goat is actually sacrificed. he asks: how do participants come to believe in a series of speeches and actions -the novice's death and the goat's consent to sacrifice -that are obviously false? he answers that ritual action creates an extraordinary space of reflexivity with regard to the ordinary relations that constitute the group. while the ritual for male novices is a 'dissimulation' , in which the relations between initiated and uninitiated are constantly reversed in such a way that the moment of death becomes uncertain, the ritual of goat sacrifice, says houseman, is a simulation of consent, in which the silencing of the goat through the consumption of herbs mimics the consent of male hunters to their initiation. the ritual is reflexive in the sense that it stages the condition of the ritual itself -the secrecy known by initiators and unknown by the initiatedthrough the manipulations of daily relations between humans and nonhumans, whose asymmetries are reflected as in a mirror. similarly, i suggest that we call 'reverse scenarios' the ritual performances by which simulators reflect playfully on the relations between humans and birds in the imagination of a disease that could affect them both. simulations, i argue, are far more than mere 'rehearsals' of a pandemic drama: they are catalysts in the transformation of human/nonhuman relations into asymmetrical biopolitical and ontological processes. to support this argument, i will describe three ethnographic cases in hong kong, taiwan, and singapore. these three territories have competed at the global level since the sars crisis in to be the best 'sentinel posts' where pandemic pathogens coming from china can be detected (abraham ) . as hubs for the intense circulation of persons and commodities in asia, but also as repositories of chinese traditional relations between humans and birds, they have prepared for the catastrophic effects of a bird flu outbreak. but while the hong kong government regularly culls its poultry and sends warning signals from the chinese border, taiwan and singapore rarely had to cull their poultry and rather invested in scenarios for the simulation of pandemic. taiwan, on the other side, shares with hong kong the monitoring of black-faced spoonbills, considered as one of asia's most threatened and charismatic species. this article thus connects the rationalities of preparedness with the economies of human/animal relations in three different but interconnected settings. it will examine indoor and outdoor simulations of avian influenza in singapore and hong kong, and compare them with simulations of botulism in taiwan. however, my analysis is not restricted to simulations of bird diseases in east asia, but highlights general traits of disaster simulation as a technique of preparedness. by looking at the relations between humans and birds in these three contexts through their common exposure to emerging pathogens, this article also analyses the relations between national states in asia as they have to manage a common disaster. since simulations of bird diseases connect relations at different scales, from the microbiological to the biopolitical, this article combines science studies, ethnography of rituals, and political economy through an anthropology of 'more-than-human' relations (helmreich & kirksey ; kohn ; sagan ) . in july , i was visiting gavin smith, who was then an associate professor at the duke graduate medical school of the national university of singapore (nus). i had known gavin in hong kong while he was working in the state key laboratory of emerging infectious diseases at the department of microbiology of the university of hong kong. born in australia, gavin had studied botany and ecology at the university of melbourne, and then moved to hong kong for a ph.d. in molecular systematics. gavin had first analysed the genome of fungi, then of the sars coronavirus, then of bird flu viruses. he described this development of his research as a reduction of the size of the living beings he was sequencing, and a refinement of the data and results he could produce. gavin and his team relied strongly on the collaboration between the state key laboratory of emerging infectious diseases and the university of shantou. this university had been created by the hong kong tycoon li ka-shing, who opened it in in his native guangdong, with the approval and administrative support of the chinese authorities. it provided the state key laboratory of emerging infectious diseases with samples collected in poultry markets in fujian province, thus offering a real-time surveillance of influenza strains emerging in this 'epicentre' of pandemic flu. but after the publications of gavin's team showed the role of the chinese poultry industry in the emergence of these new strains (smith et al. ) , the guangdong authorities had severely restricted hong kong virologists' access to these samples. gavin then moved to singapore in , where he had more freedom to continue his fundamental research, and more funding from international institutions. he had shifted from the sentinel post, where the new strains of avian influenza emerged, such as the h n virus in (keck ) , to a place where he could simulate the evolution of flu viruses in high-tech computers. there was no need to be close to the site where viruses emerge, he explained to me, as he could simulate viral emergence through the use of genetic data banks. singapore was then considered the new 'pole of excellence' for biological research. the small city-state founded by lee kwan yew in at the end of the malay peninsula had converted its industrial and financial power, owing to its position on the commercial trade routes between east and west, into an economy of knowledge and information, with high investment in biotechnologies (ong ; ) . the nus graduate medical school was located just next to the ministry of health and the singapore general hospital, in the centre of the city. it had been created in to train high-tech medical leaders on the model of the duke university school of medicine in north carolina. the programme in emerging infectious diseases, for which gavin had been hired to work, was headed by wang linfa, who was also leading a team on bat viruses at the australian animal health laboratory in geelong. his programme was running projects for the surveillance of emerging infectious diseases, particularly influenza and other respiratory diseases, in singapore and the rest of southeast asia. gavin's career took a meaningful turn when his team published two major articles at the height of the h n pandemic. the first one, entitled 'dating the emergence of pandemic influenza viruses' , was published just after the emergence of the h n virus in mexico in april . it showed that genetic components of the h n pandemic virus circulated among pigs and humans as early as , thus challenging the commonly held view that spanish flu jumped from birds to humans in . in the context of the new h n 'swine flu' , this article stressed the need for intensified surveillance of pigs to detect emerging flu viruses before they become pandemic. 'if future pandemics arise in this manner' , gavin and his team concluded, 'this interval may provide the best opportunity for health authorities to intervene to mitigate the effects of a pandemic or even to abort its emergence' (smith, bahl, vijaykrishna, et al. : ) . this conclusion was immediately reinforced by gavin's team's second publication, entitled 'origins and evolutionary genomics of the swine-origin h n influenza a epidemic' , published in nature at the end of , in which they showed that a 'twin' virus bearing the same genetic sequence as the pandemic h n had been identified in pigs in hong kong in . gavin's conclusion was not that the asian swine industry was to blame for the emergence of h n , but that there was a better surveillance of the animal reservoir for influenza viruses (waterfowl and pigs) in hong kong than in the united states. the team's paper ended, 'despite widespread influenza surveillance in humans, the lack of systematic swine surveillance allowed for the undetected persistence and evolution of this potentially pandemic strain for many years' (smith, vijaykrishna, bahl, et al. : . in july , i took a course at the hong kong university pasteur research centre in bioinformatics, during which gavin and his team partners, vijay and justin, explained to virology students how to obtain this kind of result. bioinformatics is a method to analyse the massive amount of biological data available on the web -particularly through the website of the us national center for biotechnology information, genbank -with the help of dedicated software. this software, called blast (basic local alignment search tool) or msa (multiple sequence analysis), calculates the probability that genetic sequences derive from one another. such a procedure, called alignment, aims at approximating the real descent relationships between viruses through a calculation of the optimal 'tree of life' , based on the darwinian hypothesis that life expands in a rational manner to maximize fitness capacities (mackenzie ) . for gavin and his team, however, bioinformatics was not only about probability calculation. in the construction of a phylogenetic tree, biological knowledge is necessary because some correlations proposed by the computer make no sense in an evolutionary perspective, as they can be due to errors in sequencing or genetic deletion. to decide which correlations to take into account and which to consider as irrelevant, virologists use other software (such as bootstrap, jukes cantor, or tamura) providing the probability of correlations based on a given scenario. as for other techniques of preparedness, probability is not enough to simulate a coming disaster: it requires a work of imagination (lakoff ) . peter galison has shown that computer simulation emerged in the field of particle physics as a 'subculture' among experimenters and theoreticians under the 'monte carlo' programme funded by nasa in the s to simulate a nuclear explosion. simulation replaces experimentation when the data needed for the theory are too numerous and complex to be processed with traditional instruments, creating a 'trading zone' in which different professional groups share a common language or 'pidgin' (galison : ) . similarly, bioinformatics produces new images shared by microbiologists, computer scientists, and public health executives in the anticipation of epidemics. software such as bootstrap can be considered as an accessory or decoy to trap the live bird viruses through the sequences that have been stored in genbank. gavin opened the course with a simulation of the work his team had done a few months before on the h n virus, presented as a desktop exercise of what to do when a new virus emerges. 'imagine we've received this new sequence from atlanta. paste it to blast, and take as much information as possible. make a tree so big you can never print it on a sheet of paper: it will be good starting material before reducing the inquiry' . gavin and his team explained that in contrast to other virologists working on flu viruses, they had decided to use the eight segments of the virus's rna, not just the two segments that shape the h and n proteins, usually considered to be the most significant markers of antigen evolution. they could thus build eight parallel evolutionary trees which, by their similarities, gave an indication of the real evolution of the whole flu virus. there was nothing secret in the images of pandemic viruses built by these microbiologists, unlike simulations of nuclear explosions built indoors by particle physicists (gusterson ) : all the phylogenetic trees produced by gavin and his team were publicly available on websites. drawing back the 'molecular clock' based on the estimated kinship relations between viruses, virologists could see the branches where evolutionary ruptures occur and pathogens jump from one species to another, such as the emergence of the h n pandemic in and . following continuities between genetic sequences, they exhibited the discontinuities between evolutionary niches. gavin said that when a virus jumps from one species to another, it inaugurates a new set of lines, as the 'immunity pressure' of the environment creates an 'evolutionary bottleneck' in which this mutation can replicate. drawing back these lines then lead him to what he named 'the most recent common ancestor' . 'i love those trees' , he added. the amount of information provided in a single image was correlated to the unity of an evolutionary hypothesis drawing this information back to a common ancestor. historians of science have shown the power of evolutionary trees in the books through which darwinism came to be accepted as a new worldview (bredekamp ; helmreich ), and their reframing in global health under the notion of an animal reservoir in which emerging pathogens spill over from animals to humans (king ; lynteris ) . but i was mostly intrigued by the way gavin and his team turned sequences into images through an anticipatory mode of reasoning that i call 'reverse scenario' . natasha schull proposes the term in her work with on-line gamblers, to describe the way they 'cope with the necessarily uncertain futures of any hand by returning them to a point in the past and confronting them with a branching diversity of outcomes that might have emerged from it' ( : ). it applies well to the practices of 'virus hunters' who use 'reverse engineering' to reconstruct potentially pandemic pathogens such as the h n virus (caduff : ; napier : ) . just as a gambler speculates how much he could have won if he had played this or that card, gavin imagines what could have happened if the h n virus had been detected in pigs prior to or . virus sequencing allows him to trace potential connections between birds, pigs, and humans, and to imagine other futures of cross-species transmission. yet we don't know how birds (and pigs) are actually involved in the construction of pandemic scenarios, because we don't see how virologists take virus samples from birds. we thus need to turn from desktop simulations to 'real-ground' exercises organized by public health officials and birdwatchers. after my visit to gavin smith at nus duke graduate medical school, i went to a nearby building to meet jeffery cutter at the singapore ministry of health. trained as an epidemiologist, jeffery cutter was the director of the communicable diseases division of the ministry of health, co-ordinating preparedness for emerging infectious diseases in singapore. 'there are million passengers every year at singapore changi airport' , he told me, 'so there is a high probability that emerging infectious diseases will come to singapore. we need to be prepared' . during the sars crisis in , he said, people were infected by the new coronavirus, with thirty-three deaths. they were all treated at the tan tock seng hospital, which had been designated by the government as an isolation hospital for sars patients. at the peak of the crisis, all schools in the country were closed for ten days, and home quarantine was established for more than , people known to have come into close contact with a sars-infected person. prime minister goh chok tong said publicly that sars could possibly become the worst crisis singapore had faced since independence. when a journalist asked him if he was being alarmist, goh responded: 'well, i think i'm being realistic because we do not quite know how this will develop. this is a global problem and we are at the early stage of the disease' (zolli ) . jeffery cutter introduced me to yoong cheong wong, head of the emergency preparedness & response division at the ministry of health. mr wong was a former policeman in charge of organizing exercises for emerging infectious diseases in hospitals. the first national exercise for influenza in singapore was organized in , after the first cases of human-to-human transmission of h n were suspected in thailand. called 'sparrowhawk' , it was organized in two stages: a table-top discussion and assessment of pandemic response plans among six hospitals in the country between april and june; and a practical exercise on - july, in which the six designated hospitals had to manage potential patients and share information about their circulation. mr wong explained that a thousand people were involved in the real-ground drill, mostly volunteers from grassroots organizations and nurses from training institutions. while patients moved from one hospital to another, some hospitals assessed the behaviour of others and gradually raised the number of casualties. the main question, according to mr wong, was: 'if there are casualties in one hospital, which resources do they need?' the goal of these exercises is officially the identification of unplanned gaps in coordination between the actors who manage epidemics. but the actual criticism of planners most often focuses on the drills' lack of realism. 'we try our best to do it as real as possible' , said mr wong, 'but everyone knew it was just an exercise' . to explain the improvement between 'sparrowhawk' exercises in and in singapore, an official leaflet notes, 'the exercises were activated unannounced to inject greater realism. the ministry of health emergency medical staff turned up without prior justification at the general ward of the exercise hospital and "triggered" the simulated case of human infection with avian influenza' (unsic : ) . realism, in this case, came from the fact that people were surprised, and yet they knew that they were faking the epidemic. what does it mean for a simulation to be realistic? here the notion of 'reverse scenario' is useful. just as microbiologists imagine what could have happened if viruses had been stopped in their animal reservoir, public health planners imagine what would happen if contagious patients were stopped before entering hospitals. but in both cases, death is not performed in the scenario. by contrast, another type of exercise conducted in singapore was very real. on july , the agriculture and veterinary authority (ava) organized a drill in one of the poultry slaughterhouses on the border with malaysia. there are no authorized poultry farms on the territory and only five chicken farms for eggs, which constrains singapore to import and slaughter million live chickens from malaysia every year. malaysian farmers need to be licensed by the ava to import their poultry to singapore, and are always regarded with suspicion by border authorities. and yet no case of h n has been found in singapore. i was able to watch the drill on-line because it was streamed widely on a number of websites. the name, 'exercise gallus vii' , referred to the fact that it was the seventh avian influenza exercise conducted by the ava since . it took place in the biggest of the ten slaughterhouses in singapore run by soonly food processing industry, which processed , chickens daily, providing per cent of the fresh chicken meat in singapore (asia one ). the scenario for the exercise was the following: , chickens had been infected with h n and should be killed and destroyed, according to emergency response plans. about employees of the slaughterhouse, mostly indians, had to be screened for their temperature, take an antiviral drug, and then wear personal protective equipment (boots, cap, mask, glasses, gloves) on the back of which their name was written. the 'affected' chickens were placed in green cages on belts, immersed in water, and electrocuted. their cadavers were then placed inside two layers of biohazard bags to be incinerated. dr yap him ho, director of the quarantine and inspection group, declared on television, 'to make sure that ava is prepared for any incursion, the main thing we want to do for this exercise is to train our officers, as well as the other parties that are involved in the contingency planning, to be familiar with the steps of the procedures' (straits times ). although much could be said on the paternalistic ethnic, gender, class, and age divides that structured these exercises, i want to focus on the distinction between humans and animals. while the simulation at the clinic was animated by a sense of urgency and scarcity of resources confronted with a fake pandemic, the simulation at the slaughterhouse was quietly following the procedures in actually killing false positive chickens. i was also intrigued by the fact that while the hong kong government organized many such exercises on the human side, they had never simulated bird flu in poultry farms, because outbreaks occurred regularly in farms on its territory. while singapore authorities actually killed poultry for a disease that remained virtual, hong kong authorities simulated the transmission of bird flu from chickens to humans because it was already circulating among birds. although avian influenza kills birds as well as humans, the reverse scenario of a pandemic represents massive death in a different mode for humans and for birds, depending on past experiences of pathogens crossing borders between species. i now turn to the simulation of bird flu in hong kong. on november , hong kong co-ordinated a desktop exercise called 'great wall' which simulated a virtual cluster of three human infections with h n in a family returning to hong kong and macau after their visit to a poultry market in mainland china. the goal of the exercise was 'to synchronize the three systems of pandemic preparedness to engender an effective response among them' (unsic : ) . the exercise opened with a ceremony attended by the vice-minister of the chinese ministry of health, wang longde. it was considered as a success in creating good relations between mainland china and the former british and portuguese colonies. while the sars coronavirus had caused a division between china and the former colonies in because of beijing's reluctance to share information (abraham ) , 'great wall' unified the country against an imagined enemy, pandemic avian influenza, but it instantiated ruptures between humans and birds. in january , after long discussions with the centre for health protection, i was allowed to participate in an exercise in a hong kong hospital. the centre for health protection was created by the department of health after the sars crisis to anticipate outbreaks similar to sars through active surveillance and communication (leung & bacon-shone ) . within this centre, the emergency response branch, headed by a police officer, was in charge of writing scenarios and organizing simulations. twice a year, a field exercise was held in hong kong, with observers from china and overseas, bearing the name of natural entities: maple, cypress, chestnut, redwood, eagle, jadeite, and so on. there was no epidemic simulation in hong kong in because the emergency response branch considered the management of the h n virus in the spring and autumn to be a 'real-life exercise' . 'exercise redwood' took place in the clinic of shau kei wan, located in the workingclass district of hong kong island. the following scenario was distributed to the participants and posted at major public buildings. confirmed human cases of bird flu had been reported in hong kong's neighbouring countries, as well as a rising trend in patient attendance with influenza-like illness in hong kong hospitals. live poultry had tested positive for avian influenza in hong kong's markets and were then culled at farms and markets. a member of the staff participating in the culling was reported to carry the h n virus, as was an -year-old boy who had played with live poultry. four clinics were designated in hong kong for triage. only the final part of the scenario was held in shau kei wan; the first part was meant to provide a plausible context. the official purpose of the simulation was to co-ordinate hospital services in the management of patients with influenza-like illness. eighty actors playing patients came in through the front door of the hospital and were sent to different departments depending on their symptoms (pulmonary conditions, tuberculosis, etc.). twenty 'players' treated them in the services, and two 'simulators' communicated with other hospitals on a hotline. those who were diagnosed with h n were evacuated by ambulance through the back door of the hospital, where the media took pictures. the head of the department of health gave a press conference after visiting the hospital, but the journalists asked him about new bacteria found in a private jacuzzi, not about the exercise itself. the drill's success was not questioned; it was successful because it had been held. the scenario was designed in such a way that no surprising event could happen: the only reality that came up was the bacteria in the jacuzzi, not the virus in bird markets. all the actors i saw looked young and relaxed, wearing blue caps and casual clothes. their symptoms were described on a tag they wore around their necks, indicating their name, address, nationality, sex, and age. these cards were red or green depending on whether they had bird flu or only influenza-like symptoms. they did not have to fake illness; their only role was to move to the designated departments. in another exercise organized by the centre for health protection, a plane was evacuated because a patient had been found with influenza-like symptoms; those who sat next to the patient received a red tag, and those who sat at a good distance received a yellow tag. what was remarkable in 'exercise redwood' was the absence of tension or anxiety in the medical staff's behaviour. although humanitarian ngos consider triage to be an ethical issue when a higher number of patients is met with limited resources (nguyen ; redfield ) , the medical staff of the shau kei wan clinic only separated symptomatic and asymptomatic patients to avoid the spread of the disease. the tension of the situationwho would be considered a spreader, who would receive treatment first -was delegated to objects: tags and caps. people were reduced to bearers of signs that circulated fluidly in the hospital under the gaze of the media. while the medical staff of the hospital played their own role, the actors playing patients with influenza-like illness came from a humanitarian association, the auxiliary medical service (ams). this association, created in to deal with the influx of chinese refugees, was registered in under the security department of the hong kong government. its , members are trained for disaster management in hong kong and outside. one of them described it to me as 'after-work entertainment' , 'a place to meet other singles'; it is an elite association where similar people express and share moral values. during their own exercises, performed every month, they train how to rescue victims of car accidents or fires. they simulate heartbeats on dummies with fake hearts. 'patients cannot fake the heart rate or the respiratory rhythm' , said the organizer, 'so they have tags' . tags have an indirect realistic effect, while dummies can actually simulate the heartbeat of an injured victim. members of the ams, who describe their own exercises as significant moments in the life of the association, were frustrated by 'exercise redwood' . from their perspective, there is a sharp difference between regular accident rescue exercises and extraordinary epidemic evacuation drills that co-ordinate several departments. one of the actors said he felt 'passive' , playing on the ambivalence of the term: as we had experienced sars in , we all can forecast how we would behave in another similar situation, like avian flu. being a citizen, we are quite passive; i believe that we should follow the guidelines and the government's advice so as to prevent ourselves from getting affected. but in the exercise, we were being passive. it can be said, consequently, that when they simulate patients in an epidemic exercise, members of the ams literally act as if they were dummies. there is thus a fundamental distinction in the real-ground exercises between actors and players. while actors are passive, reduced to the objects that 'act' or 'speak for them' , players and simulators introduce uncertainty by the way they combine these objects in the scenario. if actors have to appear 'real' to produce good images in the media, the simulators play on the fictional possibilities of the scenario. the distinction between simulators and actors in real-ground simulations runs parallel to the distinction between virologists and public health planners in desktop exercises: while actors and planners only follow their roles in the exercise, simulators and virologists explore the potentialities of reverse scenarios. another example shows how real-ground exercises combine the virtual and the actual as desktop simulation does. in an exercise called 'jadeite' , organized in january , members of the emergency response branch were simulating the evacuation of a residential building on computers, and the scenario specified that they had to evacuate the simulation room to a 'fallback room' . the simulation room, from which the vulnerability of vital infrastructures in hong kong was virtually assessed, thus came to be seen itself as a material environment under threat. the head of the emergency response branch who described this exercise to me said it was 'more fun than a movie' , as if images had suddenly burst through the screen. in this reversal of the scenario, simulators became actors, and fiction reality. neither a ritual performance nor a scientific model of prediction, the simulation was, for this former policeman, a game he enjoyed playing. animals take part in simulations in a general category that can be called 'passive actors' . if there was no need to simulate the culling of poultry because it regularly happened in hong kong markets, simulators for the evacuation of residential buildings in hong kong planned that some residents were accompanied by pets that should be handled with care by the agriculture department, because their reaction to the evacuation was unknown, just as simulators of the evacuation of planes planned how to handle 'reluctant potential patients' . the real opposition in simulations is thus not between humans and animals but between poultry, handled as commodities that can be destroyed, ordinary citizens and pets, considered as 'passive actors' that should be handled with care, and simulators, changing the rules of the game. more than sharp ontological distinctions between fiction and reality or between animals and humans, there is a virtual gradient of actors in the anticipation of massive death produced by simulation. the use of accessories and animals in simulations of disasters is indeed an essential part of their 'realism' . tracy davis has shown that people coming from the world of theatre were hired by cold war experts to implement scenarios of nuclear blast through the design of accessories. simulation designers were, therefore, less concerned with the participation of the public than with the realism of the objects. after an exercise organized in coventry in , prime minister winston churchill complained about the high degree of realism of the simulations, which he considered a waste of public money. 'who thought of the blood-stained old woman with the birdcage? i hope there is not going to be any more of this sort of thing at government expense' (quoted in davis : ) . women were the main targets of civil defence after the second world war, as they had been the targets of public health campaigns against microbes at the beginning of the twentieth century, because they were in charge of the household with children and pets. animals were portrayed as good accessories of nuclear blast simulations not only because they were good laboratory models (masco : ) , but also because they were part of a familiar landscape disrupted by an extraordinary event. the extraordinary context of the simulation thus provides the opportunity to display a series of apparent contradictions: people become objects; animals become people; actors turn out to be passive; fiction enters into reality. this capacity to displace oppositions in an extraordinary context through reverse scenarios brings simulations close to rituals. however, if simulations can be considered as rituals of public health administration, justifying the work of virus hunters who sound the alarm about future pandemics, it doesn't mean that there is a secret worldview shared by simulators (gusterson ) . rather, simulations display openly contradictions that public health administrations have to solve, often by the use of sacrifice in operations of culling (of infected poultry) or triage (of suspected patients). they create a tension between two techniques of power: those of biologists and simulators who follow viruses as they mutate between species, which i describe as cynegetic, and those of public health officials who have to protect some populations against others, which i call pastoral. to support this hypothesis, i will now turn to simulations organized by birdwatchers. can we say that birdwatchers take the perspectives of threatened wild birds as virologists take the perspective of poultry infected with flu viruses? how do humans in charge of the protection of animals cope with the oppositions we have seen in reverse scenarios of pandemics? birdwatchers have been involved in the surveillance of the avian reservoir of influenza viruses. public health and agriculture authorities realized that they could not follow the mutations of flu viruses in wild birds, and collaborated with birdwatching associations to monitor potential cases in wild bird reserves and natural environments. in hong kong and taiwan, birdwatching practices, a privilege of british and american expatriates until the s, have become popular among chinese middle classes with the development of a leisure society, the commercialization of camera equipment, and the awareness of the vulnerability of the environment (choy ) . birdwatching has taken the form of a 'citizen science' with the opening of websites where amateurs post their observations and experts turn them into statistical data. every year, bird races offer opportunities for birdwatchers to compete in observing the highest number of birds on a designated territory. thus, birdwatching practices, like simulations, have virtual and actual aspects, orientated by the imagination of a disaster: the extinction of bird species. in hong kong and taiwan, the introduction of birdwatching was linked to techniques of preparedness and concerns for biosecurity. the main wild bird reserve in hong kong, mai po, is situated on the estuary of the pearl river delta and on the border with mainland china. after , british officers used to sit there with their binoculars to trace chinese refugees or to signal an attack by the chinese army, and took this opportunity to inventory the more than bird species in hong kong. hong kong and taiwan were part of the migratory animal pathological survey, a programme of surveillance of pathogens carried by birds (particularly japanese encephalitis). through this programme, british and american ornithologists trained chinese workers to band birds and collect samples. transforming birds into data and following the evolution of their numbers has been a way to simulate threats coming from birds since the second world war (keck ) . methods derived from us wildlife management have changed the perception of birds in the last twenty years in taiwan and hong kong, with the introduction of the concept of the flyway. species that fly from japan and korea to australia, along what came to be called the east asian-australian flyway, have been shown to have declined owing to the urbanization and development of the chinese coast. climate change is also supposed to damage the places where wild birds feed and roost on their migratory routes. among the bird species affected by these changes, one of the most charismatic is the black-faced spoonbill, a waterbird breeding in japan and korea in the summer and migrating to south china in the winter. in the s, the number of these birds was estimated to be , , but thanks to the conservation efforts shared by the countries to which they migrate, it increased to , at the end of the s. wetlands have been developed in hong kong, taiwan, and fujian as shelters on their flyways. images of spoonbills abound in schools, environmental agencies, and natural reserves, often portrayed as funny birds smiling to the public. to understand how reverse scenarios of disasters enter the management of spoonbills in china, we have to go beyond these anthropomorphic images, and look at how they actually perform in simulations. in the winter of - , seventy-three black-faced spoonbills were found dead from botulism in taijiang national park. the wild bird society of tainan consequently organized a campaign to vaccinate spoonbills against botulism, and used decoys to train their staff on how to safely handle the birds. since then, drills have been regularly organized for bird protectors to learn how to manipulate fake spoonbills with caution. these decoys are also used to attract spoonbills for gps monitoring. carved in wood and painted in black and white, they are posted in the wetlands close to traps. decoys are different from images of spoonbills on posters: wildlife managers interact with them as if they were alive, because of their accurate mimicking. the use of decoys is a traditional feature of bird hunting. by contrast with lures, which attract birds based on their appetites, decoys attribute intentions to prey (schaeffer : ) . in england, duck decoys take the form of pondside wooden houses into which ducks are attracted by a fake dog, because hunters have observed that ducks swim towards the dog to signal that it has been seen. in the same way, the fake spoonbill is used as a decoy because it creates a situation of communication with the bird. but at the same time, the fake spoonbill is used as a dummy by birders who train to manipulate spoonbills in risky situations, as in epidemic simulations. the use of spoonbill decoys mixes hunting techniques and pastoral techniques because decoys are considered both as intentional agents and as objects that should be manipulated with care. this hypothesis was confirmed on april when the wild bird federation of tainan led me to a site where three black-faced spoonbills had been trapped -a very rare event, which i was considered lucky to have witnessed. birdwatchers had found shelter in a taoist temple on the banks of the marshes, and they turned on some buddhist music to soothe the birds. with very calm gestures, a man equipped with gloves and a mask sewed a gps satellite tracking device around the waist of the spoonbill, while a woman held it gently but firmly. five other birdwatchers watched them with amusement, taking pictures and making comments on the bird's reactions. the man explained to me that he had to be cautious because it was a young spoonbill, so the weight of the satellite tracking device had to be imposed on its body in such a way that it would not hamper its growth or unbalance its flight. how to build techniques of monitoring that do not kill animals considered as indexes of the fate of their species is a major concern for wildlife managers, who often talk about the sacrifice of individual animals when they die as the result of an improper monitoring device (benson ) . but taiwanese birdwatchers focused the discussion on how to properly release these birds so that they would not be sacrificed but become sentinels of a threatened species. the release of birds is a major ritual concern in south china, known as fangsheng (literally 'let live'). this practice finds its roots in aristocratic practices of opening the cages of birds who sang well, and was codified in taoist rituals as a specific sequence of releasing a live animal; but it has developed massively in recent centuries with its qualification by buddhists as a practice of compassion that increases the 'merits' (gongde) of those who release live animals (handlin smith ) . in hong kong and taiwan, buddhist associations entered into discussion with birdwatching societies because many birds were found dead after they were bought in bird markets and released in surrounding natural parks. these associations had to warn through posters that releasing birds could cause the death of birds, because they were released in an improper environment, and the death of humans, since some of the birds found dead after the release carried avian flu (severinghaus & chi ) . consequently, when they released a bird equipped with gps that they had learned to manipulate through the use of decoys, taiwanese birdwatchers inserted a ritual sequence into a simulation practice. while the ritual introduced the bird into a cycle of life and death, the simulation used the decoy to produce signs of future threats for birds and humans. the black-faced spoonbills were released in the taijiang national park with the hope that they would fly over to hong kong or the fujian coast, where their signals could be captured. it should be noted that the taiwan straits are also the sites of military exercises or drills through which threats coming from china are mitigated. to prepare for an attack from the people's republic of china, the taiwanese centers for disease control was organizing exercises simulating the use of bioweapons in a public space, such as sars, smallpox, and avian flu virus (rollet : ) . the release of a black-faced spoonbill in the same chinese straits mimics and reverses the scenario of an avian flu outbreak from china. instead of carrying information on the potential war between two long-term enemies, it produces signals on the changes of bird habitats that concern birds as well as humans. while in the public health simulations birds are considered as carriers of infectious diseases, birdwatchers' simulations frame them as living beings with which humans share pathogens as signs of communication. another practice with birds in taiwan clarifies by contrast their role in simulations. according to peta, more than a million pigeons are released every day from boats in the taiwan straits by pigeon-racing clubs, and only per cent survive to come back to their shelter. huge amounts of money (an estimated us$ billion) are spent in bets on those which will return, welcomed as heroes if they are first, killed if they are too slow. this is neither a ritual nor a simulation but a gambling practice through which birds crossing the sea between china and taiwan are qualified as political signifiers. the reverse scenario of the game, producing strange identifications between humans and birds, tells the story of a pigeon successfully returning home while others fail and die in the taiwan straits. releasing a bird in taiwan can thus appear as a simulation when it is embedded in the framework of an environmental flyway, as a ritual when it mobilizes a cosmological view of the circulation of souls between humans and animals, or as a game when it is organized on the border separating two competing territories. simulation, ritual, and play are three frameworks to mitigate the uncertainties of catching and releasing a potentially sick bird. i have considered three stages where bird diseases are simulated: computer simulations of avian influenza by microbiologists; outdoor performances of pandemic influenza by public health administrations; and exercises of manipulating threatened birds by birdwatchers. these three types of simulation displace the problem of sacrifice: that is, the definition of those who deserve to live and those who will die. microbiological surveillance of viruses moves away from the site of emergence where birds are killed to prevent the spread of pathogens to humans, and traces continuities between humans and animals as a reservoir where viruses silently mutate. simulations of epidemics don't address the problem of triage between humans in a situation of exception, but rather configure new relations between humans and animals through accessories in a performance. exercises of vaccinating and releasing potentially sick birds don't raise the issue of how many birds can die for the sake of the species, but rather reflect on how to handle a bird with care in a political environment where they carry signals of threat. in the reverse scenarios of simulations, birds appear not as sources of infection that must be eradicated, but as sentinels with which humans can communicate to imagine potential futures. simulations, therefore, should be analysed not only as a pastoral technique of power, as ways to mobilize populations under a common threat in which some are sacrificed for the sake of others, but also as a cynegetic technique of power, creating relations of identification between humans and animals around a perceived uncertainty at the borders between species. in the world of databased science and transparency of communication, simulations of bird diseases imply playing like animals or with animals to anticipate the (im)possibility of a mass extinction, thus mobilizing elementary forms of identification. in the cases i have considered, the question of the realism of exercises is a way to draw attention to the circulation of objects that recast relations between humans and birds by simulating the diseases they share. the use of computer software, accessories, and decoys in the three types of simulations i have analysed blurs the sharp opposition between humans and nonhumans. these objects can be considered as decoys because they carry the intentions that humans attribute to animals and shift their perception from inanimate objects to living beings. while scenarios of bird-generated epidemics play on the asymmetries between humans and birds, the horizon of the simulation (the extinction of the human or of a bird species) integrates them as common actors of a game. simulations can thus be considered as reflexive rituals because they display the uncertainties of the beings they play with and help to mitigate their threats. framing simulation as an operation unfolding between the spheres of mimetic play and reflexive ritual, and at the same time performing a series of subject-object reversals, i have argued for the need to approach this key apparatus of preparedness through a lens that allows for the mixing of pastoral and cynegetic techniques. what i have called in this article 'avian preparedness' takes place in a long history of simulating bird movements, from classical divination by roman augurs to medieval bird hunting and modern birdwatching. the specificity of contemporary forms of anticipation through sentinels, simulation, or stockpiling is that the distinction between cynegetic techniques of preparedness, taking the perspectives of birds on future threats through imagination and communication, and pastoral techniques of prevention, protecting human or nonhuman populations from external dangers through risk calculation, has become more difficult to make and yet more urgent. this article has argued for such a distinction, while opening the stage for future analyses of simulations as forms of play and ritual. this research was made possible by a project on simulations of disasters headed by sandrine revet at sciences po paris in - . i am grateful to her and to marc elie and guillaume lachenal for the discussions we had on simulations, as well as to the four anonymous reviewers and the editors of the jrai, who helped me improve the writing of this article. this approach was launched in by the wildlife conservation society, and then endorsed by the international organizations for human and animal health (http://www.oneworldonehealth.org/, accessed february ). contrary to other viruses such as smallpox, flu viruses don't have their genetic information encoded in dna (a double-stranded helix of nucleic acid) but in rna (a single-stranded ribonucleic acid). this explains why they mutate more randomly. anonymous interview by email after a questionnaire 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in taiwan an influenza epicentre? models, simulations and their objects dating the emergence of pandemic influenza viruses emergence and predominance of an h n influenza variant in china origins and evolutionary genomics of the swine-origin h n influenza a epidemic culling exercise. razor tv simulation exercises on influenza pandemic responses in the asia-pacific region flight ways: life and loss at the edge of extinction seeking refuge: birds and landscapes of the pacific flyway learning from sars. andrewzolli.com cet article décrit les relations entre humains, animaux, artefacts et pathogènes dans les simulations de désastres, en considérant les maladies qui affectent les oiseaux dans trois territoires sentinelles aux frontières de la chine comme des cas ethnographiques. en s'appuyant sur les distinctions entre la simulation, le ritual et le jeu, il montre que l'engagement des acteurs dans l'imaginaire des simulations, qu'ils décrivent sous le terme de « réalisme », renverse réflexivement les oppositions entre les humains and les non-humains, l'actif et le passif, la fiction et la réalité qui organisent la vie quotidienne. en empruntant les concepts de l'anthropologie des sociétés de chasseurs, il montre que les simulations de maladies aviaires, lorsqu'elles sont perçues comme des signes d'une potentielle extinction d'espèce, recourentà des techniques de pouvoir cynégétiques, dans lesquelles des humains et des animauxéchangent symétriquement leurs perspectives, et pas seulementà des techniques pastoralistes, dans lesquelles les humains sont au-dessus de la population qu'ils surveillent et parfois sacrifient.frédéric keck is a researcher at the laboratoire d'anthropologie sociale (collège de france, ehess, cnrs, psl). he has conducted research on the history of social anthropology and on the contemporary management of animal diseases, and headed the research department of the musée du quai branly.laboratoire d 'anthropologie sociale, rue cardinal lemoine, paris, key: cord- -nk iyg authors: chin, wei chien benny; bouffanais, roland title: spatial super-spreaders and super-susceptibles in human movement networks date: - - journal: sci rep doi: . /s - - -z sha: doc_id: cord_uid: nk iyg as lockdowns and stay-at-home orders start to be lifted across the globe, governments are struggling to establish effective and practical guidelines to reopen their economies. in dense urban environments with people returning to work and public transportation resuming full capacity, enforcing strict social distancing measures will be extremely challenging, if not practically impossible. governments are thus paying close attention to particular locations that may become the next cluster of disease spreading. indeed, certain places, like some people, can be “super-spreaders”. is a bustling train station in a central business district more or less susceptible and vulnerable as compared to teeming bus interchanges in the suburbs? here, we propose a quantitative and systematic framework to identify spatial super-spreaders and the novel concept of super-susceptibles, i.e. respectively, places most likely to contribute to disease spread or to people contracting it. our proposed data-analytic framework is based on the daily-aggregated ridership data of public transport in singapore. by constructing the directed and weighted human movement networks and integrating human flow intensity with two neighborhood diversity metrics, we are able to pinpoint super-spreader and super-susceptible locations. our results reveal that most super-spreaders are also super-susceptibles and that counterintuitively, busy peripheral bus interchanges are riskier places than crowded central train stations. our analysis is based on data from singapore, but can be readily adapted and extended for any other major urban center. it therefore serves as a useful framework for devising targeted and cost-effective preventive measures for urban planning and epidemiological preparedness. | ( ) : | https://doi.org/ . /s - - -z www.nature.com/scientificreports/ is the low-high outliers, that is any location with low density of disease cases which is surrounded by high density locations, thereby making it more vulnerable as it has a higher probability to report a higher number of cases in the following time period . in the field of network science, the concepts of 'spreaders' and 'receivers' first appeared in the hyperlink-induced topic search (hits) algorithm as hubs and authorities, respectively. in the hits algorithm, hubs describe highly influential nodes, while authorities represent highly popular destination nodes. to sum-up, the spatial super-susceptibles correspond to the susceptible locations in a spatial diffusion network. these locations are identified as being more vulnerable within the network as they are the destination of more people, hence generating a higher probability of being visited by infected agents. the spatial super-susceptibles are vulnerable locations as they are prone to disease infection thereby having the potential to become hotbeds for disease spreading to the rest of a city or region. note that if a place is both spatial super-spreader and spatial super-susceptible, it would require particular attention since it would pose the risk of simultaneously being a hotbed of infection and disease spreader. identifying these places would therefore be critical in the fight with infectious diseases such as in this article, we report a study aimed at systematically identifying the spatial super-spreaders and spatial super-susceptibles in the spatial human network of the city-state of the republic of singapore. the particular choice of singapore stems from it having: ( ) been hit early in the first wave of infection directly from wuhan and with a systematic tracking and mapping of infected people , ( ) one of the highest population densities in southeast asia, ( ) a dense and highly interconnected human mobility and transportation networks , , and ( ) detailed and reliable data for the construction of spatial networks . as mentioned earlier, a spatial super-spreader is a locus with a high outflow of people-i.e. a place where a lot of people are originated from and those people are moving to a high variety of places. in the same vein, a spatial super-susceptible is a destination for a large number of individuals originating from different places. hence, this work proposes a systematic data-centric framework enabling the identification of spatial locations, which should be targeted by public health agencies in the event of an epidemic such as covid- . with these critical places identified, policy makers would then be able to implement cost-effective targeted responses with prevention and intervention measures directly connected to the level of vulnerability of a given location. this section is divided into three parts: descriptions of (a) the study area, (b) the flow data, and (c) the metrics and indexes. study area. this study focuses on the public transportation flow network in singapore. the city-state primarily occupies an island located in southeast asia with a total surface area of about . km . as of , the total population of singapore is about . million people (with a population density of about , . per km ), in which . % are residents (citizens and permanent residents) and . % are non-residents (foreigners with long-term passes). according to the general household survey , about . % students and . % working person relies on bus or rail transport services to travel to schools or work places, thereby making public transportation the primary mode of transportation in singapore. as a result, the density of people using the public transports during the morning and evening peaks are high, and the distance between people at the stations and vehicles is short. hence, a direct consequence of the high population density combined with a high rate of people using public transportation is that physical distancing is extremely challenging if not impossible during regular operations. this issue is a serious concern when facing the spreading of a highly contagious disease such as to analyze the data, we consider the administrative subzone level spatial boundaries (from the singapore master plan ) as the analysis unit. the residential population density (from the general household survey ) are shown in fig. . there are five regions (central, west, north, north east, and east), with planning areas, and subzones . some of the subzones contain no residential population (white areas), which include airports and airbases (e.g. changi airport in the east region) and industrial parks or ports (e.g. jurong island and bukom at the south of the west region, and simpang north and south at the north region). although these places lack residential population, they are the workplaces (destinations) of a large number of individuals. the darker color areas indicate the home for a large number of people; in other words, a large number of journeys starting from and ending at these locations. weekday and weekend flow networks. we used the origin-destination (od) ridership data of bus and train to generate the public transport flow networks. the od ridership data is systematically collected by the singapore land transport authority (lta is a government statutory board under the ministry of transport) through api calls . in this study, we used the ridership from november to january . in terms of temporal resolution, the od ridership data provides hourly passenger flows between each pair of bus stops or train stations (including mass rapid transit and light rail transit). the raw data are then aggregated into weekdays (a total of days in november , days in december and days in january ) or weekends ( days in both november and december and days in january). the total number of trips for trains and buses starting from november to june are shown in fig. s (see supplementary material). as the raw data records the flow between od pairs of bus stops or train stations, we spatially aggregate the data into flows between subzones, according to the bus stop or train station locations. a total of subzones (out of a total of ) contained at least one bus stop or one train station. these subzones then form the nodes ( nodes) of the weighted direct network, with flows between nodes corresponding to the weight of directed edges. a total of , edges were found, with a vast majority ( , edges or %) being edges across subzones, | ( ) : | https://doi.org/ . /s - - -z www.nature.com/scientificreports/ and less than % (exactly edges) were within-subzone flows (i.e. corresponding to self-loops from the network perspective). given that very limited number of such intra-subzone flows, they were ignored in this study. to carry out this study, we introduce two indexes, namely the spreader index (spi) and the susceptible index (sui) to search for the spatial super-spreaders (ssp) and spatial super-susceptibles (sss). both indexes sui and spi are quantitatively determined and calculated using two key elements: ( ) the local strength of human in-and outflows, and ( ) the diversity of their respective neighborhoods . the local strength of in-and outflows for a given location is the number of people coming to or leaving from the location, i.e. respectively the weighted in-degree and weighted out-degree of the corresponding node. the neighborhood diversity is captured and quantified by two types of concepts: ( ) the diversity of zones and ( ) the diversity of coreness. the diversity of zones , refers to people that are coming from different parts of the city. as for the diversity of coreness [ ] [ ] [ ] , it refers to people either coming from the core or from the periphery of the country. more details about what constitutes core and periphery is given in step below. we applied this analysis framework to the singapore public transport flow network, and identified the ssp and sss using the sui and spi indexes. the population flow patterns are expected to be different for weekdays and weekends. thus, the flow data were separated into weekday and weekend ones. the calculation flow of the spatial spreader and spatial susceptible indexes is detailed in fig. . the first part consists in aggregating the bus and train od flow data to subzones as mentioned earlier. that top layer provides the main data for the calculation, i.e. two weighted and directed networks: weekday and weekend flow networks. these networks are subsequently used to compute three network characteristic measurements, including degree centrality (step ), community detection (step ), and k-shell decomposition (step ), which are described in full details in the following subsections. the degree centrality is used as a proxy for the intensity of the local out-and inflows, whereas the community detection and k-shell decomposition results enable the computation of neighborhood diversity, including zone-entropy and coreness-entropy as introduced below. finally, in the last step (step ), the three network characteristics are used to calculate the sui and spi. step : degree centrality. the degree centrality in this study includes both the non-weighted and weighted inand out-degrees. the non-weighted and weighted versions of the degree centrality represent different concepts in terms of network characteristics. the non-weighted in-degree and out-degree are the number of links (or edges) that are pointed to and from a subzone, respectively. this non-weighted degree centrality measures the number of relationships that a particular subzone has. as for the weighted in-degree and out-degree, they correspond to the summation of incoming/outgoing flows for a given subzone, respectively. this weighted version of degree centrality indicates the total strength of a node in terms of gathering flows or spreading flows without accounting for the actual number of (incoming or outgoing) edges. in this study, the weighted degree centrality is used to represent the local intensity of nodes for the calculation of the sui and spi. the weighted degree centrality is scaled within the unit interval (see eq. ( ) for weighted outdegree and eq. ( ) for weighted in-degree), where outdegree(i) and indegree(i) are respectively the weighted out-degree and weighted in-degree of node i, o is the set of all out-degree nodes, and i is the set of all in-degree nodes. on the other hand, both non-weighted and weighted degree centralities are used in the weighted k-shell decomposition analysis performed as step . ( ) www.nature.com/scientificreports/ step : zone-entropy. this study uses a community detection method (mapequation algorithm ) to identify the zones from the flow network, instead of using the administrative spatial boundaries (i.e. the boundaries of planning areas and regions as defined by the singapore government in its master plan ) that were designed and selected for governance and political purposes. the communities from this flow network analysis capture both the strength and direction of flows, which reflect the spatial activity of people derived from their daily commuting/mobility behaviors . as the community distribution is identified for weekday and weekend networks, similarly the distribution should be differentiated between weekdays and weekends. mapequation is used to identify the communities in the flow networks . this algorithm considers the direction and weight of edges to identify the strongly connected nodes in a directed and weighted network. this particular algorithm is different from modularity-based community detection methods since mapequation's calculation concept emphasizes the strength of flows in community, i.e. higher flow intensities within a community than between communities (flows cycling within communities). mapequation captures the effect of direction while ensuring large amount of flows are kept within the community. moreover, the communities obtained with mapequation are used as the zones that contain strong human flows cycle, which is quantified with the concept of zone-entropy. note that to maintain the spatial continuous properties of the community, we integrate a distance decay effect in the flow intensity calculation (see eq. ( )) before running mapequation: where f(o, d) is the number of people moving from the origin subzone o to the destination subzone d, distance (o, d) is the distance between the two subzones, and f ′ (o, d) is the actual flow intensity incorporating the distance decay effect. first, we run the mapequation algorithm on the two networks (weekdays & weekends), and identify the zone (set of communities z = {z , z , . . . , z max } with z j = {n| ∀ n belongs to community j} ) in which each subzone (node) belongs to. then, for each subzone, the incoming/outgoing neighbors' zones are retrieved from the results together with the weights of incoming/outgoing edges (w(j, i) or w(i, j)). the neighbors' zone information and flow weights are used to calculate the normalized entropy ( h zone neigh (i) ) using eqs. ( )- ( ) . the entropy is normalized using the total number of zones in the network to enable a comparison between nodes. note that the zone-entropy value ranges between and as a consequence of this normalization. www.nature.com/scientificreports/ step : coreness-entropy. the k-shell decomposition is a method to label the coreness (k-shell levels) of nodes in a network based on the connectivity structure . because the edges of the flow networks were weighted, we use the weighted k-shell decomposition , which is an extended version that consider both the number of links (degree) and the weights of links while labeling coreness. the coreness of a location indicates the position of the location in the range from periphery (low k-shell levels) to core (high k-shell levels). in a population flow network, the core locations indicate the common origins or destinations for a large number of passengers. in this study, we first run the weighed k-shell decomposition using the non-weighted and weighted in-/ out-degree (from step ) to calculate the in/out-k-shell levels for each subzone. then, the k-shell levels are grouped into core (in-/out-core) or periphery (in/out-non-core) using the median value as a cutoff. finally, for each node, its incoming/outgoing neighbors' core/non-core information is integrated with the flow weights to calculate the so-called coreness-entropy ( h core neigh (i) ) as defined in eqs. ( )- ( ) . the entropy is normalized using the total number of coreness levels (binary levels here, i.e. c = {core, periphery} ), to facilitate the comparison of the results between nodes. note that the coreness-entropy value ranges between and after this normalization. step : spatial spreader and susceptible indexes. the spatial spreader index (spi) and spatial susceptible index (sui) are base on the general concepts of the framework proposed by fu et al. and zhang et al. . however, the exact indices are largely modified to account for the specificities of our study. specifically, the spi and sui calculations are based on a geometric average of three key network metrics. the spi (see eq. ( )) is the geometric average of the local normalized weighted out-degree ( nwoutdegree(i) ), the zone-entropy of outgoing neighbors ( h zone outneigh (i) ), and the out-coreness-entropy of the outgoing neighbors ( h core outneigh (i) ). to understand this particular definition, one may for instance consider the case for which a node's spi is high: this node has a high volume of outgoing flows (high local intensity), half of the flows are directed to the core area and the other half to the non-core area (periphery); these flows are equally divided into different zones (high out-neighbors' zoneentropy). in other words, a high spi subzone has a large number of travelers originating from there, and these individuals are on their way to both core and periphery places, which are located in various zones. therefore, with such a high spi index value, the disease spreading would be facilitated within a short period of time. the flow intensity and diversity measurements are all normalized in the unit interval, and consequently the geometric average also varies between zero and one. the spatial susceptible index sui (see eq. ( )) is constructed in a completely similar way as the spi, with the exception that we are considering all incoming components as opposed to outgoing ones in the spi: e.g. local normalized weighted in-degree ( nwindegree(i) ), the zone-entropy of incoming neighbors ( h zone inneigh (i) ), and the in-coreness-entropy of incoming neighbors ( h core inneigh (i) ). again, the concept associated with the sui is better understood when considering a subzone with large incoming flows: half of the flows are coming from the core area and the other half from the non-core area, and these flows are equally coming from different zones. in other words, this subzone is a destination for a large number of travelers originating from various zones and their origins of movement contain both core and periphery areas. therefore, a high sui subzone is expected to be a place where travelers would be more vulnerable and sensitive to being infected. like the spi, the sui varies in the unit interval. both spi and sui are calculated as the geometric average of the three components, including normalized weighted degree, zone-entropy and coreness-entropy. we have also tested the arithmetic average of these three , if neigh = inneigh. ln |core(all)| , scientific reports | ( ) : | https://doi.org/ . /s - - -z www.nature.com/scientificreports/ components (see fig. s in supplementary material). we chose the geometric average method because the two proposed indexes are meant to be used for identifying super-spreader and super-susceptible locales. thus, only when all the three components are high, the spreading effectiveness of a subzone shall be considered high. local intensity of human movement flows. the spatial distribution of the non-weighted/weighted in-degree and out-degree for weekdays are shown in fig . to observe the spatial distribution of the in-and out-degree, the townships are separated into four groups using the %, % and % percentile of the corresponding degree values as cutoffs, thereby giving the "low", "mid-low", "mid-high" and "high" intensities. it appears that the patterns for the non-weighted and weighted in-degrees (top row) are similar to those of their out-degree counterparts (bottom row). this points to the fact that inflows and outflows are fairly balanced, which is expected for daily aggregated data associated with steady human movements. for the non-weighted degree measurements (left column), the high in-and out-degree subzones appear to be mainly concentrated at the east, north east and central regions, whereas the west and north have a higher number of lower degree subzones. these results are correlated with the distribution of human density in singapore, namely high to very high in the east, north east and central regions, and lower in the west and north of the island. for weighted degree measurements (right column), the east region has higher degree subzones; the number of high degree subzones drop in the central region; north, north east, and west regions have relatively more higher degree subzones when compared with their non-weighted counterparts. the distribution of the non-weighted measurements for weekends are essentially the same as the results for weekdays. figure displays the differences in weighted in-and out-degree between weekdays and weekends. most subzones are in the lightest green or purple colors, thereby indicating that their degree measurements are only very slightly larger than each other (the differences are less than . times). these subzones have a similar number of people using public transportation during weekdays and weekends. only a few subzones are in dark colors indicating larger changes as compared to weekdays. these subzones reveal a notably different usage of public transportation at these locations between weekdays and weekends; the changes of usage for weekdays are twice larger than weekends (dark purple), or the other way round (dark green). community detection. as discussed in the "materials and methods" section, a critical component of our network analysis is based on community detection. figure shows the spatial distribution of communities for both weekdays and weekends. the mapequation algorithm with the provided data reveals different commu- figure . spatial distribution of the degree centralities for the weekday dataset. left column (a,c) shows the distribution for non-weighted measurements and the right column (b,d) shows the distribution for weighted measurements of the degree. the top row (a,b) displays the in-degree, while the bottom row (c,d) refers to the out-degree. the townships are separated into four groups using the %, % and % percentile as breaks, thereby giving the "low", "mid-low", "mid-high" and "high" intensities. generated with python ( . . ), matplotlib ( . . ) and geopandas ( . . ). | ( ) : | https://doi.org/ . /s - - -z www.nature.com/scientificreports/ nities for both weekday flow network and weekend flow network. most communities are spatially continuous as the flow data is integrated with the inverse of the distance. however, some exceptions exist in both weekday and weekend communities (e.g. weekday and weekend community # ). the spatially-continuous patterns are expected given the spatial embedding of our networks and it indicates, as expected, that interactions between closer subzones are effectively stronger. on the other hand, the few spatially-split communities appear to be the by-product of a strong flow of human movement between two spatially-distant locations with sparser spaces between them. although weekday communities and weekend ones are different-some are split and others have different boundaries-overall, they show some notable similarities (e.g. weekday community # and weekend community # ). this observation can be attributed to two particular features of singapore: ( ) given the limited available land, singapore has a dense and compact urban landscape with a high level of mixed-use areas, be them residential, industrial and/or commercial, ( ) a non-negligible fraction of the working population is active on saturdays, which creates a high flow of travelers with the same commuting patterns as during weekdays. for instance, in the western region, weekday communities # and # are extremely similar with weekend communities # and # . these particular communities are fairly large with a heavy mixed-use of residential and industrial areas, where people have similar daily activities within a week. the north east region (ner) contains three similar communities during weekdays and weekends (community # (upper part), # , and part of # during weekdays, and the similar patterns of # (upper part), # , and # during weekends). the north region (nr) is split into multiple communities (community # (lower part), # , # , # , # , # during weekdays, and # (lower part), # , # , # , # during weekends). the identified communities # , # , # , # , # , # during weekdays, and communities # , # , # , # , # during weekends are similar and fit well with the central region (cr), which is the central business district of singapore. the community detection results show that the boundaries of human activity can be changed between weekdays and weekends. community # in weekends appears to be an area resulting from the merger of communities # , # and part of # during weekdays. this indicates that the area has stronger human movement interactions during weekends than weekdays, probably because the area is mostly residential with few shopping places providing daily needs products and necessities. in summary, the human movement boundaries are not fixed to a static pattern, and it is usually smaller than the shape of the known regional/administrative boundaries. coreness. the spatial distribution of the core area is shown in fig. . as detailed in the "materials and methods" section, the calculation of coreness is separated into two parts for each network, one of which uses the (weighted or unweighted) in-degree, and the other the (weighted or unweighted) out-degree. hence, two sets of coreness results (outgoing core area and incoming core area) are obtained for each network. some areas are identified as core in both incoming and outgoing directions (red subzones in fig. ), some are core for either incoming (pink subzones in fig. ) or outgoing (purple subzones in fig. ) but not both. however, the vast majority of areas are core ones from both the incoming and outgoing flows perspective. these red areas happen to have a notable overlap with residential areas with a high population density, thereby indicating that places where people live would always have high incoming and outgoing flow: a core area of human movement and commuting. spreader and susceptible indexes. the calculation of spreader and susceptible indexes require access to the local normalized in-degree and out-degree centrality, as well as the incoming and outgoing neighborhood zone-entropy (eqs. ( )-( )) and coreness-entropy (eqs. ( )-( )). note that these three key indicators (local weighted degree, zone-entropy and coreness-entropy) are in the unit interval, i.e. with variations between zero and one. figure shows the local out-and in-degree (left column), the outgoing and incoming neighborhood zone-entropy (central column) and coreness-entropy (right column) of the weekday (first two rows) and weekend (bottom two rows) flow networks. for observation purposes, the subzones were grouped into "low", "midlow", "mid-high" and "high" categories using the %, % and % percentile of each variables as cutoffs. the www.nature.com/scientificreports/ spatial distribution shows notable differences between centrality, zone-entropy and coreness-entropy. in addition, high levels of local weighted out-and in-degree are mostly concentrated in the east, north east, and central regions. as for the zone-entropy, these high levels are primarily located in the north and central regions, while high levels of coreness-entropy are mostly found in subzones in the north region. essentially, most of the subzones have high levels of one, two or even three of these key indicators. however, only subzones with high levels of all three indicators are ssp or sss. the distribution of the spreader index (spi) and susceptible index (sui) of each subzone for weekdays and weekends are shown in fig. . all four distributions suggest a similar poisson-like type of distribution, with a mean value between . and . (solid vertical lines). a detailed comparison between the two indexes and the three components is given in fig. s (see supplementary material). the fact that these mean values are very close for both indexes on weekdays and weekends is in line with our previous comment related to an expected balance between incoming and outgoing flows of human movement. however, for our analysis the locations of interest are those that are outliers corresponding to large spi and/or sui values. using the interquartile range (iqr) method, the outliers are identified as the subzones located above the q + . www.nature.com/scientificreports/ quartile ( q ) is also shown in fig. as a reference level (dotted vertical lines). the subzones that lay between q and q + . × iqr are categorized as secondary-spreaders or secondary-susceptibles. for comparison purposes, we tested the arithmetic average of the three components and compared it with the geometric average results (fig. s in the supplementary material); we also present fig. s (see supplementary material) to highlight the differences between the spi or sui, and the geometric average of either two of the three components (degree, zone-entropy, and coreness-entropy). this analysis reveals that a non-negligible number of locations exhibit large spi and/or sui values, thereby contributing to our identification process of spatial super spreaders and spatial super susceptibles. comparison with population density. the spatial distribution of population can naturally be considered to be key to understanding the spreadability and susceptibility of a given place. indeed, places with higher population density could be suspected to have higher spreadability of and susceptibility to an infectious disease. to test this hypothesis, we compare the subzones' spi and sui with the residential population density (see fig. ). the low correlation coefficients (including the pearson coefficient and the kendall tau are below . ) indicate that the spi and sui are not correlated with population density. interestingly, some low population figure . distribution of core/non-core areas from the weighted k-shell decomposition. the coreness in (a) refers to weekday flow data, while in (b) it is for weekend flow data. red-colored areas are for subzones identified as both incoming and outgoing core areas, purple-colored areas refer to solely outgoing core subzones, and pink-colored subzones highlight solely incoming core subzones. generated with python ( . . ), matplotlib www.nature.com/scientificreports/ density subzones have a high spi or sui. these subzones may be categorized as business or commercial land use areas, hence the low or zero residential population. on the other hand, some of the high residential population density subzones (i.e. above , ) have a low spi or sui. this may because their public transport flow structure is relatively simple, i.e. the outgoing or incoming flows are connecting with places with similar features (in the same zone or with the same coreness level). since residential population distribution represents the spatial patterns of where people live, it is only one type of the destination of population movements, and it therefore lacks the capability to capture places where people work and interact with each other, e.g. commercial area, business area and transport hubs. susceptibility vs. spreadability. while both spi and sui are calculated based on the same spatial flow network, they capture fundamentally different concepts in relation with disease spreading interactions as compared to classical influential node concept in network science . the key differences between the calculation of spi and sui is the flow direction, i.e. incoming flow to a node or outgoing flow from a node. in fig. , we compare the outgoing and incoming measurements for the three components (weighted degree, zone entropy, and coreness entropy), and the two indexes (spi and sui). strong correlations exist between the normalized weighted in-and out-degree (nw in-degree and nw out-degree, in fig. a for weekdays and (e) for weekends, both correlation coefficients are above . ). this is expected as we consider daily average flows to compute the weighted in-and out-degree, i.e. the people who leave their home area in the morning will eventually go back to their home area at some point during the day. differences between the zone entropy of incoming and outgoing neighbors can be observed in fig. b ,f (for weekdays and weekends, respectively, with pearson coefficient figure . spatial distribution of the three key indicators: weighted degree, zone-entropy and coreness-entropy. left column: local weighted in-and out-degrees; central column: outgoing or incoming zone-entropy; right column: outgoing or incoming coreness-entropy. first two rows: weekdays; bottom two rows: weekends. the subzones are separated into four groups using the %, % and % percentile as cutoffs, thereby giving the "low", "mid-low", "mid-high" and "high" categories. generated with python ( . . ), matplotlib ( . . ) and geopandas ( . . ). (fig. d for weekdays and (h) for weekends) show the relationship between sui (horizontal axis) and spi (vertical axis). since both indexes are geometric averages of the previous three directed components, in overall it shows correlated patterns because of the degree and zone-entropy, and the subzones with larger indexes (i.e. q ≤ spi ≤ q + . iqr and q ≤ sui ≤ q + . iqr ) tends to scattered within the box that is composed by the dashed ( q ) and dotted ( q + . iqr ) reference lines. this study focuses on the disease spreading process, thus emphasizing the differences between the outgoing and incoming directions. a subzone with high spi indicates that it has a stronger capability to affect other subzones due to the fact that a lot of people are leaving from this subzone, and they are moving to a high variety of places. on the other hand, a subzone with high sui indicates that it is easily affected by other subzones owing to an intense flow of people coming from a large variety of places. figure shows that the number of people leaving from a subzone is highly correlated to the number of people going to the subzone; but the diversity in terms of zone-and coreness-entropy shows differences between the subzones' incoming and outgoing neighbors. for instance, the coreness-entropy of a subzone's incoming neighbor can be high while its outgoing neighbor's coreness-entropy is low. although the correlation between spi and sui is high, we can still observe some deviations between them, especially beyond q and below q + . iqr. and super-susceptible (sss) is shown in fig. for weekdays and in fig. for weekends. for weekday flow movement (see fig. ), subzones are identified as ssp (red-colored zones in fig. a ) corresponding to www.nature.com/scientificreports/ spi ≥ q + . × iqr ; subzones are identified as sss (red-colored zones in fig. b ) corresponding to sui ≥ q + . × iqr . it is worth noting that subzones overlap in both figures, thereby corresponding to both spatial super-spreaders and super-susceptibles (subzones a-i in both figures, shown as red-colored subzones with a purple border). this indicates that most of the subzones with the highest spi values would also have the highest sui values, and vice versa. in fig. a , all identified ssp are also identified as sss. in fig. b , two subzones-j khatib, and k tampines east-are identified as sss only, with a lower spi ( q ≤ spi < q + . × iqr). the weekend distributions exhibit slightly different patterns. there are subzones identified as ssp on weekends, with of them also being identified as ssp on weekdays (subzones a to h in fig. a) ; none of which are less than q in the previous figure. similarly, all weekend sss are either super-or secondary-susceptibles on weekdays, and vice versa. a total of sss are found with the weekend human movement network (fig. b) ; of them (subzones a to i) are also weekend ssp; of which overlap with those of the weekday sss results, the other two subzones-j boulevard, and k bukit batok central-are promoted from weekday secondary-susceptibles subzones (pink subzones in fig. b ). this result further confirms that the spi and sui are not dramatically different between weekdays and weekends. there are eight subzones (a to i except h in fig. ), and (a to h in fig. ) , including three at the west region (choa chu kang central, jurong gateway, and jurong west central), two at the central region (maritime square and toa payoh central), and three at the north region (sembawang central, woodlands regional centre and yishun west) are identified as both ssp and sss (in red) in both weekdays and weekends. during weekdays, most of the identified ssp or sss areas belong to the regional core that contained a higher density of human activity. the eight ssp and sss can be separated into two types. the first type consists of five subzones (a, c, e, f, and i in fig. ), which contain high population density; the second type consists of the other three subzones (b jurong gateway, d maritime square, and h woodlands regional centre in fig. ) associated with a lower population density. the subzones in the first type are typical residential area, where the intensity of human activity are high due to the extensive need to travel out during the day time and travel back in the evening. on the other hand, the subzones in the second type are regional hubs of public transportation, which naturally attract a large population flows. for example, maritime square contains harbourfront mrt, which is the terminal station of two one counter-intuitive observation can be made from figs. and : the cbd contains less ssp and sss as one could expect. the cbd of singapore is located at the southern central part of the central region. high intensity of human activity exists within the cbd area. as shown in fig. , most of the subzones in the cbd have either a low weighted degree or a low neighborhood coreness-entropy. the low weighted degree probably finds its origin in the smallness of the area itself, which limits the catchment of incoming and outgoing flows. as for the low coreness-entropy, we trace it to the fact that a majority of the people are circulating within the cbd, which are mainly composed by the core area (fig. ). this result indicates that the cbd workplaces are less influential in terms of quickly spreading the disease to the rest of the city/island, but a contagious disease would quickly spread inside the cbd area as a consequence of its strong internal flows. in summary, the key influential areas are clearly identified as being the regional transport hubs, which connect the residential areas with the rest of the country. the concept of super-spreader was originally introduced in the field of social network analysis to identify the most influential persons or nodes within a given social network. these persons could be opinion leaders, trend setters, public figures within a group of people , . furthermore, this concept of super-spreader individual has been borrowed by epidemiologists to identify and study the abnormally high spreading activity of a small group of individuals , in large populations during an epidemic outbreak. while previous studies focused on the identification of super-spreaders within a social network-nodes are individuals and edges represent the existence of interactions between two persons (binary edge)-this study focused instead on spatial networks of population flow with nodes representing physical locations and weighted/ directed edges representing flows of human movement. this study sought to extend the concept of super-spreader to spatial interaction networks, with the objective of identifying possible spatial super-spreader locations-a set of locations that have the most influential effects in terms of disease spreading. the concept and calculation method were also reversed to uncover another group of critical locations: the most vulnerable places defined as super-susceptibles. our results based on large-scale data analytics show that most of the ssp are also sss. this is reasonable and somehow expected given the nature of the daily population flow network. specifically, since we are considering daily-aggregated data, the number of people who are leaving from a place can be expected to be of the same order as the number of people who are going to this place, i.e. we are in the presence of balanced commuting flows and the larger the outgoing flow intensity, the larger the incoming flow intensity. based on the results, the places with intense flows have higher potential to be both ssp and sss, and this is captured by the directed nature of the www.nature.com/scientificreports/ networks and the incorporation of the weighted in-degree or out-degree in our calculations. it is worth noting that our results are in good agreement with previous studies based on the k-shell decomposition method: the core nodes of a social group tend to be, in general, the most influential ones , . besides the local incoming and outgoing flow intensities, this study also considers two critical neighborhood diversities of these networks: the zone-entropy and coreness-entropy. the diversity of neighborhood is especially important while identifying multiple super-spreaders from a network , . the zone-entropy is used to measure if the outgoing flows are directed towards more zones within the city-state. for instance, if the outgoing flows from a given place are converging to one zone only, this place can only affect one of the zones among all throughout singapore, thus its influential power is clearly weak. conversely, if human movement originating from one place flows to many zones across the country, its influential power is relatively high. in addition, coreness-entropy captures the diversity of flows to or from core or periphery areas. if the flows are all directed towards one of the periphery or core, its influential power is somehow limited to this particular type of areas. conversely, if human movement flows to both core and periphery areas, this clearly indicates that whenever an outbreak happens at this place, it could quickly affect and spread to both core and periphery areas. these two diversity metrics complement one another and are combined in the calculation framework for differentiating places with high density of flows into strong and weak influential places (see materials & methods) . this study enables us to establish a list of subzones, which have a strong capability in terms of diseases spreading, as well as a list of subzones, which are more vulnerable in terms of being a place of high risk of contagion. in summary, the identified subzones are found to be mainly in the core area of residential and transportation figure . the spatial distribution of (a) spreader index (spi), and (b) susceptible index (sui) for weekdays. the subzones with purple border in (a,b) respectively indicate the super-susceptible ( sui ≥ q + . × iqr ) and super-spreader ( spi ≥ q + . × iqr ). generated with python ( . . ), matplotlib ( . . ) and geopandas ( . . ). | ( ) : | https://doi.org/ . /s - - -z www.nature.com/scientificreports/ hubs. these places have high population density and activity, such as transportation hubs or community hubs. therefore, these places should be targeted by public health agencies, with higher resource allocations and disease monitoring aimed at prevention and intervention purposes. for example, public health agencies could consider these locations while planning to setup body temperature checkpoints, or to provide personal hygiene toolkits, or also setting up advertisements related to appropriate behaviors to counteract the ongoing epidemics. moreover, since these locations are more vulnerable and more influential, they should get more attention while setting up differentiated policies such as the temporary closure of some businesses or restrictions on large-scale human activities as opposed to a blanket lockdown across the country. the proposed network analysis framework rests upon the integration of the local flow intensity with neighborhood diversity measures-zone and coreness-to assess the effective spreading ability of particular locations. from the theoretical perspective, the proposed framework considers weighted and directed interactions between nodes (places) to identify super-spreaders and super-susceptibles. from the practical perspective, this study presents a quantitative and systematic framework to identify the key influential and vulnerable locations based on public transport flow data usually available by most transportation agencies in metropolitan areas. it is worth noting that there are several limitations to this study. first, our analysis is limited to human flow associated with the use of public transportation, which is high in places like singapore or other continental european cities but could be much lower in other urban areas with far less developed public transportation networks, such as in the united states for instance. in addition, our data only includes ridership of buses and trains and misses out on other important means of public transportation, including taxis, private-for-hire automobiles www.nature.com/scientificreports/ (cars, motorcycles, shuttle buses or vans), and active transportation (by walking, bicycle, skateboard, scooter, personal mobility devices, etc.). some of the subzones currently do not have bus stops or train stations. however, as mentioned previously, public transportation by bus and train in singapore is fairly high-more than % of daily commuting-thereby confirming the importance of the obtained results, as being representative of key human movement patterns. second, singapore is an island country with its northern national border connected to malaysia through two land checkpoints. unfortunately, these cross-border flows are not included in this study. many workers and students commute daily between singapore and the state of johor in malaysia. there are some dedicated bus services directly connecting stations in johor bahru, malaysia and various places across singapore, including woodlands at the north region, jurong east at the west region, and bugis at the central region, etc. since these data were ignored, the in/out-flows of these places in singapore are certainly underestimated. third, inter-mode trip transfers and bus transfers are not captured in the dataset used to carry out our study. trip transfers between mass rapid transit (mrt) lines are captured from the tap-in and tap-out records, i.e. passengers changing lines at some interchanges. but the od data for buses only records the direct flow between bus stops, i.e. the records present only the tap-in and tap-out bus information, the records of the exchange of bus services are not shown/captured in the data. on the other hand, the data about changing from bus to train and vice versa is also unfortunately not available. therefore, we can only capture direct bus services and this naturally limits the movement of travelers to the existing direct bus/train services. fourth, the short-time scale dynamics throughout a day is ignored. indeed, we considered daily-aggregated data. however, a higher temporal resolution could be considered (say on an hourly basis), which could reveal different patterns of ssp and sss. the temporal evolution of the sui and spi indexes would be the topic of a future study. on the other hand, a long-term analysis may also provide insights into the evolution of spi and sui or spatial super-spreaders and super-susceptibles over time. the bi-monthly analysis of spi and sui (fig. s -s ) , and identified ssp and sss (fig. s -s ) are given in supplementary material. however, the distribution pattern for the long-term analysis requires a more in depth investigation and discussion owing to a possibly large number of unidentified factors that may affect the overall human movement structure. in summary, we have developed for the first time a framework allowing the identification of spatial superspreader and super-susceptible locations. we believe that our results and analysis could be extended in two key directions. first, our analysis would benefit from being complemented by working with epidemiologists specialized in simulations of disease spreading through human contact networks. this would integrate our results with differential spreading across more or less vulnerable places. specifically, the dynamic patterns of disease propagation could be observed from the simulation models, and thus the effects of the ssp and sss could be quantified in terms of its actual contamination rate in the population. second, the geography, demography, and social-economic of the spatial super-spreaders and super-susceptibles could be accounted for and included in our analysis using some statistical models, to identify the potential social and physical environmental factors that made these locations super-spreaders and super-susceptibles. in conclusion, it is well known that dealing with the reopening of economies and cities after a blanket lockdown requires a finely calibrated approach from governments. although, here we used the singapore public transport flow data to build these networks as a case study, similar analyses can readily be carried out using the exact same process in order to uncover the ssp and sss in any large urban center. our data-driven methodology, analysis and results offer an effective way of devising targeted and localized preventive measures when lifting stay-at-home orders. such targeted measures for vulnerable locations are also critical in order to optimize government resources in the face of economic decline. the datasets-generated from the singapore lta database -used for this study are available from the following spatial_spreader_susceptible_data repository: https ://githu b.com/wcchi n/spati al_sprea der_susce ptibl e_data. coronavirus 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precautionary measures transportation and territorial development in the singapore extended metropolitan region republic of singapore. passenger volume by origin destination bus stops & passenger volume by origin destination train stations general household survey master plan subzone boundary (no sea the map equation a k -shell decomposition method for weighted networks a model of internet topology using k-shell decomposition identifying and ranking influential spreaders in complex networks by neighborhood coreness a computer movie simulating urban growth in the detroit region searching for superspreaders of information in real-world social media the effect of superspreading on epidemic outbreak size distributions this research was supported by an sutd grant (cities sector: pie-sgp-ctrs- ). w.c.b.c. conceived and conducted the experiment and the data analysis. w.c.b.c. and r.b. analyzed the results and wrote the manuscript. all authors reviewed the manuscript. the authors declare no competing interests. supplementary information is available for this paper at https ://doi.org/ . /s - - -z.correspondence and requests for materials should be addressed to r.b.reprints and permissions information is available at www.nature.com/reprints.publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.open access this article is licensed under a creative commons attribution . international license, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the creative commons licence, and indicate if changes were made. the images or other third party material in this article are included in the article's creative commons licence, unless indicated otherwise in a credit line to the material. if material is not included in the article's creative commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. to view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/ . /. key: cord- - dv zsp authors: tan, kimberly-anne; thadani, vishaal nanik; chan, daniel; oh, jacob yoong-leong; liu, gabriel ka-po title: addressing coronavirus disease in spine surgery: a rapid national consensus using the delphi method via teleconference date: - - journal: asian spine j doi: . /asj. . sha: doc_id: cord_uid: dv zsp the magnitude and potential duration of the current coronavirus disease (covid- ) pandemic is something that most doctors currently in practice have yet to experience. while considerable information regarding covid- is being published every day, it is challenging to filter out the most relevant or appropriate information for our individual practice. the spine society of singapore convened via a teleconference on april , to collaborate on a national level and share collective wisdom in order to tackle the ongoing crisis. in the teleconference, spine surgeons from across various hospitals in singapore constituted the panel of experts. the following topics were discussed: repurposing of surgeons, continuity of spine services, introduction of telemedicine, triaging of spinal surgeries, preoperative testing, new challenges in performing spine surgery, and preparing for the post-pandemic era. while some issues required only the sharing of best practices, the delphi panel method was adopted to form a consensus on others. existing spine specific triage guidelines were debated and a locally accepted set of guidelines was established. although preoperative testing is currently not performed routinely, the panel voted in favor of its implementation because they concluded that it is vital to protect themselves, their colleagues, and their patients. solutions to operating room specific concerns were also discussed. this article reflects the opinions and insights shared during this meeting and reviews the evidence relevant to the issues that were raised. the rapid consensus reached during the teleconference has enabled us to be concerted, and thus stronger, in our national efforts to provide the best standard of care via our spine services in these challenging times. we believe that this article will provide some guidance for addressing covid- in spine surgery and encourage other national/regional societies to conduct similar discussions that would help their navigation of this pandemic. coronavirus disease , caused by the severe acute respiratory syndrome coronavirus- (sars-cov- ), was declared a worldwide pandemic on march , by the world health organization [ ] . while exceptional amounts of healthcare an d economic resources have been, and continue to be, diverted toward fighting this virus, the end of this modern-day world appears farther away. the magnitude and potential duration of this covid- pandemic is something that most doctors currently in practice have yet to experience. both within and beyond the realm of the field of orthopedics, new perspectives, recommendations, and guidelines in relation to covid- are being published every day, and this has been most useful in helping us survive in these unprecedented times. however, with a considerably high volume of information coming in, it is often difficult to identify the information that is most relevant or appropriate to individual practice. a phrase that has been increasingly used throughout this pandemic encapsulates the situation accurately: "we are in the same storm, but not the same boat. " this aptly describes the imperative for respective orthopedic societies to form a consensus on a national and subspecialty-specific level to tackle the ongoing crisis. to address this, the spine society of singapore (sss), comprising orthopedic and neurosurgical spine surgeons from institutions across singapore, convened via a teleconference on the evening of april , . this article reflects the opinions and insights shared during the meeting and reviews the evidence relevant to the various issues discussed. the index case of covid- in singapore was an imported case from wuhan, china, reported on january , [ ] . the subsequent month saw the progressive implementation of proactive measures to slow the spread of covid- , including strict border controls, aggressive contact tracing, law-enforced quarantine in government facilities, and a low threshold for covid- diagnostic swab tests. the efficacy of these swift draconian measures, guided in-part by bitter lessons learned during the sars pandemic [ ] , was reflected by the low rate of new covid- cases, garnering singapore international praise for what appeared an early flattening of the curve [ , ] . however, this victory was relatively short-lived because the rapid spread of covid- within migrant laborer dormitories emerged and soon resulted in singapore having the highest number of confirmed cases among all south east asian countries by april , [ ] . this second wave of infection has highlighted the vulnerability of such underprivileged groups as well as the need to protect them. in response to the increasing rates of community spread, singapore went into lockdown on april , and remains in lockdown at the time of writing this report [ ] . during the aforementioned sss teleconference, spine surgeons from across various hospitals in singapore, including all the public hospital heads of service, constituted the expert panel. all other local spine surgeons and orthopedic trainees who had expressed interest were invited to attend as members of the audience. the chairman of the meeting first updated the panel on the latest developments and evidence on covid- , with a focus on details relevant to spine surgery. key issues were highlighted as per the section headings to follow. while some issues required only a sharing of the best practices, the delphi panel method was adopted to form a consensus on issues [ ] , such as the triaging of spinal surgeries, preoperative testing, and new challenges during the surgery. similar to that in several other countries [ ] [ ] [ ] , the orthopedic workforce in singapore is being repurposed in the aggressive management of the covid- pandemic [ , ] . spine services have inevitably experienced diversion of their manpower; however, with the culling of all elective load, most tertiary center-based spine services have not faced many consequences. however, smaller orthopedic spine services have had to adapt their rosters. while orthopedic spine surgeons in the latter context have usually already established close ties with their neurosurgeon colleagues, covid- has mandated greater interdepartmental collaboration for ensuring the undisrupted provision of spine services despite diminished manpower. segregation of intra-department personnel is advised, especially in larger hospitals where this can be practically achieved. within a tertiary hospital's orthopedic department, consultants of the same subspecialty can divide themselves into two groups and strictly ensure that members of each group do not come in contact with one other. some orthopedic departments have split themselves into teams to manage clinics and operating theaters. segregation formats should also apply to the junior staff members who are attached to the teams of their respective consultants. constant availability of care is paramount in orthopedic subspecialties, such as spine and trauma, that routinely receive patients who require urgent surgical intervention. such segregation measures would help ensure continuity of service in case one of the subspecialty teams become contaminated and require to be quarantined. across all public hospitals in singapore, surgical inpatient and outpatient workloads have already been reduced by % as per the government directive. the method used to achieve this in the outpatient setting is left to the discretion of individual spine surgeons, although the guiding principle has been, as described by soh et al. [ ] , "all non-urgent spine appointments, such as referrals for osteoporotic compression fractures, or acute back pain without neurology, [being] rescheduled to later dates.'' rescheduled patients are offered repeat analgesia prescriptions that they can collect without presenting to the clinic and given thorough return advice. postoperative visits within weeks of surgery have not been postponed because these fall under "essential services. " operating theaters are now running at about % capacity to ensure the conservation of resources, such as intensive care unit beds, personal protective equipment (ppe), and propofol, as well as to allow the diversion of nursing and anesthesia manpower for covid- management. consequently, all elective cases have been cancelled, and only urgent or semi-urgent cases are being treated. however, given the inherently wide spectrum and time-sensitive nature in which spine pathologies tend to present, triaging spine cases while balancing the duties of a spine surgeon and managing covid- cases has proven challenging (as discussed in a subsequent section). tan tock seng hospital and its affiliated national centre for infectious diseases have collectively been designated as singapore's epicenter of the fight against co-vid- . all ambulances transporting patients with nonrespiratory and non-life-threatening conditions are being diverted away from this epicenter to other hospitals. nationwide efforts to keep orthopedic inpatient admissions low have been aided by the public's fear of being exposed to the virus within a hospital environment. however, it is difficult to deter some neurology-free, acute onset back pain, or sciatica patients from seeking hospitalization owing to their inability to cope with their symptoms at home. similar to the situation before the break out of the covid- pandemic, these patients continue to be admitted for appropriate work up and pain control before being discharged as early as possible to free up hospital beds. however, outpatient physiotherapy services (integral for the treatment of these patients) have been suspended following the implementation of lockdown laws. a new beginning? the aforementioned challenges in clinical practice brought about by the covid- pandemic raise the question of whether we can use present-day technology to improve patient care. in order to address the lack of outpatient physiotherapy services during the covid- pandemic, telerehabilitation may prove a worthwhile solution. telerehabilitation services were already gaining popularity before the covid- pandemic because patients started to embrace the convenience and flexibility it affords [ ] . in conjunction with wearables, telerehabilitation can also be used by surgeons to monitor their patients' postoperative functional outcomes [ ] . for example, a simple wearable device with an in-built pedometer could inform a surgeon about the postoperative improvement in the degree of spinal stenosis and claudication. rather than endless postponement of outpatient visits, where appropriate, spine surgeons should attempt to convert some of these into teleconsultations. this is especially applicable for simple cases, such as symptom review appointments for chronic back pain or appointments scheduled to analyze the imaging results. while a full physical examination is not possible during a teleconsultation, valuable information can be gained by asking the patient to demonstrate things, such as gait and power, or to perform tasks such as buttoning a shirt. many spine services in singapore have started trial teleconsultations to help provide continuity of care despite covid- . this has elicited a mixed response from the patients. in general, older patients find the technology challenging, while younger patients are glad to be spared a physical visit. the shift in our meetings, teaching sessions, and confer-ences to online platforms has been an excellent way for us to familiarize ourselves with teleconferencing technology and to identify potential issues early to improve patient experience. although the technology has already been available for few years, covid- has encouraged doctors and patients to embrace and explore telemedicine [ ] ; while the covid- pandemic is temporary, telemedicine is expected to continue in future clinical practices. thus far, only three sets of spine surgery-specific triage guidelines have been published in response to covid- [ ] [ ] [ ] . during the sss teleconference, local spine surgeons largely agreed with these existing guidelines; however, they also debated over the following few: ( ) cervical or thoracic myelopathy secondary to spinal stenosis should be considered semi-urgent if the patient has experienced recent or rapid deterioration. all other myelopathy cases should be considered elective, although the progressive nature of this disease warrants that these remaining cases be prioritized once elective surgeries are resumed. care should be taken to avoid postponing these cases for too long (> - months), especially since we cannot predict the length of this crisis, and meanwhile, the list of patients requiring surgery will continue to grow. ( ) according to the national health service (nhs) guidelines, metastatic spinal cord compression (mscc) patients should not be offered surgery if resources are limited to the point where only selective emergency spinal surgery can be performed [ ] . however, the north american spine society (nass) guidelines categorized mscc as its highest triage tier and recommended against its postponement [ ] . while sss acknowledged the stance of the nhs that the tendency for poorer prognosis and potential for significant resource utilization by mscc patients meant that they should be given lower priority in times when resources are critically limited, it also recognized that cancer prognosis (as per the treating oncologist) as well as preoperative neurological function were crucial outcome determinants that need to be remembered. tumor histology should also be considered because it influences to patient prognosis [ , ] . sss thus stratified mscc patients as per these factors, as shown in table [ ] [ ] [ ] . ( ) chronic and persistent neurological deficit (that is relatively stable and not progressive) due to neurological compression, such as a foot drop from lumbar spondylosis or spondylolisthesis, should be managed conservatively during the crisis. however, if the case can be effectively treated via smaller day procedures, such as nerve root blocks, endoscopy, and microdiscectomy, they may be considered for the procedure sooner (during crisis time); however, these cases should not be prioritized over any other cases that have already been defined as urgent or semi-urgent (table ) [ ] [ ] [ ] . the sss used the terminology "urgent, " "semi-urgent, " and "elective, " to define the hierarchy of triage for surgery. an urgent case was defined as one that should not be postponed despite the ongoing crisis, a semi-urgent case was defined as one that should be allowed to proceed during the crisis if resources are available, and an elective case was defined as one that should be postponed until after the crisis. table summarizes the consensus of singapore's spine surgeons on how to triage spine surgeries during the covid- crisis [ ] [ ] [ ] and has been adapted from the comprehensive nass guidelines to reflect the local opinion [ ] . the orthopedic spine service of the national university hospital has had a long-standing tradition of auditing all upcoming spine surgery cases every week and has reported this to be especially beneficial during the covid- pandemic where resource availability is constantly changing. while the following set of guidelines provide a framework to help spine services triage their patients, the need to continually evaluate the operating lists on a case-by-case and resource-dependent basis remains crucial during this pandemic. preoperative testing for covid- would play a key role in providing safety for all the stakeholders involved in non-emergency surgeries. the relevant types of testing that are currently available include real time reverse transcription polymerase chain reaction (rt-pcr), the current gold standard [ , ] , and serological testing for antibodies. rt-pcr may be performed with nasopharyngeal (np), oropharyngeal (op) or bronchoalveolar lavage fluid (bal). inadequate sampling, illness duration at the time of testing, and a low real time viral load may affect the sensitivity of the test. while bal rt-pcr samples provide the best sensitivity ( . %) [ ] , op and np testing are used owing to their practical and less invasive nature. initial np rt-pcr testing is more sensitive than op testing in both severe ( . % versus . %) and mild ( . % versus . %) covid- cases [ ] . a separate study demonstrated improvement in nt-pcr sensitivity (from . %- . %) when repeated after hours in patients who initially tested negative [ ] . thus, np rt-pcr is the current recommended investigation [ ] . conflicting findings, varying accessibility, and rapid innovation make it challenging to recommend a single ideal serological test [ ] . however, the use of available serological testing as an adjunct with either np or op rt-pcr has been shown to yield combined sensitivities of > % [ , ] . currently, in singapore, unless there is reason to suspect that a patient has contracted covid- , preoperative testing for the virus is not performed. member surgeons of the sss find this lack of preoperative testing concerning, especially in light of the current local situation where community spread is sufficiently rampant to warrant a nationwide lockdown. while acknowledging that newer testing kits may soon prove faster or more sensitive [ ] , based on the aforementioned evidence, the authors propose the implementation of a preoperative testing protocol, as shown in fig. . ideally, days before the surgery, patients should be admitted to isolation rooms in a contained ward designated for preoperative covid- testing. if the designation of such a contained ward is not feasible, the patients may be required to self-quarantine at home for days before the surgery, and travel between the hospital and home for testing strictly via private transport while donning n respirators (national institute for occupational safety and health-approved respirators). as a standalone test, computed tomography (ct) imaging of the chest reportedly yields the best sensitivity ( %- %) for covid- diagnosis [ , ] ; although it would offer a great advantage in preoperative testing, considering the resource limitations, the authors feel that any available ct scanners would be better utilized in actual covid- management; thus, this modality has not been included in our proposed protocol. to protect ourselves, our families, our colleagues and our patients, preoperative testing for covid- should be implemented as early as possible [ ] urgent -progressive or severe neurological deficit due to neurologic compression resulting from: -trauma -disc herniation, especially if resulting in cauda equina syndrome -infection (e.g., epidural abscesses) -tumor -spinal instability from any cause at risk of causing neurological injury (e.g., tlics score ≥ [ ] , sins score ≥ [ ] ) a) -surgical site infections semi-urgent -myelopathy due to spinal stenosis with recent or rapid deterioration -tumors causing neurological compromise or spinal instability (sins score > ) in cases that do not meet above urgent criteria -infections yet to cause neurological deficit/spinal instability, but with inadequate response to pharmacological treatment -spinal conditions causing intractable pain or severe functional limitations that have failed conservative management (to consider day procedures such as nerve root blocks, endoscopy, or microdiscectomy where appropriate) elective -myelopathy due to spinal stenosis with neither recent nor rapid deterioration -chronic and persistent neurological deficit due to neurological compression, that does not already fall into the above categories b) -spondylolisthesis, spinal stenosis, or any degenerative spinal conditions that can be managed conservatively (at least for the duration of the crisis) b) -deformity corrections (e.g., scoliosis, kyphosis, flatback syndrome) -revision surgery that does not fall into the above categories tlics, thoracolumbar injury classification and severity; sins, spinal instability neoplastic score. a) tumor cases are considered urgent if the following criteria are met: ( ) present neurology no worse than the american spinal injury association [ ] c ( ) prognosis > year. if these criteria are not met, and the patient remains a surgical candidate, then the case is considered semi-urgent. b) may consider up triaging to semi-urgent if condition can be effectively treated by day procedures such as nerve root blocks, endoscopy or microdiscectomy, but not to take precedence over any urgent or semi-urgent cases already defined above. several new challenges in the performance of spine surgery have arisen owing to the covid- pandemic. total intravenous anesthesia (tiva), and thus intraoperative neuromonitoring, are rapidly becoming unaffordable luxuries, considering the global shortage of propofol and the need to conserve these for the present and future co-vid- patients requiring mechanical ventilation. while the use of tiva and intraoperative monitoring remains warranted in cervical spine surgery as well as in cord compression cases, spine surgeons should be much more judicious in its use in any other types of spine surgery that is being performed during this pandemic. full ppe should be used when managing patients in whom covid- infection has not been ruled out. current recommendations on ppe effective against co-vid- include either a pair of protective goggles or a face shield [ , ] ; however, both the gears cause poor visualization when operating with a microscope. while day procedures, such as microdiscectomies, have become more relevant during the present resource-limited time, this challenge has begun to frustrate many spine surgeons. however, one of the authors recently decided to try a pair of swimming goggles and found the visibility of his surgical field to be better than that with the use of conventional ppe options (anti-fog swimming goggles are advised). alternatively, this may also be a good opportunity for spine services to try or invest in a digital microscope. spine surgery often involves frequent and prolonged use of diathermies and high-speed burrs that are known to generate aerosols [ , ] . while there neither been a reported case where covid- transmission occurred from patient to surgeon within the operating room, nor the existence of studies sampling these aerosols to determine their viral titers, the knowledge that significant sars-cov- viral loads can be found in the blood of infected patients is concerning to spine surgeons [ , ] . therefore, the use of these tools should be minimized as much as possible. where appropriate, kerrison punches and osteotomes should be preferred over high-speed burrs. although the relative vascularity of the spinal soft tissues effectively precludes the use of a scalpel blade in favor of a cutting diathermy, by keeping the sucker close to the diathermy tip, aerosolization can be minimized by eliminating as much of the aerosol as possible before it disperses [ ] . it is advised that full ppe be worn by all operating room personnel during these aerosol generating procedures; further, it is recommended that these procedures be performed in facilities with high-efficiency particulate air filters and closed circuit ventilation [ , , ] . with countless outpatient appointments and surgeries being postponed and re-postponed, spine surgeons worldwide are bracing for the inevitable post-pandemic increase in surgical patients. while we remain hopeful regarding the ready availability of a covid- vaccine in the near future, this is an ideal scenario that is not being depended on by majority of the medical community. the current reality is that if and when the situation improves, there will be slow and cautious reinstatement of our clinical capacities, with persistent risk of recurrent waves of co-vid- . therefore, in this immediate post-pandemic era, it is likely that operating lists will remain stringent and that the triaging of cases will remain necessary. preoperative testing for covid- should continue, and the use of telemedicine in our outpatient services requires further development. spine surgeons should take advantage of this critical time to adapt as much as possible because our clinical practice may never be the same again. the sss teleconference discussed many important issues that affect spine surgery in the presence of the covid- pandemic. the rapid consensus has enabled us to be concerted, and thus stronger, in our national efforts to provide the best standard of care via our spine services in this challenging time. we hope that this article provides some guidance in addressing covid- in spine surgery and encourages other 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considerations in patients with covid- : what orthopaedic surgeons should know key: cord- -ecg s a authors: chia, ming li; him chau, dickson hong; lim, kheng sit; yang liu, christopher wei; tan, hiang khoon; tan, yan ru title: managing covid- in a novel, rapidly deployable community isolation quarantine facility date: - - journal: ann intern med doi: . /m - sha: doc_id: cord_uid: ecg s a singapore is one of the most densely populated small island–states in the world. during the coronavirus disease (covid- ) pandemic, singapore implemented large-scale institutional isolation units called community care facilities (ccfs) to combat the outbreak in the community by housing low-risk covid- patients from april to august . the ccfs were created rapidly by converting existing public spaces and used a protocolized system, augmented by telemedicine to enable a low health care worker–patient ratio ( health care workers for beds), to operate these unique facilities. in the first month, a total of patients were admitted to halls, in-house medical consults occurred, patients were transferred to a hospital, patient died weeks after discharge, and no health care workers became infected. this article shares the authors' experience in operating these massive-scale isolation facilities while prioritizing safety for all and ensuring holistic patient care in the face of a public health crisis and lean health care resources. singapore is one of the most densely populated small islandstates in the world. during the coronavirus disease (covid- ) pandemic, singapore implemented large-scale institutional isolation units called community care facilities (ccfs) to combat the outbreak in the community by housing low-risk covid- patients from april to august . the ccfs were created rapidly by converting existing public spaces and used a protocolized system, augmented by telemedicine to enable a low health care worker-patient ratio ( health care workers for beds), to operate these unique facilities. in the first month, a total of patients were admitted to halls, in-house medical consults occurred, patients were transferred to a hospital, patient died weeks after discharge, and no health care workers became infected. this article shares the authors' experience in operating these massive-scale isolation facilities while prioritizing safety for all and ensuring holistic patient care in the face of a public health crisis and lean health care resources. annals.org ann intern med. doi: . /m - for author, article, and disclosure information, see end of text. this article was published at annals.org on september . * all authors contributed equally to the work reported in this article. i n singapore, the construction industry employs approximately foreign workers. in april, an outbreak of coronavirus disease (covid- ) occurred among these workers, who lived in crowded dormitories ( ) . as of august , covid- cases were reported in singapore, . % of which involved foreign workers living in dormitories ( ) . as such, isolation centers called community care facilities (ccfs) were set up throughout the country to house patients with covid- who were at low risk for dying of the disease. the admission of patients to ccfs was mandated by the infectious diseases act, which authorizes the director of medical services to order any person who is-or suspected to be-infected with or carrying an infectious disease or who is a contact of such a person to be detained and isolated in a hospital or other place. the ccfs act as a step-down care facility after diagnosis and admit low-risk foreign workers from dormitories or patients who have recovered well in the hospital and have been discharged. patients may stay in the ccf for up to weeks and are then transferred to another step-down isolation facility to serve the rest of the minimum -day isolation period after diagnosis. singapore's public health care system is divided into clusters ( ), each of which was tasked with operating the several ccfs rapidly created to manage the covid- outbreak. this article focuses on the initial experience (in may ) of the singhealth cluster, which ran halls to ( beds) of the ccf@expo facility. singapore expo has square meters of column-free, indoor space spread over halls. with a maximum capacity of beds, ccf@expo is one of the largest isolation facilities of its kind. the first halls were retrofitted to purpose over days and the remaining halls within days. each hall was repurposed to accommodate patients, with due consideration given to fire emergencies and contingency plans. the . -× . -m twin-sharing patient cubicles were constructed with partition boards (figure) . patients were allowed to move freely within their designated hall. each hall was equipped with medical consultation rooms, pharmacies, self-monitoring stations, wi-fi access, recreational amenities, water dispensers, showers and toilets, and self-service laundry facilities. radiologic service was provided by vehicles retrofitted with imaging machines. because monitoring of vital signs is resource intensive, a patient self-monitoring strategy was used. fifteen self-monitoring stations were set up in each hall, with digital sphygmomanometers, pulse oximeters, thermometers, and computer tablets. instructions written in several languages guided patients in using the monitors, recording their vital signs on a computer tablet, and disinfecting the station after each use without supervision. the data were evaluated twice daily by a member of the health care team situated outside the halls. each hall had primary care medical consultation rooms with pharmacy cabinets. it also had sickbays for short-term patient monitoring-for example, if a patient was awaiting transfer to a hospital or a response to treatment. pharmacists from singapore general hospital were responsible for stocking key essential medications, such as antihistamines, antitussives, antibiotics, analgesics, antihypertensives, and diabetic medications, and packaging them to facilitate dispensing at ccf@expo. physicians prescribed and directly dispensed these drugs from the pharmacy cabinets. the electronic health record system in place monitored the pharmacy repository and ensured an adequate stockpile. unidirectional laminar airflow was created in the hall to prevent contamination of the surroundings. side entrances and wall spaces were sealed, and a negative pressure of . pa ( . atm) was generated, with the outflow air filtered through a hepa (high-efficiency particulate air) system before being released into the outside environment. two-doored anterooms were created at the hall's entry and exit points to ensure unidirectional airflow. security cameras were placed to monitor for any unauthorized exits. ccf@expo was operated by a team of administrators, pharmacists, doctors, and allied health staff (affectionately called "angels" and from various disciplines, including nursing and physiotherapy) mobilized layout plan of ccf@expo halls to . the facility had distinct areas: green, red, and orange. the green area was for rest and meals for the staff. the red area is where patients were housed. staff entered the red area through a designated double-door entrance located at even-numbered halls and exited via odd-numbered halls. patients were allowed to roam freely. the orange area is where patients departed busses or were picked up by ambulances. (image courtesy of singex.) managing covid- in a community isolation quarantine facility from the singhealth cluster. the angels performed the same tasks of screening and monitoring the patients. round-the-clock medical care was provided, with both doctors and angels assigned to -hour shifts. during the day shift ( a.m. to p.m.), each hall was staffed by or doctors and to angels. during the night shift ( p.m. to a.m.), staffing was reduced to doctor and angels per hall. staff safety was paramount. all personnel had to be trained in the fitting and use of n masks and other personal protective equipment (ppe) before deployment. illustrated instructions were placed at gowning and degowning stations to remind staff of the proper steps for putting on and taking off their ppe. trainers also were placed at these stations to ensure that staff adhered to the gowning and degowning procedures. each health care worker was allowed in the hall for a period not exceeding hours over a continuous stretch. clean areas were made available to all staff for rest periods. to ensure the facility's safety and prevent unauthorized exit, security officers were stationed in each hall during each shift. a separate security team was available if needed. the ministry of health (moh) controlled the disposition of each patient with a positive covid- test result (defined as a positive result on polymerase chain reaction swab testing). the moh devised a risk-based classification system including symptoms, vital signs, age, existing comorbid conditions, national early warning system (news) score (appendix figure, available at annals.org) ( ), body mass index, level of activities of daily living, radiologic findings, and date of disease onset. although several groups of patients were considered low risk, those chosen for admission to ccf@expo generally were young and had no severe symptoms (such as dyspnea), no serious medical comorbid conditions, normal vital signs, and a news score of or less. the news score is a composite value based on commonly used parameters (respiratory rate, oxygen saturation, supplemental oxygen requirement, temperature, blood pressure, heart rate, and level of consciousness). a score lower than in a patient with acute illness indicates that he or she is at low risk for deterioration ( ) . chest radiography was performed in all patients older than years. if pulmonary consolidation was detected on a radiograph, the patient was transferred to a general hospital. a team of angels was tasked with screening all patients referred to the facility by the moh for admission. patients were evaluated for serious medical comorbid conditions (such as ischemic heart disease or renal failure) and abnormal vital signs. if any abnormality was detected, the patient was referred to a physician who decided whether they were suitable for admission to ccf@expo. patients determined to be unsuitable were transferred to a general hospital for further care. on admission to the facility, patients received an orientation booklet that was written in their native language and included infographics. the booklet con-tained information on the patient's responsibility for monitoring their own medical condition as well as the medical facilities available to them-namely, the process for obtaining a medical consultation both during and after office hours, code blue buttons, and selfmonitoring stations. two medical consultation rooms were staffed by physicians from a.m. to noon and p.m. to p.m. daily. during these times, patients could present to the consultation rooms as they would to a primary care provider in the community. for urgent after-hours consultations, patients were instructed to see a physician via teleconsultation; for emergencies, patients were instructed to press one of the code blue buttons located in highly visible areas. in addition, a hotline was created to answer any urgent queries from patients. we also actively surveyed for a secondary disease outbreak, such as chickenpox, measles, or gastroenteritis. although some of the physicians staffing the facility were specialists, the degree of care was kept at the primary care level. patients who needed further investigations or were acutely ill were transferred to a general hospital via an ambulance dedicated to patients with covid- . during the night ( p.m. to a.m.), only security officers manned the halls; medical staff were stationed in the green area outside the hall. for medical consults after hours, a videoconference-enabled computer terminal was placed in one of the medical consultation rooms and was kept on live stream throughout this period. a physician monitored the videoconference via a computer terminal located in the clean area. keeping the videoconference on live stream throughout the whole period was necessary, because instructing the patients on how to set up the computer for a teleconference would be difficult. patients used a vital sign self-monitoring system that allowed detection of those whose condition may have been deteriorating. each patient was instructed to measure their vital signs at a self-monitoring station at several points during the day. if a substantially abnormal sign (defined as systolic blood pressure > or < mm hg, diastolic blood pressure > mm hg, heart rate > beats/min, or spo [oxygen saturation as measured by pulse oximetry] < %) was noted, the patient was asked to present to the medical consult room for review. telephone reminders were used to ensure adherence to vital sign monitoring. in the rare event a patient did not have a working mobile phone, a patient experience team was tasked with helping to secure one. apart from looking after patients' health, a patient experience team was created to ensure general wellbeing and to maintain morale among those housed at ccf@expo. the team made sure that information was easily understood by the patients. it also provided psy- annals of internal medicine chological support while a medical humanities team provided language translation and translators. the group organized hairdressing and financial services, counseling, and culturally appropriate movie screenings, and ensured that dietary requirements were met. the team was also critical in preventing mass unrest within the halls. the facility had a free wireless connection so families could be kept up to date on their loved one's progress. these services were provided at no cost to patients. under moh authority, patients were discharged from all isolation facilities after day of illness. the start of illness was determined by the date of onset of the first symptoms or, for asymptomatic patients, the date of the first positive swab test result. it has been demonstrated that severe acute respiratory syndrome coronavirus (sars-cov- ) is probably not viable after the second week of illness, despite the persistence of rna detected on polymerase chain reaction assay ( ) . therefore, it was deemed unlikely that persons would be contagious after day of illness, and day was chosen to err on the side of caution ( , ) . most of our patients stayed at ccf@expo for around weeks, after which they were discharged to other step-down facilities to complete the remaining isolation period. an audit of the first month's cases ( may to june ) showed that a total of patients were admitted to the facility during this period. each day, there were . admissions (sd, . ), . discharges (sd, . ), . bed occupancies (sd, . ), and . medical consults (sd, . ). patient characteristics and early outcomes are provided in the table. a total of medical consultations occurred during the audit period; diagnoses made during the consultations are aggregated in the appendix table ( available at annals.org). patients presented for various reasons, both related and unrelated to covid- ; the most common were minor respiratory conditions, gastrointestinal conditions, and musculoskeletal disorder. the reasons for patient transfer to a general hospital are listed in the table. of the patients admitted to ccf@expo, . % (n = ) were transferred to a general hospital (table) . of this group, patient required intensive care for post-covid- pneumonia complicated by staphylococcus aureus pyogenic myopericarditis and polymicrobial bacteremia. this patient was subsequently discharged well from the general hospital. one patient died of a massive pulmonary embolism weeks after his discharge from the facility. adherence to vital sign monitoring was . % after telephone reminders were issued. between may and june , a mean of . patients (sd, . ) presented each day with persistently abnormal vital signs requiring a consult. isolation strategies may be divided broadly into institution-based and home-based isolation. the predominant problem with home-based isolation is the reliance on personal adherence. consequently, a modeling study showed that institution-based isolation is times more efficient than home-based isolation in reducing the number of covid- cases ( ) . like many countries, singapore decided to pursue an institution-based isolation strategy. before the pandemic, acute hospitals in singapore had a total of beds ( ), including intensive care beds ( ). if we contained the disease by hospitalizing patients with covid- , as was the strategy adopted in singapore during the sars outbreak ( ), the nation's health care infrastructure would have been rapidly overwhelmed. foreign workers made up most of the covid- cases in singapore. to control the spread of the virus, the country underwent a lockdown from april to june , and foreign workers were confined to their dormitories. to encourage foreign workers to report symptoms, the ministry of manpower issued an advisory in april managing covid- in a community isolation quarantine facility mandating that they be paid their salaries, through government assistance, during the lockdown period. workers who were diagnosed with covid- and subject to treatment order under the infectious diseases act were reassured that treatment would be provided at no cost them. ccf@expo was partly modeled after the fangcang shelter hospitals, the first large-scale covid- isolation facilities, which were built quickly by modifying exhibition centers and stadiums in wuhan, china ( - ) . however, ccf@expo's design included a few unique considerations. first, it served as an isolation facility rather than a hospital. as such, patients who were identified to be at risk for deterioration were sent to a general hospital for further evaluation and monitoring. second, the staffing level at the facility was low to avoid overwhelming the health care system. third, the facility served a unique population-foreign workers living in crowded dormitories who were predominantly non-english speaking and had low literacy rates. we addressed the first and second issues by admitting only patients presumed to have a low risk for death and who could participate in self-monitoring. patients could have no serious medical comorbid conditions and had to be mostly asymptomatic. to address the high patient-health care staff ratio, we designed the facility as an isolation unit with primary care support, rather than using the admission and consultation process typically seen in a hospital setting (detailed clerking, daily rounding). instead, we relied on the patients to be responsible for their self-monitoring. the rapid conversion of an existing facility, together with a low patient-staff ratio, also allowed our facility to be functional within a short period. regarding the third issue, the patients were a unique group. many had difficulties communicating in english, and some were illiterate. to mitigate this challenge, we created admission kits (containing screening questions for suitability for admission to the facility) that were translated into various languages and also included infographics. in the medical consultation rooms, posters containing translated phrases and infographics were plastered on the walls. if these were insufficient, telephone translators were used. apart from language issues, we recognized that a high level of anxiety was present among persons housed at ccf@expo. therefore, the patient experience team canvassed the halls to collect feedback from the patients. this information led us to provide culturally appropriate food, modify lighting in the halls to mimic natural day-night lighting, and offer hairdressing services. a substantial challenge that we faced was the switch in mindset from tertiary to primary care. most of our team members were used to providing care in a high-volume center, and mental barriers existed early on among the team in delivering medical care at the primary level. overall, patient died, weeks after he was discharged from ccf@expo, of massive pulmonary thromboembolism after covid- . even considering the young age of our patients, this death rate is substantially lower than the rates reported in most countries ( ) . we postulate that the reason for this low mortality is the high covid- detection rate among asymptomatic persons because of compulsory mass testing of the foreign worker dormitories in singapore. although mandated institution-based isolation is highly effective from a public health perspective, we acknowledge that it substantially restricts individual freedom. it also may be a disincentive for patients to come forward if they have symptoms or have been in contact with others who have tested positive for covid- . on a practical note, implementing these isolation measures met with little resistance, which may be a result of the collectivistic culture of asian societies ( ) . however, applying such a strategy in countries with an individualistic culture (where individual freedom is more highly valued) or in less economically developed nations may be more difficult. nevertheless, the experience gleaned at ccf@expo shows that institution-based isolation can probably be performed safely outside the hospital setting. this approach prevents health care infrastructure from becoming overwhelmed by curtailing the spread of the virus, thereby reducing bed use in acute hospitals, without the need for a large staff. a substantial proportion of stable patients with covid- can be isolated safely outside a hospital setting with a small health care team. isolation facilities can be created rapidly to care for patients without serious adverse outcomes. lastly, the use of technology, telemedicine, and patient self-monitoring is effective in managing a large cohort of stable patients with covid- . the relationship between infectious diseases and housing maintenance in indigenous australian households singapore ministry of health. covid- situation report reorganisation of healthcare system into three integrated clusters to better meet future healthcare needs. accessed at www.moh.gov.sg/news-highlights/details /reorganisation-of-healthcare-system-into-three-integrated-clusters -to-better-meet-future-healthcare-needs on standardising the assessment of acute illness severity in the nhs. report of a working party epidemiology and control of sars in singapore fangcang shelter hospitals: a novel concept for responding to public health emergencies large-scale public venues as medical emergency sites in disasters: lessons from covid- and the use of fangcang shelter hospitals in wuhan, china fangcang shelter hospitals in covid- pandemic: the practice and its significance incidence and mortality of pulmonary embolism in covid- : a systematic review and metaanalysis country comparison: individualism. accessed at www.hofstede-insights.com/country-comparison/singapore/#:~:text =in% individualist% societies% people% are,and% their % direct% family% only.&text=singapore% c% with% a % score% of,other% in% exchange% for% loyalty) on medicine and public issues managing covid- in a community isolation quarantine facility current author addresses: dr. chia: moh holdings. maritime square department of urology, singapore general hospital, college road department of anaesthesiology, college road critical revision for important intellectual content key: cord- -swr l ur authors: liu, zhenghong; teo, tess lin; lim, mian jie; nadarajan, gayathri devi; segaram, shashi s/o chandra; thangarajoo, sanda; wee, liang en; wee, jeremy choon peng; tan, kenneth boon kiat title: dynamic emergency department response to the evolving covid‐ pandemic: the experience of a tertiary hospital in singapore date: - - journal: j am coll emerg physicians open doi: . /emp . sha: doc_id: cord_uid: swr l ur the coronavirus disease (covid‐ ) pandemic has placed large stressors on emergency departments (eds) worldwide. as the pandemic progressed, eds faced changing patient epidemiology and numbers. our ed needed to rapidly transform to deal with the risk of covid‐ . having limited floor space, we opted for a phased, dynamic response that allowed us to adapt the ed multiple times as the epidemiology of the pandemic evolved. the principles behind our response include guiding ed operations with data, enhancing infection control practices, and being prepared to transform areas of the ed to care for different groups of patients. our experience can serve to guide other eds in planning their response to surge capacity and ed operations during such pandemics. covid- . given that even a single patient in a crowded ed can potentially ignite a nosocomial outbreak of a novel respiratory pathogen, with devastating consequences and the prospect of ed closure, , it is crucial to ensure that hospital eds can continue to operate safely throughout the covid- pandemic, without becoming hotbeds for disease transmission. singapore general hospital is singapore's oldest and largest hospital with a total of beds, and the current ed was built in . over the years, the daily ed patient load has increased from roughly to a day, but spatial constraints have limited the physical expansion of the department. the first case of covid- in singapore was diagnosed on presentation to our ed on january , and picked up because of increased vigilance. over the next few months, our ed rapidly developed and implemented a response plan that maximized the limited physical space and allowed our ed to appropriately manage patients with different risk profiles for covid- ,while simultaneously maintaining adequate protection for other patients and staff. in this paper, we describe this response, with a focus on phased adaptations to deal with successive waves of covid- cases and evolving epidemiology. we also describe the challenges faced in rapidly converting various patient areas to support higher-acuity care. as of the time of writing, although multiple studies have described their institution's ed response to covid- at various timepoints, , [ ] [ ] [ ] to the best of our knowledge, an overall multiphased ed response guided by evolving covid- epidemiology has yet to be described in the peer-reviewed literature. we believe this description can serve as a potential planning model for other eds, especially those facing similar space constraints, as eds start preparing for the "new normal" and successive waves of covid- . to date, singapore has faced several waves of covid- patients, each with distinct epidemiology. , during the first wave of cases from mid-march to early april , "imported cases," comprising travelers and returning singaporeans, predominated. from march , onwards, the singaporean government barred inbound travel; from june , , travel curbs were lifted, but all travelers were required to serve a -day stay-home-notice period and undergo covid- testing. in the second wave, patients deemed to have caught covid- in the local community, termed "community cases," predominated. the number of community cases rose at the end of march, peaked in mid-april and have been declining up to the time of writing (july ). in the third and largest wave, cases among migrant workers staying in purpose-built dormitories ("dormitory cases") predominated, with a significant number of asymptomatic cases. a significant spike occurred in mid-april, with a daily maximum of patients diagnosed on april , ( figure ). in response to the spike in cases, a nationwide "circuit breaker" period was declared from april , to june , . during this partial lockdown period, all non-essential services and schools were closed and public gatherings were prohibited. to cope with the significant rise in "dormitory cases," the singapore government pre-positioned medical teams at dormitories to manage patients with mild symptoms. this greatly reduced the number of patients presenting to hospital eds and smoothed out the expected peak in ed attendances despite a huge spike in detected covid- cases. (figure ). having experienced a previous outbreak of severe acute respiratory syndrome in , our hospital's ed has since been divided into "clean" and "dirty" zones, with provision for isolation facilities in the "dirty" zone. (figure ): . the "dirty" zone, otherwise termed as a "fever area," is a space in the department with separate access to the ambulance dropoff area. it is designed to manage ambulatory and non-ambulatory patients at risk of communicable diseases. this area is equipped with its own -bed negative-pressure isolation area, its own triage room, x-ray suite, toilets, and registration counter. all effluent air is hepa (high-efficiency particulate air) filtered and ventilation is separate from the rest of the ed. outside of outbreak scenarios, this area is utilized for cases suspected of having infectious pathogens requiring isolation, such as tuberculosis and measles. . the "clean" zone, which typically handles the bulk of patients, con- . our resuscitation room consists of bays. should there be a need, bays can be sealed off with sliding doors to create negative pressure rooms. essentially, the resuscitation room can accommodate both "clean" and "dirty" patients. during any crisis response, medical care can be delivered at levels: conventional care, contingency care, and crisis care (figure ). departments and health systems aim to remain at the conventional and contingency phases of the response to ensure that patient care is not compromised. to achieve this, our ed adopted the following guiding principles during the ongoing covid- outbreak: . phased, dynamic response: the ed response plan was continuously adapted to meet changing needs as the crisis unfolded, with repurposing of patient areas in response to changing trends in patient numbers and epidemiology. which included both clinical syndromes as well as epidemiology. our institution adopted a broader set of screening criteria compared to official case definitions for suspect covid- cases, in order to achieve higher pickup of cases. separate patient areas were created to segregate patients of different covid- risk profiles, with specific areas for patients requiring ambulatory, non-ambulatory, and resuscitation level care. we break down our response into broad phases. these phases reflect our response to national-level directives, evolving risk profile, and trends in patient distribution. the details of the changes in floor space can be visualized in figure . to prepare for the anticipated surge in ambulatory cases from returning travellers, we took over the adjacent ambulatory surgery center (asc) to create an additional unit capable of caring for patients in individually partitioned cubicles ( figure ). an adjacent link way was converted to serve as an additional waiting area for patients. this area could hold up to stable patients who were waiting for general laboratory and diagnostic imaging results and were expected to be discharged after. on march , , as part of the national containment response, our hospital was tasked with receiving covid- suspect cases referred from primary care and transported by a dedicated ambulance service. before this, these cases were received at the national centre for infectious diseases (ncid), a purpose-built facility that had been designated to lead the national response. patients who did not meet triage criteria for the fsa were managed in the "fever areas" (eg, converted asc) of the main ed. in mid-may, because of the diminishing number of patients being received at the fsa, the patient consultation service at fsa was stopped, as the "fever areas" in the main ed were sufficient to handle the numbers of suspected covid- cases requiring ambulatory care. however, the fsa was held in a state of standby readiness, should there be a resurgence of ambulatory suspect cases. during the second and third phases of the pandemic, our ed saw a rising number of covid- suspects who required non-ambulatory care. non-ambulatory patients were generally less stable and needed to be managed in the main ed to deal with possible deterioration, instead of being managed off-site. rather than expanding ed capacity for these patients, our ed adapted its existing spaces to changing epidemiologic risk. in general, patients requiring non-ambulatory care in the first phase of our response were at low risk of covid- , given that imported cases on march , , our hospital's ed was tasked to receive % of the daily national ambulance load that was diverted away from tan tock seng hospital (ttsh), the second-largest tertiary hospital co-located with the ncid. ttsh had now reached maximum occupancy because of the pressure on admissions and could no longer freely accept cases through its ed. at the same time, our ed was also experiencing an increase in non-ambulatory suspect covid- cases, given the older age profile of patients presenting during this phase. to manage this surge, our ed expanded the capacity for non-ambulatory patients by converting a room in the observation ward to handle non-ambulatory patients with ari. as the number of imported cases and dormitory cases was dwindling, our ed prepared for a surge in community cases, especially after the lifting of social restrictions. taking into account our rapidly aging population, we expected a higher proportion of covid- suspects to be non-ambulatory. recognizing the diminishing value of epidemio-logical risk factors such as travel and contact history in distinguishing covid- cases, all patients with compatible clinical syndromes were deemed potential covid- suspects. furthermore, patients could also be minimally symptomatic or even asymptomatic. , our ed thus converted the entire observation ward into a "clean zone," and the entire cca to a "dirty zone" for handling of non-ambulatory cases. we termed these zones aricca (ari critical care area) and naricca (non-ari critical care area). our ed also reinforced emphasis on enhanced infection control measures, given the increased risk of an unsuspected covid- case presenting outside of containment because of the decreased value of epidemiological risk factors for triage. as the pandemic progressed, it became apparent that preexisting resuscitation rooms were not ideal. these facilities had multiple patients of different covid- risk profiles in fairly close proximity and had a high number of aerosolizing procedures being done. we opted to convert a procedure room into a new resuscitation area. initially, all patients requiring isolation were concurrently managed in our resuscitation room, which has built-in isolation capabilities. however, there were difficulties in properly segregating the patients of different risk profiles, as the facility was built for isolating up to patients. this meant that the medical team had to ensure a rapid throughput to be able to cope with the increasing numbers of critically ill patients with moderate to high covid- risk. as this often proved to be challenging, our ed started planning for further measures in phase . to further minimize the risk of cross-contamination in high-risk areas where aerosol-generating procedures (eg, intubations) were frequently performed, we converted procedure rooms into resuscitation rooms meant for patients with low covid- risk. these were cases with strictly no contact history, travel history, or ari symptoms. cases with unclear risk profile were still seen in the usual resuscitation area, now used for patients with moderate/high risk for covid- . the repurposed resuscitation area was termed "clean resus." we chose to convert procedure rooms to the new "clean resus" because of their large size, availability of oxygen and air wall outlets, and close proximity to the existing resuscitation area. with the addition of cubicles outside the procedure room as a monitoring area (with postresuscitation monitoring capabilities but unable to support airway management), the clean resus was able to manage up to critically ill patients. conversion of the "clean resus" area took weeks, as approval had to be obtained from hospital infection control and the national environmental agency, for the airflow and the radiation shielding capability, respectively. because of the limited time available to familiarize our entire department with the "clean resus" area, it was paramount that the setup be intuitive. the layout of our usual resuscitation area (henceforth termed "dirty resus") was replicated in the "clean resus" area, with all equipment and drugs contained in specially designed, mobile "resus trolleys" that were laid out in the exact same configuration as the airway, circulation, and monitoring panels of the dirty resus. this modular design also had a secondary advantage -it allowed us to recreate a resuscitation area anywhere in the department by simply wheeling the "resus trolleys" to the designated location should the need arise. simulation sessions were also held to stress test the workflow and familiarize staff with the set up. prior to covid- , the department has always had a compulsory surgical mask policy for all medical staff. since the start of phase , donning an n respirator was made compulsory for medical staff in all areas of the department. when dealing with patients at risk of covid- , medical staff donned goggles, disposable gowns, and gloves in addition to their n masks. when performing aerosolizing procedures, staff wore powered air purifying respirators. all staff working in the ed underwent twice-daily temperature monitoring, with results entered into an electronic surveillance system; staff who had fever or ari symptoms were required to report to the singapore general hospital staff clinic during office hours and to the ed after hours, and covid- testing was performed for symptomatic staff. staff would be placed on medical leave until results of covid- testing were known. measures were taken to protect our patients as well. knowing that some patients with covid- might present atypically, the wearing of surgical masks by all patients and visitors was made compulsory. physical distancing measures were also implemented in patient waiting areas and staff rest areas. lastly, as the physical structure of the department did not allow for completely separate routes of patient transport (to the ward, for example), arrangements were made for the transport route of any potential covid- patient to be cordoned off by security personnel prior to movement. given that the added ed capacity posed a challenge for timely contact tracing over multiple sites, our ed leveraged on technology to deploy a real-time location tracking system using radiofrequency identification tags, enabling the specific location and movement of individual patients to be rapidly retrieved for epidemiological investigations. from january to june , , our ed handled a total of , suspected cases of covid- . roughly two thirds of patients ( . %, / ) were seen in ambulatory areas, whereas the remainder were seen in non-ambulatory areas. of the ambulatory patients, the majority ( . %, / ) were managed in the "fever areas" of the main ed (existing "fever area," and "fever area extension" created by converting the adjacent asc), and the remaining cases ( . %, / ) were managed off-site at the fsa. out of the ≥ , suspect cases handled in the ed, a total of cases ( . %, / ) eventually tested positive for covid- . despite extensive epidemiologic investigations, no evidence of healthcare-associated transmission of covid- was detected at the ed level, and < % of covid- cases ( . %, / ) were managed outside of the designated "fever areas" in the ed, likely because of the broad criteria used to identify suspected covid- cases. despite intensive ongoing staff surveillance and wide availability of covid- testing for staff, only one non-clinical staff working in the ed tested positive for covid- , likely attributed to community acquisition. enhanced infection control precautions likely limited further intrahospital transmission; despite testing of all staff close contacts, no additional cases were detected. however, enhanced distancing required our ed to be decongested further, which posed significant challenges given limited floor space. although our ed did not see a huge spike in severely ill patients that some hospitals did, given the resumption of elective procedures that may create increased demand for inpatient beds and increase ed wait-times, as well as an anticipated increase in permitted visitors (from one companion to two), increased crowding in the ed may pose an infection control issue. this may require the reopening of overflow areas to recreate the increased capacity needed for enhanced physical distancing. lastly, the department workforce was augmented with additional doctors and nurses from other departments during this period. with the return of day-to-day work in the hospital, the additional personnel will be reduced. this will decrease our ability to have separate doctors managing all the newly created areas and cross-coverage will be required. we hope to mitigate the infection control risks by allocating cross-coverage within similar risk zones. in conclusion, a phased, dynamic ed response to the evolving covid- pandemic allowed for containment of covid- at the ed level without compromising patient care. as our department awaits the completion of a brand-new ed in the next few years, we will take these lessons and apply them as we prepare for a new environment. similarly, we believe that other eds might benefit from our experiences managing covid- with limited physical space. we would like to thank the doctors, nurses and allied health staff in the emergency department for their tireless commitment. we would like to thank the infectious diseases department for their expert advice. we would also like to thank ms nicole sim and ms loo shin yi for their assistance with the attendance statistics for this manuscript, and the entire ed administration team for supporting operations during this trying time. covid- in singapore-current experience: critical global issues that require attention and action clinical assessment of covid- outbreak among 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situations: a letter report reducing hospital admissions for covid- at a dedicated screening centre in singapore disease outbreak surge response: how a singapore tertiary hospital converted a multi-storey carpark into a flu screening area to respond to the covid- pandemic estimation of the asymptomatic ratio of novel coronavirus infections (covid- ) asymptomatic transmission, the achilles' heel of current strategies to control covid- containment of covid- cases among healthcare workers:the role of surveillance, early detection, and outbreak management minimising intra-hospital transmission of covid- : the role of social distancing containment of covid- amongst ancillary healthcare workers: an integral component of infection control emergency department 'outbreak rostering' to meet challenges of covid- covid- : a&e visits in england fall by % in week after lockdown it's what was happening in italy': the hospital at the center of new york's covid- crisis respiratory surveillance wards as a strategy to reduce nosocomial transmission of covid- through early detection: the experience of a tertiary-care hospital in singapore containing covid- outside the isolation ward: the impact of an infection control bundle on environmental contamination and transmission in a cohorted general ward preventing intra-hospital infection and transmission of covid- in healthcare workers dynamic emergency department response to the evolving covid- pandemic: the experience of a tertiary hospital the authors declare no conflicts of interest key: cord- - q k k authors: gu, xiaoqiong; tay, qi xiang martin; te, shu harn; saeidi, nazanin; goh, shin giek; kushmaro, ariel; thompson, janelle r.; gin, karina yew-hoong title: geospatial distribution of viromes in tropical freshwater ecosystems date: - - journal: water res doi: . /j.watres. . . sha: doc_id: cord_uid: q k k this study seeks to understand the general distribution of virome abundance and diversity in tropical freshwater ecosystems in singapore and the geospatial distribution of the virome under different landuse patterns. correlations between diversity, environmental parameters and land use patterns were analyzed and significant correlations were highlighted. overall, the majority ( . %) of the annotated virome belonged to bacteriophages. the percentage of caudovirales was higher in reservoirs whereas the percentages of dicistroviridae, microviridae and circoviridae were higher in tributaries. reservoirs showed a higher shannon-index virome diversity compared to upstream tributaries. land use (urbanized, agriculture and parkland areas) influenced the characteristics of the virome distribution pattern. dicistroviridae and microviridae were enriched in urbanized tributaries while mimiviridae, phycodnaviridae, siphoviridae and podoviridae were enriched in parkland reservoirs. several sequences closely related to the emerging zoonotic virus, cyclovirus, and the human-related virus (human picobirnavirus), were also detected. in addition, the relative abundance of pmmov (pepper mild mottle virus) sequences was significantly correlated with rt-qpcr measurements ( . < r < . , p < . ). this study shows that spatial factors (e.g., reservoirs/tributaries, land use) are the main drivers of the viral community structure in tropical freshwater ecosystems. viruses are the most abundant living entities on earth and all living entities are associated with at least one virus which can control microbial communities (ackermann, ) . viral metagenomics have been reported widely in water cycles, especially marine waters, to evaluate the role of viruses in microbial diversity and biogeochemical cycling (angly et al., ; breitbart et al., ; cassman et al., ; culley et al., ) . determining the factors in constructing the viral community is important for both understanding and manipulating ecosystems (dinsdale et al., ) . factors shaping the viral community in freshwater ecosystems can include temporal factors, geospatial factors, natural disturbances (e.g., typhoon) and human activities (djikeng et al., ; emerson et al., ; fancello et al., ; ge et al., ; hwang et al., ; l opez-bueno et al., ; skvortsov et al., ; tseng et al., ) . among all the factors, land use activities is a major factor in shaping waterborne viromes. land use changes are the primary drivers of the viral community and a range of associated infectious waterborne disease outbreaks (patz et al. (patz et al. , . in the water cycle, agriculture brings excess nutrients and agricultural chemicals to surface waters, causing oxygen depletion and increasing algal blooms (foley et al., ) . urbanization degrades water quality through surface runoff, and human pathogenic viruses have been detected more frequently in watersheds with dominant urban and agricultural land cover (corsi et al., ; lenaker et al., ) . furthermore, human expansion into wildlife habitats or construction of zoos and animal parks provide opportunities for humanwildlife interactions, thus, increasing the risk for the possible transmission of zoonotic viruses to human populations (patz et al., ) . these different anthropogenic activities harbor diverse and distinct viral hosts, including bacteria, plants, wild animals and humans. it is hypothesized that the environment surrounding these reservoirs may favor distinct viral predators and further change the viral community characterization. however, up till now, studies of land use impacts on the virome community in freshwater ecosystems are still limited as they mainly rely on traditional methodology (culture-based method or qpcr/rt-qpcr), which focuses on limited human virus targets without considering the whole picture of the viral community in the water environment (corsi et al., ; lenaker et al., ) . to date, there is no systematic report focusing on the geospatial distribution and diversity of viromes in natural surface waters and how they may be impacted by human activities and the effect of different land use. in addition, emerging viral pathogens of zoonotic origin could also be discovered through viral metagenomics, for which information is very limited. singapore is a highly urbanized island located in the tropics with an area of . km , and a population of . million in (department of statistics singapore, ). water is a scarce resource in this country and a total of reservoirs are used to collect rainwater and surface waters for potable water supplies. increasingly, selected reservoirs are being used as focal points for sporting events (kayaking and dragon boating) and recreational activities so that the public can enjoy and appreciate water resources. as such, good water quality is needed to protect recreational users of these water bodies. previous studies have detected waterborne viral pathogens (e.g., norovirus gi/gii, adenovirus, rotavirus and astrovirus) in singapore water bodies using qpcr/rt-qpcr (aw and gin, ; aw et al., ; rezaeinejad et al., ) . thus, continued surveillance of these viral targets as well as a broader range of viral targets expanded to the virome community coupled with land use information, could provide important data and new dimensions for managing the safety of water resources. for these reasons, understanding the geospatial distribution of viromes is needed. in this study, seven tropical reservoirs with diverse upstream land use functions (i.e., urbanized, agricultural and parkland areas) were examined. the viral community structure and virome populations specific to each of these environments were systematically investigated together with the characteristics of the watershed. by conducting a complete virome analysis of these freshwater ecosystems (especially viral pathogens and fecal viral indicators), a comprehensive picture of the links between the virome community structure and specific land use activities could be elucidated and thus, used to conduct risk assessment of associated waterborne disease. this information would be important for environmental management at a macroscopic level to protect public health. thus, the objectives of this study were to: ) investigate the overall virome distribution and diversity in diverse freshwater ecosystems (reservoirs/tributaries) in a tropical environment, ) compare the virome community based on the different land use patterns, ) assess the extent of human-related pathogenic viruses in surface waters, especially emerging zoonotic and human-related viruses, which may have been undetected before. a total of seven reservoirs and three catchments were sampled in singapore during january (northeast monsoon) and april (inter-monsoon period), (table s ). in total, sampling points were surveyed, comprising of locations in the reservoirs and locations in the tributaries. only reservoirs , and had corresponding tributary sampling points. the study sites were divided into categories based on their geospatial characteristics: urbanized, agricultural and parkland areas (table ) . apart from storing water and preventing flood control, some of the reservoirs (i.e., r - , e ) also catered for recreational activities such as kayaking, dragon boating and water skiing. all the upstream tributary sites were designated as non-recreational areas. physical-chemical parameters, including temperature, ph, turbidity, conductivity, salinity, total dissolved solids (tds) and dissolved oxygen (do) were measured on site using a hanna meter probe (hi multiparameter meter; hanna instruments). -hour rainfall data were obtained from the singapore historical daily records ( http://www.weather.gov.sg/climate-historical-daily/ ). . . . primary concentration, secondary concentration and viral nucleic acids extraction -l water samples were collected from each sampling location in three -l carboys. the raw-water sample was immediately transported to the lab and concentrated through a hollow fiber ultrafiltration unit with blocking and elution buffer (hemoflow fresenius hf s, germany) to a final volume of ml. the hollow fiber ultrafilter was purged with nanopure water for min and pre-treated with ml of blocking solution ( . g of napp in l of nanopure water) for min. after that, the water sample was recirculated until a final volume of approximately e ml was reached. an elution step was carried out by recirculating around ml of elution buffer ( . g of napp, ml of tween , and ml of antiform in l of nanopure water) for min. both retentate and eluent were combined to a final volume of ml during primary concentration. ml of primary concentrate was further processed to enrich viral particles in a secondary concentration step through polyethylene glycol (peg) precipitation ( % peg (w/v) and . m nacl) after ph adjustment (ph ¼ . ) (jaykus et al., ) . after incubation of the mixture at c for h followed by , g for min, the pellet was dissolved in ml of phosphate buffer saline (pbs, ph . ) with an equal volume of chloroform. after centrifugation at g for min, the supernatant was filtered through a . mm sterile syringe and further concentrated to a final volume of ml using a kda ultracentrifugal filter device (merck millipore, ireland). after primary and secondary concentration, ml of viral nucleic acids (dna and rna) was extracted using the qiaamp viral rna mini kit (qiagen, hilden, germany) and then stored at À c (saeidi et al., ) . in order to quantify the human pathogens in reservoirs and their tributaries using qpcr/rt-qpcr, viral targets were performed to include: ( ) four genotypes of male-specific coliphages (frna gi-frna giv); ( ) ten human viral pathogens and ( ) one plant viral pathogen/microbial indicator (i.e., pmmov) ( table s ). the majority of targets belonged to group iv ssrna (þ) except for adenovirus (group i dsdna) and rotavirus (group iii dsrna). the details of qpcr/rt-qpcr primers and probes are listed in table s . the extracted viral nucleic acids were reverse transcribed using improm-ii reverse transcription system for detecting rna viruses following manufacturer's instructions (promega, usa). rt products were stored at À c for later analysis. qpcr/rt-qpcr was carried out in a steponeplus real-time pcr system (applied biosystems, usa) using faststart universal probe master (rox) (roche, germany) following miqe guidelines (bustin et al., ). the extracted nucleic acids were reverse transcribed and amplified to obtain a sufficient quantity of dna and cdna (wang et al., ) . to ensure there was no microbial contamination, the negative control was run in % agarose gel and ascertained that no dna gel band was present in the negative control lane. after purification of viral dna and cdna, samples were sent to scelse (singapore centre on environmental life sciences engineering). in total, libraries and one negative control library using illumina truseq nano dna library kit were constructed. the sequencing libraries with a corresponding insert size and adapters were prepared accordingly as previously described (ng et al., ) . the illumina's phix control library was used as standard. the libraries were then pooled and sequenced in one lane with equimolar concentrations on an illumina hiseq sequencer in rapid mode at a final concentration of pm and a read-length of bp pairedend (v sequencing reagents). the overview of the virome datasets is detailed in table s . the effect of the negative control is ignored, as explained in the supplementary information. meanwhile, s rrna gene amplicon sequencing was applied to the same batch of samples at sites e to characterize the bacteria community. a total volume of ml water samples from primary concentration was centrifuged at , g for min. after removing the supernatant, the pellet was transferred to a power-soil ® bead tube (mo bio laboratories, inc., carlsbad, ca) for dna extraction with a final volume of ml. genomic dna (gdna) was amplified for the marker gene targeting the s rrna variable regions v to v using the universal pyrotaq primer set ( wf and r) (rinke et al., ) . samples were sequenced in the university of illinois, research resources center -dna services facility and sequence preprocessing as described previously (te et al., ) . the biological data (subsampled otus) were square-root transformed to reduce the dominance of major otus before putting into primerv for pcoa and correlation analyses. the sequencing data were trimmed to remove adaptors, low quality reads, "primer b" sequences which were used for random amplification and phix reads following the bbtools instruction (version . ). reads were then de novo assembled into contigs by clc genomics (version . . ) through cross-assembly strategy. the assembly setting in clc genomics is: minimum contig length of bp and similarity fraction . . contigs were then uploaded into the metavir and virsorter pipeline. briefly, metavir pipeline will first extract open reading frames (orfs) from contigs through the metageneannotator. all predicted orfs were then compared to the national centre for biotechnology information (ncbi) refseqvirus protein database ( . . ) using a reference-dependent taxonomic analysis, with the threshold of bit score and an e-value cut-off of À . after getting the best blast hit affiliation of each predicted gene, annotation of each contig was made based on the lowest common ancestor (roux et al., ) . in addition, metavir pipeline will compute the genes affiliated to the pfam database for function analysis. virsorter identified category viral signal (pretty sure) and category viral signal (quite sure) from the assembled sequence and the viral signal included bacterial and archaeal viruses (roux et al., ) . in particular, human-related viruses were extracted from met-avir results and further examined to search against ncbi nonredundant nucleotide database (downloaded in june ) through blastn search for nucleotide similarity and query coverage (e-value < e- ). in order to quantify the relative abundance of each contig within different libraries, reads were remapped to contigs using novoalign (hercus, ) . this absolute matrix was used for quantifying the relative abundance of taxonomy assignment. since every contig has its weight in quantifying virus concentration, to standardize and quantify every contig's relative abundance between each library, rpkm (reads per kilobase of "transcript" per million mapped reads) was used after remapping trimmed reads to each contig across different libraries (mortazavi et al., ; reyes et al., ) . rpkm was calculated as followed: rpkm ¼ trimmed reads mapped to each contig per library the total trimmed reads mapped to this library ðmillionÞ*this contig length ðkbpÞ this matrix was equivalent to an otu table for pcoa analysis. the non-normalized matrix of reads mapping to each contig per sample (absolute reads matrix) was used and rarefied to , reads per sample (the smallest sample size in absolute reads matrix of taxonomy affiliated viruses was , ) to calculate a-diversity. "observed species" and "shannon diversity index" were calculated for each sample using macqiime (version . . ) with the iteration set at . multivariate analysis of viral community composition under different treatments (e.g., landuse, reservoir/tributaries, monsoon/ inter-monsoon season) was conducted using anosim in primerv and permanovaþ. the similarity of each pair of samples in terms of biotic characteristics was calculated using bray-curtis similarity. rpkm of the total contigs and of the virsorter category and phages were log plus one transformed before inputting into pri-merv for pcoa and correlation analyses. all the reference genomes of qpcr/rt-qpcr viral targets were downloaded from ncbi and accession numbers are detailed in table s . mapping was performed using the clc genomics workbench . . based on the default setting (mismatch gap ¼ , with the linear gap cost, length fraction: . , similarity fraction is based on the specific targets, at medium ( %) medium-high ( %) and high ( %, % or %) three levels) (table s ). the threshold of three levels could represent the nucleotide variation within groups of these viral targets (de graaf et al., ; doceul et al., ) . the proportion of mapping reads equals the number of mapping reads in each library divided by the total reads in the library. all geospatial analyses were performed using arcgis v. (esri, aylesbury, uk) and the percentage of different land use in different reservoirs and their tributaries are detailed in table . land-use shape files were obtained from the singapore land authority and pub (singapore's national water agency). four different layers of map were used for analysis: (i) catchment land-use shape files, (ii) river shape files, (iii) sub-catchment shape files and (iv) drain line maps. wgs_ _web_mercator_auxiliary_sphere was used as the projection coordinate system while gcs_wgs_ /svy singapore was used as the geographic coordinate system. population data was downloaded from the singapore statistics website (http://www.singstat.gov.sg/statistics/browse-by-theme/ geographic-distribution, basic demographic characteristic ) and the population density was calculated based on the total population within the planning area divided by the planning area which covered the drainage area for that sampling point. the shape file of master plan of planning boundary no sea was used as the reference map for the planning area classification (https://data. gov.sg/dataset/master-plan- -planning-area-boundary-no-sea, department of statistics singapore). all the statistical tests including one-way anova and spearman rank correlations were performed using ibm spss (ibm, portsmouth, uk). environmental parameters were log plus one transformed before correlating with a-diversity index as the raw data were right skewed. graphs were plotted using microsoft excel ( ) and originpro (originlab, northampton, ma). virome datasets were deposited in ncbi sequence read archive (sra) under accession no. srr - . s rrna sequences were deposited in ncbi sra under accession no. srr - . environmental parameters of the study sites (i.e., reservoirs and tributaries points) are illustrated in table s . the temperature remained relatively stable for all the sampling points, ranging from to . c with a mean value . c. ph ranged from . to . with a mean value . . other environmental parameters varied more, including conductivity ( . e . ms/cm, mean: . ms/cm), tds ( . e ppm, mean: ppm), do ( . e . ppm, mean: . ppm) and turbidity ( . e . fnu, mean: . fnu). the -hour rainfall and -day rainfall ranged from to . mm (mean: . mm) and e . mm (mean: . mm), respectively. the -hour rainfall and -day rainfall had higher mean values (i.e., . mm and . mm, respectively) during the northeast monsoon (jan) and lower mean values (i.e., . mm and . mm, respectively) during the inter-monsoon (apr). table summarizes the land use percentage and the population density for the reservoir catchments. to better evaluate land use impacts on the viral community, the sampling sites were classified into three categories: urbanized areas, agriculture areas and parkland areas. sites , and included approximately e % residential and urban land use, and as such can be regarded as urbanized areas. site had less than % of residential and urban areas, with about e % green and e % agricultural areas. site was the only sampling location with a reasonable percentage of agriculture area; therefore, site was considered as agricultural. site and site had similar land use percentage with more than % of the land covered with green areas; thus, it was considered as parkland. site included % of residential and urban categories. however, unlike sites e , there was no drain directly connected to the reservoir at this site and hence, the chance for possible viral contamination was relatively small. therefore, site was classified as parkland areas as well as site and site . the land use category clustering of the seven different sites illustrated the reasonability of our land use category classification (fig. s ). the population density was obtained from the singapore department of statistics. among the sample locations, sites , and had the highest population densities (> people/km ) while sites , and had the lowest (< people/km ). a total of . hundred million high-quality hiseq sequencing reads of samples were obtained from different reservoirs and their tributaries in singapore during the monsoon and inter-monsoon periods (table s ). these were assembled across different libraries and , contigs were generated with an average length of bp (n ¼ bp). on average, . % ± . % reads mapped back to the assembled contigs per library (min: . %, max . %). of the , contigs, , contigs were annotated using metavir pipeline. based on the absolute reads matrix (the number of reads mapped to each family in each sample) and the metavir annotation result, on average, . % was annotated and a total of families were identified (fig. ) . the majority ( . %) of these reads belonged to the caudovirales (myoviridae, siphoviridae and podoviridae). this was followed by reads for phycodnaviridae and mimiviridae (whose hosts belong to algae and amoeba) which were retrieved at percentages of . % and . %, respectively. apart from these major viral families, other families such as dicistrovidae, microviridae, circoviridae, iridoviridae and poxviridae were also present in our study. . % were unclassified viral sequences and more than % were unassigned (na) sequences. function analysis of the , viral contigs identified , genes and , ( . %) of the genes encoded hypothetical proteins or conserved hypothetical proteins. the most retrieved pfam annotations showed that phage terminase enzyme, phage portal and phage integrase were responsible for the phage function (table s ) . fig. a shows the taxonomic percentage of virome in reservoirs and their tributaries (sites , and ). fluctuation could be observed within tributaries at the same sampling site. in contrast, virome composition in reservoirs was similar across several sampling points in singapore and shows a more stable pattern than the tributaries (fig. b) . on average, caudovirales accounts for . % among all the annotated viruses in all the tributaries (sites , and ) with a proportion of . % and . % in jan and apr, respectively. for the reservoirs, caudovirales comprises an average of . % among all the annotated viruses with a proportion of . % and . % in jan and apr, respectively. note that the percentage of caudovirales was higher in all the reservoirs than in all the tributaries. in contrast, the percentage of dicistroviridae was higher in tributaries ( . %) than in reservoirs ( . %) in jan (tables s and s ). the percentage of microviridae and circoviridae in tributaries was approximately . % (reservoirs: . %) and . % ( . %), respectively. the shift in composition was observed as the percentage of caudovirales decreased while the percentage of dicistroviridae, microviridae and circoviridae subsequently increased, as locations changed from reservoirs to tributaries. viral communities in different reservoirs in terms of land use impact were compared and the majority of viral communities were largely conserved and stable at the family level with myoviridae, siphoviridae and podoviridae as the main family level, and small differences observed in dicistroviridae and other families (fig. b) . both the richness and diversity (observed species and shannon diversity) was calculated on the taxonomically affiliated viruses from the subsampled absolute reads matrix. the species richness of viral samples from reservoirs with tributaries comprising mostly agriculture and urbanized areas had a similar amount of species while those from parkland areas showed lower viral richness, which was reasonable as parkland areas would generally receive less viral contamination. it was also noted that the viral species richness from tributaries was also lower than their corresponding reservoirs. the average shannon diversity of reservoirs and tributaries was computed as . and . respectively and a one-way anova test showed that the shannon-diversity of tributaries was significantly smaller than those from reservoirs (p < . ). this indicated that tributaries were more likely to be dominated by selected species compared to the reservoirs (fig. s ) and this may be related to the viral host's presence (e.g., bacteria, archaea, algae, insects, plants, animals). future studies could explore this further. a spearman rank correlation was carried out between richness and diversity (observed species and shannon index calculated by macqiime), environmental parameters and the land use pattern ( table ). the correlation coefficient showed that the richness index of observed species was significantly positively correlated with rainfall and agriculture while the shannon index was negatively correlated with ph. when looking at the b-diversity of the microbial community (< . mm) structure, the distribution of rpkm (< . mm microbial fig. a and b ). this pattern was consistent with the bacterial community geospatial distribution ( fig. e and f) . mimiviridae, phycodnaviridae, podoviridae and siphoviridae were enriched in parkland areas (spearman r ¼ . e . to pco ) whereas dicistroviridae and microviridae were enriched in urbanized areas (spearman r ¼ À . to pco ) (fig. a) . acidobacteria, actinobacteria and verrucomicrobia were enriched in parkland areas (spearman r ¼ À . to . to pco ), cyanobacteria were enriched in agricultural areas (r ¼ À . to pco ) whereas proteobacteria were enriched in urbanized and agricultural areas (spearman r ¼ À . to pco ) (fig. e ), comparable to a recent study conducted in singapore showing that proteobacteria were enriched in horticultural and residential samples (nshimyimana et al., ) . the microbial community (< . mm) and virsorter category and phage community in the seven reservoirs both showed distinctly different distributions within reservoirs/tributaries and within different sites ( fig. c and d) . different sampling points of reservoirs at sites and did not show any difference. for sites , and , the microbial community shared a similar contig profile even though they did not share the same land use pattern (i.e., sites and : urbanized area; site : agriculture area). noticeably, urbanized area site showed a slightly different pattern when compared with the other three reservoirs, perhaps due to potential different viral host communities (site is near the construction sites). the microbial community in the tributaries for sites , and were much more variable spatially and temporally, compared to the reservoir microbial community. in our study, contigs were affiliated to human picobirnaviruses and contigs were affiliated to cycloviruses. they had a higher relative abundance in the urbanized and agricultural reservoirs and all the tributaries (fig. ) . possible viral contamination could be from urban drains including those from housing estates, sewer leakage and construction sites. although previous studies have detected enteric viruses in urban catchments in singapore (aw and gin, ; aw et al., ; liang et al., ; rezaeinejad et al., ) , our metagenomics sequencing was unable to find contigs assigned to the enteric viruses commonly detected in singapore surface waters (e.g., norovirus gi, norovirus gii, adenovirus, rotavirus). however, several fecal indicators including pmmov, frnagi (ms ) and frnagiii (qbeta), were detected in our samples. interestingly, in our study, the pmmov-affiliated contigs had a higher nucleotide similarity ( . %e . %) with the average query coverage of . % (table ), suggesting that pmmov is a highly conserved virus with a lower evolution rate in the surface water environment. this result is similar with a recent study, where pmmov detected in % of surface water samples shared e % nucleotide identity with pmmov reference genome (rosiles-gonz alez et al., ). . . correlation of metagenomics data with molecular assays for selected viral targets qpcr/rt-qpcr was conducted to detect and quantify the concentration of the common enteric and zoonotic viruses in the surveyed communities. viral targets ( viral pathogens, fþ malespecific coliphages and plant virus) were measured and the detection frequency was between and . % across all the samples (table s ). the viral pathogens detected in this study using qpcr/rt-qpcr included enteric viruses (adenovirus, astrovirus, rotavirus, norovirus gi, norovirus gii, enterovirus and aichi virus) and other zoonotic viruses (e.g. hepatitis e virus, saporo virus). reads mapping to human-infective viruses were rare and were not observed to assemble into contigs. high-quality reads from different libraries were aligned to the viral pathogen database (vipr/ird) and mapped to viral reference genomes in ncbi (table s ). few reads ( e reads per library) were assigned to the human-infective viruses norovirus and saporo virus using both vip pipeline and standalone pipeline (results not shown) (li et al., ) , and e reads per library were mapped to human viral pathogens reference genome at the e % nucleotide similarity level. no significant correlations were observed between qpcr measurements and read mapping for these viruses. these results suggest that metagenomics is less sensitive at detecting lowabundance viral pathogens against a background of a large proportion of bacteriophages. a total of targets were found in both the metagenomics (contigs) and qpcr data. of these, pmmov showed a good spearman rank correlation (p < . ) ( table ). spearman rank correlation was carried out between the pmmov molecular results and the corresponding metagenomics data in terms of contigs level and reads level (table ). in terms of contigs level, all pmmovaffiliated contigs showed a significant good correlation between molecular results and metagenomics data ( . < r < . , p < . ). in terms of reads level, out of the libraries, libraries ( . %) had reads mapping to the pmmov reference genome (nc_ . ) with % identity to the reference genome. based on all the samples, the spearman rank correlation coefficient was . (p < . ) ( table ) . this study is the first to correlate land use impact with freshwater water viromes in an urban tropical environment using illumina hiseq sequencing. it is noteworthy that metagenomics of dna viruses and rna viruses have been often considered separately and that studies of dna viruses are far more than rna virome analysis. this disparity is largely a result of technical challenges presented by rna metagenomics as rna is fragile and needs to be reverse transcribed into dna. thus up till now, the majority of the virome metagenomics papers studied either dna or rna (but not both). moreover, the amplification protocol reported in these earlier studies may have influenced the final outcome (l opez- bueno et al., ; rodriguez-brito et al., ) . for dna viruses, the genomiphi kit (ge healthcare) has been used for amplification through dna polymerase phi but it was discovered that it has a bias towards single-stranded circular dna viruses. for rna virome analysis, random priming mediated sequence independent single primer amplification (rp-sispa) was used in lake needwood, maryland (djikeng et al., ) . wang et al. ( ) developed a protocol capable of amplifying dna and rna viruses simultaneously. this was subsequently tested in reclaimed water, plasma samples, wastewater and ballast water (bibby and peccia, ; kim et al., ; rosario et al., ; wylie et al., ) . rna viruses account for more than % of the viral pathogens due to their adaptive abilities (mutations, recombinations or reassortments) to infect novel hosts easily (temmam et al., ) . in our study, . % of viruses are dna viruses whereas . % are rna viruses among annotated viral families. among all the viral pathogens detected by metagenomics, contigs affiliated to human picobirnaviruses are dna viruses whereas contigs affiliated to cyclovirus are rna viruses. the simultaneous application of combining both dna and rna metagenomics enabled the identification of a much larger numbers of viral sequences, especially for human-related viruses. this was the approach taken in our study here. in this geospatial metagenomics study, we identified virome abundance and diversity in different reservoirs and tributaries. due to insufficient viral genome sequencing information in the ncbi, . % of the virome genome had no significant hits and bacteriophages were the most abundant organisms in the matrix, which is in agreement with previous studies of surface water viromes (mohiuddin and schellhorn, ; skvortsov et al., ; tseng et al., ) . phages, considered to be the most abundant and diverse biological entities on earth, play an important role in a ms belongs to the group of frna gi (animal-specific indicator) and qbeta belongs to the group of frna giii (human-specific indicator). spearman rank correlation between qpcr (gc/ ml) and metagenomics data (rpkm) on pmmov (n ¼ ). shaping biological and geochemical processes at the global scale (díaz-muñoz and koskella, ) . they may also be responsible for human health in spite of the fact that they do not infect humans. this is because some phages can convey new properties of coding for toxin production to the host bacteria, thus converting harmless bacteria into pathogens (grabow, ) , for example, the shiga toxin-converting phages have been known to change the pathogenicity of e. coli o :h (muniesa and jofre, ) . tributaries were found to have a higher proportion of microviridae and dicistroviridae. the hosts of microviridae belonged to enterobacteriaceae and obligate parasitic bacteria (roux et al., ) . most of the enterobacteriaceae taxa strains are pathogenic, for example, virulent strains of e. coli and klebsiella pneumonia. enterobacteriaceae occurred more in tributaries, which may contribute to the distribution and abundance of microviridae in tributaries. the hosts of dicistroviridae are soil-inhabiting invertebrates (e.g., aphids and ants, which are common in tropical singapore). thus, the fact that tributaries harbor the viral hosts, indicate that the viruses may be released from catchments and be washed into the tributary periodically. the smaller spatial variation pattern of larger reservoirs compared with tributaries was not surprising, as reservoirs tend to be more resilient to urban and storm water runoff than their tributaries. in previous studies, freshwater microbial communities have been found to be resilient to natural disturbances (tseng et al., ) . activities on a-diversity and community structure when correlating a-diversity with environmental parameters and land use factors, it was found that ph had a significant correlation among all the environmental parameters (r ¼ À . , p < . ). ph is a key factor in determining virus infectivity where low ph (ph < ) has been found to significantly reduce phage survivability ( e %) (jurczak-kurek et al., ) , even though the ph range in this study is relatively small ( . e . ), it is likely that these differences could make a difference in viral a-diversity in our study. a moderate correlation with rainfall (r ¼ . , p < . ) was observed which could be due to heavy rainfall flushing terrestrial bacteria, viruses and nutrients to the reservoir (tseng et al., ) . precipitation was found to be the major factor affecting the microbial community in a subtropical reservoir in taiwan (tseng et al., ) . singapore is characterized by two main monsoon seasons: the northeast monsoon (decemberemarch) and southwest monsoon season (juneeseptember). -hour rainfall during the sampling times during the monsoon and inter-monsoon season showed a significant difference between january ( . mm) and april ( . mm) (one-way anova, f ¼ . , pvalue ¼ . ), which could have contributed to the characterization of the virome composition. based on land use category, observed species were also found to be significantly correlated with agriculture land use (r ¼ . , p < . ). this could be expected as intensive agriculture has been reported to bring nutrients and agricultural chemicals to the water cycle (foley et al., ) , which in turn, disturbs the microbial community indirectly (tseng et al., ) . agricultural intensification has been associated with pathogen emergence transmission between wildlife and domestic animal populations and human populations, which in turn, could increase the species of zoonotic viruses (pulliam et al., ) . jones et al. ( ) concluded that agricultural practices are one of the socioeconomic drivers in the spatial distribution of emerging infectious diseases. however, the non-significant correlation between diversity and other land use types does not necessarily suggest weak connections between the viral community and land use factor, since a-diversity indices (shannon diversity and observed species) are just one aspect of characterizing the viral community and does not necessarily represent a complete view. b-diversity analysis indicated that mimiviridae, phycodnaviridae, siphoviridae and podoviridae were enriched in reservoirs of parkland areas while dicistroviridae and microviridae were enriched in tributaries of urban areas (fig. a) . siphoviridae, podoviridae and microviridae belong to bacteriophage, which may be associated with parkland and urban enriched bacteria (i.e., actinobacteria, verrucomicrobia, chloroflexi, acidobacteria and proteobacteria) in our study (fig. e) . overall, viral diversity in the surveyed reservoirs ( < h < ) was higher than that reported in a subtropical reservoir in taiwan ( . < h < . ) (tseng et al., ) . these differences could be due to the geographical (latitudinal gradient) differences in microbial diversity, as low-latitude tropical ecosystems tend to lead to higher biological diversity (chown and convey, ; fuhrman et al., ) . kim et al. ( ) reported that viruses had higher richness near the equator and lower richness at higher latitude, similar to human pathogen species (guernier et al., ) . however, these comparisons between the diversity in freshwater virome studies need further confirmation due to different indices used (chao , simpson index, shannon index, and observed species) and diverse calculation methods applied (e.g., phaccs, qiime, catchall). by using phaccs based on the contig spectra generated by circonspect, tseng et al. ( ) derived a shannon diversity (h) range from . to and from . k to . k viral genotypes in one subtropical freshwater reservoir, which was lower than the ocean's virome shannon diversity in british columbia, the gulf of mexico and the sargasso sea (h of . , . and . , respectively) (angly et al., ) . the difference in methods used in published papers makes it difficult to draw comparable conclusions. a standard pipeline in deriving the viral diversity in ecology is required in order to make comparisons of viral diversity across diverse aquatic ecosystems from different studies. the graphs of pcoa analysis in both reservoirs and tributaries indicated that the land use pattern around the surveyed areas had an important impact on characterizing the virome community. even though the viral communities at the family level were conserved across different reservoirs, the pcoa plots suggested a dynamic shift in differences between contig levels of the viral community in terms of land use. the geospatial distribution patterns in the surface water environment could have resulted from both direct and indirect factors. on the one hand, the different land use patterns could also introduce foreign viral contamination into water bodies directly through urban/agriculture runoff, precipitation, leaking sewers, etc., while the viral community itself can be indirectly changed and characterized by the relationship to their hosts in specific environments. the runoff from the surrounding areas can also bring specific bacteria, or other vectors and nutrients into the reservoirs and the tributaries (tseng et al., ) . even though previous studies have shown the correlation between land use and water-borne viral pathogens (corsi et al., ; lenaker et al., ) , ours is the first study correlating land use cover with the whole viral community, thus overcoming the limitations of investigating specific viruses and providing comprehensive information on the community structure with the relationship of land use cover. viral pathogens could be introduced into reservoirs and tributaries through urban and storm water runoff. although enteric viruses (e.g., adenovirus, norovirus, rotavirus, enterovirus, etc.) could not be detected with viral metagenomics in our study, past studies have shown that they are prevalent in tributaries using qpcr and thus, need to be carefully monitored for quantifying risk assessment and providing guidelines for water recreational activities (aw and gin, ; aw et al., ) . vergara et al. ( ) quantified illness risks of norovirus in an urban catchment in singapore by using quantitative microbial risk assessment. the finding reported mean probability of illness associated with norovirus were . and . in the scenario of primary contact recreation of adults and children, which is below the usepa guideline value of . (usepa, ) . in addition, other potential emerging viral pathogens (e.g., hepatitis e virus, coronavirus, cyclovirus, bird flu virus), which may originate from wildlife and indigenous animals in tropical forests or animal parks can also spread to neighboring tributaries, potentially causing disease to humans. according to jones et al. ( ) , the emerging infectious diseases are dominated by zoonoses ( . %) and the majority of these are from wildlife ( . %), with an increasing trend and more hotspots concentrated in lower-latitude developing countries. in this study, we observed sequences related to the humaninfective virus, human picobirnavirus and the emerging zoonotic virus, cyclovirus. human picobirnavirus, a bi-segmented doublestranded rna virus, has been detected in both healthy and unhealthy human beings. it has also been found to be prevalent ( % detection frequency) in raw sewage samples collected in the united states (symonds et al., ) . the pathogenicity of human picobirnaviruses has not been established and it has been suggested as an opportunistic pathogen which might cause diarrhea (giordano et al., ; grohmann et al., ) . as metagenomics can only provide relative abundance, further studies are needed using qpcr in order to determine absolute concentrations and to better evaluate health risks. viruses belonging to the circoviridae (approximately . % of the virome) may be involved in disease in vertebrate animals and plants. a large proportion was found to belong to swan circoviruses ( %) and circoviridae ldmd- ( %). two contigs found in the present study were assigned to the suggested cyclovirus-vn which originated from human samples in vietnam (garigliany et al., ) . indeed, cyclovirus vn was initially reported to be restricted to central and southern vietnam but was subsequently detected in both farm animals and human clinical samples from africa, indicating their geographic transmission capacity (garigliany et al., ; van doorn et al., ) . in singapore, human cyclovirus vs (cycv-vs ) was previously found in singapore harbor water by using a metagenomics approach (kim et al., ) . the contig shared a . % nucleotide similarity with human cyclovirus vn (kf ) with a query coverage of . %. the discovery of cyclovirus vn in freshwater tributaries in the densely populated area of site in our study indicates a possible transmission of the emerging human cyclovirus in the singapore urban water cycle. further risk assessment of host populations should be conducted for these water environments (van doorn et al., ) . samples from sites , and had lower occurrence rate (both rpkm and absolute reads matrix) and concentration of human picobirnavirus and cyclovirus affiliated viruses, consistent with lower human population density (< people/km ) except for reservoir . the exception of reservoir (explained in results . ) suggested that drainage points could also be significant drivers in shaping the viral communities as well as land use cover and population density. higher population density could result in high occurrence of human-related viruses (lenaker et al., ) . here, the population density to some extent could reflect the hotspots of human-related viruses. limitation of using population density to quantify human activities and human-related viral hosts in our study exists as the population density referred to is the resident population. however, the mobile population such as those associated with modern transportation, tourism, business travel and immigration could also contribute to dissemination of these highimpact pathogens (arguin et al., ). in addition, public holidays could introduce variation in population numbers to commercial and recreational areas based on lifestyle choices. thereafter, more detailed data will be needed in order to track and investigate the human-related virus transmission patterns through virus-host interaction. in our sequencing data, the absence of the majority of enteric viruses in surface waters is reasonable. a potentially relatively low abundance of human-related viruses in our surface water system and insufficient sequencing coverage could have resulted in rare sequences not being assembled into contigs for further downstream analysis. in contrast with our freshwater ecosystem, a previous study of sewage sludge samples revealed a large number of human viral pathogens, unveiling types of human viruses (bibby and peccia, ) . this result is expected as the sludge matrix harbors large amounts of human-related viruses and the concentrations of viral pathogens are much higher. in our study, a good spearman rank correlation ( . < r < . , p < . ) for the indicator virus pmmov was discovered as the qpcr/rt-qpcr concentrations of this target are relatively higher (pmmov geomean: . gc/l). this suggests that viral metagenomics, to some extent, is a conservative estimate of the true viral abundance, based on validation of rt-qpcr data with rpkm in relative abundance of contigs, especially for contigs with a higher qpcr concentration. similar results were also obtained in a previous study where a significant correlation (p < . ) between qpcr and rpkm across viral taxa in clinical samples was obtained (graf et al., ) . overall, viral metagenomics has its advantage in the simultaneous discovery of the entire set of targets in the community in spite of the intrinsic limitation of downstream bioinformatics (i.e., assembly efficiency and database bias). it can pave the way in finding emerging zoonotic viruses and alternative plausible fecal indicators in predicting viral pathogens in the future. after zooming into the specific and desired targets using high throughput sequencing, gene-specific pcr or qpcr (e.g., cyclovirus-vn) could be further investigated to confirm the presence of these potential viral pathogens and zoonotic viruses to reveal the epidemiology or transmission patterns of these viral pathogens (kim et al., ) . this study has shed light on the diversity of the viral communities in tropical reservoirs and their tributaries with different land use. correlations between the diversity index, physical-chemical parameters and land use patterns showed that environmental parameters (i.e., ph and precipitation) and spatial factors (e.g., reservoirs/tributaries, land use) are the main drivers 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freshwater reservoir subject to climatic disturbances identification of a new cyclovirus in cerebrospinal fluid of patients with acute central nervous system infections risk assessment of noroviruses and human adenoviruses in recreational surface waters microarray-based detection and genotyping of viral pathogens sequence analysis of the human virome in febrile and afebrile children this research grant is supported by the singapore national research foundation under its environment and water research programme and administered by pub, singapore's national water agency (ref: -iris- [idd / / ]). we would like to thank national university of singapore and center for environmental sensing and modeling (censam) for supporting this research. supplementary data related to this article can be found at https://doi.org/ . /j.watres. . . . key: cord- -g umdcn authors: he, zonglin; chin, yiqiao; huang, jian; he, yi; akinwunmi, babatunde o.; yu, shinning; zhang, casper j.p.; ming, wai-kit title: meteorological factors and domestic new cases of coronavirus disease (covid- ) in nine asian cities: a time-series analysis date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: g umdcn aim to investigate the associations of meteorological factors and the daily new cases of coronavirus disease (covid- ) in nine asian cities. method pearson correlation and generalized additive modeling were performed to assess the relationships between daily new covid- cases and meteorological factors (daily average temperature and relative humidity) with the most updated data currently available. results the pearson correlation showed that daily new confirmed cases of covid- were more correlated with the average temperature than with relative humidity. daily new confirmed cases were negatively correlated with the average temperature in beijing (r=- . , p< . ), shanghai (r=- . , p< . ), and guangzhou (r=- . , p< . ) , yet in contrast, positively correlated with that in japan (r= . , p< . ). in most of the cities (shanghai, guangzhou, hong kong, seoul, tokyo, and kuala lumpur), generalized additive modeling analysis showed the number of daily new confirmed cases was positively associated with both average temperature and relative humidity, especially in lagged d model, where a positive influence of temperature on the daily new confirmed cases was discerned in cities except in beijing, wuhan, korea, and malaysia. nevertheless, the results were inconsistent across cities and lagged time, suggesting meteorological factors were unlikely to greatly influence the covid- epidemic. conclusion the associations between meteorological factors and the number of covid- daily cases are inconsistent across cities and lagged time. large-scale public health measures and expanded regional research are still required until a vaccine becomes available and herd immunity is established. in december , several cases of pneumonia with an unknown etiology were reported in wuhan, hubei province, china ( ) . a novel strain of coronavirus was identified from the nasopharyngeal swab specimens of the infected, which was later designated as severe acute respiratory syndrome coronavirus (sars-cov- ), and the resulting pneumonia as coronavirus disease . with the number of the infected soaring up, on st january, , the world health organization (who) has declared the outbreak of covid- as a public health emergency of international concern (pheic) ( ) . sars-cov- , pertaining to the coronaviridae, is an enveloped, single-stranded, positive-sense rna virus, which is closely related to sars-like coronaviruses, and based on the phylogenetic analysis, these coronaviruses have a common ancestor that resembles the bat coronavirus hku - ( , ) . evidence has shown that the sars-cov- can transmit between human through respiratory droplets, fecal-oral route, direct contacts, and aerosols ( ) ( ) ( ) . moreover, the long incubation period ( to days) increases the difficulty of controlling the covid- outbreak. studies have shown the mean incubation period was . days (ranged from . to . days, % confidence interval (ci): . - . ) ( ) , and another study estimated the mean incubation period to be . days (ranged from to days) ( ) . by march , , more than countries had confirmed cases, with more than , confirmed cases and , mortalities globally, among which , ( . %) confirmed cases and , ( . %) mortalities were reported outside of china ( ) . human respiratory pathogens (bacterial pathogens like pneumococcus and viruses like rubella and influenza) usually exhibit an annual pattern showing an increase in incidence during winter, and decrease during the summer (seasonality). despite much data on influenza, respiratory syncytial virus, and the sars outbreak following the pattern, it is difficult to predict whether covid- would follow the trend and will be eliminated in the coming summer, as our understanding of the forces driving the seasonality of infectious diseases remains limited. since influenza is a common viral disease, a proportion of the population already possesses some levels of immunity and when more patients recover, herd immunity constrain the transmission of the virus. the low or absent prevalence trend of sars or mers-cov in the summer was also mentioned to be strongly relied on the use of effective therapeutic treatment and strict public health measures ( , ) . however, sars-cov- is a novel virus to humans, immunity to this ongoing virus pandemic is limited and an effective pharmaceutical therapy or vaccine prevention is yet to be found. the seasonality in the outbreak of respiratory infectious diseases might be due to the seasonal variation of host physiology (susceptibility, individual immunity and herd immunity) ( ) , genetics ( ) , viral stability ( , ) and infectivity ( ) ( ) ( ) ( ) , latent infectors constantly shedding viruses ( , ) , and the atmospheric dispersion and trans-ocean inter-continental migration ( ) ( ) ( ) ( ) , which are mainly driven by the meteorological factors, including the temperature and humidity ( ) . geological features and latitude play a major role in forming a meteorological pattern. lowen et al. assumed the seasonality of influenza and respiratory syncytial virus (rsv) epidemics in temperate climates mainly attributable to the low absolute humidity ( ) , and the following factors associated with it, namely the low temperature, increased population, and low micronutrient levels (such as low vitamin d levels) ( , ) . during the winter in temperate zones, the temperature and humidity are low, characterized by dryness and coldness, and viruses are more easily to be transmitted via aerosols than direct or indirect contact, where the low temperature renders the virus viable and stable in aerosols, and on the surface. however, in the rainy seasons of tropical regions, where the weather is hot and wet, the aerosol transmission decreases but the transmission by direct contact increases ( ) ; although the high temperature can decrease the stability of the virus and reduce the level of aerosolization of the viral droplet, with the increased temperature, the amount of virus deposited on surfaces increases ( ) . because of the relatively stable structure of the coronaviruses, the infectivity of the coronavirus would not be affected upon circumstances of a relative humidity > % and a temperature of - ˚c ( ) . for example, the transmission of sars is more efficient in the temperature between ˚c and ˚c, the widely use of air-conditioning also provides a shelter for the breeding and transmitting of sars, where the virus is stable for weeks at room temperature ( ) . sars-cov- has many similarities with the sars-cov- , but whether meteorological factors influenced the viral transmission have not been established. therefore, in the present study, we aimed to examine the relationship between meteorological factors and the number of covid- daily cases in asian cities at different latitudes. we obtained daily meteorological data from the national meteorological information center (http://cdc.cma.gov.cn/). the data were collected from meteorological stations in beijing, wuhan, shanghai, guangzhou, hong kong, seoul, tokyo, kuala lumpur and singapore. where data from the national meteorological stations were not available, we obtained data from the timeanddate (https://www.timeanddate.com/). we retrieved the highest and lowest temperatures and humidity in four different quarters of the day and computed the average values of temperature and humidity for that day. the daily number of domestic covid- cases in five cities in china (namely wuhan, beijing, shanghai, guangzhou, and hong kong) and singapore were obtained from the ministry of health in china and singapore, respectively. given that the daily number of domestic cases at the city level in japan, korea and malaysia were not available from the corresponding ministry of health, as an alternative, we used the number of domestic cases at the national level in these three countries for analysis. the clinical criterion for the diagnosis of covid- was based on the high-throughput sequencing or rt-pcr assay by nasopharyngeal swab. we evaluated the normality of the daily new cases and meteorological data by examining their skewness and kurtosis. we also estimated the pearson correlation and covariances between the daily covid- new cases and daily meteorological factors using stata . . generalized additive models (gams) with a poisson family and logarithm link function were used to estimate the associations of daily covid- new cases with average temperature and relative humidity. gams are useful for identifying exposure-response relationships from various types of data, particularly in exploring nonparametric relationships ( ) . the gam analysis was performed in r software (version . . ) using the package "mgcv". we first established a basic temporal model for covid- cases without including meteorological variables. to adjust for long-term trends and seasonality, we included penalized spline functions of time in the model. the degree of freedom (df) for time was optimized by minimizing of the absolute values of the partial autocorrelation function (pacf) of residuals for lags up to days ( ) ( ) ( ) ( ) . additionally, the selection of an optimal model was based on the lowest akaike's information criterion (aic). secondly, we built meteorological models based on the temporal models to account for the lagged effect of meteorological variables and the incubation period of covid- ( , ) . specifically, we examined the effect of meteorological variables with different time lags including one-day lag (lag d), three-day lag (lag d), five-day lag (lag d), single-week lag (lag d), and two-week lag (lag ) to capture immediate effects and lagged effects, respectively. automated penalized splines were used to fit the association between the daily new cases and each of the meteorological variables. the date when the accumulated cases exceeded in each city or country was selected as the inception of the date incorporated in the model to equalize the starting speed of outbreak and thus avoid miss-interpretation and overfitting. to control for the autocorrelation, the model's residuals were examined for serial correlation using pacf. default plots showing the smooth components of a fitted gam were produced. the percentage of deviance explained by each variable was calculated, which represents the scale of a linear predictor that contributes to the component smooth functions. at last, the graph of smooth components were grouped based on similar latitudes to mitigate the influence by latitude. the daily new cases of covid- and meteorological data from january to march , ( days) in nine different cities are shown in table . during the study period, the temperature in the five cities in china ranged from - to . ℃, with that ranging from - to ℃ in beijing, from to ℃ in shanghai, from . to . ℃ in guangzhou, from to . ℃ in wuhan, and from . to . ℃ in hong kong. the temperature in singapore ranged from . to . ℃, in seoul from - . to . ℃, in tokyo from . to . ℃, and in kuala lumpur from . to . ℃. figures and show the distribution of daily covid- new cases associated with average temperature and average relative humidity over time, respectively. pearson's correlations between daily covid- cases and meteorological factors are shown in table . daily confirmed new cases were negatively correlated with average temperature in beijing (r = - . , p < . ), shanghai (r = - . , p < . ), and guangzhou (r = - . , p < . ), and, in contrast, positively correlated with that in japan (r = . , p < . ). the correlation between average temperature and relative humidity was found positive in shanghai, guangzhou, hong kong, korea, and japan, and negative in beijing, wuhan, singapore, and malaysia according to the pairwise pearson correlation test ( table ) . the final gam model of daily covid- new cases incorporated date (time-series), average temperature, and mean relative humidity. ,~( , ) log , = + < ( , ) + > ( , ) + d ( ℎ , ) where the terms f to f are the smoothing functions, and β is the intercept. all estimates and significance levels were listed in supplementary table . the models with the best performance (lowest aic) for each city is as follows: no-lag model for shanghai and singapore, lag d model for beijing and wuhan, lag d model for guangzhou, korea, and kuala lumpur, and lag d model for hong kong and japan (table ) . gam results were reported using the smoothing components plot for temperature and relative humidity in figures and , respectively. the smoothing components plots demonstrated the estimated smoothing spline functions with the linear effect subtracted out, and each panel represented the weighted sum of basis functions for each time-varying covariate and is corresponding to the hypothesized model. the significant smoothers indicated that the correlations between new cases of covid- and explanatory variables were non-linear. as shown in figure , the no-lag model suggested that holding all linear and the other nonlinear terms fixed, daily new cases of covid- tended to show no influence by the temperature, but the cases number decreased when temperature reached , , and , in beijing, hong kong, and singapore, respectively (p < . for all, figure ). while the magnitude of results might look small relative to the base rate of case accrual, these plots were on the log-case scale, so the effect on the case number is multiplicative. the distributions of covid- cases displayed greater uncertainty at lower temperature in beijing and wuhan. beijing and wuhan has fluctuating patterns throughout the six models both regarding temperature and relative humidity except in lag d and lag d model for wuhan, which might be due to the change of diagnostic method on february , when a total of , cases were added. nevertheless, the relationship between relative humidity and new cases were less evident in the no-lag model, and the distributions of covid- cases displayed greater uncertainty in wuhan. nevertheless, in the lag d model, distribution of covid- in beijing, wuhan, hong kong and malaysia revealed great uncertainty and high non-linearity. a hump of the increase was observed at around ℃ in singapore. after the hump, the cases started to decrease in singapore when temperature increases. a liner increase can be found in guangzhou. likewise, a significantly non-linear pattern was found in wuhan between the relative humidity and covid- cases. figure shows that during the study period, relative humidity has a positive effects for singapore, hong kong as well as malaysia constantly, with a linear pattern, yet a negative effects were discerned in seoul when humidity greater than % in a nonlinear way. in lag d model, the temperature has a positive influence on the daily new cases in shanghai and singapore in a linear pattern, and in guangzhou when the temperature was greater than ℃, in hong kong when temperature was greater than ℃, and in japan when temperature was between - ℃ and - ℃ in a non-linear pattern. specifically, the distribution of the covid- new cases in beijing, wuhan, and kuala lumpur was greatly fluctuating. regarding the relative humidity, in lag d model, wuhan, guangzhou, and kuala lumpur showed significant curvilinearity. a positive association between relative humidity and new cases can be found in singapore, while a negative pattern was observed in hong kong when relative humidity greater than % ( figure ). in the lag d model, covid- new cases in shanghai, guangzhou, and singapore when temperature less than ℃ were negatively correlated ( figure ) . a positive pattern can be discerned significantly in tokyo when temperature was lower than ℃, and in hong kong as well as in kuala lumpur. regarding the relative humidity, except for wuhan and guangzhou that displayed highly fluctuating pattern, no evident effects could be discerned. in the lag d and lag d models, beijing, wuhan, and kuala lumpur (only in lag d model) showed great uncertainty of the relationship between temperature and daily new cases. moreover, shanghai and singapore have different and inverse effects between lag d and d models, where, in the lag d model, shanghai showed a negative pattern and singapore showed a positive pattern while in the lag d model, shanghai showed a positive pattern and singapore showed a negative pattern. concerning the relative humidity, likewise, beijing, wuhan, and guangzhou (only in lag d model) displayed great uncertainty and curvilinearity ( figure ) . hong kong shows a positive pattern in both two model. nevertheless, shanghai and singapore still showed inverse effects in the lag d and d models, where in the lag d model, both shanghai and singapore showed positive patterns while in the lag d model, shanghai and singapore showed negative patterns. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint . https://doi.org/ . / . . . doi: medrxiv preprint in this study, we investigated the associations between meteorological factors and patterns of daily new cases of covid- across nine asian cities. our analyses suggest a positive relationship between temperature and daily new cases of covid- in guangzhou, singapore (except in the lagged d model), hong kong (except in the lagged d and d model) and beijing (high curvilinearity). relative humidity positively with the number of daily new cases in singapore (except in the lagged d model), hong kong (except in the lagged d model). negative association between relative humidity and the number of daily new cases was only observed in shanghai consistently. associations of temperature and relative humidity on the daily new cases were less evident in tokyo, seoul and kuala lumpur. the relationships in wuhan presented a great fluctuating pattern. therefore, our analysis suggest, unlike influenza, seasonality of covid- may not be expected, and the epidemic is unlikely to fade out itself when summer comes. researchers have long been investigating how meteorological factors affect the viral infectivity, where the gam has been frequently used, as it allows smooth components to be estimated for time, meteorological factors and other covariates, together with a non-smoothed period effect. experiments in the last century reported that the influenza virus is more stable in cool and dry air ( , ) . and with increasing temperature, the viability of the influenza virus in aerosol or droplets( ), and the aerosol transmission diminishes ( ) . lowen et al. reported that aerosol transmission of influenza between guinea pigs was completely blocked at temperature higher than °c despite evidence of continuous viral shedding from infectious individuals; nevertheless, the direct contact transmission was not influenced, which was equally efficient at ° c and ° c ( ) . chan et al. reported that the viability of sars virus was rapidly lost (> log ) at high temperatures ( • c) and high relative humidity (> %) ( ) . the better stability of the sars coronavirus at low temperatures and low humidity environment might facilitate its transmission in the community in subtropical areas (such as hong kong) during the spring and in air-conditioned environments. this might also explain why some asian countries in tropical areas (such as malaysia, indonesia or thailand) with high temperatures and high relative humidity environment did not have major community outbreaks of sars. however, such an explanation is not currently convincing regarding the results in the present study, where the increase of the temperature increases the daily new cases of covid- in some of the investigated communities. the high temperature and high relative humidity in the tropical asian countries like singapore, and malaysia also seems to have little influence on the expanding daily new cases ( figure ). however, this could have been confounded by multiple factors. there are several reasons underlying the continuously expanding covid- cases in singapore and malaysia, such as the high population density, massive gatherings, the use of air-conditioning and shortage of medical resources ( ) . the sars-cov- can persist at room temperature for up to days, and its heat sensitivity rendered it susceptible to increased temperature, affecting its persistence in the outdoor environment. however, coronavirus was still found to be infective up to two weeks in the air-condition environment ( ) . as air-conditioners may increase the probability of spreading, it may be advisable to reduce the use of air-conditioners and keep ventilation. moreover, during low temperature and high humidity, it is advisable to avoid massive gathering, as evidences are also supporting transmission by direct contact or close contact at the tropical area . humidity can influence aerosol transmission via altering the proportion of respiratory droplets undergoing aerosolization, and influencing the stability and viability of the virus within these aerosols. respiratory droplets are generated in the high humidity of the respiratory tract. on entering an environment with low humidity, respiratory droplets reduce in size within seconds due to evaporation. at higher environmental humidity, respiratory droplets evaporate more slowly, and hence are larger and settle faster, and less aerosol nuclei are produced ( , ). previous studies have shown that influenza transmission between mice reduced as relative humidity increased from % to % ( , ) . moreover, humidity can also influence indirect transmission by changing the mass of respiratory droplets accumulating on surfaces, and affecting the survival of the virus on surfaces. while increased humidity reduces the number of droplet nuclei formed, the same mechanisms (reduced droplet evaporation and faster droplet settling) result in a greater mass of respiratory droplets on surfaces ( , ). area with relatively low temperature and humidity has a higher infection rate comparing with tropical areas because the cold and dry weather is suitable for virus to survive and transmit ( ). viability of influenza virus appears greater at lower humidity, and progressively reduced influenza survival with increasing relative humidity over the range from % to %, with an increase in survival at % relative humidity, the mechanisms underlying which may be due to the low evaporation from droplets at high relative humidity maintain the solute concentration thus protecting the virus ( , ) . alongside, - o n zone has become a zone for transmitting covid- with similar average temperature of - ℃ and - % humidity, which may be influenced by transoceanic migration of virus, but the underlying mechanism is still not understood ( ). moreover, under laboratory conditions with constant humidity and temperature, circadian and circannual rhythms in variation of susceptibility of hosts (mice) have been observed ( , ) . mice were substantially more susceptible to invasive pneumococcal disease in early morning hours than any other time of day( ), and more susceptible to influenza in winter than in summer ( ) which was thought to be attributable to the daily and seasonal variation of melatonin ( ). in addition, even in areas where many spend summers in air-conditioned spaces, marked annual variations in incidence constantly exist, and similar strains of virus appear almost simultaneously across vast stretches of oceans in areas of similar latitude around the globe ( , ) . therefore, although a higher temperature is associated with lower effectiveness of virus transmission, yet it does not necessarily suggest a lower chance for virus to survive. the natural fading out of the virus in summer is unlikely given the widespread use of air conditioners in developed areas and the dense population in the city area. until an effective vaccine becomes widely available for the establishment of herd immunity and the discovery of efficient pharmaceutical therapies, strict public-health measures should be implemented, including social distancing, quarantine, tracing, facemask wearing, and promotion of hand washing. this is the first study to statistically analyze the relationship between meteorological factors and the daily new cases of covid- . because of the non-linear nature of the data, we also performed gams to quantitate and visualize the relationship using splines functions. however, there are several limitations. firstly, numbers of cases in malaysia, korea, and japan were obtained from the epidemiologic reports released by the department of health in the corresponding countries, instead of a daily update of case numbers, which is not available for these countries. hence, some cases might be missing. secondly, the duration of the study period was short and the number of cases in malaysia, singapore and japan were small. thirdly, we only considered two meteorological factors (temperature and humidity) in this study. other covariates such as wind speed, pollutant concentration, population density, air conditioning use, rainfall, which could also influence the spread of covid- , were not included. moreover, while we collected the meteorological data from the capital cities of malaysia, japan, and korea, the number of domestic cases at the national level in these three countries was used for analysis due to lack of available data at their city level. most importantly, we did not incorporate the public health measures into the modelling, which may greatly confound the results, but we chose the date when accumulated confirmed cases exceeding , based on the postulation that a certain level of public health measures had been carried out at that time, thus the confounding effects can be mitigated at some point. in this study, we found inconsistent associations between temperature and relative humidity and the number of covid- daily cases across cities and time. therefore, unlike influenza, seasonality of covid- may not be expected, and the epidemic is unlikely to fade out when summer arrives. strict public health measures such as social distancing, quarantine, tracing, facemask wearing, and promotion of hand washing are needed until a vaccine becomes widely available and induce the herd immunity among the community. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study the world health organization. statement on the second meeting of the international health regulations ( ) emergency committee regarding the outbreak of novel coronavirus 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ii. some factors affecting the incidence of transmitted infection the role of host genetics in susceptibility to influenza: a systematic review virus survival as a seasonal factor in influenza and poliomyelitis medicine. experimental air-borne influenza infection. i. influence of humidity on survival of virus in air humidity and respiratory virus transmission in tropical and temperate settings global patterns in seasonal activity of influenza a/h n , a/h n , and b from to : viral coexistence and latitudinal gradients high temperature ( c) blocks aerosol but not contact transmission of influenza virus coronavirus disease (covid- ): situation report persistence and transmission of natural type i feline coronavirus infection acute and persistent infection of human neural cell lines by human coronavirus oc the epidemiology of influenza the persistence of influenza a in human populations infection. a new concept of the epidemic process of influenza a virus impact of atmospheric dispersion and transport of viral aerosols on the epidemiology of influenza infection. humidity and respiratory virus transmission in tropical and temperate settings global influenza seasonality: reconciling patterns across temperate and tropical regions influenza seasonality: underlying causes and modeling theories environmental predictors of seasonal influenza epidemics across temperate and tropical climates the effects of temperature and relative humidity on the viability of the sars coronavirus generalized additive models for medical research confounding and effect modification in the short-term effects of ambient particles on total mortality: results from european key: cord- - u zxsam authors: fisher, d.; tambyah, p.a.; lin, r.t.p.; jureen, r.; cook, a.r.; lim, a.; ong, b.; balm, m.; ng, t.m.; hsu, l.y. title: sustained meticillin-resistant staphylococcus aureus control in a hyper-endemic tertiary acute care hospital with infrastructure challenges in singapore date: - - journal: j hosp infect doi: . /j.jhin. . . sha: doc_id: cord_uid: u zxsam background: meticillin-resistant staphylococcus aureus (mrsa) has been entrenched in singapore hospitals since the s, with an excess of non-duplicate cases of infections ( bacteraemia episodes) each year in our -bed university hospital. approximately % of our hospital beds are used as isolation facilities. aim: to study the impact of an mrsa control bundle that was implemented via gradual geographic extension across hospital wards. methods: the bundle included active surveillance on admission and transfer/discharge to identify ward-based acquisition of mrsa, isolation and cohorting of mrsa-infected patients, enhanced hand hygiene initiatives, and publicly displayed feedback of mrsa acquisition and hand hygiene compliance rates. implementation was between october and june in order to provide lead-time for the incremental development of infrastructural capacity, and to develop an ethic of infection prevention among staff. results were analysed via interrupted time-series analysis. findings: mrsa infections fell midway through the implementation, with mrsa bacteraemia declining from . [ % confidence interval (ci): . – . ] cases per inpatient-days in the first quarter of to . ( % ci: . – . ) cases per inpatient-days in the first quarter of . mrsa acquisition rates fell a year after the programme had been fully implemented, whereas hand hygiene compliance rose significantly from % ( % ci: – ) in the first quarter of to % ( % ci: – ) in the first quarter of . conclusion: successful staged implementation of an mrsa bundle in a hyper-endemic setting is sustainable and represents a model that may be adapted for similar settings. sustained meticillin-resistant staphylococcus aureus control in a hyper-endemic tertiary acute care hospital with infrastructure challenges in singapore introduction since the worldwide establishment of healthcareassociated meticillin-resistant staphylococcus aureus (mrsa), sustainable reductions have been demonstrated in several parts of the world. the netherlands has maintained mrsa levels of < . % and managed outbreaks successfully using a search and destroy policy. scandinavian countries and western australia cite similar success stories, as has the veteran affairs chain of hospitals in the usa after the establishment of an mrsa bundle. e more reports from across australia, france, and the uk have also shown significant reductions in mrsa infections in the last few years. e effective interventions for controlling mrsa transmission in a hospital setting are well known and include active surveillance, improving hand hygiene compliance, and isolating all mrsa cases, whereas general strategies such as obtaining focused and committed hospital leadership are critical towards lowering implementation barriers and improving sustainability. , , , such successes are rare in asia and parts of the world where mrsa is hyper-endemic, and where high antimicrobial resistance rates in other nosocomial bacteria result in competition for limited resources and isolation facilities e infrastructural hurdles that have been difficult to overcome. , estimates of the burden of mrsa in singapore and at the national university hospital of singapore (nuh) have been published in separate reports which describe the issue microbiologically, and clinically. , more than mrsa infections including at least bloodstream infections were previously seen per year at nuh. the sheer volume of cases coupled with infrastructural and societal constraints traditionally has hindered mrsa control efforts here. few beds are available for contact isolation despite negative pressure isolation rooms being built after the severe acute respiratory syndrome (sars) outbreak in . there is insufficient capacity to isolate all mrsa patients, as they constitute up to % of all inpatients, and prioritizing mrsa would impair the ability to isolate or cohort patients with other transmissible diseases. adding to the problem is the average daily bed occupancy rate exceeding % e the result of a recent, rapid population boom in singapore. in , the senior hospital management at nuh, in response to endemic rates of mrsa infections of % and large numbers of clinical infections, called for a more aggressive response. we describe our strategy to contain mrsa in a hyper-endemic hospital with infrastructural constraints and its implementation, as well as analyse its impact via time-series analysis. we conducted a prospective interrupted time-series study at nuh e a -bed acute care tertiary university in singapore. the intervention (described further below) was implemented via gradual geographic extension between october and june . the intervention comprised a series of mrsa control measures put together as a bundle, and included: À active surveillance for mrsa carriage. this consisted of swabs of nares, axillae and groin (plus any wounds) cultured on chromogenic agar mrsa select (bio-rad laboratories, marnes-la-coquette, france). patients not known to have mrsa had entry swabs, while those who had been in a hospital ward > h, had no prior positive mrsa cultures (screening or clinical) and had not died, also had exit swabs upon discharge or transfer from the ward. À promotion of hand hygiene. this was done primarily via educational and socio-behavioural measures. hand hygiene education focused on the world health organization (who) 'five moments for hand hygiene', which was audited. continuous reminders were developed, including via posters in wards, computer screensavers, and audio on ward entry. hospital-wide training programmes ran in and annually to coincide with the who world hand hygiene day. all frontline clinical staff had to participate in a compulsory min training programme and assessment over one week on both years. a sticker placed on the staff identification tag confirmed certification. all new staff received the same programme at orientation. to further reinforce the message, the clinical examination template in the national university of singapore final mbbs degree stipulated a deduction in marks for failed hand hygiene. À auditing of hand hygiene compliance. this was performed primarily by appointed ward liaison nurses that had been trained by infection control nurses, supplemented and cross-checked by medical and nursing students who were engaged via innovative educational programmes in which they were trained as auditors and observed staff in their work covertly. À isolation or cohorting of mrsa-positive patients. such patients were placed in isolation or, more usually, in a designated cohort cubicle, established on each ward. periodic snapshots of cohorting compliance were undertaken. a close relationship between the bed management unit and the project stakeholders was developed to facilitate the siting of mrsa-positive patients. À public and regular feedback of results. data on hand hygiene compliance and mrsa acquisition were posted on ward-based 'dashboards' that had been requested by hospital administration. the signage was publicly displayed, ward-specific and updated monthly. À other measures included a bare-below-the-elbows policy for all clinical staff, coloured bracelets to identify all colonized and infected patients, and cash rewards (of around us$ ) for exemplary performances by wards or departments with regards to hand hygiene compliance and mrsa transmission rates to enjoy a celebratory lunch or similar. À to ensure that any progress made was primarily due to the mrsa bundle and not changes in prescribing habits, surveillance of major classes of antibiotics (fluoroquinolones, carbapenems, third or fourth generation cephalosporins and vancomycin) was undertaken from using pharmacy-based electronic data. this was expressed as defined daily doses (ddd) per inpatient-days. in order to fully implement this in an mrsa-hyper-endemic hospital with infrastructural and resource constraints, the mrsa bundle was implemented via planned gradual geographic extension over years e a few wards at a time. this would allow lead-time for the incremental development of infrastructural capacity in a number of areas including the number of microbiology laboratory technical staff and an infection control data management system. it was also believed that a gradual introduction would help the growth of an ethic of infection prevention among staff. to improve the odds of sustainability, two actions were undertaken simultaneously. first, an overall mrsa taskforce was formed that included members of the senior hospital management, comprising the chair of the medical board, chief operations officer, director of nursing, the infection control chair and a full-time mrsa data manager among others. second, an assessment of the local clinical and economic impact of mrsa infections was undertaken. the key indicators for improvement included: collectively, these indicators would represent the overall burden of mrsa infections in the institution, the likelihood of mrsa acquisition in mrsa-naïve patients during their hospitalization, and the overall infection control adherence among healthcare staff. process indicators included cohorting compliance rates and active surveillance testing rates as well as the results of hand hygiene compliance audits. preliminary analysis of pre-intervention time-series yielded non-significant autoregressive coefficients, suggesting that the observed autocorrelations at lag across the entire time-series resulted from gradual changes in disease incidence rather than inherent correlations between time-windows. subsequent analysis accounted for autocorrelation by modelling changes in the mean incidence or proportion as a function of time. the numbers of mrsa clinical cases and mrsa bacteraemia cases per quarter were modelled as poisson with mean m(t) per hospital inpatient-day. extending the model to negative binomial to account for super-poisson heterogeneity did not improve the fit. the quarterly number of positive exit swabs among initially non-colonized patients was assumed to be binomial with proportion p(t). both models used linear (on a log or logit scale) changes in location with time, with a single change in gradient allowed. for the number of mrsa or bacteraemia cases, the models have the form: log mðtÞ ¼ a À bðt À sÞ ðt>sÞ À gðs À tÞ ðt < sÞ where a quantifies average incidence at the temporal change point, s, while b(g) characterizes per-quarter increase (decrease) in incidence after (before) s, and (a) ¼ if a is true and otherwise. a similar model, replacing log m(t) by logit p(t), was used for within-hospital colonization and handwashing performance. the parameters a, b, g and s, were inferred independently of the time-course of interventions, thereby to assess the plausibility that interventions coincided with the inferred changepoint, s. because the likelihood surface suggested that the maximum likelihood estimate of s, in particular, may not be normally distributed, bayesian methods were used to derive % confidence intervals (cis), taking uniform prior distributions over the parameter support, using markov chain monte carlo samplers with , samples and every th retained, with multivariate normal proposals with covariance tuned on trial runs. approximate p-values were obtained by extending credible intervals by analogy to the relationship between p-values and the end-points of confidence intervals. point estimates reported were maximum likelihood estimates or posterior modes. all analysis was performed in the r statistical environment. the programme was initiated in october in a single orthopaedic ward, followed by a subsequent roll-out to all targeted wards within the hospital that was completed by june (figure ). by the end of june , all adult intensive care units, and up to % of general wards including the majority of surgical general wards, had been included in the programme. figure shows the incidence-density of all mrsa clinical isolates since , all mrsa blood isolates since , and mrsa acquisition rates since . there is strong evidence of a rising incidence of all mrsa clinical cases until a peak in the first quarter of ( % ci: q - to q - ) with a notable decline thereafter ( figure a) ; this peak is consistent with the completion of the roll-out by the end of the second quarter of (p ¼ . ) but not with the first roll-out of the programme in the fourth quarter of (p ¼ . ). the decline after the change-point was . times ( % ci: . e . ) as rapid as the preceding rise. the mrsa acquisition rate is presented in figure b empirical and modelled mrsa bacteraemia rates are presented in figure c . here, there was a significant fall from . cases ( % ci: . e . ) per inpatient-days in the first quarter of to . cases ( % ci: . e . ) in the first quarter of , but no evidence of the fall levelling off, with the % ci for a change-point spanning almost the entire period of recorded data. the evolution of hand hygiene compliance is displayed in figure d . compliance rose significantly since audits started, from % ( % ci: e %) in the first quarter of to % ( % ci: e %) in the first quarter of . there was, however, evidence that compliance stalled around the last quarter of ( % ci: q - to q - ) with a rate of change after that time that was not statistically distinguishable from (p ¼ . ). throughout the period of the study, the changes in consumption of the antibiotics measured did not correlate with the improvement in mrsa rates (figure ) , and therefore antibiotic prescription per se did not affect mrsa rates at our institute. our results reinforce the concept that an 'mrsa bundle' comprising standard well-known mrsa control measures is able to bring down mrsa transmission and infection rates substantially, even in a setting where mrsa is hyper-endemic. , , this study has shown significant declines in mrsa acquisitions, all clinical specimens and also bacteraemias. concurrently there was no decline in antibiotic prescribing habits. adding to the likelihood that the interventions caused the mrsa improvements is the fact that vancomycin-resistant enterococci and clostridium difficile rates have increased at our hospital (unpublished data) while multidrug-resistant gramnegative infection rates have remained stable. our approach can perhaps be extrapolated to other similar settings, as it shows how implementation barriers in terms of manpower, cultural and infrastructural constraints can be overcome using a gradual and staged roll-out of the mrsa bundle, with active involvement of senior hospital management. kotter broadly mapped out the process of initiating and sustaining change efforts more than a decade ago. sustainability is critical in such efforts, and requires cultural change. data management and communication was key to sustaining the change. one full-time member of staff was appointed to collate and feed performance metrics back to ward-based healthcare workers, nurse managers, the infection control team and senior management. ward-specific hand hygiene compliance data from trained auditors and mrsa acquisition rates were posted graphically each quarter in publicly displayed dashboards on each ward. efforts toward prevention of mrsa acquisition and infection have become embedded in the culture of clinical medicine at nuh. the plateau seen in the data after significant gains suggests that the improvements are sustainable but that better results are unlikely in the absence of further intervention. potential further interventions beyond those already implemented include those related to technological advancement or cutting edge research. screening of healthcare staff was not implemented because of both operational concerns e a significant proportion of staff are likely to be colonized but it would be impossible to lay all of them off work during the period required for mrsa decolonization as well as the concern that mrsa recolonization would be common in a hyper-endemic setting. nonetheless, this will be considered in the future as mrsa rates fail to decline further. decolonization (of patients or staff) remains controversial beyond some preoperative indications and further work in this regard is underway at our institution. it is conceivable that reducing the reservoir of mrsa may prevent transmission, and therefore infection rates. the predictable development of mupirocin resistance is of particular concern and evaluating carbapenem use alternative agents is another priority for research in mrsa control globally. current efforts are labour-intensive and carry a risk of fatigue. maintenance of data allows the tracking of progress and may help to prevent history from repeating itself if a trend toward the original baseline appears. patients who are colonized but do not develop infection are invisible in the absence of active surveillance, so this monitoring of acquisition (without infection) allows a more 'upstream' view of the progress of infection control interventions. manual hand hygiene audits using trained auditors are inefficient because they are labour intensive, and are made inaccurate by the hawthorne effect and necessarily small sample sizes, generally only on weekdays and daytime hours. technological solutions are evolving and could potentially feature in the infection control programme of tomorrow. functionality and evidence of cost-effectiveness remain barriers to such technology. active surveillance testing was a cornerstone of our bundle. whereas we used culture-based techniques, molecular testing would be more timely and sensitive, albeit it carries a risk in the regional setting of potentially missing certain mrsa strains with arginine-catabolic mobile elements (acme) inserted into orfx, and incurring greater operational costs. there are several limitations of this work. first, this was a non-randomized before-and-after study design involving a single institution. however, this is a common issue in infection control studies and not one that is easily overcome because of the nature of such studies. during this period, there was no concomitant decrease in other nosocomial antibiotic-resistant pathogens such as carbapenem-resistant acinetobacter baumannii or extended-spectrum beta-lactamase-producing enterobacteriaceae (data not shown) that would suggest an overall decline in antimicrobial resistance rates. clinical practices also did not change substantially. second, the nature of the intervention is such that several measures were included in a single 'bundle', and the individual effect of each measure cannot be determined. nonetheless, such 'care bundles' are now accepted in clinical practice, and their effects are greater collectively than when introduced as separate measures. in conclusion, hospitals confronting hyper-endemic mrsa with high infection rates and infrastructural and/or resource constraints can introduce sustainable improvement, provided that a proactive team including senior management leadership is driving it. data maintenance of process and outcome measures and good communication are essential. low prevalence of methicillin-resistant staphylococcus aureus (mrsa) at hospital admission in the netherlands: the value of search and destroy and restrictive antibiotic use increasing incidence but decreasing in-hospital mortality of adult staphylococcus aureus bacteraemia between methicillin resistant staphylococcus aureus in norway methicillin-resistant staphylococcus aureus veterans affairs initiative to prevent methicillin-resistant staphylococcus aureus infections outcomes from the first years of the australian national hand hygiene initiative national program for prevention of healthcare-associated infections and antimicrobial resistance e : positive trends, but perseverance needed trends in sources of methicillinresistant staphylococcus aureus (mrsa) bacteraemia: data from the national mandatory surveillance of mrsa bacteraemia in england evaluation of the national clean your hands campaign to reduce staphylococcus aureus bacteraemia and clostridium difficile infection in hospitals in england and wales by improved hand hygiene: four year, prospective, ecological, interrupted time series study getting started kit: reduce methicillinresistant staphylococcus aureus (mrsa) infection; how-to guide. cambridge, ma: institute for healthcare improvement emergence and resurgence of meticillin-resistant staphylococcus aureus as a public-health threat high burden of antimicrobial resistance in asia antimicrobial drug resistance in singapore hospitals methicillin-resistant staphylococcus aureus control in singapore e moving forward overcrowding and understaffing in modern health-care systems: key determinants in meticillin-resistant staphylococcus aureus transmission evaluation of mrsa select, a new chromogenic medium for the detection of nasal carriage of methicillin-resistant staphylococcus aureus the challenge of introducing a hand hygiene standard to clinical examinations teaching hand hygiene to medical students using a hands-on approach economic and clinical impact of nosocomial methicillin-resistant staphylococcus aureus infections in singapore: a matched caseecontrol study r: a language and environment for statistical computing. vienna: r foundation for statistical computing leading change: why transformational efforts fail methicillin-resistant staphylococcus aureus throat colonization among healthcare workers during an outbreak in singapore general hospital routine hand hygiene audit by direct observation: has nemesis arrived? arginine catabolic mobile element in methicillin-resistant staphylococcus aureus (mrsa) clonal group st -mrsa-iii isolates in singapore: implications for pcr-based screening tests care bundles; the holy grail of infectious risk management in hospital? this work was funded internally by the national university hospital. key: cord- -xo xop k authors: tan, li feng; seetharaman, santhosh kumar title: covid- outbreak in nursing homes in singapore date: - - journal: j microbiol immunol infect doi: . /j.jmii. . . sha: doc_id: cord_uid: xo xop k nan covid- is a global pandemic with extensive community spread in many countries . ltcfs have been identified as particularly vulnerable due to the older age of the residents who are likely to have multiple chronic illnesses . despite initial success in containing covid- transmission, singapore's rate of community transmission increased exponentially in mid-march as the pandemic spread across the world and overseas travellers returned to singapore (figure ). singapore has ltcf places as of . % are run by the government, % by non-profit organisations and % by the private sector. the first case of covid- in a ltcf was detected on st march . as of th april , ltcfs in singapore have detected covid- cases. despite accounting for < . % of total cases in singapore, deaths of ltcf residents due to covid- account for % of the total fatalities. this is similar to many developed countries where mortality rates are disproportionately high amongst nh residents. many preventive strategies were put in place early on to prevent the spread of covid- to ltcfs . these included early pre-emptive management of ltcf residents with respiratory symptoms, transfer protocols between hospitals and ltcfs, increased temperature screening and social distancing and segregation of staff and residents. after the first ltcf case was detected, the ministry of health moved to suspend all visitors to all ltcfs for month, implemented compulsory safe distancing for all residents and split-zones for ltcfs with more than residents. staff were reminded not to turn up for work if unwell. despite these tough measures, covid- still found its way into nursing homes in singapore (figure ). this spread coincides with the exponential community transmission in singapore especially amongst work pass holders, a proportion of whom work in ltcf. this is similar to the situation in other countries where ltcf often face staff shortages that are exacerbated by the current pandemic situation. staff management is a key pillar in any preventive strategy in ltcfs . however, preventing covid- transmission to ltcfs remains a challenge if community transmission is not well-controlled. this is because staff remain vulnerable to catching the virus and inadvertently spreading it to ltcf residents especially as the severe acute respiratory syndrome coronavirus (sars-cov- ) is highly contagious even while asymptomatic . thus far, covid- has not been widespread amongst ltcfs in singapore and the numbers remain under control. however until global and local community transmission is well under control, ltcfs cannot let their guard down and must continue to implement policies to protect this particularly vulnerable group. covid- pandemic in long-term care facilities insight into novel coronavirus -an updated intrim review and lessons from sars-cov and mers-cov and nursing homes preventing the spread of covid- to nursing homes: experience from a singapore geriatric centre figure key: cord- -jqi ylrx authors: lin, ray junhao; lee, tau hong; lye, david cb title: from sars to covid‐ : the singapore journey date: - - journal: med j aust doi: . /mja . sha: doc_id: cord_uid: jqi ylrx nan s ingapore is a densely populated city-state of . million and a global travel hub. these characteristics make it particularly susceptible to the importation of communicable diseases and consequent outbreaks. the severe acute respiratory syndrome (sars) outbreak challenged the nation's public health system and now the coronavirus disease (covid- ) pandemic is presenting a greater challenge. since december , the virus responsible for covid- , sars-cov- , has spread to more than countries and over million cases have been reported. singapore diagnosed its first case on january . in , sars infected people and killed in singapore, exposing the weaknesses of the epidemiological surveillance and health care system for emerging infectious diseases. learning from the outbreak, singapore introduced several key measures to strengthen its pandemic management capabilities. the disease outbreak response system condition framework was established. this framework serves as the foundation for the national responses to any outbreak and is divided into four levels of incremental severity (green, yellow, orange and red), based on risk assessment of the public health impact of the disease and the current disease situation in singapore (box ). the goal and extent of public health response measures are in response to the level of threat. , infrastructure for outbreak management was significantly augmented. isolation facilities in public hospitals have been increased. the national centre for infectious diseases (ncid), a -bed purpose-built infectious disease management facility with integrated clinical, laboratory and epidemiological functions has replaced the isolation-bed communicable disease centre as the centrepiece of pandemic management in singapore. , national stockpiles of personal protective equipment (ppe), critical medications and vaccines for up to months were established. professional personnel and training of health care workers in outbreak response were expanded, with the number of infectious disease physicians rising from in to in . since , the singapore ministry of health has conducted regular -yearly scenario-based simulation exercises at all public hospitals to evaluate and provide feedback on their pandemic response plans. public engagement and education were crucial components in the public health response to outbreaks. consistent public communication was effected through press releases and media coverage of the epidemic, while an education campaign was mounted to educate singaporeans on the disease and appropriate behaviour to prevent transmission. it was apparent from sars that clear leadership and direction was essential for a government-wide, coordinated response towards the outbreak. a ministerial committee, first established during the sars outbreak to provide guidance and decisions on strategies for containment of the outbreak, was convened in the covid- pandemic as a multiministry taskforce co-chaired by the minister for health and the minister for national development. , this taskforce has the ability to recommend and implement whole-of-government policies to deal with issues related to covid- . to reduce the transmission of sars-cov- , singapore has adopted a strategy of active case detection and containment through several means. with the goal of identifying every case of covid- , several complementary detection methods were employed. a local case definition for suspect cases of covid- was first established on january based on clinical and epidemiological criteria. , this definition was constantly updated to adapt to the evolving global and local situation (supporting information). dissemination of the criteria to all physicians in singapore was via text messages and emails, and criteria-based screening was implemented at all clinics and hospitals nationally. patients fulfilling criteria were referred from primary care clinics to the ncid, while those presenting to hospital emergency departments were isolated in airborne infection isolation rooms and tested. at the ncid, a purpose-built outbreak screening centre was activated to evaluate suspect cases. suspect cases were stratified into low and high risk groups (box ). high risk suspect cases were admitted, isolated and tested for sars-cov- . low risk suspect cases had a single nasopharyngeal swab test and were discharged with a written advisory to self-isolate at home. phone surveillance for symptom progression was performed and patients with persistent symptoms or positive swab results were recalled for further evaluation or isolation. on march , a total of low risk suspect cases had been evaluated, of whom were recalled for positive test results. patients with confirmed covid- underwent detailed interviews for activity mapping to guide contact tracing and cluster investigations. a mobile phone application (app) was also developed by the ministry of health and the government technology agency to facilitate contact tracing in the community. devices with the app installed exchange anonymised proximity information by means of bluetooth relative signal strength indicator readings across time to approximate the proximity and duration of an encounter between two users. this information is then obtained by the ministry of health from the device of a patient, reducing the time and effort required for contact tracing. on april, the app had achieved a % population adoption rate, with . million users in singapore. identified close contacts were placed in quarantine either at home or government quarantine facilities while casual contacts were placed on phone surveillance (supporting information). with the above measures, the daily incidence of imported cases steadily decreased from a peak of cases per day on march to zero cases per day since april (box ). drawing from the public engagement efforts in sars, public education efforts in singapore emphasised social responsibility and appropriate behaviour. messages on regular handwashing, appropriate use of masks when unwell, seeking medical treatment early and staying home when unwell were conveyed through print and broadcast media as well as social media platforms. the public was advised to obtain accurate and factual information from reliable sources including government websites, facebook and instagram. daily updates on the covid- situation with anonymised information on positive cases were shared publicly though the ministry of health website while misinformation was quickly dispelled to prevent public anxiety and speculation. singaporeans with respiratory symptoms were encouraged to seek treatment at public health preparedness clinics, a network of over primary health clinics that provide subsidised care and extended medical leave of up to days. this allowed possible mild covid- cases to self-isolate at home and reduce community transmission. those with progressive symptoms were advised to return to the same doctor for evaluation and further testing. at the workplace, employers were encouraged to conduct regular temperature and health monitoring for employees, as well as to implement business continuity plans, such as working from home or segregated teams to reduce mixing of workers. fever screening through thermal scanners was implemented at points of entry of most buildings and facilities. from march, entertainment venues were closed and large scale gatherings were cancelled. however, with the rising number of locally acquired cases in the community as well as the emergence of large clusters within foreign worker dormitories in early april, a set of "circuit-breaker" measures was implemented from april. all non-essential workplaces were closed, schools were physically closed but moved to home-based learning, and food establishments were only allowed to provide takeaway and delivery services. there are about million lower wage foreign workers on work permit in singapore. about live at close quarters in densely populated dormitories. specific measures were needed to curtail the spread of disease within these dormitories. movement of workers in and out of the dormitories was prohibited and these dormitories were gazetted as isolation facilities. asymptomatic workers were relocated to other facilities for quarantine, while medical facilities and triage clinics were set up within the dormitories to facilitate diagnosis and treatment of symptomatic workers. workers who tested positive were transferred to community isolation facilities if they had mild symptoms, or to the ncid and public hospitals for further treatment and isolation. to limit transmission within the dormitories, safe distancing measures were implemented to prevent intermingling of workers, including regulating access to common areas and recreation facilities, limiting workers to their rooms, and delivering meals to the rooms. cleaning and sanitation regimes were also intensified. , patients in the ncid were placed in individual negative pressure isolation rooms and reviewed daily by medical teams. the workforce was augmented by a structured just-in-time training program was rolled out by the infection prevention and control department to train newly deployed staff in ppe use. to standardise the collection of clinical and epidemiological data, and guide clinical management, covid- clinical pathways were implemented. all admitted suspect cases received an initial chest x-ray and were tested for sars-cov- by means of rt-pcr from respiratory specimens over two consecutive days. clinicians were given the liberty to perform additional tests based on clinical or epidemiological grounds. suspect cases were deisolated or discharged if they fulfilled the in-house discharge criteria. patients who tested positive were managed as inpatients until their symptoms had resolved and they had one negative nasopharyngeal swab result per day on two consecutive days. a wearable continuous patient monitoring system was used to monitor patient parameters to reduce health care worker exposure and ppe use. as standard of care, complete blood counts and kidney and liver function tests were performed, and c-reactive protein and lactate dehydrogenase levels were measured. respiratory samples were tested for influenza and other respiratory viruses with a multiplex pcr assay. all patients received supportive therapy, including supplemental oxygen when needed. patients clinically suspected of having communityacquired pneumonia received empirical antibiotics and oral oseltamivir. agents with possible antiviral effect on sars-cov- were offered to patients meeting inhouse guidelines. co-formulated lopinavir-ritonavir ( mg/ mg twice daily orally for up to days) with or without interferon beta- b ( million units every other day for days) was prescribed to selected patients who required oxygen supplementation or had pneumonia, after shared decision making and provision of verbal informed consent. patients with risk factors for severe disease and requiring supplementary oxygen were referred to a multidisciplinary icu team, comprising critical care and infectious disease specialists. , patients expected to deteriorate were pre-emptively transferred to the dedicated outbreak icu for monitoring. intubation, if required, was performed electively in full ppe. non-invasive ventilation was disallowed to reduce generation of aerosol. on-site extracorporeal membrane oxygenation support was available for patients assessed to be suitable. to cope with the emergence of large number of foreign worker dormitory cases, the ncid ramped up its bed capacity to beds, beyond the predetermined number of , through cohorting of positive cases. patients assessed as having mild symptoms and no risk factors for disease progression were transferred to community isolation facilities until they could be de-isolated and discharged, while those with risk factors or moderate to severe disease continued to be managed in the ncid. as of april, of patients had been transferred to the community isolation facility. since the transmission of sars-cov- to health care workers was reported on january , twicedaily temperature monitoring was mandated for all frontline health care workers in all public hospitals. health care workers in direct contact with covid- patients who developed fever or symptoms of acute respiratory infection were encouraged to declare their symptoms to their superiors and present themselves to the screening centre, to be managed based on their exposure risk (box ). a health care worker with protected exposure was defined as one who was, at least, wearing a surgical mask. if symptomatic, the health care worker was tested, given days of medical leave and placed under phone surveillance for symptom progression. those with unprotected exposure were quarantined if asymptomatic, while those with symptoms were managed as high risk suspect cases. before returning to work, health care workers who tested negative and had completed the duration of medical leave, were assessed at the occupational health clinic for resolution of symptoms. as of april, a total of health care workers had been evaluated, of whom had been admitted and ( . %) had tested positive. these strategies aimed to delay the peak in number of covid- cases in singapore and avoid overwhelming the health care system, which may have contributed to high case fatality rates in hubei, china and italy. flattening the curve buys time for additional measures to be put in place. adequate time is needed for purchase of equipment, health care worker deployment, logistical arrangement and operational planning. in our experience, about % of patients are admitted to the icu. increase in requirement for icu beds is anticipated. planning for such additional resources should be guided by experience and evidence, and adjustments must be made in an agile manner. to deal with the numbers of positive cases admitted under current policy, those with low risk and mild disease should be identified using predictive scores for subsequent safe transition of care to the outpatient setting to free up hospital resources to manage patients with severe disease. as valuable medical resources are diverted to manage the pandemic, it is important to maintain an acceptable level of care for patients with other medical conditions. clinic sessions that were disrupted and elective surgeries that were delayed should be ramped up to clear the backlog of patients requiring care. covid- impacted the training of medical students and junior doctors as cross-institutional staff movement was restricted and lectures and bedside tutorials were cancelled. [ ] [ ] [ ] these were somewhat mitigated by online learning. with no signs of the pandemic abating, all countries must increase medical capabilities to deal with the surge in patients. a concerted whole-of-government approach is paramount to combat covid- , as its impact is not just on human health. social unrest, political instability, economic depression and food security are potential issues that may further threaten our wellbeing. pandemic preparedness: nationally-led simulation to test hospital systems the singaporean response to the sars outbreak: knowledge sufficiency versus public trust evaluation of the effectiveness of surveillance and containment measures for the first patients with covid- in singapore how does tracetogether work? investigation of three clusters of covid- in singapore: implications for surveillance and response measures scaling up of covid- testing ministry of health singapore. situation report - circuit breaker to minimise further spread of covid- containing covid- spread at foreign worker dormitories tackling transmissions in migrant worker clusters testing for sars-cov- : can we stop at two? de-isolating covid- suspect cases: a continuing challenge epidemiologic features and clinical course of patients infected with sars-cov- in singapore clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease pneumonia in wuhan, china preparing for the most critically ill patients with covid- : the potential role of extracorporeal membrane oxygenation clinical features of patients infected with novel coronavirus in wuhan, china facing covid- in italyethics, logistics, and therapeutics on the epidemic's front line covid- and its impact on neurosurgery: our early experience in singapore love in the time of coronavirus: training and service during covid- going virtual to support anatomy education: a stop gap in the midst of the covid- pandemic additional supporting information is included with the online version of this article. key: cord- - fgtjouu authors: hutton, thomas a title: service industries, globalization, and urban restructuring within the asia-pacific: new development trajectories and planning responses date: - - journal: prog plann doi: . /s - ( ) - sha: doc_id: cord_uid: fgtjouu while industralization programmes have been central to the development of asia-pacific states and city-regions over the past half-century, service industries are increasingly important as instruments of urban growth and change. the purpose of this paper is to establish service industries as increasingly significant aspects of urban development within the asia-pacific, and to propose a conceptual and analytical framework for scholarly investigation within this important research domain. to this end the paper explores a sequence of related themes and issues, concerning the larger developmental implications of urban services growth (or tertiarization), the facets of urban transformation associated with tertiarization, and a preliminary typology of urban service functions which acknowledges the rich diversity of service vocations and stages of development within the asia-pacific. the paper concludes that “advanced services”—specialized, intermediate service industries, advanced-technology services, and creative service industries—will be quite crucial to the development of city-regions within the asia-pacific, with respect to employment growth and human capital formation, to the urban economic (or export) base, to the operation of flexible production systems, and to competitive advantage. the development of these urban service poles will require innovative policy commitments and regulatory adjustments, as will the multi-centred specialized urban service corridors which function as engines of regional economic growth, and which provide platforms for national modernization and responses to the pressures (and opportunities) of globalization. to date, urban and regional development strategies for service industries within the asia-pacific have privileged globalization, industrial restructuring, and modernization aims, but there is also an encouraging record of more progressive planning experimentation in some jurisdictions, incorporating principles of sustainability and co-operative development. there is also increasing interest in policies to support cultural and creative industries among asia-pacific city-regions, informed by some recent urban policy experimentation in this domain. these experiences can offer models for further policy and programmatic innovation in the st century, as service industries continue to play larger roles in urban and regional development within the asia-pacific. introduction: service industries and urban transformation service industries have accounted for an increasing share of labour, output, and trade among the advanced economies of the organization for economic co-operation and development (oecd) over the last quarter century. this phenomenon of sustained growth in services (both in absolute and relative terms) can be observed at the national level among oecd member countries in terms of the changing composition of gross domestic product (gdp) and employment, but is especially pronounced at the urban or city-region scale. final demand service industries (for example retail, education, and most government services) are strongly tied to large metropolitan consumer markets, while intermediate services are even more spatially centralized, reflecting the influence of urban and agglomeration economies on the locational pattern of specialized, contact-intensive services. following the protracted decline of traditional manufacturing, service industries have led employment growth among most advanced city-regions over the last three decades. but the significance of service industries to urban (and especially metropolitan) development extends beyond measures of growth, as important as these are, to encompass comprehensive processes of change. at the broadest theoretical level we can discern intimate associations between service industries and redefining urban socio-economic processes and stylistic innovation over the past century. the growth of high-rise office complexes was an integral feature of the production of modernist urban landscapes, while advanced service industries have been central to the experiences of post-industrialism, flexible specialization, and post-modernism which have transformed urban landscapes, production sectors, and occupational structures over the past several decades. more particularly, service industries are directly involved in fundamental shifts in the urban economic base and industrial structure, but are also deeply implicated in the reconfiguration of regional structure, the metropolitan space-economy, and urban form. the rapid growth of service occupations among the most advanced post-industrial cities has also had profound implications for urban class structure and for the metropolitan social morphology, and is associated with the evolution of urban culture and even political preferences. in addition to these internal facets of urban transformation, service industries are also influential in the repositioning of cities and city-regions within external networks and systems. growth in urban service exports and trade may be significant in the recasting of city -hinterland relations, and in the reordering of national urban hierarchies, and is quite decisive in the emergence of global city-regions. at the apex of the global city hierarchy the most privileged status is associated with high concentrations of specialized banking and finance, and the projection of corporate power, as well as encompassing a more diversified ensemble of specialized service industries. these far-reaching aspects of urban service growth (or tertiarization) are most pronounced within the mature societies of europe and north america, but are increasingly relevant to an appreciation of urban growth and change within asia-pacific cities. the purpose of this paper is to propose a framework for investigating the influence of service industries on urban development within the asia-pacific, with an emphasis on dimensions of transformational change, both within the metropolis, and at the broader urban systems level. this entails an assessment of economic implications of tertiarization for cities and city-regions within the asia-pacific, including the emergence of new urban functions or vocations, and constituent shifts in the urban economic base, employment structure, and mix of industries. advanced or specialized services-especially, banking and finance, business and trade services, professional and 'informational' service activities, among others-are increasingly associated with modernization aspirations among the region's post-industrial, late-industrial and transitional societies, as reflected in development strategies and programmes. however, the parameters of urban change within the asia-pacific associated with tertiarization extend beyond this economic dimension to encompass impacts of service industry growth on urban structure and form, the built environment, social class and social morphology: i.e. the comprehensive facets of transformation (and re-imaging) of cities increasingly engaged in advanced services production, exchange, trade and consumption. our conceptual point of departure is that the expansion of services activity within asia-pacific cities and city-regions represents not only incremental urban growth and change, but, rather, consequential shifts in the role of urban areas within advanced production systems, in the globalization of trade flows, and in new social divisions of production labour. accordingly, the analytical focus will be on service industries and activities which the research literature has identified as 'propulsive' in urban growth and development; i.e. intermediate (rather than final demand) services, specialized service industries, and knowledge-and technology-based or informational services. at the same time, the record of urban services growth within the asia-pacific region discloses wide variations in stages of services development and mixes of service activity from place to place, and this variegation must be acknowledged in the interests of presenting a more rounded perspective on the experience than an exclusive discussion of leading edge examples would allow. indeed, some of the most interesting and instructive stories of urban tertiarization within the asia-pacific concern the juxtaposition of informal and advanced services in transitional societies, with ensuing social, land use, and planning conflicts. following this introduction, the paper offers a discussion of contrasts in developmental trajectories between the 'mature' atlantic core regions and those of the dynamic pacific core (chapter ), including an acknowledgement of industrialization as the dominant development paradigm for much of the asia-pacific since the s. defining elements of advanced urban tertiarization are identified, and are constituted within a taxonomy of global cities' service functions. the following section (chapter ) addresses both commonalities and contrasts in service industry developments among city-regions of the atlantic and pacific cores, and identifies five principal implications of service growth for urban change within the asia-pacific. these include the role of service industries in reshaping urban development trajectories, in the reconfiguration of urban space, and in urban social and cultural change, as well as the ramifications of accelerated tertiarization for the everyday experiences of city life and for urban identity and image. next, the paper offers a typology of urban services development within the asia-pacific (chapter ), derived from levels of services specialization as well as from urban scale. the spatial development of specialized services production within the asia-pacific is described, including both polarized patterns and more extended territories of tertiary sector growth, observed in the form of incipient urban corridors. these corridors (or clusters) represent a functionally specialized form of territorial development which exhibit features of co-operation as well as competition, and in part express policy responses to the pressures of globalization. the two final substantive chapters address planning issues and experiences associated with the development of the urban service sector. the first (chapter ) describes the basic evolution of local policy responses to urban tertiarization over the last quarter-century, from early development control policy regimes imposed to manage negative externalities of rapid service industry growth, to more balanced approaches, which combined developmental as well as regulatory elements. this chapter concludes with a set of important processes and events which have shaped a new policy environment for urban service industries in the early st century. next, chapter extends this discussion, by introducing a framework of six strategic urban policy models which are deployed in cities within the asia-pacific, including experiments in progressive planning (co-operative regional development, sustainable city-regions), as well as familiar models associated with globalization and restructuring objectives. the paper concludes with suggestions for a research agenda, emphasizing developmental and transformational implications of service industry growth for city-regions within the asia-pacific. there are of course different approaches to conceptualizing the units of 'world geography' apart from the standard continental divisions, as a spectrum of historical, socio-cultural, political and economic considerations can be imposed upon the standard geo-physical patterns. for much of the post-war period the idea of a tripartite structure of spheres organised crudely along ideological lines and developmental progress emerged as a descriptive convention, including a developed, essentially democratic-capitalistic 'first world', comprised of a hegemonic us bloc and its allies in north america, western europe, japan and australia; secondly, the comecon (council for mutual economic aid) group of nations, largely dominated by the ussr and concentrated within eastern europe and asia, but also including cuba; and, finally, a 'third world' of 'developing' countries, ostensibly non-aligned, but including many de facto client states of either the us or the ussr. with the collapse of the 'second' (comecon) world (comecon) world - , and the increasing pluralism within the first and third worlds implied in the post-modern viewpoint, there has been a renewed interest in (re) conceiving global geography or world regional patterns. in this regard lewis and wigen acknowledge the tendency of world regional frameworks "to grossly flatten the complexities of global geography", but assert that "some form of baseline heuristic scheme is necessary for teaching and thinking about metageography" (lewis and wigen, : ) . to this end their conceptual preference is to ignore political and ecological boundaries, and to instead focus upon historical processes, to give primacy to "the spatial contours of assemblages of ideas, practices, and social institutions that give human communities their distinction and coherence" (lewis and wigen, : ) , and to consider not only internal attributes but external relations. see martin w. lewis atlantic core, due in large part to earlier industrialization, and a longer record of tertiarization, but there is now a well-developed pattern of higher-echelon global cities within the asia-pacific (rimmer, ; preston, ) (fig. ) . these cities are centres of advanced industrial and services production, and are linked by capital flows, technology transfer, transportation and communication networks, and patterns of cultural exchange and diffusion, typifying aspects of international and global codependency. the second-order world cities achieve a level of global reach via the presence of certain specialized industry groups, propulsive firms, or influential international institutions, and thus comprise essential elements of the global economy. global city status is conventionally associated with comparative concentrations of intermediate banking and finance, headquarters of mncs, 'producer' services (stanback et al., ) and international gateway functions. however, increasingly global city status encompasses other suites of specialized service industries, including design, knowledge, and technology-based activities, in part reflecting scott's thesis concerning the transformational convergence of culture and urban economic development (scott, ) , as well as the competitive advantage of metropolitan cities for creative and informational services (table ) . this city-centred growth pattern is complemented by complex and distinctive forms of regional development, which include ( ) multi-centred urban growth corridors or 'megalopolitan' regions, such as the classic new york -new jersey conurbation (gottmann, ) , and the randstat urban corridor in the old atlantic core, and the example of the 'extended metropolitan regions ' (mcgee, ) of east asia and southeast asia, such as jakarta -bandung, beijing -tianjin, and tokyo -kawasaki -yokohama, within the asia-pacific sphere; ( ) 'lead regions' comprised of innovative industry complexes and propulsive firm networks, exemplified by baden -württemburg, the veneto, the ile de france, and the london-oxford -cambridge technology triangle within the old core (storper and salais, ) , and the kanto plain, orange county, and silicon valley (scott, ) within the pacific sphere; and ( ) incipient trans-border 'growth triangles' (and other geoeconomic constructs), illustrated by the singapore -johore -riau development triangle, and the cascadia metropolitan bio-region of the pacific north west, and, in the atlantic old core, the transmarche region, and the emerging baltic development zone which aspires to foster mutually beneficial development in northern germany, the former soviet baltic states of latvia, estonia and lithuania, and scandinavia. these new and emerging growth territories may exhibit positive spread effects of regional development generally lacking in less advanced zones table principal suites of specialized service industries for global city-regions i (suites of specialized service functions) banking and finance commercial, merchant, and investment banks; securities and brokerages; stock exchanges; non-depository financial institutions; insurance and re-insurance; industrial-commercial real estate and property development corporate control head offices of international and global corporations and multi-nationals; 'propulsive' corporations and firms producer services specialized, export-capable intermediate service industries and firms; corporate law and accounting firms; management consulting, consulting engineers gateway roles major international airports; major seaports; international telecommunications facilities capital functions national capitals; state/province/regional capitals and administration; offices of international agencies tourism and conventions international tourism and convention industries; major international fairs and expositions advanced-technology services software developers; it firms; internet providers; 'dot.com' firms creative services and applied design architects; industrial design; graphic artists/design; fashion design; interior design; landscape design education and knowledge major national and international universities and colleges; r&d operations and science parks; major 'think tanks' and other research/ knowledge-based institutions culture and heritage major museums and galleries; national libraries and archives; culturally defining heritage buildings, sites, and precincts of the global economy, and suggest possibilities of functional complementarity and reciprocal specialization, as well as the familiar exigencies of competitive advantage. in the aggregate, these characteristics-technology-intensive production, high quality economic infrastructure, productive human and social capital, superior external trade mechanisms and capacity, and the distinctive spatial patterns of growth described above -constitute defining aspects of development within the world's dominant economic spheres. these attributes affirm the exalted economic status of the mature atlantic core and the dynamic pacific core, define the trajectory of development at the leading edge of change and transformation, and suggest the power of convergence, interdependence, and hierarchy acknowledged as important facets of globalization. while important commonalities can be discerned, there are fundamental contrasts in the development experiences and transformational vectors of the atlantic and pacific spheres, as well as innumerable variations in the circumstances and growth paths of individual nations and regions within each of these dominant, supra-continental realms (see yeung and lo, ) . the inexhaustible differentiation of regional histories, political traditions and structures of governance, culture and geographical and environmental factors are seen to underpin the persistence of variegation and exceptionalism among regions and localities within both the old and new cores. the confluence of exogenous forces, including the rise of mnes, and increasing market integration and technological diffusion, has imposed some measure of developmental convergence and commonality across international space (as well as increasing disparities within urban social structures), but there are after all limits to the homogenizing effects of globalization, as the recent scholarly development literature attests. without denying the impressive global sweep of mnes and speculative capital, it is essential to acknowledge the significance of (largely) localized development influences, such as site and environment, the structures of social networks and civic institutions, and the quality of public policy and regulation. in an insightful book aimed at 'reasserting the power of the local', a number of scholars enrich the discourse on globalization by an elucidation of factors which reaffirm the power of local identity, and which provide some friction to the movement of capital and firms. storper, notably, asserts the significance of 'territorialization' in embedding some specialized forms of economic activity within specific locations, beyond the more generic considerations of urban agglomeration which can bind (especially contact-intensive) firms to central places, such as higher-order service enterprises which cluster within the corporate complex of the central business district (cbd). in this interpretation, a firm or activity is "fully territorialized when its economic viability is rooted in assets (including practices and relations) that are not available in many other places and that cannot be easily or rapidly created in places that lack them" (storper, : ) . this concept of territorialization can also incorporate the quality of civic institutions and civil society as influences on economic development and socio-economic welfare, as disclosed in putnam's seminal study of regional and community development in italy (putnam et al., ) . other important factors of locality that can influence differentiation in patterns of economic growth and development are exemplified by amenity attributes, which may include access to education and learning opportunities, and community levels of tolerance and equity, as well as air and water quality, leisure, and recreational opportunities. thus, the forces of globalization, as powerful and pervasive as they demonstrably are, may be significantly tempered, mitigated, or renegotiated at regional and local levels. this more nuanced interpretation of the interactions and tensions between global imperatives and local (or domestic) factors provides a useful backdrop for inquiry into the comparative developmental conditions between the atlantic and pacific cores, a task that has assumed greater importance both in the wake of the asia-pacific's dynamism over much of the past three decades, as well as the serious downturn that commenced in mid- in many east and southeast asian economies. this crisis, which delivered a major check to the continued growth and progress of many of the leading economies of the region, presents a complex set of economic, socio-cultural and political issues and underlying causes that vary widely from place to place, but certainly includes important structural factors (relating to governance, policy, regulation, and financial supervision), as well as more transitory or cyclical attributes (mcleod and garnaut, ). an apparent recovery process can be discerned in some of the asia-pacific economies, but the experience is likely to be protracted and wrenching for many, as the (now decade-long) recession in japan seems to attest. sustained recovery (and, more pointedly, a shift from growth to development) will require major adjustments to the political structures of asia-pacific states, as well as to the governance of corporations and industrial enterprises, and to the supervision and regulation of banks and financial institutions. both the depth and breadth of this economic downturn (and attendant social and political upheavals), and the quarter century or so of recurrent high growth levels that preceded it, raise questions concerning the contrasting trajectories of development within the mature atlantic economies and those of the new core of the pacific basin, as well as the factors underlying these patterns of differentiation. certainly one of the most salient and defining contrasts in the post-war trajectories of the atlantic and pacific spheres concerns the relative status and roles of the secondary (manufacturing) and tertiary (service) sectors, respectively, and the ensembles of policy, market and socio-demographic influences on these distinctive sectoral specializations. beyond the obvious reality that the leading states of both the pacific and atlantic spheres contain advanced industrial production sectors, and are experiencing growth in tertiary activity, it is important to acknowledge that while the growth of services represents a dominant motif of the economic and social reconstruction of western economies and societies, the accelerated growth of manufacturing industry and employment has been the principal story in the rise of the asia-pacific economies over the past four decades. among the mature economies of the oecd, concentrated within the old atlantic core, this same period has seen a massive contraction of production capacity and labour in basic industries, especially in fordist mass-production manufacturing, manifested most dramatically by wrenching processes of industrial decline (consisting mostly of outright factory closures but also some measure of locational decentralization) within long-established inner-city industrial precincts of large-and medium-size cities, and consequent losses of employment, income and revenue (noyelle and stanback, ) . new industries characterized by flexible specialization processes and technology-intensive outputs have emerged in 'lead regions' and 'new production spaces' (scott, ) within the atlantic core, so aggregate manufacturing output has held up or even increased (by value) in some areas (coffey, ) , but in general manufacturing activity has lost ground in relative terms in most oecd regions. over the past half-century, services have been essential features of the development of metropolitan cities (gottmann, ) . more specifically, intermediate services have emerged as increasingly strategic and propulsive elements of advanced production systems, as observed in successive rounds of industrial restructuring, in new divisions of labour, and in the rise of service-based global cities and new urban service poles (table ) . at the same time, the post-war period has seen among the most advanced societies the sustained expansion of service industries which (with related shifts in industrial production processes) have profoundly changed the economic base, industrial mix, labour force, land use and physical form of city-regions within the atlantic zone. service sector growth has thus constituted a central feature of economic restructuring among advanced nations and regions, with service-type occupations leading employment formation not only in the tertiary and quaternary (or informational) sectors, but also in manufacturing, where the growth of management, clerical, sales and technical workers has exceeded that for direct production workers and operatives in most cases. in general scholarly attention to the growth and development of service activities has evolved as follows: (a) an early interest in the growth of high-rise offices in the cbds of the largest metropolitan cities, including important theoretical and conceptual contributions (gottmann, ) , (b) a stream of empirical studies of office location, emphasizing regional policy implications and urban planning problems (daniels, ; goddard, ) , (c) growing interest in the social ramifications of services growth (bell, ) , (d) a sharper analytical focus on business, 'producer' and other intermediate services, and their role in urban and regional development (noyelle and stanback, ) , and in the operation of 'flexible' industrial regimes, (e) assessments of the global dimensions of services development, especially in banking and finance, as well as in producer services and communications (daniels, ), (f) acknowledgement of the importance of specialized services in the emergence of the 'informational city' and urban society (castells, ) , and (g) explorations of the intersections between tertiarization, occupational shifts, urban class (re)formation, and community-level impacts, especially in the metropolitan core (ley, ) . ( ) producer services as key to flexible specialization production regimes (coffey) ( ) emergence of integrated sevice-technology-production systems ( ) internalized service production ( ) externalized service production ( ) globalized service production ( ) but these structural consequences of tertiarization extend well beyond the economic dimension, as the sustained expansion of service labour (and concomitant decline in bluecollar workers) within the atlantic core regions has led in turn to the reformation of urban society, in terms of social class, community and neighbourhood patterns, culture, and political values and preferences, as documented in scholarly treatments of post-industrial society (summarized in table (a)). the tight spatial bonding of specialized, contactintensive service industries within intricate input -output relations has been instrumental in the reformation of urban structure and land use within the metropolitan core (gottmann, ; hutton and ley, ) . tertiarization has also generated more comprehensive changes in metropolitan structure, as seen principally in the emergence of specialized service nodes and clusters which dominate the space-economies of advanced city-regions, and also in urban form and the built environment, exemplified in the growth of the central city corporate complex, new districts of services production and consumption on the cbd fringe and inner city (including design and technology-based services), regional office and retail centres, and proto-urban forms which incorporate advanced service industries within 'edge cities' (garreau, ) (table (b)) . while tertiarization stands as the definitive and most consequential feature of economic growth and social change among western or atlantic nations and regions over the post-war period, industrialization has represented the principal development modality for much of the asia-pacific since the s and s. (although there have been to be sure important shifts in agriculture and other forms of primary and staple production in many pacific nations.) there is of course considerable variation in the temporal sequencing, specific industry emphasis, scale and stage of manufacturing growth among individual nations (and even among regions and sub-regions), but accelerated industrialization, supported in most cases by state policies and programmes, has been central to the expansion of every high growth asian-pacific state (douglass, ) , including ( ) the japanese ascendancy, seen in the industrial development of the japanese archipelago (especially within the principal conurbations of honshu but also including urban centres in kyushu and hokkaido) over much of the present century, with accelerated development of production in industrial and consumer goods from the s, including see garreau ( ) for an original contribution to our understanding of this spatial and socio-economic phenomenon. i am making a broad distinction here between economic systems in which manufacturing or (alternatively) services are dominant. it is of course possible to perceive services as 'industrial activities', as detailed divisions of 'service industries' are conventionally depicted within sectoral aggregations in standard industrial classification catalogues, for statistical purposes. moreover, there is a general preference for positioning service industries as co-dependent elements of integrated production systems (gershuny, ) . at the same time, industrialization as a development paradigm within the asia-pacific has certainly implied a powerful emphasis on the growth of manufacturing industries, industrial companies and conglomerates, factories and industrial labour, in the form of factory workers, assembly line employment, and operatives. jonathan rigg's analysis of modernization and development in southeast asia includes a special chapter addressing the idea (and reality) of 'the factory world' as a defining feature of this experience (rigg, : - ) . table defining attributes of advanced urban tertiarization defining conditions within highly tertiarized cities (a) urban industrial structure, economic base, employment and class sectoral/industrial structure tertiary sector larger than secondary sector; service industries growing faster than manufacturing industries both in relative and absolute terms industrial output services share of urban/regional gdp growing faster than manufacturing share market orientation/production linkages intermediate sector services growing faster than final demand services; specialized services and manufacturing co-dependent elements of advanced production systems urban economic base services comprise large and increasing share of urban economic base; significant and growing volume of specialized service exports and trade employment . % of urban employment in service industries occupational structure rapid growth of executives, managers, professionals; emerging social division of service labour favouring knowledge-and technology-based service workers, design, creative and cultural services urban class structure emerging hegemony of 'new middle class' (ley, ) of upper-tier service cohorts urban social morphology extensive social upgrading (gentrification) in older inner city neighbourhoods; growth of inner city loft housing and 'live-work'/'work-live' studios; increasing social displacement and inter-group tensions (b) urban spatial structure, space-economy, form, image and identity urban/metropolitan structure service industries dominant elements of urban core and (established or incipient) metropolitan sub-centres urban space-economy specialized service clusters and corridors dominant features of urban/ metropolitan space-economy (cbd corporate complex, seaports and airports, distribution centres, retail centres, higher education institutions, government and public administration, business parks, r&d parks] inner city landscapes new and emerging precincts of specialized services: applied design, creative and cultural services; internet providers and 'dot.com' firms; cultural centres; higher education; professional sports and entertainment; public recreation; live-work studios and new artist/artisan neighbourhoods urban form mix of modernist-post-modernist urban forms: high-rise office precincts in cbd and metro sub-centres, as well as new services domiciled in 'reconstructed' services production and consumption landscapes within inner city and inner suburbs; 'edge cities' and proto-urban forms on the metropolitan periphery infrastructure derived demand for transportation and other infrastructure associated with urban tertiarization identity post-industrialism; post-modernity image 'global' or 'world' city (hall, friedmann, sassen) ; 'informational city/society' (castells) ; 'transactional city' (gottmann) the expansion of global-scale industrial conglomerates and mncs; ( ) the origins of takeoff growth among the newly industrializing countries (nics), with accelerated industrialization initiated in taiwan and hong kong in the s, and singapore and south korea about a decade later (mcgee and lin, ) ; ( ) the later emergence of the 'threshold' or 'near' nics, notably malaysia and thailand, which retain important bases of agriculture and staple production outside the principal metropolitan zones, but which have experienced substantial manufacturing growth over the past two decades; ( ) the tumultuous growth and transformation of china, dating from the ideologically impelled industrialization programme enunciated in the series of -year economic plans commencing in the period - , to the industrial stimulus generated by the economic liberalization policies launched in , and then to the more recent expansion of advanced manufacturing in the lower yangtze, pearl river delta, and certain other coastal regions; ( ) the larger role played by industrial development in the transition of other populous agrarian nations, notably indonesia and the philippines; and ( ) the current economic restructuring programme in vietnam, associated with the 'doi moi' policy of economic and social renovation. in addition to these important examples, industrialization also represents a goal (or ideal) of lagging states within the region, such as laos, burma and north korea, although the realization of these industrial aspirations has been seriously impeded by a prejudicial mélange of factors including war, flawed development models, governmental corruption and administrative incompetence, lack of capital and other resources, and isolation. these national industrialization programmes and trajectories also featured important urban and regional dimensions. by the s, the asia-pacific sphere included a number of world-scale industrial metropoles, such as tokyo, nagoya, osaka, seoul, taipei, hong kong and shanghai, while by the s manufacturing emerged as an important feature of the metropolitan space-economies of southeast asian primate cities, including bangkok, jakarta, kuala lumpur, and manila (douglass, ) . beyond these large-scale urban industrial complexes, manufacturing activity increased within the metropolitan periphery, exurban areas, and even rural zones, for instance in the lower yangtze region, within the chinese special enterprise zones (sezs), within designated receptor areas (such as penang) for japanese foreign direct investment (fdi), and within desakota areas of east and southeast asia, proliferating the spatial milieux for industrial production in the region. even in pacific america, within which urban tertiarization processes are generally advanced, some city-regions have exhibited greater buoyancy in manufacturing than many of the older industrial cities of the great lakes region and eastern seaboard, within the broadly defined atlantic core. over the past two decades, los angeles, the san francisco bay area, seattle and even vancouver have experienced significant growth in advanced manufacturing such as aerospace and electronics (and in some basic production industries as well, such as garment production) within their regional territories, in contrast to the record of industrial decline in many other north american metropolitan areas, although to be sure they have also experienced high growth in service industries, and contractions in some traditional industries. at the end of the th century, then, industrialization represented the dominant trajectory for many states and regions within the asia-pacific, constituted a significant aspect of growth (together with specialized services) in some of the more advanced economies of the pacific realm, and remained an aspiration of lessdeveloped, agrarian and staple-dominated countries in the region. these industrialization trajectories will continue to be highly influential in the development of asia-pacific cityregions in the new century, but it is equally clear that service industries will emerge as increasingly significant features of urban growth and change, a theme we will explore in the following chapters. to date there has been relatively little scholarly attention paid to the development of service industries and employment within the asia-pacific, with the notable exception of case studies of cities within which services (especially advanced or 'higher-order' services) are playing significant roles (taylor and kwok, ) , and specialist studies of banking, finance and investment, and transportation and communications. the research emphasis has tended to be on multinational service corporations and international trade in services (waelbroeck et al., ; thrift, ; unctad, ; sieh-lee, ; lasserre and redding, ) , rather than on services development and associated issues for cities and city-regions. this situation reflects, to some extent, the pervasive influence of industrialization as a development paradigm within much of the pacific realm, emphasizing the primacy of manufacturing and industrial production within the growth trajectories of many asia-pacific states, regions and societies. the hegemony of the industrialization paradigm has created a kind of shadow effect within the scholarly literature on the economic development of the pacific basin, within which services are customarily treated as elements of the traditional urban retail or commercial sector, as essentially ancillary activities which can be effectively subsumed within industrialization processes and systems, or as special, almost aberrant features of exceptional cases such as hong kong and singapore. indeed, many of the region's leading service industries and corporations (notably banks, trading companies, and ocean freight lines) were established to facilitate manufacturing growth and the expansion of trade in goods, thus comprising essential features of the asia-pacific's industrialization experience. moreover, service industries, including modern, advanced services, are now sufficiently well-represented in a broad sampling of national and regional jurisdictions, and are now so increasingly central to the economic and social transformation of pacific cities, that a more incisive investigation of services growth trends and associated impacts is clearly merited (o'connor, ) . the centrepieces of urban service sectors within the asia-pacific are of course the large national and multinational service industry corporations, including the major banks and financial institutions (including brokerages and securities companies), trading houses, property firms, integrated construction and development corporations, and the leading airlines and hotel groups. these are, as is well known, highly concentrated within to illustrate, rigg's generally excellent and insightful treatment of 'modernization and development' in southeast asia offers only a single index reference to 'services' (and that one brief discussion in the text pertains to informal service activities), in the interest of focussing on the very important developments in agriculture and manufacturing, although modern service industries have certainly been instrumental to the growth of singapore, are of more than marginal significance to the development of malaysia and thailand, and are important features in the economic landscapes of the primate cities of southeast asian nations, including indonesia, the philippines and vietnam. the region's first-and second-tier global cities, especially tokyo, osaka, seoul, taipei, hong kong, singapore, los angeles, san francisco, and sydney. many of these financial corporations and other large service enterprises have become extensively globalized, enhancing the status of the cities within which they are domiciled; but a significant proportion of these corporations have been seriously damaged by the events of and after, and there have already been a number of major bankruptcies, with, no doubt, more to follow. the corporate power of cities within the asia-pacific is therefore pervasive, but by no means immutable. at a smaller scale, we can identify the full range of intermediate or producer services which, as in the mature economies of the atlantic sphere, typically include corporate legal firms and accountancies, management consulting firms, public relations and personnel companies, technical service operations, as well as planning and architectural firms which cater wholly or in part to the corporate sector. at the vanguard of growth and change there are also an expanding number of firms in the computer software and knowledge industry groups that are so crucial to the progress of advanced, information-based economies. in general, however, this intermediate services subsector (comprised mainly of small-and medium-size firms) is somewhat less well-developed in asia than is the case among the leading regional and national economies of europe and north america, where the producer services are seen as essential to the efficient operation of flexible production regimes, and have constituted the most dynamic elements of these economies and labour forces over the past two decades. this disparity is reflected in the large balance of trade deficits in specialized services incurred by most pacific asian nations (daniels and o'connor, ) . we can provisionally attribute the (relatively) less developed nature of intermediate services within the asia-pacific to a number of factors and conditions, including the perhaps obvious observation that services are generally at a less mature stage than among the more advanced atlantic core economies. however, there are also important structural factors as well. these include, notably, contrasts in the regulatory conditions and legal and contractual regimes between countries, which impose different kinds and levels of requirements upon firms domiciled within these jurisdictions. within many of the western societies these regulatory and legal regimes have become exceedingly complex and demanding, giving rise to specialized intermediate service firms which provide expert advice to corporations on a subcontracting basis, as the demand arises. within the asian realm, as we have already noted, many of these specialized service inputs are generated either internally within the corporation, as is the case with some of the larger korean and japanese conglomerates; or, as is the practice in many firms in china and southeast asia, are supplied by a network of advisors defined by kinship and social relations. moreover, there has been a substantial (if spatially and temporally uneven) growth of producer services within the asia-pacific, reflecting "the wide socio-cultural heterogeneity in this region and the distance between trade centres" (ho, : ) . at the leading edge of change among a growing number of asia-pacific societies, the implications of service industry growth may at least selectively reflect the experience of the mature economies of the atlantic-centred core, within which specialized service industries ( ) represent both agents and outcomes of economic restructuring, as well as leading elements of overall urban and regional transformation; ( ) constitute (with technology and manufacturing) co-dependent elements of advanced, flexible production systems; ( ) are associated with important, and in some cases defining, new divisions of labour and social class reformation; ( ) reflect, in part, increasing income levels and consumption rates within host societies; and ( ) have become significant elements of inter-regional and international trade flows, reflecting inter alia externalization tendencies and aspects of competitive advantage for specialized services production, export, and trade. as observed among the mature industrial (or post-industrial) societies of the atlantic sphere, too, service industries within the asia-pacific tend not to be distributed evenly across national territories, but are instead concentrated within urban regions, reflecting the spatial association between consumer services and their residentiary markets, and the even more centralized patterns of highly agglomerative intermediate (or producer) services. there is also a tendency toward greater levels of specialization in services production among larger cities, although there are to be sure some notable exceptions to this. this correlation between tertiarization levels, growth rates and degrees of specialization is of course most easily observed among the region's major corporate centres, such as tokyo, hong kong, and singapore, but the familiar spatial manifestations of service industry growth (cbds, corporate complexes, commercial strips and nodes, and the like) are features of a growing roster of asia-pacific cityregions, although their specific form may be locally distinctive. the study of specialized service industries within the asia-pacific, then, as in the atlantic sphere, necessarily implies an urban emphasis. these important commonalities notwithstanding, even at the most generalized level of analysis we can readily identify some defining distinctions between current services growth rates, development patterns and interdependencies within the new core of the asia-pacific, and those observed within the atlantic-centred old core. as in other facets of urban development, it is essential to achieve an appreciation of signifying contrasts in urbanization experiences in the asia-pacific, as distinct from the patterns of urban development within the atlantic core (lin, ) . these contrasts include the following: . generally higher growth rates of service industries and employment among asia-pacific nations and city-regions over the past decade and a half, reflecting more incipient stages of tertiarization in many asian jurisdictions and, broadly, more buoyant economic conditions over the past two decades or so. by way of contrast, service growth in europe has been (as daniels notes) slow or even stagnant (daniels, ) . (it must, however, be acknowledged that the depressed condition of certain asian currencies and financial markets are diminishing growth expectations in financial and service sectors among certain business centres over the short-to medium-term, and ensuing political instability and social unrest will almost inevitably exacerbate those impacts. moreover, urban service sector growth rates will inevitably slow among advanced cities with high existing levels of services labour, including singapore, hong kong, and japanese cities). asia-pacific city-regions, which represent in many cases significant departures from the more linear patterns of service industry growth common to the old atlantic-centred core. these contrasting tertiarization trends and processes are in part a consequence of the widely varying stages of overall development among specific national and regional jurisdictions, but are also associated with important (and in some cases decisive) policy factors and local development strategies. . the diversity of services-production linkage patterns among asia-pacific economies, which to some extent may follow the services externalization and subcontracting processes widely documented among european and north american firms, but are also exemplified in other respects by the distinctive nature of industrial organization in 'lead' asian economies in which large integrated corporations (keiretsu in japan, the chaebol in south korea) maintain internalized service supply; by the intricate entrepreneurial networks based on kinship relationships in parts of east and southeast asia (hsing, ) ; and by the intimate spatial linkages between industrial production and service providers observed in exurban or countryside production regimes in certain regions of china (marton, ) . . variation in the reconfiguration of metropolitan space-economies to accommodate the introduction of new, specialized service industry nodes and clusters, which follow to some extent the locational tendencies of services in advanced economies and city-regions; while at the same time exhibiting persistent spatial patterns derived from more traditional systems of urban and regional economic development, as exemplified in the desakota areas of southeast asia and japan, and, at a smaller scale, the intimate juxtaposition of advanced and informal service activities in central areas of developing societies (leaf, ) . in the most advanced cases, new spatial patterns of specialized services production include clusters of design, creative services, and advanced-technology service industries within reconstructed inner city precincts. . distinctive divisions of labour within urban service industries, which may appear to mimic the western model at the apex of the occupational hierarchy (i.e., the growth of managers, professionals, knowledge-based and advanced-technology workers), but also display substantial variation, derived in large part from localized culture, class structures and traditions, the pre-existing base of service workers, and region-based entrepreneurial or mercantile cultures. to these broad points of contrast in the tertiarization experiences of the asia-pacific and atlantic spheres, it is essential to highlight important differences in policy approaches and roles. within the asia-pacific, we observe a spectrum of (sometimes quite assertive and even grandiose) developmental policies and programmes designed wholly or in part to promote the growth of specialized service industries. these include the highly dirigiste approaches of japan (shapira et al., ) and singapore (ho, ) , within which central governments have assigned leading roles to advanced service industries in support of urban and national economic transformation, and enhanced roles for service industries in local economic development strategies and policies. in contrast, public policy approaches toward services among western societies have tended to emphasize regulation, including zoning, development control, and growth management, in addition to mostly episodic experiments with developmental policies, and only very exceptional attempts to undertake service industry 'megaprojects' on the heroic scale of numerous asian cities. although there are profound differences in stages and levels of tertiarization among asia-pacific city-regions, as we shall shortly see, the implications of urban service industry growth can be structured within five broad categories: ( ) a set of essentially propulsive and transformational impacts, within which services (especially advanced intermediate and knowledge-based service industries and institutions) are assigned leading roles in urban, regional and even national development; ( ) the (direct and indirect) impact of services on the internal restructuring and reconfiguration of the city-region, including regional structure, the metropolitan space-economy, and built form; ( ) services and the reformation of urban class and the city's social morphology (or ecology); ( ) implications of rapid tertiarization for the experiences of everyday life; and ( ) the role of services in the transformation of the city's image and identity. it must be emphasized that these are by no means neatly compartmentalized, discrete categories of consequence, however, as there are innumerable interactions and interdependencies between and among them. first, rapid tertiarization may have the potential to significantly accelerate the processes of urban growth and change, and to quite fundamentally modify basic urban economic functions or vocations, as reflected in the recomposition of the metropolitan industrial structure, economic base, and regional gdp. at one level, this process evokes the idea of post-industrialism, which positions service industries and occupations as ascendant features of the urban economy in a context of (relative or even absolute) contractions in basic manufacturing. however, in the asia-pacific setting the growth of specialized services can be seen as a concomitant element of advanced production systems, national modernization programmes, and globalization strategies of central and regional governments. these strategic aspirations are by no means fully realized, but they do underscore the importance of advanced services to the future development of the region. as is well known, tertiarization within many asia-pacific city-regions is impelled both by market and policy factors. this latter tendency is particularly marked in the region, as we can instance numerous examples of assertive public policy efforts both at central and local government and administrative levels designed to accelerate tertiarization (and/or deploy tertiarization as an instrument of broader economic and socio-economic transformation). examples of the deployment of policies for services in the interests of supporting or promoting transformational change include (a) synergies between national economic liberalization policies and local development strategies which have accelerated tertiarization processes (including advanced services) among designated chinese cityregions, (b) intersections between national industrial policies and urban economic programmes which have supported specialized service functions among japanese metropolitan cities, (c) ensembles of national development programmes and regulatory adjustments designed to enhance the growth of advanced, export-oriented services, as in the case of singapore since the mid- s, (d) central government support for strategic service industries as instruments of national development, accompanied by complementary local land use initiatives, as in the case of finance, producer services and information technology in malaysia, and (e) the more episodic (or less committed) support for service industries within (often somewhat schizophrenic) clusters of local development and growth management plans in sydney, melbourne, seattle, san francisco, vancouver, among other cities. the second category of urban tertiarization impacts concerns the role of services in change within the internal form and structure of the metropolis or city-region, and reflects the profound and comprehensive impacts of service industry development on the spaceeconomy of the contemporary city. the internal reordering of metropolitan space associated with rapid service industry growth incorporates processes which are multifaceted and interdependent: demand for services generates growth among service industries and firms to create a new sectoral mix within the city's economic base, and new patterns of services production and consumption as observed in the emergence of high-rise office complexes, secondary business centres, specialized service clusters (for example tertiary education and medical complexes), and new retail landscapes. these developments have visibly reconstructed urban structure and form in many american cities, but in some european cities have been situated more carefully within older districts, creating a more subtle and complex urban form, while in asia (for example in shanghai and osaka), preservation has been subordinated to the imperatives of accelerated restructuring, and has been in policy terms an afterthought at best. while market forces have constituted agents of urban respatialization, public authorities have deployed services as instruments of internal metropolitan reconfiguration within the asia-pacific, as in (a) the construction of new financial and corporate this urban 'policy schizophrenia' is associated, typically, with institutional conventions and operational practice within city and metropolitan governments. in most cases the urban 'plan' is prepared by staff planners, with input from other professionals and the broader community, and often emphasizes regulation, in terms of statutory development control functions and instruments (such as zoning, developing by-laws, and land use policies) and modern growth management modalities. by way of contrast, local economic development strategies are formulated by separate economic advisory groups, business interests, community groups and ngos, or special council committees or bodies appointed by (and accountable specifically to) the mayor or council chair, and are therefore often informed by quite different (and even oppositional) values and visions. a principal motivation behind the development of the la défence corporate complex was to protect the historic built environment of central paris from the kind of massive demolition and displacement impelled by office development in many other cities, by initiating a new 'cbd' outside the metropolitan core. this has been to a large extent realized (apart from exceptions such as the maine-montparnasse office-tower on the rive gauche), but the preservation of buildings and streetscapes in the central core of paris has been a series of struggles over the past century and a half (sutcliffe, ) . complexes, both to accelerate economic restructuring at the local level, and to support national modernization goals (as exemplified by the massive pudong project across the huangpu river from the established central district of shanghai) (yeh, ) , (b) the development of modern commercial and telecommunications infrastructure to support future world city aspirations (as seen in kuala lumpur), (c) the promotion of specialized financial and producer services in established cbds and designated subcentres to support world city status, and to maximize regional competitive advantage (with singapore presenting a vivid example), (d) the reclamation of land resources for accommodating the expansion of spatially or topographically constrained cbds (hong kong), and (e) the development of commercial and business megaprojects to diversify local economies, advance international business and financial relationships, and compete more effectively against other (often larger) centres within regional settings (as is the case with the minato mirai project in yokohama) (hutton, ) . more generically, public authorities also respond to infrastructure demand (for example airports and transit systems) derived from growth in services industries and activities (daniels, ) . the growth of service industries and occupations within asia-pacific city-regions also has important social implications, representing a third major set of urban tertiarization impacts. here, the growth of (especially advanced) service industries and related occupational cohorts generates an increasingly tertiarized labour force, which daniel bell described as a pre-condition for the emergence of a post-industrial society, over a quarter century ago (bell, ) : a contested idea, to be sure (gershuny, ) , but a seminal and prescient contribution in many ways. within the highly tertiarized city, the growth of specialized services leads to significant socio-spatial effects, including the familiar pattern of social upgrading within inner city neighbourhoods, and the formation of new suburban communities comprised largely of service workers, but also the recent emergence of a 'new middle class' of higher-echelon service labour (ley, ) . the rise of this new middle class of elite service workers (professionals, executives and managers, entrepreneurs and creative services occupations) as a presence in the inner city, a larger process than earlier, more incremental experiences of gentrification, comprises individuals who view the metropolitan core as a place to work, live, and recreate, leading to the transformation of the central city with respect to structure, land use, form, and lifestyles. there are also broader cultural connotations associated with the new middle class, as seen in shifts in tastes, values, behaviours, and even political affiliation. this new middle class enjoys a hegemonic status within the most highly tertiarized cities in the region, such as vancouver, seattle, san francisco, and sydney, and comprises the ascendant social cohort within singapore, tokyo, and hong kong, but is also observed as a growing presence (with some local variation in specific features) within the central districts of seoul, shanghai, guangzhou, and kuala lumpur, among other cities. the fourth set of impacts of service industry growth within cities of the asia-pacific concerns changes at the micro-level, what braudel termed the 'structures of everyday life' (braudel, ) . although much of the scholarly analysis of tertiarization has emphasized change within the three strategic categories described earlier, a more nuanced appreciation of the more intensely localized implications of growth in services is essential to attaining an appropriately rounded profile of the process. these include, for the purposes of illustration, the impact of service industries and the growth of service occupations on the quality of working life, and on localized displacement and dislocation at the neighbourhood and household levels (chua, (chua, , , especially within a context of industrial decline or restructuring. there is considerable potential for research on the important gender aspects of tertiarization, which may include the tendency for over-representation of females within many service occupations and industries. within the highly tertiarized societies of the old atlantic core, the past several decades have seen both the impressive progress of women within some of the credentialized service occupations, for example in law, accountancy, and planning, but also a more discouraging tendency for women to congregate in more menial, poorly paid and distinctly marginalized positions. there are also important linkages between the growth of service industries in asia-pacific cities and international migration. australian scholars have suggested that immigration can enhance the 'productive diversity' of economies, and more specifically that skilled immigrant professionals can support urban services exports, for example in sharing or transferring within the firm knowledge about overseas markets (aislabee et al., ) . lin observes that characteristics of mobility, flexibility and entrepreneurial skills are defining attributes of hong kong migrants (lin, : ) , enhancing their attractiveness to receiving urban societies and business communities. in certain cities, recent immigrants are over-represented both within entrepreneurial and management occupations, but also among more menial service occupations; this is especially the case in large global cities (sassen, ) . again, as in other facets of tertiarization, we can discern within asian labour markets some powerful resonances of trends initially observed in mature cities of the atlantic core, but there are also quite distinctive, persistent traditional socio-cultural contexts to consider. the importance of maintaining a perspective on the more localized implications of tertiarization also acknowledges the reality that the expansion of service industries by no means involves just the formal business, professional and managerial activities that have led growth among the western urban economies, but also the full range of neighbourhood shops and markets, casual restaurants and bars, and personal and retail services (to say nothing of other service establishments that may operate on, or even over, the margins of legality and social acceptance). in many asian cities, these smaller scale service operations may be viewed as an extension of the traditional population of informal service workers (itself a contested term), service activities which occupy the urban interstices between the more formal corporate business and retail structures. these can be seen as persistent features of the central city, not only among the megacities of southeast asia, such as bangkok and jakarta, but also within the downtown spaces of modern world cities such as tokyo. they are not simply residual activities, but essential, if often undervalued, operations that support the more formal service economy in different ways within the metropolitan core, including the provision of food and beverages (yasmeen, ) . these small-scale, low-return service firms survive by virtue of entrepreneurship, reliability, thrift, and knowledge of where the commercial niches exist in the modern city, and they contribute to the vitality and identity of the urban place. a final aspect of urban transformation associated with tertiarization is derived from an accumulation of the changes described earlier-economic, social, cultural, physical, and spatial-and is commonly articulated as a metamorphosis of the city's character, as perceived by citizens (constructed as 'identity') or as reconstructed by government and corporate entities and external agencies ('image'). the perceived image of a city can be substantially altered by comprehensive processes of tertiarization, as seen in the repositioning of singapore and hong kong as post-industrial, specialized service centres, although usage of decidedly obsolete nomenclature such as 'newly industrializing economies' is surprisingly persistent, as are outdated tropes like 'little dragons' or 'little tigers' (cartier, ) . in some cases national governments have supported specialized service industry projects as quite deliberate instruments of urban re-imaging, as seen in the creation of international banking and producer services in the pudong development in shanghai, and in the construction of the petronas towers in the central area of kuala lumpur. these initiatives are designed in part to underscore a commitment to modernity, and by extension to symbolize national economic progress and aspirations to global status and engagement, but also to supplant traditional (or, more pejoratively, 'backward') industries and related social groups. these more grandiose visions can be contested, especially where the elite beneficiaries of advanced service industry growth (for example professionals and managers in financial and business services, as well as cronies of rulers and oligarchs) represent a particularly visible and privileged expression of dichotomous 'development' as set against the condition of the urban masses in places like jakarta and manila. the issue of urban identity may also be deeply problematic, as the rapid growth of services elites within asian-pacific cities can presage decisive shifts in power relations (political as well as economic) within the urban community. in some cases the ascendancy of upper-tier service workers represents a new socio-economic and socio-political hegemony, implying a coincident subordination of traditional industrialsector cohorts, as well as an exacerbation of income disparities. as in other aspects of urban tertiarization within the asia-pacific, contrasts in scale and stages of development are significant, as are tendencies toward exceptionalism when case studies are subjected to closer analysis. thus, baum concluded that the sustained growth of specialized service industries, advanced-technology activities and related occupations in singapore, coupled with comprehensive public housing programmes and education investments, has resulted in a predominantly professionalized (as opposed to polarized) occupational and social structure within the city-state (baum, ) . in hong kong, where specialized services have also driven urban growth and socio-economic change (kwok, ) , the post-colonial record since includes growing poverty (about residents earn less than $ per month), attributable in some part to the inadequacies of the secondary school system, a situation which one legislator fears may lead to 'serious social instability' (lee cheuk-yan, quoted in far eastern economic review: october ). at a larger scale, a combination of market liberalization and selective tertiarization in certain chinese cities, with attendant political and bureaucratic corruption, has generated income polarization rates approaching or even exceeding the american level. this striving for new urban identities in the chinese case, with its repressed tensions and conflicts, can be seen in the shanghai government's preference for 'high class' individuals (well-educated, with the right attitudes, outlooks and professional profiles) for the glittering new towers of the pudong project (halliday, ) , a far cry indeed from the earlier communist exaltation of the urban industrial worker and fraternal colleagues in the pla and in rural peasant communes. we can also discern highly localized intersections of globalization and tertiarization in the reconstruction of identity at the district level. the proliferation of transnational retail and food services within commercial complexes is of course a ubiquitous phenomenon, as observed in places like shinkjuku and shibuya stations (and commercial subcentres) in tokyo. in hong kong, the incursion of service industry commuters in the new territories has transformed the social identity of certain of the post-war industrial communities, as seen in the transformation of tsuen wan from 'hakka enclave' to 'post-industrial city' (johnson, n.d.) . in the case of singapore, the last decade has seen the demise of the kampung kopi-tiam (informal eating places, serving authentic local fare) as a result of relentless modernization (chua, ) , and the almost total disappearance of traditional rural life, while other local retail and shopping districts have been subject to the reformation of identity associated with the tastes and behavioural preferences of affluent expatriate populations. chang deploys the term 'expatriatization' to describe a "spatial transformation in which land use increasingly reflects an expatriate bias", as typified in holland village, a local commercial centre within an affluent residential district of singapore, but one which "reflects the influence and influx of global cultures" (chang, : ) . in the most highly tertiarized cities within the asia-pacific, exemplified by san francisco, seattle, vancouver, sydney and singapore, a distinctive urban profile associated with dominant service industries and occupations within the financial and producer services now incorporates a more recent overlay of technology specialists, notably internet providers, software developers, and the so-called 'dot.com' firms. many of these firms have been concentrated within "new service production landscapes" within or proximate to the central area, exemplified by 'silicon alley' and telok ayer in singapore, yaletown in vancouver, belltown in seattle, and the northeast mission and south park districts of san francisco (hutton, ) . these technology-based service firms (which also include graphic designers, who exemplify the production synergies of technology and culture in applied design) typically exhibit employment structures dominated by young entrepreneurs and 'techies', with distinctive skills and lifestyles, underscoring both the new social divisions of labour in the urban service sector, and the highly volatile nature of urban identity in the post-modern, globalized metropolitan order. over the last years, the number of these technology-intensive firms within inner city production districts has contracted significantly, as part of the crash of the dot.coms. however, new survey research has disclosed the emergence of 'hybridized' firms combining creativity and technology toward the production of high-value goods and services, signifying a new phase of development within the metropolitan core of advanced societies (hutton, ) . these trends therefore demonstrate both the volatile nature of recent phases of service industry development, as evidenced by the accelerated processes of transition and succession, as well as the distinctive role of the inner city as site of innovation. stages of urban service industry development within the asia-pacific the preceding narrative described important distinctions in the broader tertiarization experiences as observed within the old atlantic core and the new core of the pacific realm. at the same time, there are also quite profound differences in stages or levels of service industry development among (and within) asia-pacific nations, just as there are important contrasts in levels and rates of industrialization. the construction of typologies of urban tertiarization among asia-pacific city-regions is hampered by data constraints and conceptual problems, and more recently by the shortterm impacts of the crisis of currencies and financial markets of and afterwards. although this crisis was seen to depress prospects for the asia-pacific generally, the impacts have been spatially quite uneven, and as the fiscal-economic malaise spread within the regions of the asia-pacific, and within social and political domains, it is by no means beyond the realm of possibility that the medium-to long-term outlook for certain urban centres has been seriously compromised. thus, to the overall perception of dynamism among the urban service sectors and industries of the pacific region, we must add considerable uncertainty. there is also a clear need at the outset to acknowledge the increasing complexity of overall urban development patterns, within which (we are arguing in this paper) service industries are increasingly playing larger roles. to illustrate, terry mcgee, in a retrospective paper on his concept of 'the southeast asian city' published in following years of extensive fieldwork, observed that "while urbanization levels will continue to rise there will be much differentiation between countries which will make the construction of any one model of the southeast asian city impossible" (mcgee, : ) . in this interpretation, models (or typologies) cannot reasonably function as templates of "supposedly universalizing tendencies" (mcgee, : ) , but rather should reflect the importance of specificity and exceptionalism in urban development experiences. it may at least, however, be possible to structure a basic and highly simplified typology of tertiarization stages among representative classes of asia-pacific city-regions, as a means of gaining insights into the range of urban tertiarization trajectories, the nature of specialization in services among city-regions, and the association between service development and urban hierarchy in the region. here, a typology of urban service centres within the region, while inevitably masking considerable nuance, may at least serve to depict some basic features of functional differentiation. while tertiarization stages and levels vary widely among asia-pacific city-regions, service industries are certainly performing significant roles in urban growth and development across a range of city types and urban scales. there is by no means a strict correlation between urban rank-order and level of service industry specialization within the asia-pacific region. to illustrate, there are medium-size cities with considerable global reach in terms of corporate power and important specializations in strategic service industries, such as finance and information technology (notably singapore and seattle), while a number of mega-urban regions (for example jakarta and manila; see mcgee and robinson ( ) ) contain limited advanced services capacity relative to their overall urban scale. therefore, a typology of cities engaged in specialized services production and trade should incorporate 'suites' of services specialization and developmental progression, as well as attributes of scale and hierarchy. accordingly, table positions asia-pacific cities and settlements within seven principal categories of specialized tertiary activities, distributed spatially within urban clusters, corridors, or 'outposts' within the western and eastern littorals of the pacific basin (depicted cartographically in fig. ) . at the peak of the pacific urban hierarchy we find tokyo and los angeles, the dominant corporate control centres within this extensive economic and trading zone. these massive city-regions contain to be sure huge concentrations of manufacturing, and, indeed, exhibit greater industrial strength than many of the first order global cities of the atlantic realm, such as london, paris, and new york. both tokyo and los angeles have important, global scale advanced-technology industrial sectors, situated within their metropolitan and immediately proximate territories, including orange county (in the case of los angeles) (scott, ) , and the new production spaces of the tokyo metropolitan region (tmr) (fujita and hill, ) . however, while both tokyo and los angeles retain an impressive base of modern manufacturing capacity, their most insistent claim to global city status rests on their downtown complexes of international banking and finance, and headquarters of mncs, supported by highly specialized producer services and superior international communications systems and transportation networks. los angeles and tokyo are also global centres of cultural production and dissemination, media concentration, and applied design and creative industries. they contain major universities of high international standing, including ucla and usc (los angeles), and tokyo university and waseda within the japanese capital. of these two pacific regional first-tier global cities, tokyo has conventionally been ranked as the leading centre, in view of its base of multinational head offices, and more particularly, its concentration of major banks, securities firms and trading companies, but this status may need to be reconsidered in light of the fall-out from the crisis (and, indeed, the failure to effectively address structural and institutional problems in the national banking and financial sector over the last decade). tokyo has considerable underlying industrial and overall economic power, but there is certainly the prospect of serious erosion in its financial sector over the mediumterm at least, which may jeopardize its position within the triumvirate of highest-order world centres (which also includes london and new york). fig. . asia-pacific urban service centres: hierarchy and specialization. doel and beaverstock ( ) observe that despite the claims and assumptions of fully globalized capital markets, the asian financial crisis has had relatively little negative impact on london and new york banks and financial corporations. indeed, many of the european and north american investment banks, for example, have (at least quietly) rejoiced in the misfortunes of the japanese banks in particular, as the asian financial crisis has (at least for the moment) 'seen off' their japanese competitors. category within our provisional typology includes six second-tier global cities: hong kong, singapore, seoul, osaka, san francisco, and sydney. despite significant contrasts in urban scale (to illustrate, there is seoul with a population of over million; and singapore at million), each represents a major asia-pacific financial, corporate and business centre. they are all characterized by ( ) very large cbd corporate complexes of head offices, multinationals, international banking and financial activity and producer services; ( ) strategic gateway functions and major international airports; ( ) major universities and knowledge-based institutions; ( ) large concentrations of executives, professionals, managers, entrepreneurs and other higher-order service occupations within the metropolitan labour force, and ( ) a powerful international corporate 'reach', competing in some sectors or areas with other second-(and even some first-) tier global cities. in each of these six asia-pacific financial and business centres, we also observe new precincts of specialized services within the inner city, including design and creative services, multimedia and post-production firms, internet providers and dot.com firms, reflecting the 'advanced tertiarization' stage of urban spatial development depicted in table this typology serves to highlight very broad variations in tertiarization levels among selected city-regions within apec, but even a cursory examination of individual cases discloses considerable variation in the trajectory of restructuring and service industry development within each category. for example, both singapore and hong kong specialize in advanced service industries, including finance and banking, producer and other high order services, tourism and convention activities, and higher education. each is now a major exporter of services; hong kong is ranked as the th leading exporter of services globally (hang seng bank, ) . manufacturing has declined from . % of hong kong's employment in , to only . % in , a level comparable to that of the most highly tertiarized atlantic core societies (asian development bank, ) . upper-tier service industry professionals, managers and entrepreneurs constitute the dominant social class in hong kong (kwok, ) . however, hong kong's emergence as a centre of specialized service production and trade has been impelled principally by an exceedingly liberal regulatory regime, while singapore's restructuring trajectory has been enhanced by a more direct application of policy measures. following a brief but sharp recession in , the singapore government resolved to transform the city-state from a branch-plant industrial enclave to a regional (and world) centre of tertiary production and trade, with the aim of becoming the 'switzerland of asia' by . this overarching economic development and transformation goal has been to a large extent realized, and singapore now represents a policy experience that other nations (notably china) are endeavouring to emulate. although hong kong's classically laissez-faire approach contrasts sharply with singapore's explicitly dirigiste development strategy, selective public policy initiatives have facilitated hong kong's economic restructuring. as observed by taylor and kwok ( ) , hong kong experienced an accelerated transformation process over three decades, from an 'industrial metropolis' (export manufacturing phase) in the s, to a 'postindustrial' status (information service phase) over the s, and emerging as an 'international metropolis' by the s. a sequence of policy and (especially) physical planning measures were deployed to promote economic transition and transformation, including the industrial new town programme of the s, the expansion of the hong kong cbd eastward toward wanchai and causeway bay in the s, and the recent investments in transportation infrastructure, as in the linking of hong kong with guangzhou by expressway, and the construction of the international airport at chek lap kok. there have also been substantial new public investments in tertiary education, training and housing, underscoring a substantial government commitment to upgrading the quality of hong kong's human resources and social capital. these investments and land use policy initiatives suggest that contrasts between singapore's and hong kong's approaches to economic transformation which insist on sharply dichotomous contrasts may be somewhat overstated, although the extent (and sustained commitment) of direct policy intervention in the singapore case is in many respects singular. our third category includes second-and third-tier global cities, which feature large and generally fast-growing service sectors, established on a base of world-scale manufacturing and industrial production capacity in each case. we can identify two sub-categories (table ) within this aggregation: first, three 'advanced' business and industrial centres (nagoya, kobe and taipei) situated within leading east asian economies; and secondly, a set of 'transitional' urban centres which still possess some features of early phase industrialization and a relatively large informal sector, including 'floating' or transient labour contingents (beijing, shanghai, guangzhou, bangkok, and kuala lumpur). however, each of these large cities exhibits relatively high growth in producer services, including engineering and business services. other defining attributes of these centres are ( ) important international gateway roles, ( ) major public and private sector investments in higher-order services infrastructure, and ( ) ambitious local/metropolitan strategies for new, specialized service industry roles and 'vocations', supported in most cases by national government policies and projects. the japanese experience of tertiarization provides particularly instructive case studies, in light of the priority accorded industrial development up to the s, the lead role of the central government and its constituent ministries over the last decade in assigning new development roles incorporating specialized service and technology-based industries for the major cities, and the outcomes of these initiatives among different japanese cities (edgington, ) . in general, the central government has been concerned both with the need to maintain a leading edge position in industrial production within the asia-pacific, while preparing the large cities for more advanced roles in specialized services industries, both for the domestic economy, and for trade purposes. much of the research on economic restructuring in japan has emphasized 'hard services,' notably technology, and its role in transforming both industrial production modes and urban economic structures (glasmeier, ) , while another major body of scholarship deals with the transformation of tokyo, while hong kong has initiated over the past years numerous specific projects and programmes to support the expansion of service industries, singapore has enunciated policies and programmes to promote strategic services (e.g. banking and finance, producer services, and it) within more formal policy statements and structures, consistent with the city-state's distinctive policy culture and administrative styles. the recent expansion of design and technology-based services in heritage districts outside the cbd represented one of the few 'spontaneous' (or unplanned) economic phenomena in the city-state's recent history (interview with urban redevelopment authority official, july ), although there is now policy support for cultural industries administered by the tourism development board. japan's first-order 'world city' (masai, ) . important themes concerned with tokyo's transformation include tensions and conflicts between the capital's international roles and local functions (fujita, ) , and the problems of accommodating (or, prospectively, relocating) central government functions from tokyo's metropolitan core (isomura, ) . however, there has also been some important work focusing on the restructuring (and, more specifically, tertiarization) of other principal japanese city-regions. these experiences include the economic restructuring of tokyo (machimura, ) , the expansion of advanced services such as finance, information services, and education in the major industrial city of nagoya over the last two decades (hayashi, ) , and the new emphasis on advanced knowledge-based service industries for the transition of yokohama from gateway port (and 'shadow city' for tokyo), to a more independent role as international business centre (edgington, ) . the experience of metropolitan transformation among the largest chinese city-regions over the past several decades represents a striking example of the influence of policy priorities within a command economy, and the potential for accelerated tertiarization following an adjustment of central government policy direction. following the industrialization policies and programmes of the period over the s, s, and s (including the ruinous 'great leap forward'), chinese cities "were endowed with a massive and diffuse manufacturing capacity, and provided with few incentives (until the last decade) to develop the services sector" (hamer, : ) . the economic policy reforms of (and more specifically) the mid- s embodied a recognition that modernization would require the more efficient deployment of cities and their resources, and thus heavy manufacturing was increasingly decentralized to outlying areas, and services (especially financial and producer services) were encouraged, both by economic planners in beijing, and by local authorities. in order to achieve growth in advanced production and transition to a more knowledge-based economy, hamer estimates that "up to % of the local labour force will have to be employed in the producer services sector" (hamer, : ) , a proportion that seems high even by the standard of more advanced oecd cities, but is perhaps nonetheless indicative of municipal aspirations. lin also underscores the crucial role of cities in the modernization of the chinese economy as represented by their concentrations of advanced service industries and occupations which enable higher levels of creativity, efficiency, and internationalization (lin, : - ) . recent trends in beijing, shanghai, and guangzhou serve both to generally underline the growing importance of service industries within the development trajectories of major chinese cities, while at the same time demonstrating the exceptionalism of specific cases. in beijing, an acknowledgement of the inappropriateness of the soviet-style heavy industrialization of the ancient capital, with its attendant environmental and displacement impacts, sets the stage for a new development strategy reasserting political, administrative and cultural roles. the goal of the - master plan (approved october ) is to develop the "historic city into a modern, economically prosperous and socially secure international metropolis of first class world standard in services, infrastructure and environmental quality" (mao and jin, : ) , representing an abrupt departure from the industrial city model of the s and s. as the contemporary beijing master plan invokes the re-establishment of the capital's traditional administrative and cultural roles, shanghai's current transformation recalls financial and trading functions de-emphasized following the ascendancy of the communists to power. immediately prior to the ascension of the chinese communist party in , shanghai's financial sector included foreign banks, private and government banks, trust companies, and currency exchangers: "with such a large number of financial institutions, representing a high degree of concentration of capital, shanghai was in a position to control the economy of the entire nation" (fung et al., : ) . a succession of five-year plans emphasized the primacy of manufacturing for shanghai's industrial transformation, with a particular emphasis on heavy industry and the production of capital goods. by the completion of the first five-year plan (in ), shanghai had experienced a transition from an outward-looking financial centre to the leading industrial centre of an almost autarkic chinese state. the economic policy reforms of the late s and mid- s presaged the onset of yet another fundamental change in economic priorities for shanghai, and, more specifically, for the reconstitution of shanghai's financial, trading and business service functions. to a considerable extent, this massive effort in economic restructuring is intended to offer china a strategic access to the global economy (yeh, ) , but (at least at a subtextual level) the question of achieving a competitive position vis-à-vis hong kong in financial and trade services must be acknowledged. in this respect, shanghai has certainly attracted an impressive quantity of investment in banking and commercial (and supporting public) infrastructure, as well as a growing number of mncs and mnes, but has not yet achieved the high concentrations of domestic and expatiate professional expertise in specialized services that is a defining hallmark of highest-order global cities. (indeed, as kris olds has observed, shanghai's globalization strategy has been highly dependent on the engagement of the 'global intelligence corps' of elite professionals; olds, ) . here, hong kong is likely to hold a competitive advantage over other chinese cities over the short to mediumterm by virtue of the territorialization (storper, ) of this expertise and specialized human capital. the two fundamental shifts in shanghai's development trajectory over the past several decades can be interpreted empirically. in , the 'tertiary sector' (i.e. commerce, finance, communications, science and technology, education and culture) constituted . % of shanghai's regional gdp. following years of investment in manufacturing capacity and employment, this proportion was reduced to only . % by . the intensive promotion of advanced service industries during the s resulted in an increase in the tertiary sector's share of gdp to % by , while shanghai's economic development strategy called for an increase in this proportion to about % by (fung et al., ) , led by the advanced services complex in the pudong redevelopment mega-project. (shanghai's service sector grew by % in , and by % in ; chreod ltd, ) overall, shanghai's experience of accelerated industrialization and subsequent re-tertiarization must represent one of the most dramatic episodes of economic restructuring among large metropolitan cities in the post-war period. guangzhou is, of course, smaller than beijing or shanghai, but it performs strategic gateway roles for guangdong province and southern china as a whole, and has undergone significant processes of restructuring and tertiarization (xu and yan, ) . as in other large chinese cities, economic policy priorities following entailed the transformation of guangzhou from a 'consumer city' to a 'producer city'. this strategy of large-scale industrialization was perhaps less fully realized than in the case of shanghai, because of the persistence of entrepreneurial traditions in the province, and guangzhou's distance from the national capital, which enabled at least a degree of autonomy. building on its well-established gateway and entrepôt functions, guangzhou was strategically positioned to immediately benefit from the opening up of chinese coastal cities. in the period - , growth in services exceeded that for agriculture or manufacturing, with lead tertiary sector industry groups including finance and corporate support services (nanjiang, ) . guangzhou is the urban centre for the pearl river delta economic region, which represents (with the lower yangtze region and southern fujian) major growth regions and access points for china to the broader asia-pacific and global markets (johnson, ) . the issue of whether guangzhou can extend its regional role more fully into the national realm remains an open question (tsang, ) , as are the 'terms of co-existence' with hong kong following the latter's post-colonial status as a special administrative region of the prc as of july . there is to be sure potential for complementarity as well as competition as characteristics of the relationship between guangzhou and hong kong within the pearl delta extended urban cluster, a theme to be addressed in more detail below, but over time guangzhou will aspire to greater shares of the region's international financial and business activity. the fourth aggregation of city-regions depicted in table comprises metropolitan areas characterized by the advanced tertiarization of the urban economy and labour force. this fourth category of asia-pacific cities includes two sub-groups: first, advanced, highly tertiarized cities with substantial manufacturing capacity and associated labour cohorts, and propulsive corporations, notably seattle, melbourne, and yokohama; and a larger contingent of specialized services cities with relatively modest industrial production sectors, including vancouver, portland, fukuoka, and brisbane. in many respect these jurisdictions embody features of service industry development observed within the mature urban and regional economies of the old atlantic core, which typically include (a) a dominant status for services within the metropolitan industrial mix, export base, and occupational structure; (b) the formation of corporate complexes within the cbd; (c) the emergence of new, creative services (culture, applied design, multimedia) on the cbd fringe and inner city; (d) the influence of suburban business centres and 'edge cities' in regional multinucleation; (e) intersections between services growth and changes in urban housing markets; and (f) the increasing role of services in the reformation of urban identity, politics, and lifestyles (ley and hutton, ) . at the same time, many of the city-regions within pacific america and australasia also exhibit tendencies common to other asia-pacific metropolitan areas, such as (relative) economic dynamism and higher growth rates in services, and are also linked to asia-pacific cities, markets and societies by increasingly diverse networks of trade, investment, immigration and travel. as a crucial intersection of two principal processes of urban development, large-scale immigration, especially from asian societies, has in important respects augmented urban tertiarization processes, reinforcing entrepreneurial, professional and management occupations, and contributing to export services trade by enhancing the connectivity between trading centres. we can therefore position these cities as geographically peripheral, but functionally integral, nodes of the asia-pacific urban system and as important examples of a distinctive stage of urban tertiarization within the pacific realm. the fifth category within our provisional typology of asia-pacific cities engaged in services production includes several southeast asian 'mega-urban' regions, jakarta, manila, and (more tentatively) ho chi minh city. the emergence of relatively small service sector occupational elites within mega-urban city-regions such as jakarta, and manila must be set against a vastly larger informal sector of hawkers, vendors, and peddlers, which mcgee described as the urban 'proto-proleteriat' (mcgee, ) . even in second-tier cities, such as bandung, economic restructuring incorporating both industrial development and tertiarization has promoted a deeply polarized social structure (pribadi and sofha, ) . the imposition of advanced, high order services within the central and inner-city areas of southeast asian mega-cities has produced a distinctive juxtaposition of socio-economic classes, typified in part by the persistence of shanty towns, squatter settlements and informal sector activities proximate to high-rise office towers, high-end shops and boutiques, and other accoutrements of the later th-century corporate complex (leaf, ) . as leaf observes, the explanation for this notionally incongruous pattern of traditional social morphology and modern capitalist development features "lies in the segmentation of urban land markets…which is now most commonly expressed in terms of formal and informal sectors…derived from early patterns of land use not governed by market principles" (leaf, : ) . in the case of jakarta, in which about three quarters of the population live in informal settlements (kampung), social class differentiation is expressed "not so much by zone or neighbourhood, such as what one would expect in the capitalist city, but at a more minute scale, between streetside and inner block locations within the same neighbourhood" (leaf, : ) underscoring the complex (and often deeply problematic) impact of economic restructuring on urban social structure within developing societies. the continuing economic crisis within southeast asian economies has no doubt impacted the poor disproportionately, but has also damaged the small service elite of professionals, financial and business services workers within the region's primate cities. in addition to the direct effects of this crisis on the employment and incomes of the service elite themselves, it seems likely that wider ramifications may include the diminution of the advanced services production capacity of these developing economies, as well as an erosion of the (already small) middle and upper-middle classes within their respective societies. ho chi minh city (formerly saigon) also exhibits a highly dualistic socio-economic structure, but differs from manila and jakarta in some important respects. more particularly, the introduction of the 'doi moi' (renovation) economic policy has forcefully inserted a before the 'crash' of there was a generally growing constituency favouring economic, social, cultural and even political association among the nations of the pacific basin, derived in part from a shared vision of mutual economic interests and visions of progress, as well as a preference among some observers to view the 'modernist project' in pacific asia through the western critical tradition (preston, ) . in the short term at least the fiscal and economic crisis of the past years in asia has diminished the enthusiasm of some in the americas and australasia to be associated with the wider concept of the 'asia-pacific'. there are also signs of a more 'inward' (i.e. intra-asian, as opposed to transpacific) sensibility on the part of (for example) japanese corporations and the chinese, japanese and malaysian governments, although the motivations for these attitudinal changes vary. former japanese vice-minister of finance eisuke sakakibara, for example, suggests that the membership of the us within apec precludes the latter from being a 'true regional organization,' while vice-minister ito observes that "[t]he task for asian countries is to ensure that regionalism in asian really complement global trading and financial systems, like other regional arrangements in north america and europe" (quoted in t. armstrong, 'asia is going it alone', the globe and mail, monday february : all). market presence within an established socialist political and social order, with polarizing outcomes for ho chi minh city's labour force and society. advanced services are emerging as defining elements of the new ho chi minh city as depicted in an approved mural extolling " years saigon and ho chi minh city: industrialization and modernization", the modernist imagery underscored by a dominant motif of point towers (drummond, ) . in this regard ho chi minh city is something of a 'frontier city', characterized by significant autonomy from hanoi, a situation somewhat analogous to that of guangzhou in southern china, which operates as a bastion of market enterprise in contrast to the more formal cultural and political style of beijing. at the same time, hanoi too is endeavouring to expand its engagement with the global economy in its development strategy, while maintaining a measure of local policy protection for long-established informal services, implying a bipartite planning approach to service industries (leaf, ) . the final two categories depicted in the typology of asia-pacific urban service centres comprise more narrowly specialized cities and settlements. category includes important port cities with (in most cases) substantial industrial sectors, and some service industries ancillary to port functions, but otherwise relatively underdeveloped advanced tertiary sectors. this set of port/industrial cities includes, to illustrate, pusan, kaohsiung, kitakyushu, oakland, and tacoma. a number of these cities are aggressively pursuing industrial diversification strategies in order to escape dependence on older (in some cases distinctly obsolescent) manufacturing activity; these include kitakyushu, pusan, and kaohsiung. each of these cities is actively promoting new service industries which are seen as more progressive development modes or vocations for the st century, and at least two, pusan and kitakyushu, are joint signatories to official co-operation agreements. the seventh category includes generally smaller cities and settlements specializing in travel and tourism. these include tropical centres, such as denpasar and kona, as well as the major skiing and winter sports centres of sapporo and whistler, the latter now the largest ski resort in north america. these centres may also be candidates for major international events: sapporo has hosted a winter olympics, while whistler is an integral part of vancouver's bid for the winter olympic games. as we have seen advanced services exhibit strongly polarized spatial patterns within the asia-pacific, reflecting the power of urban and agglomeration economies, and the locational centrality of higher-order services in metropolitan areas. at the same time, we can envisage the emergence of spatially extended territories of specialized services production and exchange at the broader regional level, configured as multi-centred urban corridors. these corridors (or clusters) comprise in most cases regions with a dominant first-or second-order global city and a chain of interdependent, and generally smaller, but nonetheless important urban centres. the conceptual bases for the emergence of these there is of course some ambiguity in this terminology, but in general corridors encompass essentially linear arrangements of cities, as exemplified in the pacific north west corridor (vancouver -seattle-portland), while clusters can describe patterns of functionally linked (but dispersed or non-linear in form) cities within extended regional settings (for example the california bay area, which includes san jose, the silicon valley, oakland and berkeley, as well as san francisco). specialized functional territories can be traced to gottmann's seminal idea of megalopolis (gottmann, ), whebell's theory of corridors as urban spatial systems (whebell, ) , and mcgee's notion of extended metropolitan regions (mcgee, ) . they perform strategic service functions (including finance, corporate control, administration, information and communications, cultural and gateway roles), are linked both to regional production systems and to global networks of services trade, and exhibit aspects of complementarity as well as competition. fig. shows the location of major urban service corridors or clusters within the asia-pacific sphere: five in east asia (central japan -honshu corridor, the lower yangtze corridor, the pearl river delta cluster, and the taiwanese and korean corridors); one in southeast asia (the southern malay peninsula corridor); one in australasia (the southeast australian corridor); and three on the pacific coast of north america (the southern california corridor, the california -bay area cluster, and the pacific north west corridor). reflecting the corporate power of the asia-pacific's firstorder global cities, the two most important extended urban services territories are the central japan -honshu corridor, which includes tokyo, yokohama, osaka, nagoya, and kyoto; and the southern california corridor, incorporating los angeles, anaheim, orange county, and san diego. these first-tier metropolitan services corridors contain truly global-scale concentrations of most of the specialized service industry suites listed in table , including banking and finance, corporate control, producer services, gateway functions, advanced-technology and creative services, education and culture. however, there are certainly global-or international-scale service industry concentrations situated within other principal service corridors and clusters, as exhibited in table . these include, to illustrate, the california bay area (global-scale advanced-technology and creative services, higher education, tourism), the korean corridor (banking and finance, corporate control, gateway roles), the pearl delta (banking and finance, corporate control, gateway roles), and the southern malay peninsula (banking and finance, gateway roles, advanced-technology services, education). within the more compact urban service clusters, the expansion of specialized services territories acknowledges the need to accommodate back-office functions and local services in smaller regional centres, and to situate new airports and port facilities, university sites, and research and development facilities in peripheral or exurban areas outside the dominant metropolis, with the pearl delta cluster as an example. culture, amenity and lifestyle may constitute supporting elements of intra-regional services development in some cases, notably in the transboundary pacific north west corridor. advanced services have been crucial to the post-staples development of the pacific north west; at the same time, the amenity provided by wilderness areas is widely seen as a positive inducement to the specialized services and advanced-technology industries which increasingly define the economic base of this region, and is also embedded in social values and lifestyles. within certain of the larger territories, notably the central japan -honshu corridor, the recent development of metropolitan service centres reflects the changing division of production labour at regional and even national levels, presenting possibilities of reciprocal specialization in services within hierarchical and otherwise competitive urban systems. at the same time, there are to be sure examples of the 'uneasy co-existence' of national primate and second-and third-order cities within extended clusters, derived from hegemonic inter-city relations; the examples of seoul and pusan, and tokyo and osaka, come to mind. the dynamics of regional competition and complementarity can further be illustrated by reference to the pacific north west corridor, which includes the three major ports of vancouver, seattle, and tacoma. there is to be sure considerable competition among the three ports (which is likely to increase as major shipping lines continue to rationalize their trans-pacific rotations), but we can also observe aspects of specialization and complementarity: seattle and tacoma are major container ports, while vancouver specializes in bulk commodity exports and cruise ship travel (the port of seattle has recently increased its efforts to attract cruise ship traffic, with at least a measure of success.). at a broader level, the reciprocal strengths of services specialization observed in seattle, vancouver and portland enable the north west corridor to compete in some trade sectors with the san francisco bay area cluster (for example in international gateway functions), about km to the south. in each case the emergence of these multi-nucleated, interdependent services production corridors may presage the reorganization of regional economic space to enable economies of scale, scope, and specialization, in response to the pressures (and opportunities) of globalization. within certain of these corridors, for example the yangtze delta cluster, and the southern malay peninsula corridor (incorporating singapore and the kuala lumpur -putrajaya -cyberjaya technology corridor) this developmental aspiration is a matter of quite explicit political strategy (see for example the discussion in corey, ( ) ). in the japanese case, the central government has attempted to promote complementary clusters or corridors of advanced-technology industries and services within three hierarchical levels, in order to maximize efficiency gains, and minimize damaging inter-regional competition (edgington, ) . there is a perceived need to transcend the everyday rivalries of regional competition, in order to promote powerful international-scale banking and finance, corporate control, education and culture services, production and trade platforms, along the lines of mature counterparts within the old 'atlantic core', such as the us northeastern 'megalopolis' corridor, the paris-ile de france region, and the london-oxford -cambridge triangle. a demonstration of the mutual benefits of inter-city complementarity and co-operation in this sphere may in turn facilitate broader efforts at inter-regional and international colloboration, as encouraged by douglass ( ), among others. at the moment, cities within the region tend to see themselves as entities within essentially competitive international urban systems, with an obligation to devote more policy attention and public resources to fostering competitive advantage, at the expense of planning efforts designed to enhance local welfare (thornley, ) . over the last decade or so urban policy approaches to service industry development have evolved significantly, reflecting in part a more informed appreciation of the centrality of advanced services to urban development. however, in other respects shifts in planning approach in this policy domain incorporate responses to the challenges and opportunities of globalization, and innovation in planning styles, as well as efforts to reconcile regulatory and distributive issues with important developmental aspirations. as in the fundamental processes of urban tertiarization described in preceding chapters, we observe a number of important contrasts in urban service industry policies between societies of the pacific and atlantic 'cores', notably a much stronger emphasis on growth and development aspirations among the former, as well as some commonalities. accordingly, this chapter will entail a discussion of defining shifts in urban policy approaches to service industries, leading to a presentation of six leading models of service industry models, together with illustrative reference cases, in the following chapter. we can identify several principal phases of local planning and policy responses to the growth of the urban service sector over the past quarter century. broadly, the initial period emphasized development control policies, to manage negative externalities associated with growth in speculative office development; the second phase included developmental programmes, acknowledging the increasing significance of service industries to local economies and labour markets; and the third period has seen more assertive policies which deploy advanced services as instruments of industrial restructuring, modernization, and globalization, as well as increasing policy innovation and experimentation. first, the rapid growth of offices within central city areas over the s and s gave rise to a suite of regulatory local planning policies toward the urban service sector (daniels, ) . planning concerns during this period included the implications of rapid office development for the over-specialization of the urban economy, for the displacement of non-office industries and housing, and for long-distance commuting within the regional commuter shed. indeed, the journey-to-work problem, shaped by the expansion of the cbd's office complex, and the simultaneous decentralization of the urban residential population and labour force, was broadly seen as a defining metropolitan planning issue in many city-regions (davis and hutton, ) . the planning response to high levels of central city office development over the s and s included both increasingly stringent development control policies for the core (including downzoning, the imposition of annualized development quotas or thresholds, and fiscal measures), as well as efforts to promote new office subcentres within suburban areas. local planning responses to office activity and other service industries in this critical policy phase at times took on a strongly ideological tone. in britain and in other parts of western europe, left-leaning councils actively discouraged service industries, which were seen as displacing traditional manufacturing industries. this essentially prejudicial local attitude toward service industries was in part conditioned by research which subordinated the tertiary sector to secondary manufacturing within the urban or regional economy, based on measures of export performance, productivity, and sales and employment multipliers. however, to some extent stringent local planning controls on (especially office-based) services were strongly influenced by political opposition to the speculative property market, which was seen to favour office development over industry and housing, reflecting higher returns on investment (roi) for office development relative to other land use categories. examples of this ideologically derived planning response to urban tertiarization included the greater london council and most inner city boroughs during the s and early s. urban authorities continued to experiment with development control options for service industries, but by the mid- s a more positive (or balanced) local policy approach was in evidence among a growing number of local authorities. this more favourable local policy posture toward office activity and other service industries was influenced both by the implications of industrial decline in many large-and medium-sized cities, impelled by the collapse of traditional fordist industry, as well as by new research which underscored the key roles played by specialized services in advanced (daniels, ) . more particularly, the specialized intermediate (or 'producer') services were identified as crucial to the operation of 'flexible' production systems, to high-wage urban labour formation, to industrial productivity, to the urban export base, and to local revenues. in this new situation, urban governments and planning authorities began to introduce policies for (at least selectively) encouraging important service industries, notably banking and finance, transportation, business services, higher education, and tourism (coffey, ) . examples of more positive local planning and policy instruments for the urban service sector are depicted in table , together with corresponding instances of development control and other regulatory measures, across a spectrum of local policy fields. table contrasts planning approaches toward service industries according to preferences for 'developmental' or 'growth management' policy objectives, although in practice many local authorities tended to implement a blended suite of promotional programmes and regulation . however, important examples of quite dramatic policy shifts can be referenced, notably within cities of the broadly defined asia-pacific region. in the well-known case of singapore, a short, sharp economic downturn in the mid- s led almost immediately to aggressive new policies favouring specialized, high-value, exportable services, in part reflecting concerns about the prospects for singapore's manufacturing industry and regional entrepôt roles. in hong kong, the colonial government assertively supported the expansion of office activity and other key intermediate services, exemplified by the territorial expansion of the cbd, by public investments in education, and by increased international marketing (taylor and kwok, ) . and in vancouver, a centre-left city council approved an economic development strategy which set out a series of policies and programmes to foster important service sectors and industries, together with co-operative measures to be undertaken among key institutions, labour cohorts, and business groups (city of vancouver, ) . at the same time, the city of vancouver continued to co-operate with the regional planning authority, the greater vancouver regional district, in managing externalities of rapid growth in services, for example by supporting office development in designated regional town centres (rtcs), exemplifying the tendency to 'blend' both regulatory and developmental programmes within local policy suites. the experimentation with development programmes for urban service industries over the s and s marked a significant departure from the strongly regulatory promotion of a better spatial balance between employment generation and housing growth a principal policy goal information services support for active marketing of tertiary services in domestic and international markets promote or market secondary centers in the suburbs (e.g. by publicizing cbd/ suburban rent differentials) government liaison/ 'partnerships' lobbying of central/middle tier governments to promote tertiary industry development; including for changes in government policy/regulatory environments (e.g. in the sphere of finance and banking, air bilaterals) support for government decentralization policies involving public and private sector tertiary employment source: after hutton ( ). experiences of the previous two decades. however, major changes in urban development conditions in the most recent period have led to a new phase of urban policy innovation, with policies for advanced services at the heart of much of this experimentation. these new policy conditions include the following processes, trends, and events: . continuing processes and pressures of globalization, stimulating local and regional policies promoting competitive advantage at the city-region level (as well as wellpublicized protests and demonstrations), but also encouraging interest in the possibilities of co-operative programmes between cities and local governments situated within 'extended metropolitan regions ' (mcgee et al., ) . . the severe (although spatially differentiated) impacts of major exogenous shocks on regional and national economies, including the aftermath of the / experience in new york, the bali night-club explosion of october , and the lingering effects of the fiscal and economic crisis in the asia-pacific. these impacts have included inter alia sharply diminished air travel and tourism in many regions, increasing unemployment, and problems of corporate illiquidity and bankruptcies. we can also acknowledge the recent impact of sars (severe acute respiratory syndrome) upon major asia-pacific service industries, notably airlines, hotels and retail trade. . economic and developmental implications of a series of unresolved security crises within asia and the middle east especially, including the apparently intractable palestinian question, the iraq crisis, and the problem of north korea's incipient nuclear capacity. these implications include a more problematic investment climate within affected nations and proximate regions. . the rapid rise (and even more dramatic contraction) of the so-called 'new economy', over the last years. the collapse of the dot.coms notwithstanding, however, information and telecommunications industries constitute essential features of all advanced economies, and are playing increasingly central developmental roles within the asia-pacific region (corey, ) . . the emergence of the 'urban cultural economy', underpinned by what allen scott describes as the convergence of culture and urban development, and comprising both cultural production and consumption as leading sectors within a growing number of cities and city-regions (scott, ) . cultural industries (including creative design industries, media and multimedia, and film, video and music production) represent increasingly important sectors of the urban economy, in cities such as los angeles, tokyo, kyoto, singapore, bangkok, and melbourne. . sharply divergent economic fortunes of the asia-pacific's major nation-states, including the remarkable growth of advanced industrial production and trade in china, the continuing japanese economic malaise, and slow growth in the american economy (the stagnation of american consumer markets has also seriously retarded exports from other asia-pacific nations.). . continuing processes of restructuring and transition among the advanced economies of east and southeast asia, including taiwan, south korea, and singapore, as well as in 'threshold' nics such as malaysia, thailand, and vietnam. to illustrate, an "important feature of asean economic development has been the growth of their services sector" (tongzon, : ) , as reflected in gdp and employment data. . new phases of development within the industrial structures and space-economies of asia-pacific city-regions, exemplified by processes of accelerated tertiarization, decentralization, and multinucleation among major chinese coastal city-regions (yeh and wu, ) , and by the emergence of 'new economy' clusters within inner city sites of cities such as tokyo, singapore, san francisco, and vancouver. . increasing awareness within the asia-pacific of ecological implications of accelerated development (and more particularly rapid industrialization), including resource depletion and overall environmental degradation, stimulating interest in principles of sustainable development. . exacerbation of urban social problems (increasing income disparities, social polarization, and community dislocation), both in rapidly growing states (notably china) and also in some lagging countries and regions within the asia-pacific. these social costs are discounted by some as inevitable outcomes of rapid economic growth, but there has also been evidence of interest in exploring possibilities for reducing social inequities, both in terms of new socio-political 'compromises' at national government levels (scott et al., ) , and also commitments to social planning as an integral feature of local government and administration. this illustrative listing of new development conditions inevitably masks quite highly differentiated experiences at the national, sub-national, and local levels, but may provide a backdrop to a new phase of experimentation in policy formulation and institutional innovation. clearly, these development conditions will influence new planning choices and directions across the full range of local and regional policy domains. in the aggregate, these conditions tend to 'stretch' local policy capacity and to place increasing pressure on urban planning systems, staff and resources. however, there may be promising opportunities for policy experimentation within the realm of the urban service sector, in light of the increasing centrality of service industries to trajectories of urban development, and the far-reaching implications of tertiarization for urban form and the built environment, the metropolitan space-economy, and the city's social structure (as well as derived demand for housing and transportation). in chapter we will explore some of the leading models of urban policy for service industry development within the broadly defined asia-pacific region. planning for new trajectories of services-led urban development as observed previously, urban planning and policy responses to tertiarization within the asia-pacific region include ambitious programmes which deploy service industries as instruments of development and transformation. a review of urban policy experiences over the last decade and a half discloses explicit associations between services (especially advanced, specialized and intermediate service industries) and plans for globalization, restructuring and modernization. while the mix of policy measures varies from place to place, these service industry programmes typically incorporate substantial public investments, inducements to attract private capital and the commitment of market players (foreign and domestic), adjustments to regulatory regimes, spatial planning elements, and sets of ancillary policies, notably in transportation and housing. the record of these ambitious (and even grandiose) policy initiatives includes some significant successes, in terms of the basic transformational aims (and business objectives of market actors), although the experience is also replete with examples of institutional conflicts and tensions. these include 'structural tensions' in some cases between local agencies mandated to vigorously promote growth and change, which tend to embrace narrowly economistic principles and objectives, on the one hand, and local planning departments which may prefer more holistic programmes, with broader, more inclusive public purposes. there may also be conflicts between central and local governments concerning policy preferences for service industries and economic development more generally. aside from these institutional tensions there are also growing concerns about social and environmental implications of rapid urban economic growth and transformational change. these include social costs such as community dislocation and social polarization, as well as environmental impacts which may include the destruction of heritage buildings within areas undergoing rapid change, encroachment of cities on adjacent agricultural and natural terrains, and the degradation of air and water quality within the regional biosphere. there are also examples of growing awareness of the financial and ecological costs of intense inter-city competition for investment, new service industries, and employment generation, which in some cases takes the form of a proliferation of facilities within extended metropolitan regions (as exemplified by airport development within the pearl river delta). these more problematic features of accelerated urban growth and transformation, coupled with the changing development conditions identified in the conclusion of chapter in britain this institutional tension at the local level is exemplified by the (sometimes conflictual) relationships between local 'regeneration' agencies mandated to promote new investment, industry, and job creation, and the local planning departments which perform a range of regulatory and management functions. similar tensions between local development agencies and municipal planning departments can be observed in west coast cities of north america, including vancouver. with respect to institutional tensions between local and central governments within the asia-pacific, we can cite the recurrent conflicts in development aspirations between the okinawa prefecture and tokyo ministries over the nature of okinawa's growth and change, exacerbated by structural problems of core-periphery asymmetry and dependency, as well as the increasingly problematic us armed forces bases on the principal island. , have stimulated new interest in planning innovation at the metropolitan and local government levels within the broadly defined asia-pacific region. while urban policies emphasizing transformational growth and change, underpinned by globalization and modernization aspirations, and by imperatives of competitive advantage, are still pervasive within the region, we can also discern significant interest in alternative (and perhaps more progressive) urban planning models. these include, for the purposes of illustration, experiments in sustainable urban development, community economic development (ced), and co-operative regional development. the purpose of this chapter then, is to depict the breadth of urban policy initiatives involving programmes for service industries, at the city-region and local levels, underscoring the dominance of transformational policies throughout much of the region, but disclosing as well interesting (and potentially significant) policy experimentation and innovation. while a comprehensive description of urban service industry approaches (and the programmatic details of these policies) is beyond the scope of this paper, it may at least be possible to structure a number of the leading models for comparative purposes. accordingly, table depicts six strategic policy models which deploy service industries as important instruments or modalities, together with some representative programme elements, underlying principles and values, and exemplary reference cases within the asia-pacific urban network or hierarchy. accordingly the framework of urban policy models depicted in table includes three ensembles associated with the dominant developmental paradigm of the latter period of the th century (associated with globalization aspirations, industrial restructuring, and modernization), and a set of three policy models which reflect current or emerging directions which seem to offer more progressive developmental possibilities. these latter three urban policy ensembles include policies for service industries which emphasize possibilities of co-operation with the broader regional setting, examples of initiatives which support the idea of the 'sustainable' city-region, and, finally, planning for the new urban cultural economy, acknowledging what allen scott describes as the strategic convergence between culture and urban development (scott, ) . what follows is a description and concise discussion of each of these defining urban policy models. over the past two decades both local and senior-level governments have deployed policies for certain service industries as key instruments of globalization (or internationalization) strategies within the asia-pacific region. objectives in this policy realm have included overcoming scale limitations of local markets and regional entrepôt roles (e.g. singapore and vancouver in the s); integrating regional and national economies within global markets, to attract foreign capital and promote modernization within the domestic economy (as in the case of certain chinese coastal cities since ); and pursuing strategic trade and co-operation partnerships with selected foreign cities (for example fukuoka since the early s). inter-city competition, concepts of competitive advantage, urban hierarchy; discounting of social costs (daniels, ) singapore (since mid- s); shanghai, osaka, fukuoka deregulation/privatization foreign direct investment urban mega-projects (after olds, ) service industries and 'postindustrial' trajectories pursuit of 'growth services' and propulsive intermediate service industries within context of industrial decline/obsolescence; acceptance of dislocation and displacement effects (hall, ) nagoya, hong kong, singapore land use policy change human capital investments targeted industry support programmes service industries and the 'new economy' assertive technocratic vision which privileges the future; idea of it as principal instrument of urban transformation and modernization; 're-imaging' of the city via policyinduced technological development (bunnell, ) kuala lumpur-putrajaya, singapore, vancouver support for r&d promotion of urban 'technopoles' spatial planning and land use policy service industries and the 'cooperative regional cluster' model acknowledgement of complementarity (as well as competition) among centres within extended metropolitan regions (emr's), after mcgee (douglass, ) hong kong/pearl river delta, sijori, san francisco-bay area region institutional co-ordination joint planning and marketing efforts spatial rationalization of new investment service industries and the 'sustainable city-region' model principles of social and environmental policy; idea of 'efficient and equitable' city-region; acknowledgement of sustainability as planning paradigm or framework (goldberg and hutton, ) sydney, vancouver, pearl river delta planning for suburban service industry subcentres services within 'compact' and 'complete' communities extensive designated 'green zones' service industries and the urban 'cultural economy' idea of strategic convergence between culture and urban development (scott, ) ; significance of creative industries and workforce (florida, ) los angeles, singapore, vancouver public support of the arts policy support for inner city clusters heritage planning promotion of the ' h' city we can identify a distinctive range of policy modalities that have been introduced to exploit the globalization potential of advanced, specialized service industries and institutions within the asia-pacific region. these have included: (a) building capacity in strategic urban transportation and communication, infrastructure and facilities, such as seaports, airports, and teleports; (b) promoting the export of specialized services (such as 'producer' and other intermediate services), in order to exploit local comparative advantage in services to replace diminished goods export capacity, to improve terms of trade, and to achieve greater scale economies within regional industries; (c) stimulating the globalization of cities in situ, as exemplified by the series of urbanmegaprojects (umps) within the region which have included important service industry elements, such as the pudong ump in shanghai (olds, ) , and the mm ump in yokohama, which tend to promote the inflation of local land markets, the increased presence of foreign firms and multinationals in the central areas, and the comprehensive re-imaging of the city; and (d) exploring the possibilities of mutual benefit through reciprocal, two-way trade in services (including educational and cultural services, as well as in business services) with designated cities as elements of international 'sister cities' or 'city partnerships', exemplified by fukuoka's 'global reach' programme (fukuoka municipal government, ) , and the city of vancouver's 'strategic cities' programme (city of vancouver, ). clearly there are important, substantive economic development and trade purposes associated with these globalization strategies, but there are also (explicit or implicit) reimaging aspirations in many cases. the classic example within the asia-pacific is the restoration of shanghai as a global centre of finance, corporate control, and business services, supported by assertive regional and central government policies and programmes, massive foreign investment, and the conscious engagement of elite international architects, planners, and developers in shanghai's accelerated transformation olds ( ) . other examples include yokohama's goal of escaping a constrained role as tokyo's 'shadow city' by means of the ambitious mm docklands scheme, as well as osaka's search for a larger international profile, to be furthered in part by the redevelopment of the cbd and the massive osaka -kansai international airport project. these urban globalization strategies have been centrepieces of local and regional development strategies for an increasing roster of asian-pacific cities over the past decade or so, with commensurate heavy commitments in local financial, policy, and human resources. in light of these major investments, a number of these globalization programmes have achieved a measure of success, in terms of accelerating growth, integrating cities within global markets, and other essentially economistic goals. however, there have also been significant social and environmental costs associated with these programmes, and high levels of local exposure to a variety of risks, as social and ecological values have (despite policy rhetoric to the contrary) been substantially discounted against the perceived benefits of accelerated globalization (see douglass ( ) for a treatment of the tokyo case study). the single-minded pursuit of transformational urban development through market integration, enhanced (or induced) comparative advantage in export service trade, and comprehensive local re-imaging has led to large-scale community displacement and dislocation (as in shanghai), high corporate and municipal financial exposure (yokohama's mm project, and tokyo's waterfront development), and inflation in local property markets (many instances throughout the region). these significant social and environmental costs tend to be associated with the more comprehensive, grandiose projects. correspondingly, more selective, smaller-scale or 'managed' internationalization programmes are likely to generate fewer such costs. again, examples of these more selective internationalization programmes would include the fukuoka experience, in which mutual benefit between urban communities represents an explicit aim; and the vancouver case, in which the city's internationalization programme in the s included both considerable stakeholder input, and measures to ameliorate social costs of accelerated urban globalization (hutton, ) . the development record of most cities within 'advanced' societies over the last three decades or so includes generally increasing shares of employment, gdp and exports accounted for by service industries. there have of course been debates about whether this trend toward the tertiarization of the urban labour force, output and trade represents a 'natural' process or progression, but what is incontestable is that some cities have endeavoured to accelerate the shift from basic manufacturing to services, especially specialized and intermediate service industries and employment. as noted briefly in preceding chapters, the asia-pacific region encompasses numerous case studies of this policy preference. central to the policy values underpinning urban programmes for restructuring which favour service industries and institutions is the (explicit or implicit) endorsement of the 'post-industrial thesis', first enunciated by the american sociologist daniel bell, which postulated a pronounced shift from goods to services production as a defining feature of advanced urban societies. (see table (a) and (b) for a more comprehensive set of urban tertiarization attributes). as kong chong ho has observed, cities have been obliged to respond to restructuring processes (ho, ) , including retraining programmes for displaced workers, and welfare programmes and transfer payments as well as policies to promote industrial restructuring as part of modernization strategies (hall, ) . in a number of cases, urban programmes of accelerated tertiarization have been undertaken within a context of urban-regional industrial decline or obsolescence. this has been observed within the japanese metropolitan system, where the 'hollowing out' of the national industrial economy has been deeply felt, in terms of factory closures (or relocation offshore) and protracted structural unemployment. for some of these cities, new service industries and associated labour cohorts, production and trade constitute a possible new urban development trajectory or 'vocation'. as noted earlier, too, urban development planning and programmes have been influenced by research which has established certain advanced services as urbanregional 'propulsive industries', based on associated productivity measures, inputoutput relations and sales and employment multipliers, export propensity, and skilled labour formation. here, the large-sample survey of export services undertaken by beyers et al. in the mid- s for the seattle-central puget sound economic development district (cpsedd) has been especially influential in providing an empirical justification for services-oriented metropolitan development strategies (beyers et al., ) , complemented by theoretical work undertaken by peter daniels, jean gottmann, and others. important case studies of accelerated tertiarization within the asia-pacific include singapore, hong kong, and nagoya. in the case of the former, a short but sharp recession in the mid- s stimulated a comprehensive policy research exercise in singapore, culminating in an important development policy shift favouring intermediate services with high export propensity (or potential). underpinning this defining policy shift was the work of a special subcommittee exploring the merits of manufacturing-versus services-led urban development and growth. the subcommittee concluded that advanced, specialized services enterprises "contribute about twice as much value-added as manufacturing firms" (clad, ) , and constituted a more promising growth sector than most forms of goods production. accordingly the government of singapore embarked upon a comprehensive programme to accelerate growth in specialized services in , including incentives for foreign investors, new expenditures in education and training, sweeping fiscal changes (including major tax cuts, and reductions in payroll taxes), service industry support programmes, and marketing and information strategies. in hong kong over the same period the colonial government was also engaged in policy support for an increasingly post-industrial economy and workforce. as observed by bruce taylor and reginald win-yang kwok, this accelerated tertiarization strategy comprised important policies for urban structure and land use, including major land reclamation in wanchai and causeway bay to accommodate the expansion of hong kong's cbd, the ongoing industrial new town programme in the new territories to enable relocations from the central district and kowloon, and new investments in rapid transit (taylor and kwok, ) . as a measure of the effectiveness of this programme (coupled with the influence of market-driven change), services now account for over fourfifths of hong kong's labour force, and there is more employment in intermediate (or business) services than in consumer services (asian development bank, ) . in both the hong kong and singapore examples it can be argued that these policy shifts essentially reinforced (or accelerated) post-industrial urban vocations already in progress. however, the experience of certain japanese cities offers a quite different set of policy conditions and experiences. david edgington has written extensively about the role of industrial restructuring policies for the important nagoya -chukyo region, a key part of japan's industrial heartland. he depicts schematically a progression of new industrial vocations for chukyo over the second half of the th century, which includes (first) a mix of heavy industry (aircraft production and munitions) up to the s; secondly, a shift to heavy industries (steel and petrochemicals) and consumer products over the s; followed by strong growth in auto production (toyota), heavy engineering, and light industries during the s and s. however, the last decade in the nagoya -chukyo region has seen new local (prefectural and municipal) policies and planning in support of a 'new vocation' of knowledge-intensive industries, including aerospace, advanced electronics, new ceramic materials, information technology, biotechnology, and fashion design and production (edgington, : ) . this new vocation builds upon the nagoya -chukyo region's embedded excellence in advanced industrial production, but with greatly enhanced services, design, and technology inputs to production. here, the role of local government (as distinct from the well-known national government industrial support programmes) has emphasized "strengthening regional culture, design and general amenity upgrading for chukyo" as an "important part of regional restructuring" (edgington, : ) . the nagoya -chukyo experience represents an example of complementarity between central and local governments in promoting industrial restructuring at the regional level. the emergence of a 'new economy' characterized by propulsive roles for advanced information and communications technologies (ict), although to be sure a contested concept, has stimulated considerable interest among governments and policy communities within the asia-pacific. for a number of jurisdictions, policies for supporting ict are seen as means of rejuvenating urban and regional industrial production sectors (notably in japan), while in others investments in ict, implemented by spatial planning, land use, and human capital planning programmes, provide a means of 'leapfrogging' stages of economic development (malaysia). technology-driven development has also been central to new urban development experiments, as in the case of the tsukuba science city in japan. as a planning preference, support for accelerated ict development and other new economy activity can be seen as the endorsement of an assertive technocratic vision of urban and regional development, as observed by manuel castells in his discussion of 'the informational city' (castells, ; scott, ) . ict is deployed as a key instrument of urban transformation and modernization, with both 'substantive' effects (higher productivity and value-added production; business start-ups and labour formation) and 'symbolic' outcomes (re-imaging of local/regional societies and economies), although there are to be sure concomitant costs and dislocations (bunnell, ) . within the asia-pacific, we observe a number of instructive examples of ict-driven development strategies at the urban and regional levels. there are of course the globalscale advanced-technology regional complexes of silicon valley and orange county in california, seen as essentially 'spontaneous' (i.e. market-driven) enterprises, although the role of state-supported universities and other public agencies should be acknowledged. then there are the large r&d formations (applied research, prototype development) within japan, largely funded by major japanese multinationals and industrial conglomerates, but also influenced significantly by central government ministries and agencies. these massive american and japanese r&d complexes have of course been established for many years, and represent in some ways an earlier model of technologydriven spatial development linked to large industrial corporations. a number of other, newer examples of new economy exhibit in some respects different attributes, including larger roles for government and public agencies, more emphasis on integrated service industry engagement (including creative and design services, as well as financial, business, and communications services), and contrasts in scale. the range of examples in this more recent cohort of technology-driven enterprises varies from the extensive putrajaya -cyberjaya project in malaysia, described by kenneth corey as a defining project of malaysia's national economic development programme (corey, ) , to a series of inner city new economy experiments within a large and growing number of cities, including singapore and vancouver. these recent inner city new economy projects are clearly differentiated from the 'first generation' urban and regional technopoles in a number of ways, not only in the matter of scale, location, and provenance, but also in the mix of industries and activities. key to these new inner city formations is the concept of the metropolitan core as a special, in some ways unique, 'innovative milieu', providing advantages of socio-cultural, as well as economic, agglomeration, to constituent firms. there is also, as noted, a stronger service industry element, as in both the singapore and vancouver examples the explicit strategy involves fostering developmental synergies between technology (especially ict), culture (in the form of creative and design service industries), and 'place', as expressed in the innovative milieu of the inner city. these inner city new economy sites are characterized by intense interaction (formal and informal), deployment of both 'placed-based' and 'cyber-based' production networks, and a distinctive demography, emphasizing mostly younger creative and technological workers and entrepreneurs. . . . service industries and the 'co-operative regional cluster' model as is well known, the development experience of the asia-pacific region over the past four decades has been characterized in large part by prevailing attitudes of competition for shares of investment, trade, and new employment formation, between (and among) nationstates, regions, and even cities. this animating sense of competition between jurisdictions has at times been exacerbated by contrasts in stages of development, by ideological factors, and more forcefully by the pressures of accelerating globalization. development policy postures have therefore in many cases been influenced by a perception of regional development opportunities as a 'zero-sum' process of clear 'winners' and 'losers', leading to an emphasis on nurturing localized positions of competitive advantage (douglass, ) . assumptions of development as an essentially competitive process are of course still powerful influences on policy formation within the region, but there are also significant (and likely expanding) movements toward inter-jurisdictional co-operation, shaped by progressive ideas of reciprocal trade benefits, knowledge-sharing, and developmental complementarity. this is seen at the broadest spatial scale in the establishment of the apec grouping, an association which endeavours to promote liberalized trade and cooperative development within the pacific sphere (as well as providing a counterweight to other continental-scale bodies, notably the eu and the nafta states). at the regional level asean provides a forum for dialogue and trade co-operation among the states of southeast asia. then there is a steady proliferation of less formal regional co-operative associations, including a number of such entities in northeast asia (kim, ) , and joint international development projects, exemplified by the sijori (singapore-johore-riau) growth triangle in southeast asia, and the tumen river area development project in northeast asia (marton et al., ) . many of these developmental arrangements are replete with significant institutional asymmetries and tensions, but they may suggest the possibility of greater tendencies toward regional co-operation, perhaps working over the longer term to approach the levels of engagement and co-operative commitment of the 'associative regions ' (mcgee et al., ) of the eu. more specifically, it may be possible to envisage regional co-operation arrangements based in part on the functional complementarities of regionalized service industry clusters and corridors, described in chapter . as will be recalled, it is possible to identify at least conceptually ten major service clusters or corridors within the asia-pacific, each containing multiple cities and important ensembles of specialized service industries, institutions, and facilities. as in other co-operative ventures at the regional scale, there is an initial need for governments, business interest, and other stakeholders to recognize and acknowledge possibilities of complementarity and mutual benefit associated with these complexes of specialized service industries. in the absence of joint governance, common taxation regimes, and revenue sharing (in addition to issues of (for example) labour market standards and environmental norms) these co-operative regional arrangements may be problematic, but the difficulties may not be insuperable. indeed, the nature of service industry specialization may in many cases lead itself to a broader recognition of co-operative possibilities, even in cases where inter-jurisdictional competition has been the prevailing spirit. co-ordination of investments, operations, and marketing for strategic transportation and communication facilities, for example, can enhance the comprehensiveness of 'gateway' functions for an extended regional corridor or cluster. co-operative planning and programmes for regional tourism initiatives, involving a diverse range of assets, amenities, and hosting infrastructure (e.g. hotels and convention centres) which offer greater potential attraction to visitors than the individual, localized sites within the region, can yield mutual benefits. potentially these principles of co-operation and co-ordination could apply in other important service sectors and industries, for example higher education and specialized health case, acknowledging the advantages of 'packaging' services and expertise offered by diverse firms and institutions within extended regional territories. through greater levels of co-ordination and planning of specialized service functions, regions can achieve stronger competitive positions within international and global markets. within the asia-pacific, the hong kong -pearl river delta offers a particularly instructive case study. following the economic reforms introduced by deng xiao-ping in , the pearl delta experienced extraordinary levels of growth in investment, business start-ups, employment formation and physical development. much of this growth was in the goods production sector, especially light manufacturing, but (as observed in chapter ) the prd also experienced rapid expansion in services. however, there was a chaotic pattern to much of this development, as evidenced in the growth of the shenzen special economic zone (sez), and in the proliferation of new airports within the delta. this period of rapid growth was also characterized by an almost 'free for all' competitiveness among the urban centres of the region. although the prd has experienced high levels of growth over the past two decades within an essentially competitive context, there is significant evidence of co-operation and co-ordination in recent years, especially since the establishment of the hong kong special administrative region (sar) following the reversion of the former crown colony to china in . these efforts to pursue co-operation in economic development have been documented in a recent book edited by anthony gar-on yeh et al. ( ) , titled building a competitive pearl river delta region: co-operation, co-ordination, and planning. to some extent, of course, this desire to achieve co-ordination is related to the need to avoid wasteful, inefficient duplication of functions, to preserve resources, and to rationalize spatial planning in a congested, high growth region. there is also a need to 'manage' competition between the two major centres of the region, hong kong and guangzhou (kwok and ames, ; cheung, ) . however, an important principle underpinning the increasing levels of co-operation within this administratively fragmented and complex region is the exigency of responding to pressures (and opportunities) of globalization. in this respect, the pearl river delta contains both a dense pattern of manufacturing and industrial production, as well as concentrations of specialized service industries, institutions, and functions, including banking and finance, seaports, airports, higher education, cultural and creative services, and public administration. these specialized services represent the best prospects for future growth and development in the region, and greater co-operation and co-ordination of these key services can significantly strengthen the prd's competitive position within east asia and global markets. there is considerable potential for co-operation in the planning and development of other major regional service clusters and corridors within the asia-pacific. the basic idea is to explore means of managing competition between service industries and installations within regional settings, while capitalizing on functional complementarities to achieve stronger international competitiveness. much of the regional co-operation within the region over the past years has been undertaken for areas specializing in manufacturing and industry, as in the sijori and tumen river area projects cited earlier. however, given the momentum of tertiarization within the asia-pacific, and the strategic global functions performed by certain service industries, institutions, and firms, co-operative management and co-ordination of regional service clusters present especially promising possibilities for future urban and regional development within the asia-pacific sphere. there is a need to strengthen regional governance and administration as a pre-condition, however, as the lack of effective regional institutions represents a major constraint. as an example, the association of bay area governments (abag) in the san francisco bay region provides a forum for inter-jurisdictional dialogue and a certain amount of coordination, but lacks the capacity to promote effective regional development co-operation. in addition to the transformational roles described earlier, service industries are increasingly deployed as key elements of spatial and land use planning within the asia-pacific, including a new generation of regional plans influenced by principles of sustainable development. although the specific forms of these new city-region plans of course vary from place to place, we can discern features of three important traditions of spatial (or physical) planning, as follows: (a) elements of spatial planning derived from the classic 'containment' model of planning for metropolitan city-regions, incorporating stringent development control on commercial development in the central city, the establishment of green belts or zones, and the designation and development of new (or expanding) towns on the regional periphery, as seen in the post-war planning of london and the south east region of england (hall et al., ) , and updated in the sequence of 'structure plans' for english counties in the s; (b) attributes of 'new urbanism' planning models (and related concepts) introduced in the s, which included the ideas of 'compact' (as opposed to dispersed) and 'complete' (in contrast to dormitory) communities within city-regions, an emphasis on transit-oriented development (tod) (and the increased management of automobile traffic), and a preference for 'traditional' (or 'neo-traditional') housing styles and vernaculars; and (c) principles of 'sustainability' (or 'sustainable development'), which have increasingly influenced the planning of city-regions (as well as 'natural' or 'resource regions') since the rio 'earth summit' of , and which encompass ideas of ecological preservation, biodiversity, the integrity of ecological systems, and the need to manage (and eventually reduce) the human 'ecological footprint'; i.e. the impress of human activity on the world's natural resources and biosphere. in the urban context, sustainability principles can also be applied to the city-region's economy, culture, and social 'capital'. the extent to which principles derived from these major models of urban and regional planning is dependent not only on considerations of urban scale, environmental setting, industrial structure, and growth rates, but also on the structure of urban governance, the nature of political control, characteristics of the local planning system and policy agencies, the quality of leadership, and other institutional factors. at the broadest level, however, there is a kind of structural tension associated with contemporary spatial planning for metropolitan regions, between the need for flexibility to accommodate changing locational demands of business and industry (including the so-called 'new economy' activities) and new residential preferences, on the one hand, and the imperative of deploying policies to impose a measure of order on the growth of human settlements, in accordance with ecological and social values. service industries have been assigned roles within each of the three principal spatial planning ensembles cited earlier, although these have been demonstrably subject to change. within the 'first-generation' containment models growth management, development control, and the accommodation of population growth by means of supporting designated regional centres were dominant aims, and services (including offices) were addressed primarily by a suite of regulatory policies in the early post-war programmes, as described in chapter (goddard, ) . however, a 'second generation' of regional plans in the s, derived from the containment model in britain, canada, and numerous other states, included the idea of rtcs (or commercial subcentres), within which office development and firms were assigned important roles. these new suburban or regional subcentres were intended to attract new office development, not only to manage development pressure on the cbd, but also to provide more employment opportunities in areas of rapid population and labour force growth, thereby also reducing commuting pressures. within the rubric of new urbanism, offices and other service industries were also seen as important spatial planning elements. to illustrate, concentrations of relatively high-density service development can enhance prospects for the formation of 'compact' (as opposed to dispersed and low-density) communities, while the inclusion of service functions and employment were central to the implementation of 'complete community' strategies. finally, although sustainable development has emphasized the primacy of ecological values and environmental planning, service industries have a number of important implications for sustainability planning. the status of services as the most rapidly growing elements of many urban economies has ramifications for resource consumption (including land), while the mismatch between service employment concentrations and residential development exacerbates the metropolitan commuting and traffic congestion problems, impacting regional air quality. at the same time, the fortunes of the service sector and its constituent industries also have a clear connection to the socio-economic sustainability of the metropolis, especially in light of contractions in fordist manufacturing. . . . . experiences within the asia-pacific. the highly differentiated stages of development and local institutional arrangements among asia-pacific city-regions offer a rich array of experiences in policies for service industries within spatial plans. these include a substantial sampling of metropolitan cities which have deployed containment strategies or 'structure planning' concepts, incorporating the designation of secondary office-commercial centres or subcentres. this has been especially the case in jurisdictions strongly influenced by british planning models, notably australia, canada, singapore, and hong kong, but resonances of the containment model and its defining features (green belts, new residential communities, and designated service industry subcentres) are also discernible in japanese city-regions. we can also identify aspects of the new urbanism and sustainability models in a growing number of city-region plans, although in most asian cities the experience is in incipient stages. a (necessarily concise) selection of reference cases follows. as observed earlier, the location and development of service industries within guangzhou and the pearl river delta (as well as other fast-growing chinese cityregions) has become a major spatial planning issue over the past decade, and underscores the tensions between accommodating growth and the pursuit of sustainable development. within the guangzhou city-region, the combination of liberalized development policies, a greatly expanded role for the market, and high levels of growth have reshaped urban structure and land use over the last years, as disclosed in a recent empirical study by fulong wu and anthony gar-on yeh. during this period, there has been substantial redevelopment within guangzhou's central city, but its overall spatial reconfiguration "is changing from a compact city to a dispersed metropolis as a result of reforms which introduced land values and markets to its urban areas" (wu and yeh, : ) . a measure of this dispersal and sprawl consists of industrial estates, but new service industries and commercial development, driven in large part by foreign investors, also play a role in this process. as wu and yeh conclude, "[the] conflict between urban spatial restructuring and development control is inevitable" (wu and yeh, : ) in high-growth cities characterized by the decline of central planning and inadequate local planning powers. michael leaf goes even further, asserting that in these dynamic chinese cities, "the practice of urban planning may have passed from irrelevance under the command economy of the past to gross ineffectiveness in the socialist market economy of today" (leaf, : ) . moreover, local planning systems in at least some chinese cities are developing more sophisticated planning styles, and an increasing number of planning professionals are engaged in exploring sustainability principles, so it may be that the next generation of city-region plans will incorporate stronger elements of sustainable development. other reference cases within the asia-pacific provide quite different experiences of spatial planning and contrasting perceptions of the role of services in regional sustainable development. the evolution of spatial planning in metropolitan vancouver represents a sequence of new roles for service industries, from 'containment' to sustainable development. in vancouver's first regional plan, the livable region region - (approved , the classic elements of the post-war containment spatial plan were all present, including green zones (incorporating special protection for agricultural land, an emphasis on public transit, and the designation of four regional (suburban) town centres, each of which was to attract one million square feet of office space over the term of the plan. at the same time, the regional plan proposed strong development control policies for the cbd, both to ameliorate commuting and to enhance office development prospects for the rtcs (hutton and davis, ) . two decades later, a new livable region strategic plan (lrsp) ( ) affirmed the multinucleation strategy of the earlier plan, and indeed added several new rtcs, but also introduced policies for 'compact' and 'complete' community formation, influenced by the new urbanism spirit. service industries were allocated important roles in the lrsp, as the concentration of new offices in the (now eight) rtcs would support the principle of compact settlement forms, while a more diversified range of both intermediate and final demand services (including commercial, retail, and educational services) would promote the formation of complete communities within the city-region, integrating important service functions and local employment opportunities with residential development. more recently, a new public process has been initiated by the greater vancouver regional district, the regional planning agency for metropolitan vancouver, with a view to more vigorously asserting sustainability values and principles in the lrsp. this initiative includes the possibility of strengthening the (already-substantial) ecological conservation measures of the regional plan, but there is also a new emphasis on the importance of economic sustainability as a critical planning priority. in this new planning consultation process, key informants, stakeholders, and the general public are invited to propose new ideas for enhancing the economic sustainability of the region, including the spatial planning implications of new service industry development. these include the cbd (now seen as a unique and valuable regional assets rather than principally a generator of negative externalities, as interpreted in the metropolitan plan), the eight designated rtcs, the port of vancouver, vancouver international airport, the region's universities and colleges, and a number of 'new economy' sites, both in the suburbs and in the metropolitan core. spatial planning measures for service industries that promote multinucleation within metropolitan strategies can be seen as supporting economic sustainability (nurturing of high growth service industries, building capacity for industrial transition, enhancing regional economic resilience) as well as ecological sustainability (conservation of scarce urban land resources, mitigation of commuting-related air pollution). agglomeration of advanced service industries promotes the 'cluster-driven' process of advanced urban development, as seen in the vancouver example described earlier. other important examples within the asia-pacific include the global-scale concentration of advanced-technology service industries clustered in redmond, washington, within the metropolitan seattle-king county city-region, and the recent development of sydney's north shore high-tech corridor. this corridor has seen a functional and spatial evolution over the past four decades, initiated in the s by a secondary cbd in north sydney, at the north end of the sydney harbour bridge, followed by the establishment of a major regional shopping centre in the s, and the development of macquarie university on a nearby site (o'connor et al., ) . with these activities serving as a base, the last two decades have seen the dramatic growth of new technology-based industries and advanced services: the north shore corridor is anchored by microsoft corporation at one end, and cable and wireless optics at the other, with five commercial clusters situated between these two major poles (o'connor et al., ) . by the mid- s, employment within the north shore corridor exceeded , included jobs situated within member companies of the australian information industry association (o'connor et al., ) . sheehan quotes a property consultant as describing the north shore corridor as "technology land, but it's not physical production, it's brain power and computer power, biased toward sales, service and management rather than research, development and production" (sheehan ( : ) , as quoted in o' connor et al. ( : - ) ). clearly, on this evidence, market players (investors, entrepreneurs, and professionals) have been central to the development of sydney's north shore corridor, but government and public agencies have played leading roles in terms of regional spatial planning, municipal land use policy, and in tertiary education investment. the sydney north shore corridor experience also vividly depicts the functional evolution of service industry clusters over time, in this case from a secondary office and shopping centre to an incipient high-technology site, and finally to a large-scale 'new economy' site of national significance, including advanced-technology industries and specialized service functions. urban centres within the asia-pacific region, as elsewhere, have played important roles as repositories of signifying local, regional, and national cultures, as exemplified by cities such as beijing, kyoto, and hanoi, and many others. these important cultural roles are manifested in (for example) language and dialect, in museums, galleries and archives, in institutions of higher learning, in the built environment, and in social organizations and agencies. these cultural activities have economic as well as social value, as expressed in direct employment generation and incomes, tourism receipts, and the capital value of infrastructure, including heritage buildings. these traditional cultural roles continue to be important (albeit recurrently renegotiated by political acts and social experiences, and subject to new cognitive filters), but are now significantly augmented by fresh processes of reproduction, innovation, and economic development, both in the market and public domains. over the last decade or so, we have witnessed dramatic growth in a range of creative, design-based and 'new cultural' industries. as allen scott has observed in a well-known treatment of 'the cultural economy of cities', "[a]s we enter the st century, a very marked convergence between the spheres of cultural and economic development seems to be occurring" (scott, : ) . within cities, the expansion of this new cultural sector includes film, video and music production, graphic artists, industrial design, fashion design, and architecture, as well as 'hybridized' firms which combine creative and technological outputs toward products (goods and services) imbued with high design content, including multimedia and 'new media' activities, internet graphics and imaging, and software design. again to reference scott, "an ever-widening range of economic activity is concerned with producing and marketing goods and services that are infused in one way or another with broadly aesthetic or semiotic attributes" (scott, : ) . creativity is an essential element of the city's role as centre of innovation, in cultural, industrial, and intellectual realms (hall, ) . within the broadly defined asia-pacific region we can readily identify some leading exemplars of this 'new urban cultural economy', such as los angeles (film production and post-production, music, and media), tokyo (media and communications, architecture, design-based industries), seattle (software design, music production), hong kong (music, creative and design-based industries, media and communications), singapore (advertising and corporate branding, multimedia), melbourne (creative and design-based industries), and vancouver (graphic design and multimedia). the rapid expansion of these important new industries can be seen as the most recent development phase in the continuing evolution of the urban service economy, and the enduring competitive advantage of cities for specialized cultural production, as well as the reassertion of production activity in the inner city districts of some urban areas. moreover, these new forms of specialized cultural services production are characterized by a distinctive interface with consumer markets, as many of these industries supply what scott terms 'cultural products' (scott, : ) which influence public tastes and preferences, and are concerned with differentiating consumer market segments. the 'new cultural economy' represents a leading-edge urban policy area. within the mature urban societies of the atlantic core, there is a significant record of policy innovation. for example, within the eu, there are numerous programmes for both national and local governments to support cultural industries, including the annual designation of 'european cultural cities'. at the national level, the british government has produced detailed inventories of cultural industries, including employment, sales, and exports, as well as policy guidance for local authorities. in north america richard florida has written about the crucial importance of the 'creative class' of service workers for advanced urban economies, and has emphasized the need for progressive policies (liberal immigration policies, generous public support of the arts) to attract and nurture this creative workforce (florida, ) . within the asia-pacific, the new cultural economy should emerge as an increasingly important component of service industry strategies and more comprehensive economic development programmes. in singapore, the tourism board is active in promoting activities which intersect the new economy (technology-intensive industries) and the new cultural economy, including internet design firms, advanced design, and other creative services, concentrated within designated sites in chinatown, just west of singapore's cbd. as another example, far east properties has entered into an agreement with the government of canada, nortel networks, and the eu to sponsor a new business centre in another area of traditional chinese shop houses, just east of cross street, demonstrating again the possibilities of co-operative development in the advanced service economy. the refurbishing and subsequent 'recolonization' of these important heritage districts suggests that culture and social memory can be reconciled at one level with economic innovation, although there are of course sublimated tensions in these processes of transition and appropriation (see yeoh and kong, ( ) for insightful treatments of these issues). west coast cities in north america are also active in promoting the new cultural economy sector. los angeles and san francisco have agencies which promote new activity including these new cultural economy industries. in vancouver, the municipal government has undertaken comprehensive land use and rezoning to facilitate the transformation of a large ( ha) inner city site from traditional industry, warehousing and industry to new industries which interface with the technology and cultural sectors. this project includes a new campus (great northern way campus) comprising units of four vancouver-area universities and colleges, which has been established both to stimulate industrial innovation in the larger site, and also to encourage synergies between design-based and technology-based industries. there is also support for cultural and creative service industries among certain chinese cities. as observed earlier beijing's current plan strongly endorses the city's traditional cultural role, but there is also significant innovation in contemporary art and creative industries among beijing's universities and art schools (fackler, ) . in shenzen, a new three-year study of the city's dynamic cultural industries will include empirical research on clustering, linkage patterns (both place-and web-based), and the discourse of cultural landscapes, both to enlarge scholarly appreciation of these industries, and to inform policy (li, , personal communication) . on the other hand, the city of shanghai is demolishing the warehouses along suzhou creek which have provided a distinctive milieu for artists, artisans, and other creative workers. this eradication of shanghai's artist-loft district has been criticized as inimical to the fostering of cultural industries which complement the commercial functions of world cities, and to the emergence of an important 'spontaneous' (as distinct from induced) creative services cluster. lu yongyi, a professor urban planning at tongji university, has asserted that "[i]t will be too late when they realize these ruined communities were things of value that can never be rebuilt" (fackler, ) . by way of contrast, the residential high-rise towers which will replace the suzhou creek warehouse district, while meeting to be sure social needs, are replicated throughout the city, and could have been accommodated elsewhere in the comprehensive redevelopment of shanghai. finally, an increasing number of cities are exploring the ' h city concept' as a means of supporting the lifestyles of workers engaged in creative and 'hybridized' designtechnology enterprises. research has indicated that many of these professionals, artists, and entrepreneurs have irregular working hours, and are attracted by the h urban amenities of restaurants, night clubs, and all-night 'raves', as well as alternative recreations, such as skateboarding. these all-night activities do create tensions in residential areas within the inner city. here, there are possibilities for effectively integrating social planning, cultural programmes, and advanced service industry policies to nurture the development of these important new cultural and hybridized industries which constitute ascendant features of the st century inner city among advanced urban societies. conclusion: an agenda for scholarly investigation the purpose of this exploratory paper has been to establish tertiarization as an increasingly important process of urban development within the asia-pacific. the growth of advanced service industries will be crucial to the development of asia-pacific city-regions (and indeed to national economic progress) over the first decades of the new century. more particularly, advanced, specialized service industries will be central to employment and human capital formation, to the expansion of the urban middle class, to the more efficient operation of advanced industrial production systems and trade networks, and both to urban competitive advantage and the socio-economic sustainability of asia-pacific cities. reinforcing this latter point, many of the region's large industrial metropoles will begin to 'shed' manufacturing employment (as experienced in the wrenching deindustrialization of mature atlantic city regions, and in the 'hollowing out' of japanese manufacturing capacity), and will need services growth to partially offset these contractions. at the same time, growth in advanced service industries and employment will require greater public policy commitments, not only in the areas of infrastructure and supporting systems, and in land use policies, but also in education and training. here, we can return to an earlier comparative theme addressed in this paper, by acknowledging that effective policies for services (incorporating developmental as well as regulatory elements) have been seen as lacking in the old atlantic core coffey, ) , despite a relatively early experience of growth in advanced services within the region as a whole. the cities of the asia-pacific (and their respective central and regional governments) will need to develop more innovative policy approaches toward service industries over the next decade and beyond, reflecting the increasing significance of advanced services for economic transition and modernization. moreover, it must be acknowledged that policy selection in this sphere entails value choices (and conflicts). the facilitation of advanced services growth can, as we have seen in a number of asia-pacific cities, entail the dislocation of traditional industries, informal services, and residential populations. a balance must be struck between the imperatives of economic modernization and the claims of social justice, as well as respect for diversity and pluralism. a progressive urban planning posture should support the preservation of informal services and historic city districts, both of which sustain the authenticity of local identity, while at the same time promoting the intermediate, technology-based, creative and other specialized services essential to development. the idea of sustainable development, which has been articulated in some urban strategic plans within the region (at least at a rhetorical level), may present a progressive planning framework for integrating social, economic, and ecological values. recent research has disclosed that there may in fact be significant policy complements intersecting urban sustainability and competitive advantage, including policies for compact urban structure and land use, efficient transportation and transit, and education investments (goldberg and hutton, ) , which may inter alia support advanced service industry development, as well as enhancing social welfare and ecological sustainability. to some extent the expansion of service industries within the asia-pacific has assumed basic features of the earlier urban tertiarization experience within the mature regions of the atlantic core, but in other respects has been quite distinctive. these contrasts can be attributed in part to different models of intermediate services production and exchange, to the special roles of government policy in promoting accelerated services growth, and to the marked disparities in overall development at national and regional scales within the asia-pacific. these contrasts were identified and incorporated in our provisional typology of urban service specialization. the differentiated growth rates and levels of specialization in advanced services decisively influences urban hierarchy within the region, as well as patterns of services trade and exchange, and global city-region status (rimmer, ) . indeed, one of the salient issues for the future will be the extent to which full globalization processes may override established regional service markets, for example in finance, property and real estate, among others. the specialized service centres and corridors described earlier may emerge as platforms for the globalization of services produced within the asia-pacific, as well as engines of development within the region. the narrative suggests a mandate for scholarly inquiry into the growth and development of service industries within the broadly defined pacific realm, derived from attributes of the tertiarization experience which include ( ) relatively high growth rates of service industries and employment in an expanding number of pacific societies over the past decade or so; ( ) the larger developmental implications of rapid tertiarization, whether viewed as an important extension of industrialization, or as essentially a new phase of socio-economic development; ( ) the more specific consequences of rapid services growth for urban (and more categorically metropolitan) areas, and especially the role of tertiarization in processes of urban transition and transformation; ( ) the distinctive interface between public policy and market forces in the acceleration of service industry growth in many cities and regions of the asia-pacific; and ( ) the more problematic outcomes and impacts of service industry development within the pacific new core, including displacement and polarization impacts, exacerbation of globalization pressures on existing industries and local communities, and the special problems presented by the larger economic crises within east and southeast asia in particular, a phenomenon which has had serious consequences for the service industries of the region. no doubt other themes could be elucidated (beyers, ) , but even this necessarily selective inventory of strategic considerations presents a rich, stimulating and potentially consequential agenda for scholarly research. in addition to these empirical problems and policy issues, there are important theoretical questions to be addressed, associated with the role of tertiarization processes in the structure, growth and transformation of city-regions within the asia-pacific. there is a need to reconsider urban models embedded within the industrialization paradigm, in order to accommodate the increasing influence of service industries in the development of urban regions within the pacific realm. these theoretical exercises will naturally acknowledge the centrality of industrial trends and economic factors, but will ideally transcend narrow economistic parameters to consider both the social implications of services growth, as well as the socio-cultural basis of advanced tertiarization, following the lead of progressive urban scholarship both in the atlantic and pacific spheres (moulaert and gallouj, ; kim et al., ) . more specifically, there is a clear need for conceptualization of trajectories of service sector development within the asia-pacific which embody experiences of differentiation and exceptionalism that abound within the region, as well as more widely observed features. beyond this important theoretical terrain, urban scholarship should address the relationships between the location of service industries and the reconfiguration of regional structure and the metropolitan space-economy. innovative new research in this realm includes larissa muller's work on business services in southeast asia, incorporating commentary on opportunities 'for localizing international investment' within the region (muller, ) . at the larger metropolitan scale, these models would position services as decisive influences on multinucleation, and would encompass spatial linkages between advanced services and manufacturing enterprises in regional production systems. at a more localized level, new urban spatial models should incorporate the emergence of emerging clusters of specialized services within reconstructed precincts of the inner city, including constituent ensembles of integrated services production networks. this should include research on the 'new economy' industries and cultural and creative activities which comprise the most recent phase of urban service industry development. finally, we can identify rich potential for socio-economic models of urban tertiarization that depict the role of services in social change within the region. there is an opportunity to investigate the hypothesis of a 'new middle class' (ley, ) as an ascendant social constituency among those asia-pacific cities which have experienced rapid growth in services. another research frontier concerns the new social divisions of service labour within asia-pacific cities, reflecting the convergence of culture, technology and urban milieu, observed in a growing number of new service production spaces within the region. then there is the overriding influence of global processes on the occupational and social structures of urban communities, including the role of mncs, the changing international division of production labour, innovation in telecommunications, and international migration. the extent to which these three powerful sets of forces-an ascendant new middle class of elite service workers, emerging social divisions of service labour, and globalization processes-influence social change and exacerbate social polarization tendencies within asia-pacific cities will surely assume greater theoretical and normative importance over the next decade and beyond. australian cultural diversity and export growth, office of multicultural affairs, canberra. asian development bank social transformations in the global city: singapore the coming of the post-industrial society services and the new economy: elements of a research agenda the service economy: export of services in the central puget sound region multimedia utopia? a geographical critique of high tech development in malaysia's supercorridor tropes of transboundary economic regions 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changing relationship with china: a speculative essay services in asia and the pacific: selected papers, united nations asean-eec trade in services corridors: a theory of urban system urban spatial structure in a transitional economy: the case of guangzhou development of land use and urban planning of guangzhou, centre for urban and regional studies bangkok's restaurant sector: gender, employment and consumption shanghai: transformation and modernization under china's open policy building a competitive pearl river delta region: cooperation, coordination, planning portraits of places: history, community and identity in singapore changing southeast asian cities: urbanization and the environment in international perspective the culture of cities sources for this project included extensive site visits and field trips to cities within the asia-pacific; communication with numerous colleagues, and key informants; participation in conferences and special workshops; and a review of several distinct literature domains, including the services research literature, asian urban studies, and the urban change and transformation scholarship. visits to chinese and southeast asian cities were undertaken as part of a much larger asian urban research project managed by the ubc centre for human settlements, supported by the canadian international development agency (cida centre of excellence grant # -s ). this study includes references to research undertaken by colleagues within partner institutions in asia, as well as theses produced by ubc graduate students supported by this cida grant. site visits and study tours of japanese cities were enabled by grants from the japan foundation, the japanese ministry of education, and the ubc hampton research fund. fieldwork in san francisco was supported in part by a grant from the ubc vice-president's (research) discretionary fund. an exploratory workshop on 'service industries and new trajectories of urban development within the asia-pacific', involving many of the leading international scholars in service industry scholarship and in asian urban studies was convened at the university of british columbia in march, , generously supported by the peter wall institute for advanced studies, ubc. this workshop significantly contributed to new knowledge on the role of service industries in processes of urban change within the asia-pacific, substantially informed this current paper, and generated manuscripts to be included in a new book to be co-edited by peter daniels (university of birmingham), kong chong ho (national university of singapore), and me.i also want to acknowledge the generosity of the centre for advanced studies at the national university of singapore in making possible my sojourn as visiting scholar in july of . this enabled me to liaise with (new and existing) colleagues, to conduct fieldwork, and to present a selection of findings to a cas colloquium. in particular i would like to express my appreciation to brenda yeoh, k.c. ho, peggy teo, and kris olds of cas (the latter now at the department of geography, university of wisconsin at madison), and to henry yeung of the nus department of geography.finally, i want to acknowledge the essential contributions of ubc colleagues. michael leaf (director, centre for southeast asian research, and faculty associate at chs) and david edgington (director, centre for japanese research, and associate professor in the department of geography) have generously contributed many expert insights on development planning issues in china, southeast asia, and japan. i am very grateful indeed for the administrative support of ms karen zeller, and the unfailingly professional and patient assistance of ms sharon kong in the preparation of this manuscript; for the high levels of technical assistance provided by ms christine evans; and for the excellent cartographic services of mr eric leinberger of the ubc department of geography. key: cord- -sy ncwgw authors: yap, jonathan; lee, vernon j; yau, teng yan; ng, tze pin; tor, phern-chern title: knowledge, attitudes and practices towards pandemic influenza among cases, close contacts, and healthcare workers in tropical singapore: a cross-sectional survey date: - - journal: bmc public health doi: . / - - - sha: doc_id: cord_uid: sy ncwgw background: effective influenza pandemic management requires understanding of the factors influencing behavioral changes. we aim to determine the differences in knowledge, attitudes and practices in various different cohorts and explore the pertinent factors that influenced behavior in tropical singapore. methods: we performed a cross-sectional knowledge, attitudes and practices survey in the singapore military from mid-august to early-october , among personnel in four exposure groups - laboratory-confirmed h n - cases, close contacts of cases, healthcare workers, and general personnel. results: ( . %) participants responded. the mean age was . (se . ) years old. close contacts had the highest knowledge score ( . %, p = . ) while cases had the highest practice scores ( . %, p < . ). there was a strong correlation between knowledge and practice scores (r = . , p < . ) and knowledge and attitudes scores (r = . , p < . ). the significant predictors of higher practice scores were higher knowledge scores (p < . ), malay ethnicity (p < . ), exposure group (p < . ) and lower education level (p < . ). the significant predictors for higher attitudes scores were malay ethnicity (p = . ) and higher knowledge scores (p < . ). the significant predictor for higher knowledge score was being a contact (p = . ). conclusion: knowledge is a significant influence on attitudes and practices in a pandemic, and personal experience influences practice behaviors. efforts should be targeted at educating the general population to improve practices in the current pandemic, as well as for future epidemics. background >in april , a novel strain of influenza a (h n ) surfaced and has since spread widely across the globe with substantial clinical impact [ ] . effective pandemic management requires support from the population at risk for measures undertaken to mitigate the pandemic's spread. previous studies during the severe acute respiratory syndrome (sars) outbreak in have shown that individual beliefs and perceptions play an important role in subsequent desired behavior change [ , ] . higher perceived effectiveness of measures undertaken [ , ] and higher perceived threat of the disease led to higher rates of positive behavioral change, and better knowledge also increased the uptake of preventive measures [ , ] . similarly, in an anticipated h n epidemic these factors also influenced both self and community protective behavior [ ] . during the current influenza pandemic, studies have found that the individual's emotional status mediates behavioral response [ ] and that perceived severity and susceptibility to disease and perceived effectiveness of specific behaviors resulted in the corresponding recommended behavior changes [ , ] . to increase positive perceptions, clear dissemination of information served to reduce misconceptions [ ] . at the same time, interactions with family and friends influenced behavior, and distinct regional differences in behavioral responses were noted across various countries which may be due to socio-cultural differences [ ] . it is therefore important to perform behavioral studies in different populations to understand the determinants that influence behaviors. in tropical regions, influenza exhibits different seasonal patterns with a high baseline influenza-like illness rates and multiple influenza epidemic peaks annually [ ] . this may result in different behaviors towards influenza compared to temperate countries with clear influenza seasons during winter months -for example the generally lower influenza vaccination uptake in the tropics [ ] . however, there have been few studies on the knowledge, attitudes and practices towards the influenza pandemic in a tropical setting. there have also been no studies comparing such differences in various cohorts such as influenza cases, close contacts, and healthcare workers. as such, there is a need to understand the factors influencing such behavioral changes to promote effective management of influenza pandemics in the tropical setting. singapore, a tropical island city-state in south-east asia, experienced the local spread of pandemic influenza a (h n - ) from june to october in a single typical epidemic wave. our study, conducted in the singapore military, aims to study the differences in knowledge, attitudes and practices in various different cohorts and explore the pertinent factors that influenced behavior. we performed a cross-sectional survey in the singapore military from mid-august to early-october , after the peak of the local epidemic which occurred during the first week of august in singapore [ ] . the singapore military comprises of conscript males who serve compulsory military service after high school, and nonconscript regular servicemen. most servicemen stay in camp during weekdays and return to the community/ home during weekends, resulting in interactions within the military and general communities. as part of the military's pandemic response plan, every serviceman was given an information pamphlet on pandemic influenza, with information about the virus and preventive measures that could be taken to reduce risk of transmission and infection. the servicemen were also briefed on the above with emphasis on personal hygiene measures and socially responsible behavior (for example covering the nose and mouth when sneezing and coughing). other measures implemented include daily temperature monitoring, prompt reporting of all illnesses to healthcare staff, and laboratory testing of influenza-like illness clusters. laboratory confirmed cases of h n - were isolated at home for days, while close contacts of these confirmed cases were allowed to continue working but were given post-exposure chemoprophylaxis with oseltamivir and were segregated from the rest of the military units to prevent spread. in addition, all healthcare workers were required to don personal protective equipment including n- masks during their working hours. our study population consisted of distinct exposure groups of military personnel -laboratory confirmed h n - cases, close contacts of h n - cases (defined as those who had worked or lived with a laboratory confirmed h n - case during the infectious period), healthcare workers, and other general servicemen. the military maintained a comprehensive list of all laboratory confirmed cases of h n - and their close contacts, which were identified via contact tracing. an anonymous self-administered paper questionnaire was mailed to the respective servicemen with a self addressed envelope included for return of the survey forms. questionnaires were sent to all laboratory confirmed cases and their contacts, all healthcare workers in the military and general servicemen from various representative units in the military. approval for the study was obtained from the military's research committee. we developed a questionnaire to assess the knowledge, attitudes and practices (kap) regarding pandemic influenza. the questionnaire was based on similar questionnaires on this topic [ , ] , as well as concepts of health behaviours [ , ] , and was pilot tested among military servicemen with similar profiles to the actual cohort. the questionnaire collected basic demographic data on age, sex, ethnicity, education level and housing type while is a commonly-used national proxy for socio-economic status [ ] ; and included questions on knowledge, attitudes, and practices on pandemic influenza. questions on knowledge were used to assess a servicemen's general knowledge on pandemic influenza and on the recommended response measures. questions on attitudes were used to assess perceptions towards pandemic influenza and these measures. questions on practices were used to assess the actual compliance and practice of these measures. a summary of the questions assessed are shown in table . servicemen were asked to rate their agreement with the statements in the questionnaire, which were scored either yes/no or on a point likert scale. to determine the sample size, we assumed that responses within each group were normally distributed with standard deviation of %. to detect a true difference in means between groups of %, we will need participants per group to achieve power of . and p = . . due to the smaller number of known patients and contacts available, we mailed out more survey forms to general servicemen from various units to provide a larger control group and to account for nonresponse. to determine the scores for each individual, the responses were recoded to for an undesired response and for a desired response with the exception of risk perception questions which were scored proportionate to the level of risk perception. the mean scores were summarized as percentages. chi-squared tests of significance were used for analyses of categorical variables, and analyses of variance were used for continuous variables among the four exposure groups of servicemen (patients, contacts, medical personnel and other servicemen). the relationships between knowledge, attitudes and practice scores were examined using bivariate correlational analyses and multivariate linear regression models. all the demographic variables were found to be significant predictors in the bivariate analyses in at least one exposure group of servicemen, and were hence included in the multivariate models, which included the practice scores and attitude scores as the dependent variables. all statistical analyses were performed using spss . for windows (spss inc, chicago, il), with the level of significance set at %. surgical/paper masks are effective in reducing the spread of pandemic influenza. influenza vaccination is an effective measure against influenza. tamiflu is effective for treatment of pandemic influenza a (h n ). tamiflu is effective for prophylaxis (prevention) against pandemic influenza a (h n ). it is likely that i will catch the pandemic virus. how long do you think the pandemic influenza infection will last? are you worried or distressed about the pandemic? results a total of survey forms were mailed out ( patients/contacts, healthcare workers and to general servicemen). the overall response rate was . % ( / ). the response rates for patients/contacts, healthcare workers and other servicemen were . %, . % and . % respectively. table shows the demographics of the respondents. the majority of the respondents were males aged between - years old, reflecting the typical profile of our conscript military. general soldiers were of significantly lower education level and socio-economic status (as measured by the type of housing) compared to the other exposure groups. for the entire cohort, basic general knowledge of pandemic influenza a (h n - ) was in general good with the exception of the low awareness by servicemen that influenza can be spread by touch ( . %) and that it can present with nausea/vomiting ( . %) or diarrhoea ( . %). knowledge regarding efficacy of mask use, oseltamivir and personal hygiene measures were good with more than % positive responses. risk perception of illness was moderate, with almost half of the respondents believing they would be infected with pandemic influenza. for the practices, . % of the cohort had used masks during the course of the pandemic (when ill or as prevention), . % had previous seasonal influenza vaccination, . % had practiced avoidance behaviors such as social distancing, and . % practiced personal hygiene measures. less than a third of respondents avoided seeking medical aid for influenza symptoms despite worries regarding picking up the illness at medical facilities. comparing between the exposure groups of servicemen (table ) , there was a significant difference between knowledge and practice scores. close contacts had the highest knowledge score ( . %), followed by healthcare workers ( . %), patients ( . %) and general servicemen ( . %) (p = . ). patients had the highest practice scores ( . %) followed by healthcare workers ( . %) and contacts ( . %), while general servicemen had the lowest practice score ( . %) (p < . ). there were no significant differences in attitude scores between the cohorts. a greater proportion of patients used masks ( . %) compared to the other groups ( . - %) (p < . ). healthcare workers had the highest seasonal influenza vaccination uptake ( %) as compared to between - % in other groups (p < . ). contacts had the highest practice of avoidance behaviors ( . %) as compared to . %, . % and . % in patients, healthcare workers and general servicemen respectively (p < . ). general servicemen had the lowest mask usage ( . %), vaccination uptake ( . %) and practice of avoidance behaviors ( . %). from the univariate analyses, significant predictors for higher practice scores included female sex, exposure group (patients, contacts and healthcare workers compared to general individuals), ethnicity (malay and indian compared to chinese), older age group, private housing compared to room flats, and higher knowledge and attitude scores. the significant predictors of higher attitude scores were ethnicity (malay compared to chinese) and higher knowledge scores. the significant predictors for higher knowledge scores were contacts and healthcare workers, older age group, higher education levels, and private housing compared to room flats. from the multivariate analyses adjusting for potential confounders (table ) , the final significant predictors of higher practice scores were higher knowledge scores (p < . ), malay ethnicity (p < . ) and exposure group -patients (p < . ), contacts (p = . ) and healthcare workers (p = . ). servicemen with higher education level (ie. university degree) had significantly lower practice scores (p = . ). the final significant predictors for higher attitudes scores were malay ethnicity (p = . ) and higher knowledge scores (p < . ). the final significant predictor for higher knowledge score was being a contact (p = . ). the strongest overall correlation was between knowledge and practice scores (r = . , p < . ), followed by knowledge and attitudes scores (r = . , p < . ). the weakest correlation was between attitudes and practice scores (r = . , p < . ) ( table ). all exposure groups had significant correlation between knowledge and practice scores, as well as knowledge and attitudes scores. only healthcare workers had a significant correlation between attitudes and practice scores (r = . , p < . ). our study provides evidence on the correlation between knowledge, attitudes, and practices among different exposure groups. this has substantial implications for public health educators and planners in implementing pandemic preparedness plans. it was evident that the knowledge score was the main predictor of the attitude and practice scores with strong correlation between knowledge and practice scores and knowledge and attitude scores. on the other hand, attitude scores alone did not predict practice score and the correlation between attitude and practice scores was weak. this shows that good knowledge is important to enable individuals to have better attitudes and practices in influenza risk reduction. in a previous study on sars, better knowledge was also found to equate with better adoption of precautionary practices [ ] . clear communication and provision of updated information also helped improve vigilance and preparedness during the current pandemic [ ] . a recent study found that educating the public about specific actions to reduce risks and communicating about the government's plans and resources helped to improve compliance to good practices [ ] . of interest, higher educational status in our cohort was a significant negative predictor of good practice, showing that educational status alone does not determine behaviours. two previous studies on influenza [ ] and sars [ ] also showed that education level did not have any effect on uptake of recommended behvioural patterns. regarding influenza vaccine uptake and education level, some studies have showed that a higher education level resulted in higher influenza vaccination uptake [ , ] , while another study on influenza vaccination uptake showed varying influence of education levels on influenza vaccination in different countries [ ] . as such, it is important to focus on inculcating the correct knowledge to individuals as it will influence both attitudes and practices. on the other hand, positive attitudes on its own may not translate into desired behavioral change in the absence of adequate knowledge. for the exposure groups, influenza cases had the highest practice scores of all groups. use of masks was also highest among the influenza cases. having been infected with pandemic influenza appears to have a substantial impact in behavior and adopting risk reduction practices. although most if not all of these influenza cases will not be re-infected by the same pandemic virus again, adopting these practices will place them and their close contacts at lower risk for other influenza and respiratory virus infections. at the same time, healthcare workers and contacts of influenza cases also had higher practice scores compared to general servicemen. vaccination uptake was highest among healthcare workers and avoidance behaviors were the highest among contacts of influenza cases. healthcare workers and contacts have had greater and more direct exposure to influenza cases compared to the general population and this first-hand experience may have resulted in behavioral changes. this possibly reflects the effect of actual real-life experiences with influenza on individual behavior. it will therefore be important to determine solutions to instill the same level of positive behaviors in the general population without the need for prior infection or the personal experience such as being close contacts or healthcare workers. one possible solution would be the sharing and imparting of personal experiences to the general community ethnicity may also play a role in determining practices. we found that malays (an ethnic minority) had significantly higher positive practices as compared to the chinese (the ethnic majority). the indians (another ethnic minority) also had higher practice scores as compared to the chinese although this was not statistically significant. a previous study also reported that the ethnic minority groups had a . times higher likelihood of making recommended changes during this current influenza pandemic [ ] . another multi-ethnic study on a different subject (terrorism) showed that worry and voidance behaviours were more common among minority groups, suggesting that this effect may be due to shared perceptions of vulnerability or low levels of control [ ] but further research is required to determine the actual causes for this phenomenon during epidemics. overall efforts at increasing positive behaviours should therefore be rolled out to the entire population, with special focus on the ethnic majority. we found that age, sex, and housing-type (as a proxy of socio-economic status) did not predict knowledge, attitudes or practices. however, the vast majority (> %) of our participants were from the - age group due to the inherent nature of the military and our study was not structured to detect any differences due to extremes of age. in another pandemic study in the united kingdom, younger age was found to have greater uptake of recommended behaviors but not for sex and household income [ ] . however, another study on behavioral changes during sars found that the older age had an increased beneficial effect on behavioral change but not sex [ ] . this shows the differences in behaviors in different settings and towards different threats. future studies need to be performed in different age groups in specific settings to determine the actual platforms for intervention. the possible lack of representativeness of a military cohort to the general population is an inherent limitation of this study, especially for the overall age structure. however, it does represent the behaviors of an important age group for the influenza pandemic, which affects mostly children and young adults. the questionnaire was also administered over a period of time and individuals' responses may have changed across time as they are exposed to different messages across time, include messages highlighting the pandemic's mild nature. we attempted to reduce this by starting the survey after the pandemic's peak and concluding it before the epidemic subsided. the response rate of . % may also be of concern, but the study was sufficiently powered for all groups except influenza cases which numbers were smaller. interestingly, the response rates among cases/contacts was high, and lower among healthcare workers, which may itself suggest behavioral differences which should be further studied. given the anonymous nature of the survey, we were not able to obtain any data about non-responders. finally, our study was a cross-sectional survey and may not have been able to assess the true association between knowledge, attitudes and practices, and future cohort studies should be considered to validate the findings. knowledge is a significant influence on attitudes and practices in a pandemic, and personal experience influences practice behaviors. efforts should be targeted at inculcating relevant knowledge and educating the general population to improve practices in the current pandemic, as well as for future epidemics. world health organisation: pandemic (h n ) -update an 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the pre-publication history for this paper can be accessed here knowledge, attitudes and practices towards pandemic influenza among cases, close contacts, and healthcare workers in tropical singapore: a cross-sectional survey we acknowledge the invaluable assistance provided by joseph kang, douglas wong, edmund de silva and vasanth from healthcare branch for their help in collecting the data for the study role of funding source this study was part of a singapore ministry of defence study and no additional funding was required.author details biodefence centre, ministry of defence, singapore. department of epidemiology and public health, national university of singapore, singapore. centre for health services research, national university of singapore, singapore. national centre for epidemiology and population health, australian national university, australia. healthcare branch, ministry of defence, singapore. department of psychological medicine, national university hospital, singapore. authors' contributions jy, vjl and pct conceived the study, collected the data, performed the analysis, and wrote the manuscript together. tyy collected the data and participated in the manuscript writing. tpn performed the analysis and participated in the manuscript writing. all authors have read and approved the final manuscript and the manuscript is currently not submitted for publication elsewhere. the authors declare that they have no competing interests. key: cord- -be v kuu authors: mukherjee, pratik; lim, poh lian; chow, angela; barkham, timothy; seow, eillyne; win, mar kyaw; chua, arlene; leo, yee sin; chen, mark i-cheng title: epidemiology of travel-associated pandemic (h n ) infection in patients, singapore date: - - journal: emerg infect dis doi: . /eid . sha: doc_id: cord_uid: be v kuu in june , during singapore’s pandemic influenza plan containment phase, pandemic (h n ) was introduced into the country through imported cases. to understand how travel patterns affected the initial outbreak, we examined epidemiologic and travel data for the first case-patients admitted to tan tock seng hospital, singapore, with travel-associated infection. sixty-one percent and % of patients, respectively, met us centers for disease control and prevention and world health organization temperature criteria for influenza-like illness. one fourth of the case-patients traveled after illness onset, and % became ill while traveling. regions of exposure for imported infections changed rapidly; case-patients initially arrived from north america, followed by australasia and southeast asia. case-patients on longer flights were more likely to become ill before arrival; those with shorter flights tended to become ill after arrival. thermal scanners detected fevers in % of the arriving case-patients, resulting in a shorter time to isolation. in june , during singapore's pandemic infl uenza plan containment phase, pandemic (h n ) was introduced into the country through imported cases. to understand how travel patterns affected the initial outbreak, we examined epidemiologic and travel data for the fi rst case-patients admitted to tan tock seng hospital, singapore, with travel-associated infection. sixty-one percent and % of patients, respectively, met us centers for disease control and prevention and world health organization temperature criteria for infl uenza-like illness. one fourth of the case-patients traveled after illness onset, and % became ill while traveling. regions of exposure for imported infections changed rapidly; case-patients initially arrived from north america, followed by australasia and southeast asia. case-patients on longer fl ights were more likely to become ill before arrival; those with shorter fl ights tended to become ill after arrival. thermal scanners detected fevers in % of the arriving case-patients, resulting in a shorter time to isolation. o n april , , international authorities reported cases of infection with a novel infl uenza a virus (h n ) strain of swine origin, now known as pandemic (h n ) virus; cases in the united states and clusters in mexico were confi rmed, and surveillance indicated infl uenza-like-illness (ili) had been increasing in mexico since march , ( ) . during the next months, this virus spread rapidly across the globe, resulting in > , cases and at least , deaths on continents as of august , ( ) . for most countries, the initial introduction of this virus occurred through international travel and humanto-human transmission. the role of air travel in the transmission and dissemination of respiratory infections has been examined for severe acute respiratory syndrome (sars), pneumonic plague, and extensively drug-resistant tuberculosis ( - ). grais et al. ( ) explored the possible effect of airline travel on geographic spread of pandemic infl uenza in through simulation models of the pandemic infl uenza a virus (h n ) of - , using air travel data for global cities. the effect of air travel on facilitating the transmission and dissemination of infl uenza is borne out by other recent studies suggesting that decreased volumes of air travel in the - months after the terrorist attacks in the united states on september , , delayed that winter's seasonal infl uenza peak and decreased transmission ( ) . human-to-human transmission of infl uenza during air travel has been reported to occur on fl ights of at least hours and to affect passengers seated within rows of the index case-patient ( ) . however, other reports show that respiratory infections can spread during shorter fl ights and over considerable distances within the cabin ( , ) . for the purposes of infl uenza contact tracing, the world health organization (who) has defi ned considerable exposure on aircraft as being restricted to passengers sitting in the same row or within rows of an infectious person for a fl ight time of > hours ( ) . singapore implemented the containment phase of its pandemic infl uenza plan on april , , before pandemic (h n ) was introduced into the country. public health policy during this phase was to isolate infected case-patients and quarantine exposed persons to prevent local transmission for as long as possible. during this initial period, travel from a pandemic (h n ) -affected during the containment phase, airport thermal scanners were used to detect fevers in arriving passengers at singapore's changi international airport, and health advisories were used to encourage travelers in whom infl uenza-like symptoms developed after disembarkation to seek medical care. ambulances, dedicated for this purpose only, were used to transport suspected case-patients from the airport to hospitals for screening. adults with appropriate travel histories and ili were referred to the designated screening center at tan tock seng hospital (ttsh) for treatment and isolation at the communicable disease centre. during the mitigation phase, the focus of clinical and public health efforts shifted to caring for patients with severe illness and conditions that put them at risk for complications and to reducing transmission in the community through health education and voluntary selfisolation of persons with ili. we analyzed epidemiologic and travel data as well as data regarding source of referral for case-patients in relation to time of illness onset, time of arrival in singapore, and time to isolation. understanding how travel patterns affected propagation of the fi rst pandemic wave of pandemic (h n ) virus could yield insights into how the anticipated next wave might be disseminated and provide data on the effectiveness and limitations of different interventions used to slow dissemination. we obtained demographic data and travel-related information (last port of embarkation and fl ight times) by direct interview and retrospective review of clinical notes. duration of travel, which was calculated from fl ight times and transit time within airports, was categorized into groups: short haul (< hours), medium haul ( - hours), long haul ( - hours), and extra-long haul (> hours). clinical data were collected for symptoms and date and time of symptom onset (to the nearest hour in most instances and to the nearest -hour block [midnight to : am, : am to . pm, or : pm to : pm] if the patient was unsure). symptom onset time was further categorized as before embarkation, during travel, or after disembarkation in singapore. we also categorized hospitalized case-patients on the basis of whether their symptoms met us centers for disease control and prevention (cdc) ili criteria (body temperature > . °c with either cough or sore throat in the absence of an alternative diagnosis) and who ili criteria (body temperature > °c with either cough or sore throat in the absence of an alternative diagnosis) ( , ) . a confi rmed case of pandemic (h n ) was defi ned as an ili in a patient with a temperature > . °c, cough, rhinorrhea, sore throat, or myalgia and with laboratory confi rmation of infection by real-time reverse transcription-pcr performed on respiratory samples (sputum or combined nasal and throat swab specimens). an imported, travel-associated case was defi ned as above but occurred in a person with recent travel outside singapore who had arrived in singapore during the containment period and had illness onset within days of arrival. we compared proportions by using the χ test. means were compared by use of t tests for dichotomous variables and -way analysis of variance for multichotomous variables. stata . for windows (statacorp lp, college station, tx, usa) was used for all statistical analyses. from table . infections involved equal numbers of male and female travelers and occurred predominantly in young travelers (mean age . years; % were < and % were > years of age). half of the travelers were singaporeans returning from abroad, and the other half were travelers from other countries. as shown in figure , the regions where travelers were exposed to pandemic (h n ) virus changed rapidly during the -week period of study. most of the cases in epidemiologic weeks and (may through june ) were in patients who acquired their infection in the united states; however, within weeks, this had changed dramatically, with a large proportion of cases coming from australasia in epidemiologic week (june - ). within a week, this situation changed yet again; most infections originated from southeast asia by epidemiologic weeks - (june - ). the fi rst cases of pandemic (h n ) detected among travelers arriving from the philippines (week ), thailand (week ), and indonesia (week ) indicated potential community transmission in those countries earlier than offi cial announcements. infections from southeast asian countries accounted for % of imported cases dur-ing the containment phase; the philippines were linked to % cases, mostly in weeks - . travel duration refl ects the distance between the regions of exposure and singapore (table ) . of the case-patients, % had a short travel duration (< hours), and % had a long travel duration (> hours). although most case-patients became ill after arrival at their destination, % were ill before travel and boarded their fl ight despite symptomatic illness, and % became ill while traveling. doctors based at the airport referred ( . %) of the patients to ttsh; thermal scanners used to screen arriving passengers had detected fever in of these patients. of the remaining patients, ( %) self-reported to the screening center at ttsh and ( %) were referred by doctors in the community. at the time of examination, % of case-patients had temperatures > . °c. however, only . % had temperatures > . °c and % had temperatures > °c, the temperature criteria used in the us cdc and who ili case defi nitions, respectively. considering the entire symptom complex, % of patients would have fulfi lled ili criteria as defi ned by the us cdc, and % would have fulfi lled the who criteria ( , ) . as the pandemic shifted toward asian ports of embarkation, the number of case-patients with travel durations of < hours increased (figure , panel a) . the time of symptom onset relative to arrival in singapore is shown in figure , panel b ; the fi gure does not include information for patients who were symptomatic before embarkation. time of symptom onset was progressively closer to the time of arrival in singapore for those arriving from longer distances (p = . ). patients with longer travel durations were also more likely to have onset of symptoms before arrival (p = . ). port of embarkation, clinical symptoms, and duration of travel did not predict delay to isolation ( table ) . however, case-patients referred to ttss by airport doctors had a shorter time to isolation ( . days) than self-referred patients or those referred by other sources ( . - . days). the number of case-patients referred by airport doctors increased over the -week period, but they represent only % of all travel-associated cases ( figure ). although the mean duration to isolation did not increase signifi cantly over the study period, total numbers of case-patients with delays to isolation increased as the volume of travel-associated cases rose. given singapore's position as a major travel hub, with passenger traffi c at changi international airport exceeding million in ( ) , there is an ever-present risk of importation and subsequent community transmission of emerging respiratory infections. such importation and transmission occurred during the sars epidemic of ( ) and remains a concern during the current pandemic of pandemic (h n ) virus. in any epidemic, every imported case may start a cluster of locally transmitted cases, but the number of imported cases and delays to isolation are particularly important at the start of the epidemic in determining speed of spread within the community. improving detection and shortening time to isolation of infectious persons could modify the outbreak curve and allow more time for improving community preparedness. improving detection and shortening the time to isolation of sick persons is the rationale for using airport thermal scanners. our data show that for the minority of cases detected by airport thermal scanners, detection does result in a hospital referral by an airport doctor and shorter time to isolation. however, intrinsic limitations of airport thermal scanners are that passengers have to become symptomatic before disembarking from a fl ight and have a fever high enough to be detected. our data show that > % of casepatients from all fl ights > hours had symptom onset before arrival, but overall, only % of all case-patients were detected by thermal scanners, suggesting that thermal scanners detected % of those symptomatic patients. this early detection and isolation may still have a valuable adjunctive role, especially in the initial phase of outbreaks. situations favoring the use of airport thermal scanners include shortincubation diseases and geographically distant outbreak epicenters, such that arriving passengers have been on a long-haul fl ight. however, if the converse were true, with emerging infectious diseases • www.cdc.gov/eid • vol. , no. , january transmission occurring in nearby countries and passengers arriving from short-haul fl ights, symptoms would develop in most passengers who become ill after entry and, thus, would be missed by airport thermal scanners. the fact that one fourth of the case-patients in our study boarded a plane after becoming ill and traveled despite having symptoms illustrates the role of travelers in disseminating infection in a highly interconnected world. it raises the question of whether exit screening should be considered. however, the effectiveness of exit screening will depend on the role of asymptomatic persons in transmission, and such screening will still miss persons who are incubating the infection. exit screening would severely hinder international travel, and because of its questionable effi cacy, it may not be justifi ed and may be contrary to the intent of the international health regulations ( ) because % of the case-patients in this study were self-referred and % were referred by community physicians, prevention efforts should focus on other strategies. for example, health advisories should be distributed to arriving passengers, encouraging them to seek medical care if ill, and steps should be taken to improve detection by physicians who see patients in their clinics. the importance of clinical judgment, epidemiologic history, and access to diagnostic testing is emphasized by the substantial minority of case-patients who would not have met the who or us cdc ili criteria but who did have laboratory-confi rmed infection. however, our study did have limitations: clinical features were assessed at a single time point (on arrival at the hospital screening center) and there was potential recall bias. our data demonstrate how swiftly situations can change in a fast-moving pandemic; affected areas shifted from the americas to australasia to asia within a matter of days. these rapid shifts pose a tremendous challenge to health authorities responsible for outbreak management, and they emphasize the narrow window of opportunity during which interventions can slow an epidemic. the monitor- ing of travelers fulfi lls a vital sentinel surveillance function, providing an early indicator of community transmission in countries even before transmission has been offi cially confi rmed. understanding how travel-associated infections propagated the fi rst wave of this pandemic yields rich insights into how health authorities might respond to future outbreaks of emerging respiratory infections. infl uenza a (h n )-update infl uenza a (h n )-update transmission of the severe acute respiratory syndrome on aircraft surveillance for pneumonic plague in the united states during an international emergency: a model for control of imported emerging diseases tuberculosis and air travel: who guidance in the era of drug-resistant tb transmission of infectious diseases during commercial air travel assessing the impact of airline travel on the geographic spread of pandemic infl uenza empirical evidence for the effect of airline travel on inter-regional infl uenza spread in the united states an outbreak of infl uenza aboard a commercial airliner world health organization. technical advice for case management of infl uenza a (h n ) in air transport interim guidance on case defi nitions to be used for investigations of novel infl uenza a (h n ) cases human infection with pandemic (h n ) virus: updated interim who guidance on global surveillance changi airport media release severe acute respiratory syndrome (sars) in singapore: clinical features of index patient and initial contacts we gratefully acknowledge all our healthcare colleagues in ttsh, the communicable disease centre, and the ministry of health, singapore, who have worked so hard on patient care and public health efforts during this pandemic.this study was partially funded by the national medical research council of singapore (nmrc/h n / / ).dr mukherjee is a medical offi cer in communicable epidemiology at ttsh. his research interests include disease epidemiology, clinical research, and pandemic infl uenza. key: cord- -xazsbhbw authors: tan, boon‐huan; lim, elizabeth ai‐sim; seah, shirley gek‐kheng; loo, liat‐hui; tee, nancy w.s.; lin, raymond t.p.; sugrue, richard joseph title: the incidence of human bocavirus infection among children admitted to hospital in singapore date: - - journal: j med virol doi: . /jmv. sha: doc_id: cord_uid: xazsbhbw human bocavirus (hbov) is a parvovirus, belonging to the genus bocavirus. the virus was identified recently in sweden, and has now been detected in several different countries. although it is associated with lower respiratory tract infections in pediatric patients, the incidence of hbov infection in a developed country in south east asia, has not been examined. the objective of this study was to determine the importance of hbov as a cause of lower respiratory tract infections among children admitted to hospital in singapore. five hundred nasopharyngeal swabs were collected from anonymized pediatric patients admitted to the kandang kerbau women's and children's hospital for acute respiratory infections. the specimens were tested for the presence of hbov using polymerase chain reactions. hbov was detected in . % of the patients tested, and a majority of these hbov patients exhibited lower respiratory tract infections. a significant level of coinfection with respiratory syncytial viruses and rhinoviruses was also observed in these hbov patients. the data suggest that hbov is an important cause of lower respiratory tract infections among children admitted to hospital in singapore, and is the first study examining the incidence of hbov infection in a developed country in south east asia. j. med. virol. : – , . © wiley‐liss, inc. respiratory syncytial virus (rsv), parainfluenza viruses (piv), adenovirus, rhinovirus (rhv), and influenza viruses are the most common etiological agents responsible for acute respiratory infections in children, causing either lower or upper respiratory tract infections. recently, several new viruses have been discovered that are associated with respiratory infections in children [see reviews by kahn, ; sloots et al., ] . the human metapneumovirus was first discovered in netherlands [ van der hoogen et al., ] , and is now reported to be an important global cause of lower respiratory tract infections in children. similarly, human coronavirus (hcov) nl and hku were first isolated in the netherlands [ van der hoek et al., ] , and hong kong [woo et al., ] , respectively, and have been reported to be associated with acute respiratory infections in children. both strains have been detected subsequently in patients from other countries [see reviews by van der hoek et al., ; pyrc et al., ] . a new parvovirus belonging to the genus bocavirus was identified in sweden [allander et al., ] , and its presence was associated with acute respiratory infections in pediatric patients [see reviews by kahn, ; schildgen et al., ] . this virus was referred to as human bocavirus (hbov), and it was distinct genetically from the human parvovirus b . since its initial discovery, hbov has been detected in children with lower respiratory tract infections in several different countries [see review by allander, ] . in asia, hbov has been reported in thailand [fry et al., ] , china [qu et al., ] , south korea [choi et al., ; chung et al., chung et al., , lee et al., ] , japan [ma et al., ] , and hong kong [lau et al., a] . in this study the incidence of hbov was examined in pediatric patients admitted to hospital in singapore. the data suggest that hbov is a possible cause of lower respiratory tract infections among children admitted to hospital in singapore. between october and march , nasopharyngeal swabs were obtained from pediatric patients admitted to kandang kerbau women's and children's hospital for acute respiratory infections. the specimens were tested in the hospital's microbiology laboratory for the presence of influenza virus, rsv, adenovirus, hmpv and piv as described previously [loo et al., ] . in all cases, aliquots of the clinical specimens were stored at À c until they were tested for the presence of hbov. this study was approved by the hospital's ethic committee, approval number ec/ / . the nasopharyngeal swabs were thawed and subjected to total nucleic acid extraction, using either the qiaamp viral rna minikit or the qiaamp rneasy minikit (qiagen inc., valencia, ca), according to the manufacturer's instructions. one to five microliters of the total extract were tested using pcr assays targeting hbov , hcov [escutenaire et al., ] , and rhv [hayden et al., ] . all primers were synthesized from prooligo (singapore). for the pcr testing of hbov, the reaction was performed in a ml reaction mixture containing . mm of each primer, . u platinum taq dna polymerase (invitrogen corporation, carlsbad, ca), . mm dntps, and . mm mgcl , in the conventional pcr machine. in the case of hcov, the pcr reaction was carried out in a ml reaction mixture containing sybr green rt-pcr reaction mix (biorad, hercules, ca) with . mm of each primer, and . ml of iscript reverse transcriptase (biorad) in the i-cycler (biorad). at the end of the reaction, the products were subjected to a melting curve analysis by heating the products to c for min, and then cooling to c for sec, and heating back to c at . c intervals. positive products are represented by hcov-specific melting peak as described [escutenaire et al., ] , and were confirmed by agarose gel analysis with visualisation in the presence of ethidium bromide staining. rhv identification was carried out with . mm of each forward and reverse primer, . mm of taqman probe in superscript reverse transcriptase/platinum taq enzyme reaction mix (invitrogen corporation) in the lightcycler machine (roche diagnostics, mannheim, germany). positive products were represented by an exponential increase of fluorescence captured by the f channel of the lightcycler. all amplified products were purified from agarose gel using the qiaquick gel extraction purification kit (qiagen inc.). the identity of the products were confirmed by dna sequencing using the bigdye terminator cycle sequencing kit (applied biosystems, foster city, ca) with the same primers used for pcr testings. the dna sequences were assembled using seqman (dnastar, lasergene version ). the viral sequences were aligned using the algorithm clustalw method in the program megalign (dnastar, lasergene version ). the percent sequence homology and phylogenetic trees were calculated and constructed using the neighbor-joining method at the nucleotide (nt) level, with bootstrap analysis performed on , replicates. the phylogenetic trees were viewed using treeview version . . [page, ] . the partial sequences for both the singapore hbovs and hcovs have been submitted to genbank under the accession numbers eu to , and eu to . a total of nasopharyngeal swabs were collected from pediatric patients admitted to kandang kerbau women's and children's hospital with acute respiratory infections. the patients exhibited symptoms that were consistent with both lower respiratory tract infections (bronchiolitis, bronchitis, pneumonia, chronic lung disease, asthma, and wheezing) or upper respiratory tract infections (croup, infantile pyrexia, pharnygitis). the age group of the children ranged from month to years. of the specimens collected, tested positive for rsv ( . %), for influenza a virus ( . %), for influenza b virus ( . %), for piv ( . %), for piv ; for piv ( . %), for adenovirus ( . %) and for hmpv ( . %) ( table i ). in addition, pcr analysis revealed that patients were positive for hbov ( . %), and tested positive for hcov ( . %). the clinical symptoms exhibited by the patients in which hbov was detected were compared with patients in which rsv, hmpv and hcov-nl were detected (tables i and ii ). in the current study, % of the patients in which hbov was detected presented symptoms that were consistent with lower respiratory tract infections, which compared with . % and . % for rsv and hmpv, respectively. these data placed hbov the % age distribution of patients refer to the samples that tested positive for each viral agent, relative to n, representing the no. of samples collected for the respective age group. c the respiratory infections are relative to the no. of samples that tested positive for each viral agent, and l refers to lrti with symptoms for bronchiolitis, bronchitis, pneumonia, asthma, wheezing, and chronic lung disease; u to urti with symptoms for croup or laryngotracheobronchilitis, and pharnygitis; and o to others with symptoms not defined as l or u. as the second most likely cause of lower respiratory tract infections. the incident rate for upper respiratory tract infections in patients in which hbov was detected was . %, which compared with . % and . % for rsv and hmpv, respectively. the age distribution and clinical presentation of the patients infected with hbov were examined and compared. fifty-five percent of the hbov-infected patients were year old or younger, which compared with detection rates of % and % for rsv and hmpv respectively (table i) . most reported studies on the detection of hbov have been carried out in patients who exhibited respiratory symptoms, and there were few parallel studies on healthy children. similarly, this current study did not examine the incidence of hbov in healthy children, or other pediatric patients with nonrespiratory symptoms. however, a recent report had clearly described the detection rate in healthy children to be less significant than that in children exhibiting clinical symptoms consistent with respiratory tract infections [garcia-garcia et al., ] . several reports have also noted the presence of hbov in fecal [lau et al., a; lee et al., ; vicente et al., ] and urine samples from children [pozo et al., ] , suggesting that the virus is associated with both enteric and respiratory infections. the current study did not find any symptoms of gastroenteritis presented by the hbov patients. however, this does not exclude the possibility that the virus does not cause enteric infections as fecal samples were not collected. of the three patients in whom hcov was detected, two tested positive for the hcov-nl , and one for hcov-oc . both hcov-nl patients exhibited croup, which is consistent with reports from germany, taiwan and south korea [ van der hoek et al., ; han et al., ; wu et al., ] . however, the small number of patients in which hcov was detected makes any clinical association with the presence of the virus and severity of infection impossible. it is possible that the assay used in the current study may not be sensitive enough to detect hcov in some patients. this is unlikely to be the reason, since similar low rates of hcov detection have been observed consistently elsewhere [koetz et al., ; chung et al., ; kaplan et al., ; pierangeli et al., ] . although hbov can be the single cause of lower respiratory tract infection in children, several studies have reported that hbov coinfections with other respiratory viruses resulted in an increased severity of infection [allander et al., ; choi et al., ; chung et al., ; foulongne et al., ; manning et al., ; sloots et al., ; fry et al., ] . the hbov positive specimens were therefore examined for the presence of other respiratory viruses. in of these hbov patients, hbov was the only virus detected, and lower respiratory tract infections was observed in ( . %) of single infections. interestingly, in ( . %) of the patients infected with hbov, the presence of rsv, piv and , and rhv were also detected ( table ii) . the rate of hbov coinfection was almost similar to the % coinfections reported in thai pediatric patients [chieochansin et al., ] , but less than that reported elsewhere [pozo et al., ; hindiyeh et al., ]. in the current study, both rsv and rhv each accounted for ( %) and ( %) of the coinfections respectively, with piv at ( . %). of the patients who showed evidence of coinfections with respiratory viruses, % exhibited lower respiratory tract infections, lower than that caused by single hbov infections, while % of these exhibited upper respiratory tract infections. four of the eight coinfected with rhv showed lower respiratory tract infections, compared to only two out of six patients coinfected with rsv. coinfections with more than one of the other respiratory viruses were not detected. the hbovs detected in this study were sequenced to determine the genetic relationship with other hbovs reported elsewhere. a bp region of the ns gene sequence was used to analyze the genetic relatedness of the singapore isolates as described previously [chung et al., ; sloots et al., ] . the singapore hbov isolates showed nt identity ranging from % to % with published hbov sequences. approximately % of the singapore hbov isolates were identical at the nt sequence level, and the remaining hbov isolates showed only minor nt differences. this highly conserved sequence identity is consistent with hbov which has been isolated in other countries [chung et al., ; qu et al., ] . the hbov sequences were aligned, and percent sequence homology was calculated and phylogenetic trees were constructed as described in materials and methods section. the analysis showed that the majority of the singapore hbov strains clustered with the prototype virus, st strain, that was first detected in sweden (fig. ). in addition, the singapore hbov strains appeared to be closely related to canine minute virus and bovine parvovirus than the human parvovirus fig. . phylogenetic analysis of the partial ns gene region ( bp) for hbov detected from hospitalized pediatric patients. the phylogenetic tree was constructed using the neighbour-joining method and the bootstrap values were generated in , replicates. the viral sequences from the singapore strains are represented by sin -ntu, followed by the specimen number. sin represents singapore and represents the year the specimen was collected. # sin -ntu- is the representative strain for a cluster of strains, comprising of specimen numbers sin - , , , , ; , , , , , , , , , , , , ; , , and , with % sequence similarity at the nucleotide level. the singapore hbov sequences were analyzed with the two hbov prototypes isolated in sweden, st _sweden and st _sweden (dq and dq ), and published sequences from genbank, whose strain names are reported next to their country of isolation. their accession numbers are: qpid - _australia, dq ; will _china, dq ; bj _china, dq ; cu _thailand, ef ; kr-mn _korea, mn _korea, kr-mn _korea, kr-mn _korea, dq to ; chsd , and _usa, dq , dq , and dq ; crd _usa, dq ; human parvovirus b , dq ; canine minute virus, nc ; and bovine parvovirus, nc . b , which is consistent with recent reports from other regions of the world [chung et al., ; foulongne et al., ; sloots et al., ; qu et al., ] . the main focus of this study was to detect the incidence rate of hbov in the pediatric population in singapore. as recent reports have indicated that hcovs may have a possible role in respiratory infections, their presence was also assessed in the same cohort of patients. only three hcovs were detected from the specimens. their pcr amplicons was subjected to dna sequencing to confirm their identities by blasting the sequences with published hcov sequences. sin -ntu- was confirmed to be hcov-oc , whereas both sin -ntu- and sin -ntu- were hcov-nl . the singapore hcov-nl strains showed % nt identities with each other, and with the dutch nl strains. interestingly, the phylogenetic tree constructed at the partial orf b gene region showed that the singapore hcov-nl isolates, sin -ntu- and sin -ntu- , clustered with the dutch strains, away from the rest of the hcovs including the recent strains of hcov-nl from australia and japan (fig. ) . sin -ntu- , as expected, clustered with the hcov-oc . the clustering of the hcovs was somewhat similar to that reported by escutenaire et al. [ ] . the main focus of this study was to examine the incidence of hbov infections among the pediatric patients in singapore. respiratory viruses were detected in of the specimens, giving an incident rate of . %. rsv was the most common virus detected in the current study ( . %), followed by hbov ( . %), and hmpv ( . %). the rate of hbov detection in this study was similar to that reported in china [qu et al., ] and south korea [chung et al., ] , but was higher than the reported rates in thailand [fry et al., ] , japan [ma et al., ] , and in several non-asian countries [allander et al., ; arnold et al., ; bastien et al., ; foulongne et al., ; sloots et al., ] . one reason for the difference in incidence rates could be the criteria used in the sampling population. for example, in a report by sloots et al. [ ] the study population included hospitalized and non-hospitalized patients exhibiting both lower respiratory tract infections and upper respiratory tract infections, with a wide age range from days to years. in contrast to the current study, and that reported from china and south korea, the sampling population was confined to hospitalized children exhibiting respiratory tract infections. coinfections of hbov with a range of respiratory viruses have been reported, with the highest rates at % and % in children admitted to hospital in israel [hindiyeh et al., ] and spain, respectively [pozo et al., ] . a high proportion of these hbov coinfections have been associated with either rsv, hmpv, or piv [choi et al., ; chung et al., ; fry et al., ] . the israeli study also reported a high rate of coinfection with adenoviruses [hindiyeh et al., ] . recent studies have also suggested a correlation between the severity of infection and the presence of coinfections involving hbov [allander et al., ; choi et al., ; chung et al., ; foulongne et al., ; manning et al., ; sloots et al., ; fry et al., ; see review by schildgen et al., ] . for example, in a recent study in thailand, wheezing was associated in patients infected with hbov and coinfected with rsv, piv, or rhv, compared to single infections with these viruses [fry et al., ] . in the same study, a significant number of patients presented with lower respiratory tract infections in which hbov was the only virus detected. this trend of coinfections with other respiratory viruses was also observed in the current study. in the current study, % of the coinfections with rhv caused lower respiratory tract infections in children, whereas in contrast, only % of the coinfections with rsv caused lower respiratory tract infections. interestingly, a recent study described the association of hbov coinfections with rhv-a, as well as a newly identified rhv species, designated as rhv-c by lau et al. [ b] . rhv is also an important cause of lower respiratory tract infections in children. coinfections with hbov may exacerbate the symptoms in children, giving rise to hospital admission with the requirement of intensive medical care. coinfections with rsv and hmpv have also been associated with an increase severity in respiratory infections, although this correlation remains controversial. some reports have described an increased severity in a high proportion of coinfections [greensill et al., ; semple et al., ] , whereas in others, a low proportion of co-infections or no coinfections were found [al-sonboli et al., ; mackay et al., ] . however, in the previous report [loo et al., ] and the current study, only single hmpv infections were detected among the singaporean children. the increased severity in coinfections with respiratory viruses remained to be challenged. a larger sampling population, and a longer duration for the study of coinfections will be required to confirm the correlation. in conclusion, this report describes the first comprehensive study examining the prevalence of hbov among the pediatric population in singapore. five hundred specimens were analyzed, and an infection rate for hbov at % was reported, with % of these patients were year old or younger. a significant level of coinfection was also detected in the patients with hbov, with rsv and rhv being the most common viruses detected. % of the hbov patients in which hbov was the sole agent detected showed evidence of lower respiratory tract infection, which compared with % of the hbov coinfections. this study, therefore, suggests that hbov is a significant cause of lower respiratory tract infections among the pediatric population of singapore. furthermore, the current data suggest that single infection with hbov is sufficient to cause severe respiratory infection, and the clinical significance of hbov coinfections with other respiratory viruses in singapore remains to be established. human bocavirus cloning of a human parvovirus by molecular screening of respiratory tract samples human metapneumovirus and respiratory syncytial virus disease in children phylogenetic analysis of the partial orf b region ( bp) for hcov detected from hospitalized pediatric patients. the phylogenetic tree was constructed as described for figure . the viral sequences from the singapore strains are represented by sin -ntu, followed by the specimen number. sin represents singapore and represents the year the specimen was collected. the singapore sequences were analyzed with published sequences of coronviruses obtained from genbank, whose strain names are reported next to their country or cities of isolation dq ; human coronavirus (hcov)- e ay ; hcov-hku n genotype a hong kong, dq ; hcov-hku n genotype b hong kong, dq ; hcov-hku n genotype c hong kong, dq ; hcov-nl -inmiz italy, eu hcov-nl netherlands, ay ; hcov-hku -nat usa, ef ; and hcov-oc atcc vr- , ay ; severe acute respiratory syndrome 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genome characterization of a distinct human rhinovirus (hrv) genetic cluster, probably representing a previously undetected hrv species, hrv-c, associated with acute respiratory illness in children detection of human bocavirus in children hospitalized because of acute gastroenteritis characterisation of human metapneumovirus isolated from paediatric patients in singapore detection of human bocavirus in japanese children with lower respiratory tract infections genetic diversity of human metapneumovirus over consecutive years in australia epidemiological profile and clinical associations of human bocavirus and other human parvovirus treeview: an application to display phylogenetic trees on personal computers detection and typing by molecular techniques of respiratory viruses in children hospitalised for acute respiratory high incidence of human bocavirus infection in children in spain identification of new human coronaviruses human bocavirus infection, people's republic of china human bocavirus: passenger or pathogen in acute respiratory tract infections? dual infection of infants by human metapneumovirus and human respiratory syncytial virus is strongly associated with severe bronchiolitis evidence of human coronavirus hku and human bocavirus in australian children emerging respiratory agents: new viruses for old diseases? identification of a new coronavirus croup is associated with the novel coronavirus nl human coronavirus nl , a new respiratory virus a newly discovered human pneumovirus isolated from young children with respiratory tract disease human bocavirus, a respiratory and enteric virus characterisation and complete genome sequence of a novel coronavirus, coronavirus hku , from patients with pneumonia clinical manifestations of human coronaviruses nl infection in children in taiwan key: cord- -orko fi authors: sreevalsan-nair, jaya; rani vangimalla, reddy; rajesh ghogale, pritesh title: analysis of clinical recovery-period and recovery rate estimation of the first covid- patients in singapore date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: orko fi covid- has been declared as a global pandemic by the world health organization (who) on march , . in this paper, we investigate various aspects of the clinical recovery of the first covid- patients in singapore, spanning from january to april , . this data consists of clinically recovered patients. the first part of the paper studies the descriptive statistics and the influence of demographic parameters, namely age and gender, in the clinical recovery-period of covid- patients. the second part of the paper is on identifying the distribution of the length of the recovery-period for the patients. we identify a piecewise analysis of three different periods, identified based on trends of both positive confirmation and clinical recovery of covid- . as expected, the overall recovery rate has reduced drastically during the exponential increase of incidences. however, our in-depth analysis shows that there is a shift in the age-group of incidences to the younger population, and the recovery-period of the younger population is considerably lower. here, we have estimated the recovery rate to be . . overall, the prognosis of covid- indicates an improvement in recovery rate owing to the government-mandated practices of restricted mobility of the older population and aggressive contact tracing. the viral contagion, named covid- , has been declared as a global pandemic by the world health organization on march , . the pandemic, characterized by atypical pneumonia, is caused by a virus from the coronavirus family, namely sars-cov (severe acute respiratory syndrome coronavirus- ), which is a positive-sense single-stranded rna virus. as of april , , there are , positively confirmed cases, and , deaths, spread across countries . the total number of recovered patients in an unofficial count is , out of , positively confirmed patients, which implies that the ratio of the recovered to the infected patients, r ri is ∼ . , as of april , . in this paper, we analyze the statistics of hospital recovery of patients tested positive for covid- infection in singapore [ ] . the case study of singapore has been carefully chosen owing to the reliable, accessible, and available data from the official press releases of the ministry of health (moh), government of singapore. the healthcare system of singapore has been unique in its handling of the widespread contagion in terms of imposing strict lockdown, quarantine, and isolation, and aggressive, large-scale contact tracing and testing. individuals have been confirmed positive for covid- during january -april , , of which have been discharged after clinical recovery. this gives an overall r ri higher than that of the world, as r ri = . . the positive confirmation has been made using the real-time reverse transcription polymerase chain reaction (rt-pcr) tests on respiratory samples (sputum or nasal/throat/nasopharyngeal swabs), based on experiential learning from the outbreak of sars in . similarly, the protocol for clinical recovery or hospital discharge has been based on the results on the rt-pcr tests of two consecutive samples being negative over two days [ ] . since the sars outbreak in , singapore has systematically strengthened the system of managing the spread of infectious diseases [ ] . the measures include opening dedicated facilities (the national center for infectious diseases (ncid), national public health laboratory, and more biosafety level- laboratories), increasing capacity in the public healthcare system (e.g., negative pressure isolation beds, personal protective equipment, trained health professionals), and deploying formal (digital) platforms for inter-governmental agency cooperation. for containing the spread of contagions, systems have been in place for upscaled, quick-responsive, and aggressive contact tracing at entry points of the country (airports) and through local healthcare providers. there has been a holistic improvement, supported by increased economic investment, in building expertise in infectious disease management. this organized system has thus facilitated a controlled management of the pandemic covid- in singapore with patient-wise reporting to the public. hence, a case study in singapore pertaining to the demographic analysis of clinically recovered patients enables a systematic understanding of the recovery rate (γ) of the pandemic. one of the significant benefits of aggressive contact tracing has been hospital isolation within days from the onset of symptoms [ ] . however, . % of transmission has been found to be presymptomatic [ ] , as analysed for seven clusters found in singapore. while there is an innate uncertainty from the onset of symptoms in the symptomatic cases to a positive confirmation, the hospital stay from positive confirmation to discharge upon negative results exhibits more cohesive statistics, as can be observed with similar studies in hospital stay [ ] . hence, in this work, we perform statistical analysis of the recovery-period, i.e., length of hospital stay, of covid- patients in the hospital. also, the motivation behind studying the clinical recovery of patients is to assess the overall load on the healthcare system in terms of patient occupancy as the hospital stays determines the load. the clinical recovery studied in this paper corresponds to the hospitalization period for each patient. the demographic analysis of the recovered patients gives insight to shifts in gender and age-groups in the recovery of patients. this analysis further complements the observation in the transmission rate is higher in older males with comorbidities [ ] . fitting the data of hospitalization period to a statistical distribution is essential for estimating γ. the epidemiological models are generally used to simulate the progression of a disease. the proportions of population being "susceptible," "infected," and "removed" are used in these models. "removed" implies both "recovered" and "deceased." the first two deaths in singapore owing to the covid- contagion occurred on march , . the number increased to deaths by april . owing to relatively low number of deaths in singapore due to covid- contagion during january -april , , we have assumed death/mortality/fatality rate to be in our work. thus, here, "recovery" implies the state of "clinically recovered and discharged from hospital." since the contagion has time-varying reproduction number (r t ) with characteristic trends in specific time-periods [ ] , we split the time-period of january -april , to perform a piecewise analysis of the timeline [ , ] . we perform two analyses on the periodized timeline. firstly, we study the age-gender distribution of the patients who have been confirmed positive of covid- and those who have clinically recovered. secondly, we extract the distribution of clinical recovery-periods and fit regression models. in both analyses, we discuss the observable period-wise shifts in trends and their influencing factors, thus estimating γ. the novel contribution of our work is an in-depth analysis of the clinical recovery of covid- patients to estimate the recovery rate γ, which is a key parameter in the sir (susceptible-infected-recovered) model for the disease [ ] . the data for our work has been collated from the public press releases made by the moh, the government of singapore . this dataset includes the case-id's, age, gender, positive confirmation date, discharge date, and date of onset of symptoms . the data has been cross-verified with dashboard for case details. we have analyzed this patient-wise data pertaining to age, gender, and timeline of the disease progression. we define recovery-period ∆t r as the time elapsed between positive covid- confirmation using rt-pcr test, and the discharge date from hospital after two consecutive negative results, using rt-pcr tests. owing to the strict protocols followed in the singapore healthcare system, the recovery-period can be considered equivalent to the virus shedding period. ∆t r is estimated to be days [ ] or days [ ] . we consider ∆t r as an observed count variable. age-gender distribution: there has been early evidence of the influence of both age and gender in susceptibility of covid- infection [ , ] . hence, we look at the influence of age and gender in clinical recovery of patients, with respect to the recovery-period. there are patients ( m, f) in the population confirmed covid- positive, of which patients ( m, f) have clinically recovered ( §figure (i)). the age distribution of the positively confirmed patients is ( in [ - ] , in [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . the preliminary counts indicate that the restrictions used for slowing the contagion down in the susceptible group of the population, namely the older males [ ] , have led to the shifts in distribution of contagion with respect to age and gender. there is a conspicuous shift to the younger population, namely, in the age groups [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] , and [ - ], and more evenly across both genders. here, we investigate the change in recovery rate γ owing to these shifts. periodization: as the pandemic progresses, the evolution needs to be studied piecewise in different time periods [ , ] . from the timeline of disease progression in singapore, we have identified the following significant dates: • on january , the first patient was confirmed covid- positive. • on february , the first clinically recovered patient was discharged from the hospital. these trends can be observed in the daily profile of patient counts ( §figure (ii),(iii)). assuming a zero death rate owing to the low number of deaths in singapore from covid- , we consider the following three periods: . period p during january -february , which is the period with no clinically recovered cases. . period p during february -march , which is the period of slow growth in the total/cumulative number of positively covid- confirmed cases, n i , with an increase in the total/cumulative number of clinically recovered cases, n r , and zero deaths. . period p during march -april , which is the period of exponential growth in n i , reaching n i = , slow growth in n r , and having the first deaths. recovery rate γ: the governing differential equations in the simplest sir model, also known as kermack-mckendrick model [ ] , are given as follows: β is the rate at which an infected individual infects others, γ the transition rate in sir model , n p the size of the population, n i the number of infected persons (i.e., with positive covid- confirmation), n r the number of recovered persons (i.e., clinically recovered), and n s is the number of susceptible people. the basic reproduction number or reproduction rate, r = β γ , characterizes an infection. r > implies the infection will continue to spread, and r < implies that the spread is limited and under control. currently, r for covid- is estimated to be ( . - . ) [ , ] . γ is estimated as the reciprocal of the recovery-period ∆t r , which implies that γ ∼ ( . - . ), based on estimates of ∆t r [ , ] . the transition rate must include both recovery and deceased. however, since we assume a zero death rate, the transition rate is equivalent to recovery rate, in our work. . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . figure : (i) overlapped population pyramid of age-gender distribution of population of the discharged and active (i.e., covid- positive but not discharged, including the deceased) during the same period ( active patient who is a years old female and confirmed positive on april , , has been excluded in this population pyramid). daily profile of count of patients in singapore during january -april , , (ii) who were confirmed positive for covid- , with a total of , and (iii) who got clinically recovered and were discharged from the hospitals, with a total of . the red dotted lines indicate the three periods we have introduced in this work. . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . . https://doi.org/ . / . . . doi: medrxiv preprint the absolute numbers indicate that r ri , i.e., nr ni , has increased from . at the end of p to . = + at the end of p , and again dipped to . = at the end of p . the dip is unfavorable for the scenario, given that the number of positive covid- confirmations has increased exponentially, starting the beginning of p . since r ri and γ are positively correlated, it implies a further decrease in γ. however, the absolute counts n i and n r do not explicitly show the shifts in the age-gender distribution of the infected population ( §figure (i)). thus, it is difficult to demonstrate the influence of this shift in the recovery rate γ. social distancing reduces β, thus decreasing r . at the same time, increasing γ also favours a decrease in r . in this work, we hypothesize that restricted mobilization and aggressive contact tracing would have indirectly increased γ. thus, we propose computing the time-varying ∆t r using the shifts in the age-gender distribution in the periodized timeline. recovery-period ∆t r analysis: our goal is to study the period-wise changes in ∆t r owing to the shift in the demographic structure, in order to determine the period-wise change in γ. we performed descriptive statistical analysis using median and interquartile range (iqr), followed by fitting appropriate regression models. we consider two types of regression models. firstly, we use the time-series of ∆t r and fit a line using the loess model. loess is a non-parametric local regression model for smoothening empirical time-series data [ ] and scatterplots [ ] . secondly, we use the number of patients recovering for a specific ∆t r as a count variable and fit multivariate linear regression models considering age and gender as independent variables, and ∆t r as the dependent variable. since we are using a combination of a categorical variable (gender) and numerical variable (age), we use generalized linear models (glm) for regression, which is semi-parametric. length of hospital stay (los) is a naturally skewed distribution, for which glm's such as the poisson regression model (prm) and negative binomial regression model (nbm) have been used [ ] . hence, we propose the use of prm and nbm for modeling ∆t r . for the period-wise analysis of ∆t r , we group the clinically recovered patients using two strategies. . grouping based on recovery date, g g g −cfrmdt −cfrmdt −cfrmdt : the two groups of clinically recovered patients can be obtained as per the period in which their discharge/recovery date falls, namely, p and p ( §figure (ii),(a)). g g g −cfrmdt −cfrmdt −cfrmdt corresponds to a group of patients who were discharged in p , and patients in p . . grouping based on positive confirmation date, g g g +cfrmdt +cfrmdt +cfrmdt : however, we can perform a finer-grain analysis of the groups of patients based on the period in which their date of positive confirmation/hospital admission falls ( §figure (ii),(b)). this gives us groups of patients who got tested positive in a period and got clinically recovered during the entire period of our study here. this gives us patients in p , in p , and in p . symptom-onset period ∆t so analysis: we additionally have data of the date of onset of symptoms for of the clinically recovered patients, who were confirmed positive during p and p . we define the symptom-onset period, ∆t so , as the number of days between the onset of symptoms and positive confirmation of covid- . we use the time-series of ∆t so to fit a loess model, similar to ∆t r . table gives the percentage values of the data presented in figure . table : percentage values of the age-gender structure of population confirmed positive with covid- during january -april , in singapore ( §figures (i), and (i)). descriptive statistical analysis: we present the descriptive statistics either as a ∆t r five-number summary and as "median [iqr]" of the observed count variable, i.e., ∆t r . ∆t r observed during the entire period, january -april , has the following median and iqr values: a five-number summary is (minimum, first quartile, median, third quartile, maximum) values of a (count) variable. . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. • overall: [ ] days. • gender-wise: [ . ] days for females and [ ] days for males ( §figure (i)). • we observe that the ∆t r is overall lesser in this dataset than reported in early analyses of covid- patients, i.e., days [ ] and days [ ] . the overall median of ∆t r is days, which is the same as the gender-weighted median, and the age-group-weighted median is . days. thus, the overall descriptive statistical analysis gives a conservative estimate of γ to be ∼ . the remaining work is to estimate γ more precisely based on the influence of gender and age. there is a stronger influence of age than gender on ∆t r , as the median values are similar for both genders. in contrast, it is relatively lower for the age groups of ( - ), ( - ), and ( - ) years, specifically. these age groups comprise of . %, . %, and . % of the clinically recovered patients ( §table ). this result is significant as the age group of ( - ) years contributes the highest ( . %) to the infected population. . % of the patients in this age group have been confirmed positive in p . thus, our key conclusion is that since the most susceptible group of people has lower ∆t r , the recovery rate γ is bound to increase further in the period after april compared to the value estimated in our work. the period-wise five-number summaries for ∆t r , using g g g +cfrmdt +cfrmdt +cfrmdt grouping, are: • ( , . , , . , ) for p , ( , , , , ) for p , and ( , , , , ) for p . • for females: ( , , , , ) for p , ( , , , , ) for p , and ( , . , , , ) for p . we observe similar trends when considering g g g −cfrmdt −cfrmdt −cfrmdt grouping. the range, the iqr, and the median of ∆t r decrease from p to p , when we look at the data for each gender as well as the data without the gender information. this indicates that irrespective of gender, the measure of the spread of ∆t r decreases with time, similar to the trend in the value of ∆t r . the age-wise minima reduce sharply from p to p , and increase slightly further to p , indicating an overall trend of decrease in minima. this supports the overall decrease in ∆t r value from p to p . table shows the fine-grained five-number summaries of the age-gender based box and whisker plots in figure . we observe that there is a strong influence of age on ∆t r . while the overall median values for females and males are . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . table : five-number summaries of age-gender based box and whisker plots in figure and . similar, we observe that there are variations across different age groups. in particular, for the age group of ( - ) years, the median [iqr] value of males of . [ . ] days is lower than the median value of females of [ . ] days. this also shows that there is a higher spread (iqr) of ∆t r values in males. we further observe that the gender difference in iqr arises in p in the g g g +cfrmdt +cfrmdt +cfrmdt grouping, which happens in p in the g g g −cfrmdt −cfrmdt −cfrmdt grouping. the minima and median values are overall lower in p in the g g g +cfrmdt +cfrmdt +cfrmdt than the g g g −cfrmdt −cfrmdt −cfrmdt grouping. since the protocols followed in the hospital can be perceived to be similar for patients with closer hospital admission dates, the ∆t r has more cohesive descriptive statistics in the g g g +cfrmdt +cfrmdt +cfrmdt grouping than the g g g −cfrmdt −cfrmdt −cfrmdt one. hence, we use the g g g +cfrmdt +cfrmdt +cfrmdt grouping exclusively in the regression analysis. since the symptom-onset dates have been studied [ , ] , we report the five-number summaries of ∆t so , for which data is available for p and p only. • overall: ( , , , , ) for p and ( , , , , ) for p . • for females: ( , , , , ) for p , and ( , , , , ) for p . • for males: ( , . , , , ) for p , and ( , , , , ) for p . we observe that ∆t so has similar iqr and median across p and p , irrespective of gender. we attribute to the continuous monitor of susceptible cases in singapore towards less delay in positive confirmations, thus showing a low measure of spread and low values for ∆t so . overall, we do not emphasize on analysing ∆t so owing to the clinical uncertainties involved [ ] , which do not reflect in the timeline data that we are using here. loess model: we now use the loess model to confirm the trend in the change in ∆t r . the loess model has been estimated on the time-series of the ∆t r and ∆t so values, represented as scatter plots ( §figure ). the loess model has been implemented using the stats.loess in r [ ] . we have considered the scatter plots based on the positive the loess model is a default local regression model used for a sample with less than observations in stats package in r. . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . the degrees of freedom roughly corresponds to the degree of the polynomial used to generate the fitting curve. thus, both ∆t r and ∆t so can be modeled using a th degree polynomial. higher degree polynomial implies less bias but larger variance. ∆t r has a slope of − o in p when using the loess model for the entire time period ( §figure (i)) and that of − o when using loess model for p ( §figure (ii)). thus, the key conclusion from the local regression model on the time-series is the negative slope, i.e., a downward trend in ∆t r in p , which is favorable in improving recovery rate γ. multivariate (linear) regression model: now that we have observed and concluded from both the descriptive statistical analysis and loess model that ∆t r is decreasing during the period of january -april , our next step is to predict the value of ∆t r . we experiment with the generalized linear model (glm) for a multivariate linear regression model for ∆t r using poisson (prm) and negative binomial (nbm) distributions. our choice of model and distributions are . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . . https://doi.org/ . / . . . doi: medrxiv preprint commonly used for count data [ ] , and hospital length of hospital stay (los) is commonly over-dispersed data [ ] . for each model, we use four scenarios, namely, for the entire period and for each period. we use the akaike information criterion (aic) and its corrected version for a small sample size (aic c ) for determining the goodness of fit of our proposed models. we have implemented these models using the stats.glm in r [ ] . for glm with poisson and binomial families, the dispersion is fixed at . , and the number of parameters (k) is the same as the number of coefficients in the regression model [ ] . the negative binomial distribution has an additional parameter to model over-dispersion in the data. for the number of samples (n) in the data, aic is used if n k > , and aic c is used otherwise [ ] . thus, we use aic for scenarios of the entire period and p , and aic c for p and p , owing to the relatively lesser samples ( §table ). table : results of the generalized linear models using poisson distribution and negative binomial distribution of recovery-period ∆t r using g g g +cfrmdt +cfrmdt +cfrmdt grouping. table gives the results of our models. we infer the following: • the "age" variable is significant only in the prm, and only for the scenarios of the entire period and p , with a p-value for the coefficients corresponding to the variable being less than %. • the nbm shows lower values for the median and the variance (observable from range and iqr) of deviance residuals, and aic/aic c than the prm. thus, we conclude that nbm is a better fit than prm. also, for both prm and nbm, the models for the scenarios of p and p are a better fit than those of the entire period and p . these observations may be attributed to the relatively small sample size for p and p . since we do not have a large number of variables to discard, we retain the "gender" variable in the model despite its insignificance. . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . . https://doi.org/ . / . . . doi: medrxiv preprint the key conclusion from the multivariate regression analysis is that a glm with nbm for p is the best model for us to estimate ∆t r . this helps us to estimate the value of ∆t r to be days, with the maximum likelihood of . %. the expected value of ∆t r of nbm for p is . days. hence, overall, we conclude that the estimated value of γ is . the improved γ, as per our estimate, is an outcome of the existing protocols in singapore. the approach of containment of the contagion undertaken by singapore has been government-mandated, which has ensured delays in the spread of the disease. while the spread got contained, there has been a shift in the age-group of the population getting infected. this shift has brought about the decrease in the recovery-period, ∆t r . our work has two specific limitations. firstly, our study is short of using a non-zero death/mortality/fatality rate of the disease. the number of deaths will continue to increase, warranting its consideration in the sir model. secondly, we have modeled recovery isolated from the infection. since the number of infected persons in singapore has increased exponentially since march , , the infection rate, β, and consequently, basic reproduction number r have to be re-estimated. nevertheless, our estimated γ is thus applicable for improving estimation of r until april , and for simulating/predicting disease progression using sir model beyond april . in summary, we have looked at the demographic data and timeline of the first covid- patients in singapore during january -april , . we have closely investigated the data on the positive confirmation and discharge/clinical recovery dates of patients who recovered during this time period. we have used regression analysis, subsequent to a descriptive statistical analysis, to get an estimate of recovery-period ∆t r (i.e., hospital length of stay (los)). we have found that the ∆t r is time-varying, after performing periodization to find three significant periods, namely p (january -february ), p (february -march ), and p (march -april ). the estimates of ∆t r varied from ∼ days in p to ∼ days in p to ∼ days in p . we have used the loess model for time-series data to demonstrate the negative slope of the regression curve of ∆t r in p , in particular. we then estimated period-wise ∆t r using generalized linear models for multivariate (linear) regression with poisson and negative binomial distributions for count data. this shows an improvement in the values published for ∆t r , i.e., days [ ] and days [ ] . this has led us to estimate the current recovery rate γ in the sir model to be investigation of three clusters of covid- in singapore: implications for surveillance and response measures covid- in singapore-current experience: critical global issues that require attention and action evaluation of the effectiveness of surveillance and containment measures for the first patients with covid- in singapore epresymptomatic transmission of sars-cov- -singapore predicting length of stay from an electronic patient record system: a primary total knee replacement example epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study early dynamics of transmission and control of covid- : a mathematical modelling study. the lancet infectious diseases yang, gabriel m. leung, and zijian feng. early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia containing papers of a mathematical and physical character athanasios tsakris, and constantinos siettos. data-based analysis, modelling and forecasting of the covid- outbreak hua chen, and bin cao. clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study. the lancet respiratory medicine pattern of early human-to-human transmission of wuhan locally weighted regression: an approach to regression analysis by local fitting loess:: a nonparametric, graphical tool for depicting relationships between variables r: a language and environment for statistical computing. r foundation for statistical computing a score test for overdispersion in zero-inflated poisson mixed regression model model selection and inference: a practical information-theoretic approach the authors would like to thank iiit bangalore, and particularly, the graphics-visualization-computing lab and the e-health research center, for supporting this work. key: cord- -jozrgcq authors: tan, xin quan; zhao, xiahong; lee, vernon j; loh, jin phang; tan, boon huan; koh, wee hong victor; ng, sock hoon; chen, mark i-cheng; cook, alex richard title: respiratory viral pathogens among singapore military servicemen – : epidemiology and clinical characteristics date: - - journal: bmc infect dis doi: . / - - - sha: doc_id: cord_uid: jozrgcq background: few studies have comprehensively described tropical respiratory disease surveillance in military populations. there is also a lack of studies comparing clinical characteristics of the non-influenza pathogens with influenza and amongst themselves. methods: from may through october , consenting cases of febrile respiratory illness (fri) (temperature [greater than or equal to] . degreesc with cough or sorethroat) and controls in the singapore military had clinical data and nasal washes collected prospectively. nasal washes underwent multiplex pcr, and the analysis was limited to viral mono-infections. results: % of cases tested positive for at least one virus, of whom % had multiple infections. % of the fri cases fulfilled the definition of influenza-like illness (ili), of whom % were positive for at least one virus. the most frequent etiologies for mono-infections among fri cases were influenza a(h n )pdm ( %), influenza b ( %) and coxsackevirus ( %). the sensitivity, specificity, positive predictive value and negative predictive value of ili for influenza among fri cases were %, %, % and % respectively. on logistic regression, there were marked differences in the prevalence of different symptoms and signs between viruses with fever more prevalent amongst influenza and adenovirus infections than other viruses. conclusion: there are multiple viral etiologies for fri and ili with differing clinical symptoms in the singapore military. influenza and coxsackevirus were the most common etiology for fri, while influenza and adenoviruses displayed the most febrile symptoms. further studies should explore these differences and possible interventions. influenza-like illness (ili) is often used for influenza surveillance [ ] , as influenza is a disease of global interest with % of adults developing symptomatic disease annually and with case fatalities of . % in susceptible populations [ ] . while influenza surveillance remains a priority, ili can also be caused by a wide range of viral pathogens that present with a spectrum of respiratory symptoms [ ] [ ] [ ] [ ] . in the tropics, viral respiratory pathogens have been reported to exhibit different seasonality and transmission characteristics compared to temperate climates [ , [ ] [ ] [ ] . this necessitates a better understanding of their epidemiology to assess the utility and importance of surveillance in these settings. the year-round circulation of respiratory viruses in the tropics may also predispose patients to coinfection with multiple pathogens, with implications for severity of disease [ , ] and secondary bacteria infection [ , ] . while there have been studies comparing differences in clinical presentation between influenza and non-influenza cases [ ] , few describe the epidemiology and differences in clinical presentation among various non-influenza respiratory viruses. as influenza viruses have accounted for only between . % to . % of all ili cases [ ] [ ] [ ] , it is important to understand the contribution of other respiratory pathogens to overall morbidity and to determine their epidemiological distribution and clinical presentation. to address these issues, this study explores data obtained from a respiratory disease sentinel surveillance system in the singapore military to examine the etiologic viral agents of respiratory illnesses in a tropical environment, to determine the viruses that circulate post-influenza vaccination, and to compare the differences in clinical presentation. singapore is a city-state in tropical south-east asia with a population of . million people (mid-year ). the singapore military is based on national service in which all male citizens and liable permanent residents serve for two years after high school. servicemen typically live in barracks-style accommodation on weekdays and return home on weekends. the singapore military started a sentinel respiratory disease surveillance program in major camps (including a recruit training camp) on may , tracking febrile respiratory illness (fri) cases (temperature ≥ . °c with cough or sore throat). the definition of fri contrasts with influenza-like illness (ili, defined as fever ≥ . °c with cough or sore throat) to broaden the capture of other febrile cases that also result in absenteeism while limiting cases to those with fever as an indicator of severity. this allows for detection of a larger number of respiratory pathogens. patients who visited the primary healthcare clinics in the camps between may and october during regular consultation hours who met the fri criteria were recruited. healthcare workers obtained written informed consent, administered a questionnaire, obtained clinical specimens and performed a clinical examination on partcipants. repeat consultations were excluded if the healthcare worker determined that the patient had not recovered from the first illness episode. we also obtained samples from controls (those without respiratory symptoms or acute infections), who were recruited across the year at between to persons per week. informed consent, the baseline questionnaire, and clinical specimens were obtained. from december , all recruits were administered with the influenza a(h n )pdm (flu-a(h n )pdm ) vaccine. the trivalent seasonal influenza vaccination was first introduced to recruits in december , followed henceforth by all other personnel in november . nasal washes from each side of the nose were taken from consenting participants by trained medical staff, placed in viral transport media and refrigerated. the samples were transported to the laboratory on ice for etiological testing within hours. laboratory analysis was performed in an iso accreditated laboratory for molecular diagnostics which regularly takes part in external proficiency programs such as qcmd eqa programs. detailed laboratory methods were previously described [ ] . we used the multiplex pcr strategy based on the resplex assays described below, and performed additional singleplex pcr assays to determine the influenza subtype. total nucleic acids were extracted from each specimen using the dna minikit (qiagen, inc, valencia, ca, usa) according to manufacturer's instructions. a total of μl of extract were tested with resplex i and ii (version . , qiagen, inc., valencia, ca, usa) [ ] for respiratory micro-organisms on the liquichip workstation, according to manufacturer's instructions. the resplex i and ii (version . ) assays are multiplex pcr assays coupled with bead array detection technology and can simultaneously detect and subtype different pathogens including influenza a (flu-a) and influenza b (flu-b). specimens that were resplex ii positive for flu-a were further subtyped with real-time pcr for h or h (singapore ministry of health), or for flu-a(h n )pdm . briefly, μl of total genetic extracts were tested using an in-house developed assay based on the one-step superscriptiii/platinum taq kit (invitrogen, carlsbad, ca, usa) following manufacturer's instructions on the lightcycler machine from roche or the applied biosystems real-time pcr machine ( ). the analysis was limited to viral mono-infections amongst cases to discern clinical presentations and symptom complexes associated with each pathogen. we excluded viruses with fewer than cases ( . % of the total), as the number was too small to have a reasonable sample sizethese were coronavirus hku (cov-hku ), parainfluenza (hpiv- ), hpiv- , hpiv- , influenza a(h n ) (the prepandemic strain), respiratory syncytial virus a (rsv a), rsv b, cov and bocavirus (bv). this left viruses for the subsequent analyses. the main aim was to compare the differences in clinical expressions, including individual symptoms (or signs), pairs of symptoms, and overall symptom load between patients with different viral infections. we counted the clinical symptoms/signs and calculated the corresponding empirical proportions with % confidence intervals (cis) to evaluate the overall symptom load. logistic regression analysis was used to investigate the differences in symptom expressions for each pair. differences were identified at a significance level of . . to assess the presence of paired symptoms/signs for all viruses, we conducted binomial tests to compare the joint proportions of symptom pairs occurring together to the expected proportions assuming independence of symptoms. the ratio of the observed proportion of symptom pairs relative to the product of the marginal proportion of each symptom is defined as the excess probability ratio which measures effect size. multivariate logistic regression analysis was performed to compare the risk of having an individual symptom/sign among viral mono-infections by assigning a categorical variable for all viruses as the primary predictor. potential confounding was addressed by adjusting the model for age, smoking status, asthma and heart disease. non-significant variables were dropped at a significance level of . to obtain the final model. statistical analyses were performed using the r statistical software (version . . ) [ ] . ethics approval was given by the singapore military's joint medical committee for research, and the national university of singapore's ethics review committee. the basic demographic data are described in table . participants were mostly young male adults, with other characteristics largely similar. however, there were significantly less recruits amongst controls than amongst other groups. the temporal distribution of cases is described in figure . no obvious overall seasonal pattern can be observed. the peak in june and july corresponds to the flu-a(h n )pdm pandemic [ ] . as this peak tailed off, we observed an increase in flu-b cases (starting feb-mar ). subsequently, as the flu-b cases fell, adenovirus e (adv-e) cases started to increase. coxsackie/echovirus (cv) and rhinovirus (rv) infections were consistently present in the earlier periods but appeared to tail off by , corresponding to the rise in fri cases due to other viruses. the etiologies of selected infections are illustrated in table . at least one virus was detected in of the fri cases ( . %). in ( . %) of the cases, more than one virus was detected and these were excluded. ( . %) of the fri cases fulfilled the definition of ili; ( . %) of these ili cases were positive for at least virus. of the fri mono-infection cases, ( . %) were viral. ( . %) of these cases met the definition of ili. we examined the proportion of ili cases among those with viral mono-infections (table ) . influenza viruses accounted for only % of ili. among fri cases, more than % of patients with influenza and adenovirus infections presented with ili. however, several other viral infections led to high rates of ili, including cv, human metapneumovirus (hmpv) and covs. the sensivity, specifity, positive predictive value (ppv) and negative predictive value (npv) of ili for influenza was . %, . %, . % and . % respectively. on from the multivariate analysis ( figure ), compared to most other viruses, a flu-a(h n )pdm and flu-a (h n ) less commonly resulted in sorethroat. running nose was more common in enterovirus (ev) and rv cases and less common in adv. flu-b was more likely than a majority of the other viruses to cause dry cough while ev and adv-e were less likely to cause dry cough. cov-oc and hmpv were more likely to cause cough with phlegm than the most other viruses. influenza viruses and adenoviruses were more likely to cause fever ≥ . °c. in figure , we explored the associations (and dissociations) between different clinical symptoms and signs across all viruses. some are expected, such as association of fever ≥ . °c and fever ≥ . °c and dissociation of dry cough and cough with phlegm. fever ≥ . °c was also associated with systematic complaints, such as chills, bodyache, headache and eye pain. sorethroat was associated with an injected pharynx. our study shows the different viral etiologies of ili and compares the clinical characteristics of different viral etiologies in a tropical setting. this data series only spanned three years, and initial observations showed no clear seasonal variation compared to temperate regions, similar to previous reports of overall tropical respiratory disease patterns [ , , ] . the initial peak corresponded to the flu-a(h n )pdm pandemic [ ] , with the subsequent lower incidence in the recruit population likely due to vaccination with the pandemic vaccine a year before annual seasonal vaccination was started across all personnel [ ] . the number of fri cases remained fairly consistent throughout the study period (except the pandemic). however, prevalence of pathogens varied throughout, with some negative correlation observed between the virusese.g. a drop in flu-a followed by a rise in flu-b activity, and a drop in flu-b cases followed by a rise in adenovirus activity. correlation of viral activity have previously been reported -wang et al [ ] reported negative association between rv and adv rates, while bellei et al [ ] and razanajatovo et al [ ] described concomitant rise of influenza and rv, and influenza and adv activity respectively. in addition, kasper et al reported that ili rates remained constant despite varying prevalences of influenza [ ] . this supports our findings that multiple agents are capable of causing ili, and a decrease in the prevalence of one virus was replaced by an increase in prevalence of another. further studies across a longer time period are necessary, especially for vaccine effectiveness evaluation. . % of fri and . % of ili cases were positive for a virus, similar to the . % and . % reported by studies targeting similar panel of organisms [ , , , , , ] . the remaining fri cases may be due to non-viral agents, agents beyond the ability of the test, non-infectious causes, and possible sampling errors. viruses most commonly detected in ili cases were flu-a, flu-b, and cv in that order. influenza was also the top etiologic agent for ili in some studies [ , , , , ] although other pathogens have been identified to be most prevalent in different settings, such as rsv and hmpv in france [ ] , influenza and rsv in the usa [ ] , influenza and rv in central america [ ] and china [ ] and in italy, influenza and adv [ ] . the range of pathogens indicates a need to perform local continual surveillance since prevailing pathogens differ across different populations, geographic regions and climates. the high incidence of cv warrants further studyhand, foot and mouth disease is endemic to singapore and cv is frequently identified in pediatric samples [ ] , and it is possible that cv circulates at high levels in adults also. previous studies have identified a co-infection rate of . to . % [ , , , , ] for viruses, higher than the . % found in this study despite some studies using a less extensive diagnostic panel in a similar age group. possible reasons include our highly influenza-vaccinated population or a warmer climate with higher relative humidity resulting in lower virus circulation [ ] and a study population that did not include children (studies reported higher co-infection rates amongst pediatric patients [ , ] ). in both univariate and multivariate analysis, adv and influenza viruses were more likely to cause fever (≥ . °c). this finding has been demonstrated in other studies [ , , [ ] [ ] [ ] [ ] . fever also tends to be associated with other systemic complaints such as eye pain, bodyache and headache; this may be due to cytokine mediated systematic inflammatory response [ ] and could indicate more severe disease. bellei et al's [ ] study in brazil also found that ev, rv and cov were least likely to cause fever, and that rv and ev cases were the most likely to present with rhinorrhea. cough with sputum in flu-a(h n ) and flu-a were less prevalent than in other viruses, in contrast to reports in other settings [ , [ ] [ ] [ ] . we found that flu-b cases were more likely to report dry cough, similar to other studies [ , [ ] [ ] [ ] . the heterogeneity of results across different studies highlight the difficulty of using clinical symptoms in determining the etiology of ili. we also detected a small proportion of asymptomatic individuals who tested positive for the various viruses ( table ). these could represent carriage without infection or subclinical/asymptomatic infections during periods of virus circulation. although ili is widely used to identify influenza, the traditional definition would have picked up only % of influenza infections (except untyped flu-a) that were identified as fri. adv infections also frequently fulfilled the ili definition ( . % of adv-b and . % of adv-e), as did substantial fractions of cv, hmpv, and cov. only . % of viral mono-infections that met the ili definition were due to influenza. we found a fairly high sensitivity ( . %) of ili for influenza, but a low specificity ( . %) in keeping with sensitivities of . - . % and specifities of . - % reported elsewhere [ , , , ] . color cells represent variables that are significant at the % level, and the thickness of the cell wall represents the p-value (thin means . < p < . ; medium, . < p < . ; and thick, p < . ). the odds ratios are encoded by colors where a red cell indicates an odds ratio > ; and blue otherwise. for example, for a sore throat, flu-a(unknown), flu-b, cv, rv, adv-e, cov-oc and cov-nl have more of the sore throat than iflu-a(h n )pdm indicated by the red cells in the row for flu-a (h n )pdm and corresponding columns. ppv of ili was low ( . %) compared to other studies ( . - . %) likely because these studies were conducted during influenza seasons. this is supported by the higher npv ( . %) compared to other studies ( . - . %) [ , , , ] . two tropical studies [ , ] also report low ppv of . - % and high npv of - . %. adv are as likely as influenza viruses to present with fever and tend to be captured by the ili definition. however, they are more likely to present with cough and sorethroat than influenza. it may be possible to differentiate adv and influenza infection based on rhinorrhea and other symptoms. this could be useful in surveillance and clinical management, especially when deliberating whether to start antivirals. early etiologic diagnosis of influenza has been shown to be cost effective [ ] with reduced antibiotic use and may reduce complications with early antivirals. it may be possible to combine a clinical diagnostic model with rapid testing to achieve these goals. the analysis was limited to viral mono-infections and future studies should explore co-infections and bacterial infections. this study involved predominantly young adult males, and results may not be generalizable to the overall population, necessitating further studies among various age groups and gender. there were also less recruits amongst controls than amongst other groups, and this would be an important consideration when comparing the two groups in the future. finally, the actual clinical impact of differentiating between various viral etiological agents may be limited, and we could not determine the relative severity of symptoms other than fever. our study highlights the varied etiology for fri and ili in the tropical settinginfluenza and adv and cv were all common. influenza and advs tend to present with higher fever, and vaccination should be considered. the utility of ili for tropical surveillance of influenza needs to be reviewed given the low ppv and high npv compared to temperate regions. the surveillance system has enabled the singapore military to understand the etiologic agents affecting servicemen, hence implementing and evaluating controls measures such as vaccination. figure correlation of symptoms and signs across all viruses. clinical signs or symptoms are listed by average frequency from the most to the least. binomial test is used to assess the discrepancy between the observed proportion of symptom pairs and the expected proportion of symptom pairs which is the product of the two marginal distributions by assuming symptoms develop independently. color cells represent differences that are significant at the % level, and the thickness of the cell wall represents the p-value (thin means . < p < . ; medium, . < p < . ; and thick, p < . ). the excess probability encoded by colors measures the effect size. if the observed 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key: cord- -wg sa u authors: quah, stella r. title: public image and governance of epidemics: comparing hiv/aids and sars date: - - journal: health policy doi: . /j.healthpol. . . sha: doc_id: cord_uid: wg sa u abstract a comparative analysis of the – infectious disease outbreak, severe acute respiratory syndrome (sars), and the hiv/aids epidemic that has affected the world over the past two decades reveals the significant role of socio-cultural beliefs and attitudes in the shaping of people's lifestyles and approaches to the control and prevention of epidemics. the main research question is: what can we learn from the sars experience about effective prevention of hiv/aids? the sources of data include population figures on the development of these epidemics and findings from two sociological studies of representative samples of singapore's multi-ethnic population. the comparative study illustrates the impact of cultural beliefs and attitudes in shaping the public image of these two different infectious diseases; the relevance of public image of the disease for effective prevention and control of epidemics. traditionally, the human suffering inflicted by longterm epidemics have tended to find expression in literature and the fine arts thus becoming a visible part of the collective memory and shaping the public image of the disease. for example, the impact of the bubonic and pneumonic plague or "black death" had a major influence on painters of the gothic period [ ] ; tuberculosis is featured in eugene g. o'neill's long day's journey into night; franz kafka's diaries; thomas mann's the magic mountain [ ] ; victor hugo's les misérables; dickens' nicholas nickleby, brontë's wuthering heights; verdi's la traviata [ ] . among e-mail address: socquahs@nus.edu.sg. epidemics in the past three decades (hiv/aids, sars, mad cow disease, and avian flu among others), only hiv/aids has lasted long enough to inspire artistic expressions in literature [ ] [ ] [ ] [ ] , theatre [ ] , dance [ ] , and film [ ] mostly used as vehicles for hiv/aids preventive education programs particularly in africa [ ] [ ] [ ] [ ] [ ] . one of the pioneer studies in prevention was published in by zinsser [ ] . ever since, a community of experts worldwide has been dedicated to prevention [ ] [ ] [ ] [ ] [ ] [ ] [ ] . however, despite the struggle to convey a more accurate and humane public image of aids in the past decade, the stigma attached to hiv/aids still persists as a formidable obstacle to prevention efforts [ ] [ ] [ ] . figures on the spread of the disease suggest we are losing the battle against hiv/aids especially in developing countries [ , [ ] [ ] [ ] [ ] . in china alone, the estimated number of deaths due to aids as of december (latest figures available), ranged from , to , and , persons infected with hiv/aids. the figures for thailand, the second most affected east asian country, are , - , deaths, and , persons infected with hiv (appendix a, table a . ). in contrast to the dismal hiv/aids situation, the - outbreak of severe asymptomatic respiratory syndrome or sars, offers a completely different picture for the analysis of preventive efforts. although sars, like hiv/aids, was unknown in the medical world and hit unexpectedly, there are some significant differences, particularly in their etiology, epidemiology, natural history and clinical outcomes of the two diseases. hiv/aids is asymptomatic for - years after infection so that hiv-positive persons may continue to spread the disease unknowingly. the main mode of hiv/aids transmission is through direct contact with infected body fluids or blood (sexual intercourse, use of infected needles by drug users and receiving contaminated blood transfusions). sars is caused by the sars coronavirus and characterized by airborne transmission. sars develops very rapidly, with an average incubation period of days or a range of - days after contact. within week of the illness patients show typical influenza-like symptoms such as fever, malaise, and headache with cough and diarrhoea getting worst in the second week of infection. it has been determined that "transmission occurs mainly during the second week of illness". these external signs facilitate prompt action: exposed patients may be placed under fever surveillance twice a day "in an isolation facility or ward for at least days after the last exposure to the source case(s)" [ ] . in the span of months sars infected persons, caused deaths (appendix a, table a . ) and became a widespread visible threat through the serious disruption of normal daily activities of individuals and major sectors of the economy such as transportation, commerce, industrial production, and tourism [ ] [ ] [ ] . the first probable sars case was reported in china on november and the infection spread to other countries around the world but the largest number of locally transmitted infections and deaths were reported in china, hong kong, taiwan, canada, and singapore (appendix a, table a . ). despite the fact that sars caught the world unprepared, hit at great speed, and it is very difficult to eradicate [ ] , the outbreak was contained within months, a relatively brief period of time (appendix a, table a . ). despite the medical differences (in etiology, epidemiology, natural development and clinical outcomes) between these two epidemics, i argue and attempt to demonstrate in this study that we may advance our knowledge on preventive strategies by conducting a systematic comparison of important social aspects of hiv/aids and sars. what can we learn from the sars experience about effective prevention of hiv/aids? more specifically, why were the efforts to contain and prevent the spread of a new epidemic like sars successful while it has taken years so far to contain the spread of hiv/aids and no effective solution is yet in sight? social science research has identified over the past decades a complex array of factors and conditions associated with disease prevention in individuals (micro-level analysis) as well as collectivities (macro-level analysis) but the factors and conditions vary for different diseases and there may be many other factors yet to be identified. still, contrasting the two epidemics in terms of social attitudes and beliefs at the micro-and macro-levels, will help us to elucidate some of the major obstacles to hiv/aids prevention. therefore, this paper focuses on only three possible factors: the impact of perceived severity and susceptibility to infection and the public image of the epidemic (micro-level factors); and the governance of epidemics (macro-level factor). sociology and social psychology offer some interesting explanations of the sluggishness of preventive health behavior in individuals [ , ] . among ten theories identified as the "most often used" today [ ] , the top two explanatory models are the social cognitive theory (sct) and the health belief model (hbm) [ , ] . both social theories are useful in the analysis of preventive action: they focus on the individual's capacity to make his/her own decisions, and the recognition that there are multiple and varied factors involved in a person's health-related actions. the sct explains people's health-related actions primarily in terms of their expectations of the outcome, their confidence in the success of their actions, and their ability to perform the action; but perhaps the most relevant aspect of the sct is its consideration of the individual's environment as one of the important determinants of his/her behavior [ ] . the hbm proposes that the likelihood of a person taking preventive action increases if he/she believes in his/her personal susceptibility to the illness and in the severity of the illness; perceives the preventive action as beneficial; believes that there are no barriers to action or that barriers can be overcome; believes in the net gain -benefits exceed barriers or costs-of taking preventive action [ , , ] . a comprehensive review of studies applying the hbm [ ] found the variables perceived susceptibility and perceived severity to be closely correlated and to have significant influence upon a variety of preventive behaviors. the combination of both perceived severity and perceived susceptibility labeled "perceived threat" has been found to be a more significant explanatory variable than severity and susceptibility used separately [ ] . the hbm variable influencing the perception of effective prevention of hiv/aids in three ethnic communities is perceived severity or seriousness of the disease, together with the perception of personal responsibility for contracting the disease [ ] . i ascertained perceived severity of hiv/aids in terms of the respondents' subjective perception of the likelihood of death using the close-ended question "when you think about aids, how serious do you feel it is? this approach is basically the same as that of janz et al. [ ] who define perceived severity as "one's belief of how serious a condition and its sequelae are". strecher et al. had offered earlier [ ] a wider definition of perceived severity: "personal evaluations of the probable biomedical, financial and social consequences of contracting hiv and having aids". although there are slight variations in the wording of the question asked in interviews and in the definition of perceived severity, the general consensus in the literature is that this conceptual construct, often together with perceived susceptibility, is essential in the analysis of people's motivation to take preventive action. nevertheless, as preventive health behavior is influenced by a multiplicity of factors, the hbm, sct and all the other top eight theories [ ] are limited as they offer only partial explanations of health-related behavior, but they are complementary. i include social constructs from the hbm and the sct and some relevant contextual social factors, to explore the research question "what can we learn from the sars experience about effective prevention of hiv/aids"? combining the analysis of individuals' responses with their collective implications, i attempt to demonstrate that perceived severity together with perceived susceptibility and the public image of the two epidemics help to explain some of the difference in prevention effectiveness. i test two related assumptions: ( ) a higher perception of disease severity and personal susceptibility to sars as compared to hiv/aids, contributed to the higher effectiveness of sars prevention efforts; ( ) the second assumption is two-fold: (a) in contrast to sars, the overall negative social 'image' of hiv/aids as a disease associated with particular types of individuals tends to weaken people's perception of susceptibility; (b) correspondingly, low perceived susceptibility tends to discourage public support for robust preventive efforts at the community level. these assumptions require elaboration. following the hbm, the first assumption to be tested is that a person's perception of the severity of the disease and his/her perceived susceptibility to that disease are likely to motivate him/her towards taking preventive action. all things being equal, such a commitment to prevention would weaken or be altogether absent when perceived severity and/or susceptibility are low or nil. the perceived severity of hiv/aids was ascertained through the question "when you think about aids, how serious do you feel it is? four alternative response categories were provided (see tables and a. ) . for the logistic analysis, the responses were dichotomized into high perceived severity (( ) "very serious, causes death"), and low perceived severity (( ) "not very serious" or "not serious at all" and "don't know"). perceived susceptibility to hiv/aids was ascertained by the level of agreement to the statement "aids doesn't happen to people like me" (tables and a. ). in the study of sars, perceived susceptibility was ascertained through the question "how likely do you think it is for you to contract sars"? respondents expressed their belief in their personal susceptibility by indicating whether they saw the likelihood of contracting sars as "very likely", "likely", "not very likely", "not likely at all", or did not know ( table ). the perception of severity of sars was measured by the question "if you have contracted sars, what is the likelihood of survival"? the four response categories were "very likely", "likely", "not very likely" and "not likely at all" ( table ) . the second assumption is that in contrast to sars, the overall negative public 'image' of hiv/aids as a disease associated with particular types of individuals tends to weaken people's perception of susceptibility and, correspondingly, tends to discourage public support for robust preventive efforts at the community level. the individual's 'image' of the disease shapes his/her perception of seriousness and susceptibility and thus contributes to his/her motivation to take preventive action. that 'image' of the disease and of persons affected, however, is shaped to a large extent by prevailing values and normative beliefs in the community and it is subject to change over time. this process is suggested by many sociological theories including social networks and social support theory [ ] , rational choice theory [ ] , and the sct. the sct offers the concept "reciprocal determinism" [ ] that proposes a dynamic interplay of "the person, behavior, and the environment". a eight preventive measures were considered as part of the respondents' "activities during the past days": covering the mouth with paper tissue or handkerchief when sneezing or coughing; covering the mouth with bare hand when sneezing or coughing; washing hands after sneezing or coughing; using soap or liquid hand-wash when washing hands; wearing a mask over the mouth; using serving utensils (chopsticks or spoons) for shared food when joining others for meals; when touching objects that may possible carry the sars virus (e.g., door handles, buttons in lifts), taking preventive measures (e.g., pressing lift buttons with tissue paper); washing hands as soon as possible after touching objects that may possibly carry the sars virus (e.g., door handles, buttons in lifts). b the original response categories for perceived susceptibility (that is, the perceived likelihood of contracting sars) were: "very likely", "likely", "not very likely", "not likely at all" and "don't know". for the logistic regression analysis the latter group, . % of respondents who had no idea on their susceptibility to sars, were contrasted with all other respondents who did have an assessment of their likelihood of getting infected. c the original response categories for perceived severity (that is, the likelihood of survival) were "very likely", "likely", "not very likely" and "not likely at all". for the logistic regression analysis, these responses were dichotomized into low perceived severity (survival "very likely/likely") and high perceived severity (survival "not very likely"/"not likely at all"). d the respondents' appraisal of the health authorities' crisis management was ascertained by their assessment of the distribution of information in terms of accuracy, clearness, sufficiency, timeliness, and trustworthiness in a scale from very negative (score ) to very positive (score ). the scale had high reliability (α = . ) and the mean score was . (s.d. = . ). in my view, the dynamic interaction of the individual's health-related behavior and the environment is better explained by the individual's subjective perception of the situation (for example a crisis or stressor) and the social context of the situation, as proposed by symbolic interaction and family stress theory [ ] . thus, my assumption that a person's motivation to take preventive action may also be manifested in his or her cooperation with community-based preventive measures is explained clearly by the application of the conceptual premises on community responses to stressor events formulated by reiss and oliveri [ ] . the public's perception of the scope of the problem was highlighted by these authors as part of their concept "community's punctuation of an event". they defined the community's punctuation of an event or perceived scope as "when the problem begins and when it ends and who is involved". they proposed that the community and its leaders would be more inclined to invest concerted efforts to solve a problem if three conditions are met: accountability, duty, and competence [ ] . that is, the community and its policy-makers would be most inclined to mobilize assistance and preventive efforts when these three conditions are met: the persons affected are perceived as not being accountable for the problem; they are regarded as having the duty to request outside help; they are considered as lacking the competence to solve by themselves the problem affecting them. i suggest that these three conditions shape the public image of sars and hiv/aids and add to our understanding of the disparity in prevention effectiveness of these two epidemics at the community level. the public image of hiv/aids was ascertained through one open-ended question about persons living with hiv/aids: "what kind of people do you think are most likely to get aids"? the analysis of responses revealed three types of stereotypes or 'images': 'risktakers', 'deviants', and 'victims'. only a small group of respondents had not particular image of people living with hiv/aids ( table ). the public image of sars may be ascertained indirectly through the respondents' perception of a sense of social responsibility and willingness to make some personal sacrifices in combating the disease. those perceptions reflect people's collective sense of accountability and duty and their recognition of the need for expertise to handle the crisis. referring the respondents to the measures implemented to prevent the spread of sars, they were asked their level of agreement (strongly agree to strongly disagree) with these statements: "people should be willing to make some personal sacrifices"; "people have mostly been socially responsible"; "if you did not develop symptoms of sars after having close contact with someone diagnosed with sars, would you agree to be quarantined for days?"; "if you did not develop symptoms of sars after having non-close contact with someone diagnosed with sars, would you agree to be quarantined for days"? ( table ). the condition of "competence" identified by reiss and oliveri [ ] as discussed above, has to do with expertise in handling the crisis, and thus brings in a final concept of relevance to this discussion: governance. governance is another socially significant aspect of hiv/aids and sars as a strong political will at the national level is needed to invest state resources, and to utilize knowledge and technology creatively for their detection and prevention. but these epidemics are also global problems that challenge national boundaries and the conventional idea of state sovereignty and governance, and test international cooperation, because of their mode of transmission and the increasing movement of people across countries for leisure, trade, and study among other activities. given the easiness and speed of their international transmission, these epidemics have unwittingly pushed forth a new phenomenon that fidler [ ] calls "global health governance" that is, "the proposition that governance of public health issues must include not only state actors but also non-state actors". examining the international impact of sars, this international law expert concluded that "to govern an increasingly borderless world, requires, in essence, increasingly borderless governance" [ ] . the analysis of the sars crisis management in singapore suggests that effective containment and prevention of infectious disease outbreaks requires dedicated and transparent governance at both levels, national and global. and to be successful, global governance requires timely and effective response and collaboration from sovereign nations. but as i shall discuss later, the governance approach to sars differs substantially from that applied to hiv/aids. first, a word of caution: i reiterate that this study is by necessity limited and exploratory because the two epidemics, hiv/aids and sars, are very different microbiologically and epidemiologically as indicated in the introduction; and there is a -year gap between the two surveys. the sars study was conducted as the outbreak progressed in may , years after the hiv/aids study. nonetheless, despite these methodological difficulties, i believe it is important to scrutinize available information on both epidemics in the hope of increasing our understanding of the dynamics of preventive action against hiv/aids. while the two epidemics are different in many respects, they are both serious public health threats that require a collective response [ , ] as indicated earlier. two general types of data are discussed here: population figures and data from personal interviews. the international population figures on the impact and spread of hiv/aids and sars are taken from who's published reports [ , , , [ ] [ ] [ ] . the analysis of behavior and attitudes of individuals is based on data from two separate studies i conducted in singapore as principal investigator. the data on hiv/aids are from a study of attitudes and preventive behavior regarding hiv/aids based on a survey of personal interviews with a representative stratified random sample of adults aged and older following a structured questionnaire. respondents were from the chinese, malay, and indian communities, the three largest ethnic groups in singapore. the sample characteristics and the details on measurement of the variables included in this analysis are described in tables and a. . the data discussed in this paper are part of a larger study on preventive health behavior regarding cancer, heart disease, and hiv/aids supported by a research grant from the national university of singapore. further methodological details are provided elsewhere [ ] . the new findings discussed in this paper were obtained through logistic regression analysis. the data on behavior and attitudes on sars are from a study based on telephone interviews with a representative stratified random sample of adults aged and older, following a structured questionnaire. the three main ethnic groups in singapore (chinese, malays, and indians) were proportionally represented. the interviews were conducted within the span of days, from to may, while the country was facing the sars epidemic. telephone interviews were the only data collection option because it was imperative at the time to follow the public health advice to restrict personal contact to home and the workplace, whenever possible. the main characteristics of the sample and the attitudinal measurements applied are presented in table . further methodological details of this study are described elsewhere [ ] . the new findings presented in this paper were obtained through logistic regression analysis. while the data refer to three ethnic communities in singapore the findings illustrate the impact of social attitudes upon the governance of epidemics in a high density global city. acknowledging the multiplicity of factors that may play a role in shaping the success or failure of illness prevention and containment of epidemics, this study deals only with a small number of variables. the analysis of data in both studies comprised two stages: an initial scrutiny of the main assumed correlations and attitudinal scales using partial correlation and factor analysis; logistic regression to explore the likelihood of occurrence of stereotypical images of people living with hiv/aids, the dependent variable in the hiv/aids study; and likelihood of public support of the sars crisis management, the dependent variable in the sars study. logistic regression is a very useful tool to explore the probability of occurrence of the dependent variable over the probability of it not occurring and the outcome is provided as odds ratios. the odds ratio is the odds of one variable occurring to the odds of another [ , ] . the logistic regression analysis of the public image of hiv/aids comprised three sets of variables: sociodemographic variables (gender, age, ethnicity, marital status and religion); social class factors (occupation, personal monthly income, and educational level); attitudinal factors proposed by the hbm and the sct (tendency to worry about falling ill; future orientation; sense of personal control of one's life; life satisfaction; perceived severity of hiv/aids; perceived susceptibility to hiv/aids; belief in effective prevention of hiv/aids) and perception of hiv/aids. a description of these variables is provided in table a. . five sets of variables were included in the logistic regression analysis of the public support of the sars crisis management: socio-demographic variables (gen- der; age; ethnicity; place of birth; marital status); social class (educational level and personal monthly income); health behavior variables (smoking, exercising regularly, and preventive measures against sars taken over the days preceding the interview); attitudes suggested by the hbm including perceived susceptibility and perceived severity; and attitudes on sars crisis management. to meet requirements of the logistic regression analysis the response categories of the question on perceived susceptibility were dichotomized contrasting the respondents who expressed an estimation of their likelihood of infection on the one hand, with respon-dents who have no awareness of their susceptibility to sars, on the other hand. the response categories for perceived severity were dichotomized into "high" severity (survival not very likely or not likely at all) versus "low" severity (all other responses including "don't know"). the complete list and explanation of all the variables are presented in table . the discussion follows the two related assumptions presented earlier. the first assumption to be tested is that a higher perception of disease severity and personal susceptibility to sars as compared to hiv/aids, contributed to the higher effectiveness of sars prevention efforts. show that the sars outbreak was contained within months of its onset while the hiv/aids epidemic continues undefeated after nearly three decades. would people's sense of susceptibility to these diseases and their severity contribute to that difference? the survey data from singapore on the two epidemics provide a tentative yet useful indication of the differential perception of severity and susceptibility. only . % of the respondents expressed high susceptibility to hiv/aids (table ) compared to . % of respondents in the case of sars ( table ). the corresponding figures on the expression of high perceived severity are . % of the respondents in the case of hiv/aids (table ) and only . % of the respondents in the case of sars ( table ) . the findings from the analysis of the belief in effective hiv/aids prevention in the total sample (appendix a, table a. ) indicate that people who believe that hiv/aids is very serious and fatal (high perceived severity) are significantly more inclined than those with low perceived severity to believe there are effective ways of preventing the disease. this belief in effective prevention of hiv/aids is also found among people with high future orientation, those who are inclined to worry about falling ill; it is expressed by men more than women. the nagelkerke r coefficient of . suggests that . % of the overall variation in the belief in effective prevention of hiv/aids is predicted by the variables in the model. the model predicted correctly the belief in effective hiv/aids prevention . % of the time. in the case of sars, preventive measures were being implemented as the outbreak progressed. the interviews took place in the midst of the crisis as the country and the region were coping with this completely new threat. no clear indication of effective prevention was in sight but through a steep learning process several effective preventive measures were being identified and the information transmitted from the experts to the public daily through various mass media including radio, newspapers, the internet, regular television, and a dedicated television channel set up specifically for that purpose. this special situation may explain the respondents' very low perceived severity of sars and their very high sense of susceptibility to it as ways of transmission encroached into people's daily life, for example: droplets from the sneezing or coughing of an infected person, and the touching of infected commonly used objects such as eating utensils, buttons in elevators, and door handles [ , ] . the second assumption to be explored here is that in contrast to sars, the overall negative social 'image' of hiv/aids as a disease associated with particular types of individuals tends to weaken people's perception of susceptibility and, correspondingly, tends to discourage public support for robust preventive efforts at the community level. as suggested earlier, this assumption may be examined using reiss and oliveri's [ ] concept "community's punctuation of an event" and the three conditions -accountability, duty, and competence -these authors identified as requirements for the community's positive response. in the case of hiv/aids and sars the focus is the community's endorsement of disease prevention and containment plans and their active collaboration in prevention efforts. when does the problem begin and when does it end and who is involved? the answers to these questions mark the community's punctuation of crises and show that the punctuation of the sars outbreak was rather different from that of hiv/aids. the punctuation of the sars outbreak as a crisis was very clear. sars was imported into singapore at the end of february, , when an infected vacationer returned home from hong kong where she caught the infection while staying at the same hong kong hotel where a doctor from guangzhou, china who had treated sars patients there, was residing [ ] . the unknown cause and nature of the disease deterred the assignment of blame or accountability. sars patients were not held accountable for their illness. nor were they assumed to have the expertise to solve the problem on their own although it soon became a duty for people with the publicized symptoms to seek immediate expert medical help [ , ] . the findings from the sars study in table show that . % of the respondents made a positive appraisal of the health authorities' management and control of the sars crisis; . % had the chance to express their opinions to the authorities; . % were prepared to be quarantined for days after close contact with an infected person and . % would agree to be quarantined even if there was non-close contact. further indications of the public's willingness to collaborate in preventive efforts against sars were the very positive attitudes of the majority of respondents: although about one of every two agreed that preventive measures taken against sars "have affected my personal choice and freedom in life", most respondents ( . %) agreed that "people should be willing to make some personal sacrifices" to contain the epidemic and % felt that "people have mostly been socially responsible". the findings from the logistic regression analysis of the sars study data confirm that this sense of social responsibility was a fundamental manifestation of the community's positive and compassionate 'image' of sars patients and it was significantly associated with their endorsement of the health authorities' management of the crisis in the total sample as well as among people with lower education, and ethnic minorities such as the singaporean malays (table ) . among the respondents, the endorsement of the health authorities' crisis management was particularly supported by people who perceived the community as being socially responsible; those who believed that the crisis justified making some personal sacrifices (especially with regard to movement outside their homes, restricting or changing their travel patterns, and abiding by quarantine regulations); those felt that they had the chance to be part of the effort and express their personal opinions; people who had formed an opinion on their personal susceptibility to the infection (in contrast to those who had no or very little information on sars). the nagelkerke r coefficient of . suggests the factors in the model explain . % of the variation in endorsement of the crisis management in the total population. the analysis of the same factors was repeated among three specific subgroups that have shown less positive appraisal of crisis management: the senior cohort (respondents aged and older), the lower educated (people with only primary or lower education), and malays. as illustrated in table , even among the lower educated and the malay, the sense of social responsibility was significantly associated with their endorsement of preventive efforts (dependent variable). however, perceived susceptibility to sars did not influence significantly the appraisal of crisis management by the seniors and the less educated but it did among malays in the expected direction: persons who have no idea of their susceptibility (no awareness of it) were most likely to give a negative appraisal of crisis management. no significant impact of perceived severity upon people's appraisal of crisis management was detected in the total sample or any of the three subgroups. overall, the nagelkerke r coefficients indicate that, compared to the total sample, variables in the model helped explain a larger proportion of the variance in the dependent variable among subgroups such as seniors ( . %), the less educated ( . %) and the malay community ( . %) about % of the time. these figures point to the importance of variations the perception of and responses to crises among different segments of the population given their differences in life experiences, in knowledge and level of information on the problem, and in cultural values and beliefs, among other factors. as indicated earlier, from the contextual perspective proposed by reiss and oliveri [ ] the public image of a crisis or stressor (e.g., an infectious disease epidemic) refers to the public's perception of its scope and its social acceptability. in terms of the scope of the problem -when it begins and when it ends -the quiet and prolonged way in which the hiv virus enters and destroys the immune system represents a major challenge for the mobilization of public interest and support of testing. visible signs of the disease tend to appear only in the late stages. the opposite occurred with respect to sars. two separate studies of the awareness of health threats in the united kingdom confirm these findings on impact of the public image of the problem and punctuation or scope of the event: british lay respondents and journalists were inclined to see aids as a "far-flung" risk of no immediate relevance to their lives [ , ] . regarding social acceptability, if the stressor is seen by the community as the consequence of socially unacceptable behavior, one would expect collective apathy or reluctance or opposition to the investment of public funds and efforts to contain and solve the problem. the findings in tables , and a. suggest that this appears to be the case with hiv/aids. the public image of hiv/aids tends to be shaped by normative expectations or stereotypes in the community. the large majority of the respondents ( . %) associated a particular lifestyle with the contracting of the disease thus forming negative images of people living with hiv/aids. as shown in table , over half of the respondents ( %) saw them as "risk-takers": people who engage in activities that put them at risk of infection such as having multiple sexual partners or procuring the services of commercial sex workers. another % of the respondents associated them with people who engage in 'deviant' activities such as commercial sex workers and injecting drug users who exchange infected needles. a small group ( . %) considered them as "victims" of "fate" or "bad luck" or accidental infection. only . % of the respondents did not have an opinion or image of people living with hiv/aids. practically all in this group had no information on hiv/aids. table presents some of the factors that contribute to the formation of a particular 'image' of people living with hiv/aids. the odds of seeing them as 'victims' (column b) were significantly higher among older people, those who do not think hiv/aids is a serious and deadly disease; and those who do not believe there is an effective way of preventing the illness. interestingly, the same features are exhibited by the small group who did not put a label on people living with hiv/aids (column a): they tend to be older, unaware of the severity of the disease, and unaware of any effective preventive measures. the odds of perceiving hiv/aids sufferers as 'risk-takers' that is, associating a 'risk-taking' life style with hiv/aids infection (column c), decreased by % among men; increased significantly among people who worry about falling ill and those who believe that there are effective ways of preventing the disease. the most negative 'image' or lifestyle associated with hiv/aids infection is that labeled 'deviants' (column d). the odds of having this image of hiv/aids sufferers increase significantly among women in contrast to men; among younger people in contrast to people who are or older; among those believe the disease is very severe, and among people who do not worry much about falling ill. the nagelkerke r coefficients indicate that the variables in the model explain . % of the overall variation in emphasis on the 'victim' image; . % of the emphasis on the 'risk-takers' image; . % of the emphasis on the 'deviant' image, and . % of the variance on the absence of a stereotypical image of hiv/aids sufferers. this variable is explained correctly by the variables in the model . % of the time (table ). these findings fit the international pattern: the presence of stereotypical images of people who get infected with hiv/aids is not restricted to a particular country [ , ] . state regulations on infectious diseases such as notification and surveillance systems have been in place for more than a century in many countries [ , ] and today they are followed by all state members of the united nations including singapore [ ] . but the official approach to the control and prevention of hiv/aids differs widely from that of sars and the difference has to do with the public image of the disease discussed in the preceding sections. the experience of sars in singapore provides an interesting illustration of the positive synergy between national governance and global health governance. the main features of the state's crisis management approach illustrate the situation well. those features were: (a) transparency; (b) public education; (c) multi-pronged approach; (d) legislation. in contrast to the situation in china and some other affected countries at the onset of the epidemic [ , ] , the sars situation in singapore was characterized throughout by transparency on the part of the health authorities in their reporting and distribution of a continuous flow of information to the public on new infections and deaths, locations, and contact tracing efforts and approaches. it was believed that an informed public can collaborate better and participate more effectively in containing the spread of the disease than a public kept ignorant of the seriousness of the situation. news reports on the progress of the epidemic were transmit- notes: total sample size, . * statistically significant at p = . - . . ** statistically significant at p = . - . . *** statistically significant at p = . - . . **** statistically significant at p = . or lower. ted to the public through all printed media, radio and television in all the four official languages (mandarin, malay, tamil and english). exceptional measures were taken to reach as many people as possible throughout singapore: broadcasting was resumed temporarily in some of the chinese dialects that had not been used in tv for nearly two decades; a new dedicated tv channel was set up, sarstv. singapore was the only country affected by sars to set up this public service [ ] . informing the public on the development of the epidemic went hand-in-hand with public health education whereby public information on the current state of knowledge on the disease was constantly updated at various levels of sophistication, from medical and epidemiological data in specialized publications [ , ] to newspaper articles explaining how the coronavirus attacks a healthy cell, to cartoons illustrating the proper use of masks, of serving utensils, and to take one's temperature correctly with a thermometer, and how to wash hands thoroughly, among other things. it was evident to the authorities and the population that the sars epidemic affected the daily life activities of every citizen and demanded drastic changes in lifestyle. this realization led to the implementation of a multi-pronged approach to deal with the crisis. all relevant ministries, statutory boards and other organs of the state were mobilized and non-governmental organizations and the private sector joined the effort. this approach was in fact a typical response in singapore as "ministries and government agencies had honed emergency preparedness to a fine art" [ ] . part of that preparedness was the use of legislation including quarantine laws and other preventive measures. for example, section of the infectious diseases act was amended with effect from april requiring "medical or dental practitioners to obtain information from their patients and transmit such information to the director [of medical services] to investigate the outbreak or prevent the spread of an infectious disease such as sars"; a new "patient declaration form" was used for this purpose during the outbreak [ ] . while transparency, public education, the implementation of a multi-pronged approach, and the use of legislation were characteristics of the national government's response internally, there was also transparency and close collaboration of singapore with the who and other international organizations. in his global analysis of the epidemic, fidler highlights this feature: "singapore was initially scheduled to be removed from the [who's] list of sars-affected areas on may; but, on that date, singapore reported a new case of sars to who, an indication of singapore's commitment to open reporting and cooperation with who" [ ] . a sovereign state's abiding to international guidelines, even at the expense of its own economic interests, illustrates the importance of "global health governance" to deal with infectious disease epidemics and similar health threats in the st century. the control and prevention of hiv/aids has followed a different approach. fidler [ ] correctly highlights "the conceptual and policy shifts" from standard procedures applied to infectious diseases by the who and public health experts. the international health regulations (ihr) "are the only set of international legal rules binding on who member states concerning the control of infectious diseases" [ ] . yet, in fidler's view, one distinguishing feature of the official international approach to deal with the hiv/aids epidemic was that public health experts and the who did not follow the ihr's classical "westphalian" model -that emphasizes state sovereignty and non-intervention -to deal with infectious diseases "but rather turned to international human rights law to provide governance norms for the fight against this new plague" [ ] . this conceptual shift was unique. the approach to hiv/aids was "the first time in history [that] preventing discrimination towards those affected by an epidemic became an integral part of a global strategy to prevent and control an epidemic of infectious disease" [ , ] . danziger [ ] suggests that this conceptual shift was promoted and supported by the "neoliberal democratic ideology" prevalent in western countries by the end of the th century and enthusiastic enough to lead some countries to abandon the compulsory surveillance methods and "placing protection of individual rights on a par with (or even above) the protection of the public health". apart from the ideological angle, the who's concern with human rights and particularly with the matter of discrimination of people living with hiv/aids has its roots in actual manifestations of social stigma associated with the presumed lifestyle of the first persons affected by the disease. in june and july, , five young homosexual men were diagnosed with pneumocystis carinii pneumonia and young homosexual men with kaposi's sarcoma "a rare form of cancer which had until then been associated with elderly americans"; added to the spectrum of aids features in the early s was the confirmation that one of the main forms of transmission is sexual intercourse [ ] . the spread of the epidemic has been so extensive geographically as well as socially, that people living with hiv/aids today come from all walks of life. but as the figures in appendix a, table a . indicate, the highest prevalence of hiv are still found among some distinct lifestyle groups including commercial sex workers and injecting drug users. the survey data discussed in the preceding sections suggest that the public image of hiv/aids reflects the prevalence figures among some specific groups; a large majority of respondents saw hiv/aids sufferers as following their lifestyle by personal choice. thus, their image remains negative despite public education efforts by the who, non-state organizations and non-governmental organizations. an additional aspect is the slow pace of development of the disease: people may be infected for many years without developing any symptoms and may thus continue unwittingly to infect others [ ] . the global governance approach to protect people with hiv/aids from discrimination involves avoidance of disclosure of one's health condition and of routinely or compulsory name-linked testing and other features of standard infectious disease surveillance. danziger [ ] sees this position as "possessive individualism" that demands testing to be done only if the person has consented freely and has received full information on the consequences through the process of informed consent. moreover, danziger points out that with the current stage of knowledge on hiv/aids, "there is little or no gain for a hiv-infected person to be tested and identified as hiv-positive" [ ] . this reasoning creates a dilemma because experts agree that standard infectious disease surveillance is indispensable for the effective prevention and control of infectious diseases [ , [ ] [ ] [ ] [ ] [ ] [ ] [ ] , ] that is, the beneficiaries of effective control and prevention are the rest of the community. according to danziger [ ] the dilemma has been sorted out internationally by an apparent consensus of stakeholders to consider hiv/aids as "a crisis of human rights" and not as a "public health crisis". however, with the epidemic proceeding unrelentingly, there are signs of concern. a recent development in singapore is illustrative of the range of opinions on this matter: the ministry of health announced on july that "spouses of patients with hiv will be informed of their partner's illness, regardless of whether the infected person agrees" [ ] . the newspaper report cited the case of four women who discovered they had hiv when they did their blood test during their pregnancies. the husband of one of them had been diagnosed with hiv since . previously, patients were counseled and informed consent was required. now the doctor needs only to keep the patient "appropriately informed". the spouses will be informed "in a sensitive manner" by trained personnel of a new hiv prevention unit. the infectious diseases act will be invoked as is the case with all other infectious diseases [ ] . the singapore shift towards a version closer to standard surveillance of hiv/aids is indicative of its concern for the rights of the infected person as well as the rights of the patient's partner, and of all other persons involved. the global governance of hiv/aids prevention needs to address the public image of the disease and the impact that such an image has upon efforts to mobilize the community in prevention efforts. for as long as hiv/aids is seen as a problem of particular lifestyles (that is, of specific types of people), prevention efforts such as condom use and testing are bound to have limited impact. the analysis was based on data from two separate studies of singapore residents' attitudes and behavior. given the differences in questions asked during the respective interviews, the -year difference between studies and the significant differences in the etiology, nature, and development of the two infectious diseases, the findings must be treated with caution. that said, the availability of data from the two studies offered a good opportunity for this exploratory comparison of attitudes towards and the public image of hiv/aids and sars in search of a better understanding of the social obstacles to effective prevention against hiv/aids. this exploratory comparison was guided by two main assumptions. the first assumption was that a higher perception of disease severity and personal susceptibility to sars as compared to the level of perceived susceptibility to and severity of hiv/aids, contributed to the difference in effectiveness of prevention efforts. the data from the singapore study support that assumption partially and revealed a new aspect of the problem. perceived susceptibility was high for sars but relatively low for hiv/aids. the opposite was found for perceived severity. the findings suggest that among the complex set of factors that motivate people to take preventive measures, perceived susceptibility to the disease (your subjective assessment of the likelihood of becoming infected) is more relevant than perceived severity of the disease. the data show a strong tendency for people to consider hiv/aids as peculiar to certain types of people different from themselves. thus their belief that their chances of being infected with the hiv virus are remote is not surprising. these findings on low perceived susceptibility and high perceived severity are also meaningful in the context of the second assumption tested. the second assumption explored in this study was two-fold: (a) that in contrast to sars, the overall negative social 'image' of hiv/aids as a disease associated with particular types of individuals tends to weaken people's perception of susceptibility; (b) that correspondingly, low perceived susceptibility tends to discourage public support for robust preventive efforts at the community level. the findings verify and clarify these assumptions. only out of every respondents expressed high perceived susceptibility to hiv/aids compared to out of every in the case of sars. but, as mentioned above, it was also found that the perceived severity of hiv/aids was significantly higher than the perceived severity of sars. more importantly, the labeling of people living with hiv/aids as 'risktakers' or 'deviants', was expressed by nine out of every of the respondents who believed hiv/aids was a incurable disease (high perceived severity) and believed that the disease is mostly linked to one's lifestyle choice. the challenge for health authorities is to enhance the population's perceived susceptibility to hiv/aids. the first step in this direction is the widespread distribution of accurate, clear and consis-tent information on the 'silent' nature of the disease in its early stages. the second part of this assumption was on the mobilization of the community's endorsement and active participation in the control and prevention of the epidemics. i have discussed the elements involved including the community's punctuation of the crisis and the aspects of accountability, duty, and competence. in the case of epidemics, competence is typically found at the community level and this brings us to the question of governance: how does a government deal with the health crisis represented by an infectious disease epidemic? much has been learned over the centuries around the world but each new epidemic brings new dangers. the sars outbreak tested the state's level of emergency preparedness and commitment to transparency particularly in asian countries, but it also highlighted the need for global governance of health threats that cut across national boundaries. in contrast, the hiv/aids epidemic still represents a challenge in terms of public health, political ideology, human rights, and social discrimination. the lack of success in the control and prevention of the epidemic highlights the fact that after nearly three decades the global governance of hiv/aids is still a work-in-progress. the urgency of the problem is well recognized by most world leaders and specialists with some experts warning that "new threats to [world] stability and secu-rity may emerge as the pandemic escalates" because, among other reasons, large numbers among police and armed forces in many countries and un peacekeeping forces are getting infected [ ] . the current global governance of hiv/aids requires critical scrutiny, as well as active exploration of solutions -among all types of stakeholders with differing ideological and social perspectives -to the slackness of preventive efforts against the two main behaviors that are sustaining the epidemic: "high-risk sexual activity and drug use" [ ] . one aspect of that critical scrutiny is the systematic and comparative analysis of hiv/aids global governance with the global governance of other infectious disease epidemics that have been successful. in sum, the findings on the sars and hiv/aids experiences suggest that health authorities need to navigate effectively the local and global obstacles to prevention by: (a) enhancing the public's understanding of the etiology of hiv/aids, its modes of transmission and effective preventive measures; and (b) correcting the lay public's inaccurate perception of personal susceptibility and 'the punctuation of the event'. tables a. -a. . very serious because it can cause death and has no cure serious but has some partial cure only mildly serious because does not cause death not serious at all scores range from (very serious) to (not serious at all). for the logistic regression analysis these response categories were dichotomized: ( ) "very serious" vs. ( ) all other responses perceived susceptibility to hiv/aids "aids doesn't happen to people like me" mean, . ; s.d., . ; sample size, this statement is part of a series involving cancer, heart disease and aids. respondents were asked to tell the interviewer if they strongly agree (sa), agree (a), disagree (d) or strongly disagree (sd) with each statement scores range from (sa) to (sd), with higher scores indicating higher perceived susceptibility for the logistic regression analysis these response categories were dichotomized: ( ) "sa/a" vs. ( ) all other responses belief in effective hiv/aids prevention "is there an effective way of protecting yourself from aids"? mean, . ; s.d., . ; sample size, the responses were scored as "yes" ( ) vs. "no" ( ) dependent variable: perception of people living with hiv/aids "what kind of people do you think are most likely to get hiv/aids?" during the personal interviews this open-ended question was preceded by identical questions for cancer and heart disease. factor analysis of the responses revealed three categories or 'images': (a) "victims" of "fate" or "bad luck" or accidental infection; (b) "risk-takers": people who engage in activities that put them at risk of infection such as having multiple sexual partners or procuring the services of commercial sex workers; (c) people who engage in 'deviant' activities such as commercial sex workers and injecting drug users who exchange infected needles. a fourth category comprises a small group of respondents who did not label people living with hiv/aids. each of the four categories is examined using separate logistic regression analyses (see table ) ( ) . **** personal control: high ( ) . life satisfaction: high ( ) . perceived severity: high ( ) . **** perceived susceptibility: high ( ) . nagelkerke r . variance predicted correct (%) . a see table a . for the description of measurement of belief in effective prevention. total sample size: . ** statistically significant at p = . - . . *** statistically significant at p = . - . . **** statistically significant at p = . or lower. dk publishing and national gallery of art illness as a metaphor and aids and its metaphors disease and the modern world. to the present day hiv stories: the archaeology of aids writing in france narrative in the time of aids: postcolonial kenyan women's literature the evil of the th century: poetry and aids on finding in a book of poems by norman dubie, a -year-old letter from the bookbinder to my cousin now dead of aids playing for life: performance in africa in the age of aids choreographer mark sieczkarek's 'living with aids' with the dance-factory in ghana nationalizing the gay body: aids and sentimental pedagogy in 'philadelphia'. american literary history narrative in times of crisis: aids stories in ghana playing for life: performance in africa in the age of rats, lice and history emerging issues in infectious disease epidemiology mapping the world of epidemiology. . the disease detectives disease detectives are turning to molecular techniques to uncover emerging microbes epidemiology: a science of patterns st century detectives-the laboratory professional in the prevention of infectious disease the making of a germ panic, then and now disease detectives celebrate years of successful sleuthing a critical analysis of the brazilian response to hiv/aids: lessons learned for controlling and mitigating the epidemic in developing countries measuring stigma in older and younger adults with hiv/aids: an analysis of an hiv stigma scale and initial exploration of subscales aids-related discrimination in asia treat three million people living with hiv/aids by . in: plenary address by director of hiv/aids, who at the seventh international congress on aids in asia and the pacific world health organization [who] position statement on condoms and hiv prevention the politics of emerging and resurgent infectious diseases. london: macmillan the lessons of hiv/aids world health organization. who guidelines for the global surveillance of severe acute respiratory syndrome (sars) crisis prevention and management during the sars outbreak sars, governance and the globalization of disease world health organization. who global conference on severe acute respiratory syndrome (sars)-where do we go from here? geneva: who health behavior. emerging research perspectives handbook of health behavior research health behavior and health education. theory, research and practice promoting health: intervention strategies from social and behavioral research how individuals, environments, and health behavior interact. social cognitive theory the health belief model and health behavior the health belief model hiv/aids prevention and public health education social networks and social support rational choice theory: advocacy and critique family stress management. a contextual approach family stress as community frame global atlas of infections -epidemiological fact sheet - update world health organization. summary of probable sars cases with onset of illness from summary table of areas that experienced local transmission of sars during the outbreak period from ordinary least squares and logistic regression analysis medical statistics a defining moment. how singapore beat sars at the epicentre. hong kong and the sars outbreak infectious diseases law & sars. singapore: times editions the politics of emerging and resurging infectious diseases hiv in singapore-past, present and future the sars epidemic under china's media policy online news media as interactive community bulletin boards. coverage of sars in the greater china regions the sars channel in singapore severe acute respiratory syndrome (sars) human rights and aids: the future of the pandemic new rule overrides patient confidentiality in order to protect the vulnerable aids as a social problem. the creation of social pariahs in the management of an epidemic. in: ritzer g, editor. handbook of social problems. a comparative international perspective representations of far-flung illnesses: the case of ebola in britain representations of sars in the british newspapers key: cord- -mbwgi x authors: pang, junxiong; jin, jing; loh, jin phang; tan, boon huan; koh, wee hong victor; ng, sock hoon; ho, zheng jie marc; gao, qiuhan; cook, alex r; hsu, li yang; lee, vernon j; chen, mark i cheng title: risk factors for febrile respiratory illness and mono-viral infections in a semi-closed military environment: a case-control study date: - - journal: bmc infect dis doi: . /s - - - sha: doc_id: cord_uid: mbwgi x background: febrile respiratory illness (fri) results in substantial burden in semi-closed environments. tackling risk factors may reduce transmission and infection. however, risk factors involved in one setting may not be generalizable in all settings due to differences in climate, residential environment, population genetic and cultural backgrounds. this study aims to identify risk factors of fri and mono-viral infections in a tropical military environment. methods: from year to , military personnel with temperature ≥ . °c, cough and/or sore throat, and personnel with no fever or no respiratory symptoms were recruited as cases and controls, respectively. subjects provided nasal wash specimens and answered a standardized questionnaire. resplex assays were used to determine the viral etiologies. descriptive, univariate and multivariate analyses of the variables were performed using appropriate descriptive tests and logistic regression modelling, respectively, with r program. results: a total of , fri cases and , non-fri study controls were recruited. increasing age [adjusted odds ratio (aor) = . ; % confidence interval (ci) = . - . ], recruit camp (aor = . ; % ci = . - . ) and smoker (aor = . ; % ci = . - . ) were independent risk factors of fri. malay ethnicity was positively associated with influenza a(h n )pdm (aor = . ; % ci = . - . ) and coxsackie/echovirus (aor = . ; % ci = . - . ) mono-infection. significant contact risk factors were stay-out personnel with ill household member (aor = . ; % ci = . - . ), and stay-in personnel with ill bunkmate and household member (aor = . ; % ci = . - . ). staying in camp with none ill in bunk and at home was a protective factor against fri (aor = . ; % ci = . - . ). these contact risk factors were similarly observed for the five most common viruses detected, namely adenovirus, rhinoviruses, influenza a and b, and coxsackie/echovirus. conclusion: increasing age, smoker, recruit-camp, stay-out personnel with ill household members and stay-in personnel with ill bunkmates were independent risk factors of fri in a semi-closed military environment. early identification and isolation of ill personnel from their bunk may be effective to prevent and reduce transmission and disease burden. febrile respiratory illness (fri) results in substantial disease burden in semi-closed environments such as in the households [ ] and militaries [ ] [ ] [ ] . fri is most commonly caused by viral infections, as observed in military respiratory surveillance programmes in finland [ ] , united kingdom [ , [ ] [ ] [ ] [ ] , netherlands [ ] , france [ , ] , south korea [ ] [ ] [ ] , west africa [ ] , taiwan [ ] , china [ ] , singapore [ ] [ ] [ ] [ ] [ ] [ ] , and the united states [ , [ ] [ ] [ ] [ ] [ ] . identifying risk factors of infection may provide guidance on policies and strategies for the prevention and control of fri. previous documented risk factors of fri in other countries included body mass index equal or greater than kg/m , previous respiratory tract infections [ ] , overcrowding and closed units [ , [ ] [ ] [ ] , presence of sand and dust storms, extreme temperature changes [ , ] , smoking [ ] , female, navy service, poor latrine facilities, increasing age and higher rank [ ] . however, these risk factors may not be generalizable to different environments, and may differ between specific predominant aetiological agents. the predominant viruses reported in the singapore armed forces (saf) comprised adenovirus, rhinoviruses, influenza a and b, and coxsackie/echovirus between and [ ] . adenovirus-associated respiratory disease, outbreaks and death have been reported in several countries amongst military recruits [ , , , , , , , [ ] [ ] [ ] [ ] [ ] [ ] . males and close contact with a person with respiratory symptoms within days before their own onset of illness were associated with adenovirus infection, but sleeping adjacent to someone ill with respiratory symptoms did not present higher risk to infection [ ] . influenza a and b viruses have also resulted in much morbidity in outbreaks, particularly influenza a(h n )pdm virus infection [ , , , , , , ] . some of the risk factors proposed were crowded living quarters defined as more than three personnel and age group less than year old [ ] , asthma and obesity [ ] , age group less than years old and the high proportion of military who had being seroconverted [ ] . human rhinoviruses are known to cause common cold as well as more complicated respiratory infections [ , [ ] [ ] [ ] [ ] [ ] . all known human rhinoviruses have been reported to be present in military recruits during respiratory infection [ ] . association of rhinovirus with lower respiratory tract infections is well documented [ ] . viral interference has also been proposed between rhinovirus and adenovirus infection [ ] . stress factor due to adaptation to new and different surroundings for military recruits was also proposed as risk factor for rhinovirus infection [ ] . in this study, we investigate the risk factors associated with fri and the predominant viral aetiologies of fri in a semi-closed military environment of the saf. the saf started a sentinel respiratory disease surveillance program in four major camps (including a recruit training camp) in may [ , ] to track febrile respiratory illness (fri) cases defined as patients with temperature ≥ . °c with cough or sore throat. patients visiting primary healthcare clinics in the camps between may and october during regular consultation hours who met the fri criteria were recruited. the sentinel respiratory disease surveillance program includes the written informed consent obtained by healthcare workers, a questionnaire, clinical specimens collection and a clinical examination of the participants. repeat consultations were excluded if the healthcare worker determined that the patient had not recovered from the first episode of illness. we also obtained samples from controls (those without respiratory symptoms or acute infections), who were recruited from the same medical center during the same week as the recruitment of cases with about to controls per week. this is to ensure that both cases and controls had similar health-seeking behaviour, and similar chance of exposure to a particular respiratory pathogen circulating in the same environment around the same period of the year to minimize potential misclassification bias. moreover, the controls were not matched or restricted by barrack, sex, age or symptom-onset. this is because of the fact that the aim of the study is to evaluate most of these variables as potential risk factors of fri. informed consent, the baseline questionnaire, and clinical specimens were also obtained from these controls. the questionnaire covers demographics, co-morbidities, vaccination status, stay-in camp status and contact details of ill member in bunk (for stay-in personnel) and at home (for both stay-in and stay-out personnel). stay-in personnel stay in camp on weekdays and stay outside camp only on weekends, and hence, have household members and bunkmates as their key contacts. stay-out personnel do not stay inside camp on weekdays and have to travel in and out of camp on weekdays to work. these stay-out personnel hence only have household members but no bunkmates as key contacts. before the influenza a(h n )pdm pandemic in , trivalent inactivated seasonal influenza vaccine (pre-pdm tiv) was in use. then, the pandemic monovalent influenza a(h n )pdm vaccine [pdm-a(h n )v] was first introduced to saf and administered to all recruits only from december . this was superseded by the new trivalent influenza vaccine (post-pdm tiv) which included the influenza a(h n )pdm strain, first introduced to saf in october , and routinely administered to all recruits in december , and then all other military personnel in november (fig. ). nasal washes from both side of the nose were taken by certified medical staff and sent to the laboratory for etiological testing within h. detailed laboratory methods have been described in a previous study [ , ] . briefly, we used a multiplex pcr panel which included different respiratory viruses. they are as following-adenovirus e, influenza a(h n ), rhinovirus, coxsackie/echovirus, influenza b, influenza a(h n )pdm , enterovirus (ev), human metapneumovirus (hmpv), parainfluenza (hpiv- ), hpiv- , hpiv- and hpiv- , coronavirus oc (cov-oc ), cov-nl , cov- e, cov-hku , respiratory syncytial virus a (rsv-a) and rsv-b and bocavirus (bv). additional singleplex pcr assays were then performed to determine the influenza subtype. total nucleic acids were extracted from each clinical specimen using the dna minikit (qiagen, inc, valencia, ca, usa) according to the manufacturer's instructions. a total of μl of dna extract were tested with resplex i and ii (version . , qiagen, inc., valencia, ca, usa) for the presence of respiratory micro-organisms on the liquichip workstation, according to the manufacturer's instructions. specimens that were resplex ii positive for flu-a were further subtyped with real-time pcr for h or h , or for ph n . briefly, μl of total genetic extracts were tested using an in-house developed assay based on the one-step superscriptiii/platinum taq kit (invitrogen, carlsbad, ca, usa) following the manufacturer's instructions on either the lightcycler machine from roche or the applied biosystems real-time pcr machine ( ). we compared variables of all fri subjects, and subsets of subjects with mono-viral infection (mvi) for the five most common viral pathogens (case groups) against the non-fri patients without viral infection detected from the panel (control group). specifically, the five most common viruses were influenza b, influenza a (h n ) pdm , coxsackie/echovirus, adenovirus e and rhinovirus. univariate logistic regression was conducted to identify statistically significant variables of interest. selected variables with high co-linearity were dropped, but all other variables significant at p < . were then included in a multivariable logistic regression model to determine the independent factors. the best model was determined using backward stepwise regression method. power calculation showed at least % power to detect a true positive association with effect size of . with % of the controls having the exposure of interest as cases. all tests were conducted at the % level of significance. we report odds ratio (or) and corresponding % confidence intervals (ci) where applicable. all statistical analyses were performed using an open source statistical software r . . (r core development team). written informed consent was obtained from the study participants. this study was reviewed and approved by the singapore military's joint medical committee for research, and the national university of singapore's ethics review committee. a total of , fri cases were recruited. of these, there were , fri cases ( . %) with mono-viral infection (mvi). of the , mvi cases, the five most common mvi were due to influenza b with cases ( . %), influenza a (h n )pdm with cases ( . %), coxsackie/echovirus with cases ( . %), adenovirus e with cases ( . %), and rhinovirus with cases ( %); the number of cases observed in each month from may to october is shown in fig. . of the , non-fri subjects recruited, , subjects ( . %) were confirmed to be negative for the whole panel of respiratory pathogens tested, and these served as the study controls in all subsequent analysis. the mean age of fri cases was . (± . ) as compared to . (± . ) years old for controls (p < . ; table ). a significantly higher proportion of cases ( . %) came from the recruit camp as compared to the controls ( . %; p < . ). the proportion of fri cases who had pre-pdm tiv and post-pdm tiv were significantly lower and higher than the study controls, respectively ( . % vs . %, p = . , and . % vs . %, p < . , respectively; table ). in addition, there were significant differences in the smoking status among the cases compared to the controls (p = . ), and there were significantly higher proportion of fri cases than the study controls ( . % vs . %, p = . ). in terms of movement history, there was a significantly lower proportion of cases who had travelled to other camp in the last days before clinical presentation than that of study controls ( . % vs . %; p < . ), and there were significantly higher proportion of fri cases who stayed in camp compared to the controls ( . % vs . %, p < . ; table ). increasing age was observed to be an independent risk factor for fri [adjusted odds ratio (aor) = . ; % confidence interval (ci) = . - . ; fig. (table ) . similarly, asthma (cor = . ; % = . - . ) was a potential risk factor of fri, but it was not independently associated with fri after adjusting for potential confounding factors (table ) . of the five most common mvi, increasing age was positively associated with coxsackie/echovirus(aor = . ; % ci = . - . ; fig. personnel who travelled to the community in the last days before clinical presentation had a significantly lower risk of adenovirus mono-infection (aor = . ; % ci = . - . ; fig. ) compared to personnel who did not. however, personnel travelling overseas in the last days before clinical presentation had . times higher risk of adenovirus mono-infection (aor = . ; % ci = . - . ) compared with personnel who did not travel overseas. compared to stay-out personnel with no ill household members in the last days before clinical presentation, stay-out personnel with ill household members had . times higher risk of fri (aor = . ; % ci = . - . ). moreover, compared to stay-out personnel with no ill household members, stay-in personnel who had neither ill bunkmates nor household members had . times lower risk of fri (aor = . ; % ci = . - . ). however, there was a higher risk of fri for stay-in personnel with an ill member in bunk regardless of whether they had any ill household members (aor = . ; % ci = . - . ) or not (aor = . ; % ci = . - . ) in the last days before clinical presentation. results for the analysis on each of the five most common mvi were very similar to those for all fri analysis (figs. and ). there was significantly higher risk of infection for all of the five most common mvi in stay-out personnel with ill household members compared with those who did not (fig. ) . regardless of whether they had ill household members or not, stay-in personnel with no ill bunkmates were not at significantly increased risk for any of the five most common mvi compared to stay-out personnel (with no ill household members). stayin personnel with ill bunkmates but without ill household members had significantly increased risk of all the mvi except adenovirus e (aor = . ; % ci = . - . ), where there was a non-significant increase in risk; having ill household members further increased the risk for all [ ] had simultaneously document the risk of fri due to a range of specific pathogens. in this study, we had shown that the five most common viral pathogens within our military environment was strongly associated with contact history, and had fairly similar trend of the fri risk factors identified. increasing age, recruit camp, and smokers were demographic risk factors for fri. increasing age was also reported as a risk factor for ari in us military personnel in overseas deployments [ ] . additional analyses showed that the risk was higher with increasing age for all the five mvi in this study, but only significantly so for coxsackie/ echovirus. in contrast, increasing age was previously reported to be a protective factor for seroconversion against influenza a(h n ) pdm in the local military during the initial wave of infections from june to october [ ] . these discrepant findings may be due to the changing age distribution of susceptible population towards influenza a(h n )pdm infections [ , ] , which might have shifted to involve more older individuals over the study period presented here (up to october ). in addition, this may be due to the increased in herd immunity effects among the new young cohorts of conscripts, where vaccine (initially as a monovalent formulation, and then later as part of the post-pandemic trivalent inactivated vaccine) was administered to all military recruits since november [ , ] . moreover, the lack or waning immunity against influenza a(h n )pdm in the older cohorts may have attributed to this trend, even though the individual level effects of vaccination against influenza a(h n )pdm (which was found to be significantly protective) was accounted for in the multivariate model. personnel in the recruit camp were at higher risk of fri as well as all the five most common mvi, particularly adenovirus e infection. this is likely due to the higher contact exposure rate in semi-closed environments, and increased stressors [ , , , , , , , , ] . alternatively, it could be due to the fact that personnel in non-recruit camps are already protected due to the adaptive immune response developed from the previous infections in recruit camp, where recruits usually only stay on a short term basis, before posted to non-recruit camp. smoking has been shown to increase risk of upper respiratory infection among recruits [ ] , hajj medical mission personnel [ ] , infants and children exposed to parental smoking [ ] . hence, it is not surprising to observe smoking as a risk factor of fri in our study. there are some studies that had shown that cigarette smoking impairs oral and respiratory tract immunity [ ] [ ] [ ] . this may have predispose smokers to a higher chance of viral infection resulting in fri. however, further study is warranted to investigate mechanism behind this observation. malay ethnicity was positively associated with both influenza-a(h n )pdm and coxsackie/ echovirus monoinfections. we had previously also found malays in the community to be at higher risk of influenza a(h n )pdm infection [ ] . however, a previous study in the saf found that malays conscripts actually had significantly higher score in hygiene practices and knowledge towards pandemic influenza as compared to chinese and indians [ ] . hence, there may be a potential genetic basis for the higher risk of infection in malays as compared to chinese and indians, given differences in genetic backgrounds of the hla class region which have been shown to result in weaker immune response against pathogen antigens [ ] . nevertheless, other unmeasured sociocultural and behavioural factors might explain these observations, and further studies are needed to confirm these observations and to understand the basis for the association. the protective effects of the influenza vaccine was largely in line with expectations, with the pre-pdm tiv protecting against influenza b but not against influenza a(h n )pdm , the pdm-a(h n )v protecting against influenza a(h n )pdm but not influenza b, and the post-pdm tiv protecting against both pdm-a(h n )v subtypes, as observed in our previous study [ ] . however, there were also some unexpected findings. these includes a potential protective effect (aor = . ; % ci = . - . ) of the pdm-a(h n )v against rhinovirus, and an increased risk (aor = . ; % ci = . - . ) of adenovirus e infection with the post-pdm tiv. these findings may have been due to non-specific interactions and interference between respiratory viruses which have been suggested by others [ ] , but could also have been due to the periodic nature of respiratory virus outbreaks. in particular, the post-pdm tiv period included a period of heightened adenovirus e activity (see fig. ) which might have been unrelated to changes in the vaccination policy, but which we could not adjust for due to co-linearity between the timing of these adenovirus fig. contact risk factors for fri and the five most common mono-viral infections e outbreaks and the phased roll-out of the influenza vaccine formulations. these unexpected findings would still require more scientific and epidemiological evidence for further conclusion. travelling overseas in the last days before clinical presentation was associated with a significantly increased risk for adenovirus e infection. we were not able to distinguish these as either military or personal overseas trips, but a previous outbreak of b human adenovirus e a strain in a military camp in singapore was also reported to be highly similar to other asian strains involved in outbreaks, suggesting a potential import of this strain from the neighbouring regions [ ] . as such, implementation of adenovirus vaccination may be useful to prevent sudden surge of cases with adenovirus e outbreak, given the high incidence of adenovirus infection in south-east asia [ , ] . one key finding was the relatively lower risk of fri and the five most common mvi for stay-in personnel as compared with stay-out personnel. at least for influenza b and a(h n )pdm , this could be due to the lower proportion of members in the households and the community who had the seasonal influenza vaccination [ ] , as compared to the camps where vaccination programme was implemented for all military personnel since the end of [ ] . as such, this may have resulted in a smaller pool of susceptible individuals and a larger herd immunity effects in camps as compared to within the community. the other explanation maybe that stay-in personnel have less exposure to younger household members, which was previously found to have a significant risk for seroconversion to influenza a(h n )pdm , and the risk was accentuated if the household member had fri [ ] . this also concurs with our findings on the effect of exposure to ill household members and bunkmates, and the effects are influenced by the domiciliary status of the soldier. for the five most common mvi, an ill household member was a major risk factor for stay-out personnel. moreover, the increase in risk for stay-in personnel from having ill household members was not as marked and mostly not significant. however, stay-in personnel with an ill bunkmate had a substantial increase in risk of infection. while our current study design does not allow us to attribute the cause of infection to contact with these ill household members or bunkmates, our findings do suggest that some of the transmission of these pathogens is mediated through close contacts, and support the use of preventive measures for fri aimed at reducing transmission from ill household members and bunkmates. this could be in the form of issuing advisories to emphasize hygiene during outbreaks, and identifying and isolating ill personnel early to break the transmission of fri. moreover, this finding also has potential applications in surveillance. we had previously reported on how it would be difficult for syndromic surveillance systems to detect outbreaks in larger military units given the high baseline rates of respiratory illness [ ] . given that the relevance of ill bunkmates is consistent for the predominant viral agents of fri, outbreak detection methods could instead focus on clusters of illness in those who share the same quarters, or are from the same military subunit as a reasonable proxy. we believe such an approach to syndromic surveillance deserves a prospective validation study where such clusters of illness are systematically sampled. there are several limitations to this study. first, there was the influenza a (h n )pdm pandemic in june to september during the early part of the study period, where the force of infection for influenza a (h n )pdm is likely to be higher than usual. however, the pandemic spread was well-contained with prompt protective and preventive measures such as vaccination (fig. ) , enhanced respiratory hygiene measures, isolation, quarantine, "ring prophylaxis" with oseltamivir during this period. as such, these measure are also likely to limit the risk of transmission of other circulating respiratory viruses during this specific period compared to other periods in the study. since different vaccines were used promptly and appropriately during the different study periods (fig. ) , vaccine type was used as a surrogate to account for the potential bias due to the enhanced protective and preventive measures applied during the influenza a (h n )pdm pandemic. nevertheless, this bias should be minimal because the controls were also recruited in the same period and camp as the cases. second, hand washing behaviour, allergy and military rank were not evaluated as potential risk factors of fri. this is because it was very challenging to accurately assess how frequent hand washing was performed by the soldiers. moreover, the soldiers may also tend to report the expected favourable hand washing behaviour. hence, the likelihood of recall bias and information bias are likely to be high and would make any form of interpretation challenging. allergy was not evaluated because the symptoms are very broad to specifically define as an allergy, and there would be significant potential information bias as it is less likely to clinically diagnosed allergy as compared with asthma, diabetes, hypertension and heart disease. furthermore, the aim of this study is not to study clinical signs and symptoms that are associated with fri. we did not consider military rank due to fact that there is a significant number of cases that were recruited from the recruit camp, where the population is mainly made up of recruits as compared to non-recruit camp, where the population is mainly made up of higher ranks (table ; p < . ). as such, it would be biased to include military rank as one of the variables. third, our data is limited to febrile presentations of viral respiratory infections and may not be applicable to milder acute respiratory infections. fourth, there is a lack of clinical and laboratory confirmation of the ill household members and bunkmates, and such data are hence subjected to recall bias. fifth, the prevalence for fri and mvi is about % and % respectively. as such, or values as proxies to rr would be similar for mvi, whereas the or of the risk factors for fri is likely an overestimation, to some extent, relative to rr. sixth, the resplex i assay (qiagen) was designed to also detect six bacterial respiratory pathogens. they were mycoplasma pneumoniae, chlamydophila pneumoniae, legionella pneumomophila, streptococcus pneumoniae, neisseria meningitides and haemophilus influenza , , . however, fri subjects with bacterial causes were not excluded because one of the aims of the study is to determine the potential risk factors for fri, regardless of any detected or undetected respiratory virus and/or bacteria. lastly, this study involved predominantly young adult males in a military context, and hence, the results may not be generalizable to the overall population in the community, particularly for the contact risk factors. however, during the pandemic of influenza a(h n )pdm , clustering of febrile respiratory illness by classroom contact among school children [ ] and ill workplace contacts among healthcare workers were also observed [ ] . further studies in other settings such as nursing homes which collect contact history in a similar way should be attempted. increasing age, smokers, recruit camp, stay-out personnel with ill household members and stay-in personnel with ill bunkmates were independent risk factors of fri in a semi-closed military setting. early identification and isolation of ill bunkmates may be effective to prevent and to reduce further transmission in camp. public health campaigns and policy should take these risk factors into consideration to increase the effectiveness of interventions to reduce fri in the military environment. abbreviations fri: febrile respiratory illness; aor: adjusted odds ratio; ci: confidence interval; saf: singapore armed forces; mvi: mono-viral infection. frequency of acute respiratory illnesses and circulation of respiratory viruses in households with children over surveillance seasons epidemiology of community-acquired respiratory tract infections in adults. incidence, etiology, and impact recent trends of pneumonia morbidity in us naval personnel keep your hands clean influenza c virus infection in military recruits-symptoms and clinical manifestation respiratory infections in the military symptomatic respiratory syncytial virus infection in previously healthy young adults living in a crowded military environment respiratory syncytial virus: an important cause of acute respiratory illness among young adults undergoing military training viruses associated with acute 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respiratory illness among us military recruits after the renewed use of adenovirus vaccines an assessment of electronically captured data in the patient care enhancement system (paces) for syndromic surveillance teacher led school-based surveillance can allow accurate tracking of emerging infectious diseases -evidence from serial cross-sectional surveys of febrile respiratory illness during the h n influenza pandemic in singapore the work was supported by a singapore ministry of defence funded operational research program and the centre for infectious disease epidemiology and research in the saw swee hock school of public health of the national university of singapore and national university health system. the funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. biodefence centre, ministry of defence, singapore, singapore. yale-nus college, national university of singapore, singapore, singapore. program in health services and systems research, duke-nus graduate medical school, singapore, singapore. department of statistics and applied probability, national university of singapore, singapore, singapore. department of medicine, national university of singapore, singapore, singapore.received: january accepted: july the authors declare that they have no competing interests, except for vl who had previously received unrelated research grants from gsk.authors' contribution jp wrote the manuscript and analysed the data. jj analysed the data. lyh, arc and mic revised the manuscript and assisted with data analysis. vjl conceptualized the study and revised the manuscript. bht, jpl, whvk, shn were involved in the laboratory testing of the specimens. mh and qg were involved in subject recruitment and screening. all authors read and approved the final manuscript. key: cord- -gjte i authors: mukherjee, pratik; lim, tze chwan; chawla, ashish; chou, hong; peh, wilfred c g title: adaptability and responsiveness: keys to operational measures in a regional hospital radiology department during the current covid- pandemic date: - - journal: bjr open doi: . /bjro. sha: doc_id: cord_uid: gjte i the rapid and mostly uncontrolled spread of the coronavirus disease pandemic over the past months has overwhelmed many healthcare systems worldwide. in singapore, while our public healthcare institutions were considered well prepared due to our prior experience with the sars outbreak, there was an unexpected surge of infected patients over the recent months to deal with. we describe our radiology department’s experience in modifying operational practices and implementing strict infection control measures aimed at minimizing disease transmission and mitigating the potential impact of possible staff infection. from the perspective of serving a medium-sized regional hospital and limited by physical and manpower constraints, our radiology department had to adapt quickly and modify our initial responses and practices as the disease scenario changed. we have also enumerated some guidelines for planning future radiology departments. the end of december saw the emergence of a previously unknown viral pneumonia in wuhan, capital of hubei province in china. on january , the singapore ministry of health (moh) issued a public notification of this infection cluster in wuhan. the world health organization (who) declared the novel coronavirus disease (covid- ) outbreak as a public health emergency of international concern on january and subsequently, classified it as a pandemic on march . as of may , there were million infected people around the globe across countries and territories, with , dead. the severe acute respiratory syndrome (sars) outbreak in singapore, while resulting in only infected patients over a -month period, caused deaths, with a transmission rate of . % among healthcare workers (hcws). building upon this past experience, pandemic preparedness in the singapore, particularly in the public health institutions, have been ramped up ever since, with the strong awareness that pandemic preparedness should be a continuous process and not an overnight reactive response. soon after emergence of the wuhan cluster, our local public health services started preparing to tackle this new virus. countries with recent experience of respiratory pandemics caused by novel coronaviruses (e.g., sars, middle east respiratory syndrome [mers] ) had a tendency to have developed public health pandemic response plans and implemented these at an early phase. covid- is spread mainly through direct contact with airborne respiratory droplets from infected patients, who typically present with a range of respiratory tract symptoms. asymptomatic carriers contribute to significant disease spread and pose a major hurdle in containing the disease. , chest radiographs are the first-line imaging modality for suspect cases, as well as the follow-up imaging modality to monitor the progression of disease in confirmed cases, although the multinational consensus statement from the fleischner society does not recommend daily chest radiographs in stable intubated patients with covid- . chest ct is reserved for the assessment of subtle radiographical findings, identifying characteristic features, disease prognostication and evaluation of complications such as pulmonary embolism. [ ] [ ] [ ] [ ] the american college of radiology https:// doi. org / . / bjro. abstract the rapid and mostly uncontrolled spread of the coronavirus disease pandemic over the past months has overwhelmed many healthcare systems worldwide. in singapore, while our public healthcare institutions were considered well prepared due to our prior experience with the sars outbreak, there was an unexpected surge of infected patients over the recent months to deal with. we describe our radiology department's experience in modifying operational practices and implementing strict infection control measures aimed at minimizing disease transmission and mitigating the potential impact of possible staff infection. from the perspective of serving a medium-sized regional hospital and limited by physical and manpower constraints, our radiology department had to adapt quickly and modify our initial responses and practices as the disease scenario changed. we have also enumerated some guidelines for planning future radiology departments. (acr) strongly discourages performing routine chest ct as a screening tool as a normal chest ct does not mean a person does not have covid- infection and an abnormal ct is not specific for covid- diagnosis. a normal ct should not dissuade a patient from being quarantined or provided other clinically indicated treatment when otherwise medically appropriate. some centres have even started on artificial intelligence (ai) initiatives whereby gathered data enable doctors to create simulations, whereby a patient's ct images could be used to virtually model how patients might respond to treatment. the singapore situation in singapore, the epidemic evolved in different patterns. since confirmation of the first covid- imported case in singapore on january , there has been a gradual increase in numbers of infected patients, mostly from imports and within small local clusters, in the first months or so, that is february and march . most of these initial patients were managed at the national centre for infectious diseases (ncid), a bedded purpose-built facility for handling disease outbreaks in singapore, with each of the other public hospitals receiving relatively small numbers of cases. a sudden, unexpected and rapid increase in the number of cases then occurred, rising from a total of cases on april to , cases on may . figure shows the timeline of the total number of covid- cases against the salient dates. this sustained spiking over the past months to date were mostly from rapid spreading of infection among dormitory-housed foreign workers. aggressive testing of residents of these foreign worker dormitories gave rise to the large numbers of positive cases. although most of those infected were generally young and healthy workers who were asymptomatic or had mild symptoms, this surge in numbers resulted in an overwhelming number of cases seen daily at all public hospitals, including ours, over a relatively short period of time. department situation while physical separation of facilities and workforce was possible and more readily implementable at larger thousand-bedded tertiary hospitals, it was more challenging in the radiology department of a medium-sized regional hospital such as ours, a -bed general and acute care hospital that serves more than , people living in the northern sector of singapore, where space within a fixed physical footprint was a constraint. in this article, we share our experience of mitigating and adapting to a rapidly changing pandemic situation and describe how we tried to simplify work processes, and implement and modify operational measures, as the disease unfolded over the past months or so. our approach was broadly guided by two principles: from the outbreak onset, measures were taken to keep all potential covid- cases presenting to the emergency department (ed) separate from the "cold" patients and hcws, in order to prevent cross-infection. initially, these covid- suspect cases were seen in the isolation wing of ed which had only nine rooms. to minimize potential cross-infection, portable radiographs were done for this group of patients if chest radiographs were required. due to anticipated space limitations, planning for separate "fever tent" started on january and the tent, known as the expanded screening wing (esw), became operational on february . the esw was located adjacent to the ed ( figure ). initially, we deployed a portable x-ray machine that used a computed radiography (cr) cassette. however, when the esw workload started to increase, we switched to a portable digital radiography (dr) x-ray machine. the use of this dr unit helped speed up the turnaround time (tat) for chest radiographs in suspected covid- patients. the radiographs were performed in a make-shift x-ray cubicle with a lead shield placed on one side of the cubicle. the x-ray detector was covered with a disposable plastic sheet and the machine was wiped down with % isopropyl alcohol ( figure ). the agreed-upon tat for chest radiograph was a maximum of min from the time of radiography request to completion of the radiological report. priority for reporting was given to this group of patients to assist in the ed physician's decision-making whether to up-triage or deisolate each patient. a senior radiologist was always also available ( h daily, including weekends) to render a second opinion, upon request by clinical colleagues. this was particularly useful when screening many suspected patients, as positive findings on chest radiographs allowed quick isolation and contact tracing for the patient, even before the polymerase chain reaction (pcr) test results became available. in our hospital, we have a short stay ward to accommodate ed patients whose lives were not in immediate danger (p patients). these patients stayed for a maximum of h, while they were investigated and/or observed, after which they were either discharged or admitted. to accommodate p patients who came in with respiratory symptoms suspicious of pneumonia, the hospital set up an acute respiratory wing (arw) within the current short stay ward, which became operational on february . patients on the way to the arw stopped over at the ed p radiography room to get their radiographs done, as a time-saving measure. with the increasing number of patients being sent to the arw, on march , a portable x-ray machine was parked in the corner of the arw itself, to facilitate chest radiographs and other simple radiographs for these patients. this aimed at preventing unnecessary movement of patients into the clean zone in the ed p area. one radiographer was deployed at the arw full time. once the nasal swab pcr results were available and positive for covid- and/or initial chest radiograph done in the ed showed features of pneumonia, these patients were isolated and admitted. all subsequent follow-up radiographs for these patients were performed by regular inpatient radiographer team in the isolation wards or intensive care unit (icu) as portable radiographs. we have three ct scanners, one located in the ed and two located in the main department that is sited on a different level in the hospital. our hospital does not have portable ct scanners and it was not considered a readily feasible solution, due to financial and logistical constraints. due to current existing workload, we were not able to free up a ct scanner solely for covid- patients, despite a marked reduction of number of the outpatients, particularly for clinical conditions which can be deferred. we, however, modified our pandemic response protocol and identified one of the inpatient ct scanners ("hot scanner") for imaging warded covid- confirmed cases. ct was performed only in selected cases after discussion between the radiologist and the physician-in-charge. we aimed to use the ct scanner in the main department of diagnostic radiology (ddr), nearest to the isolation wards and icu housing the covid- patients as the "hot scanner. " we also made sure that the route used to bring these patients to the radiology department was separate from the route used by non-covid- patients (figure ), in order to minimize crossinfection with regular outpatients and inpatients coming to the department. to optimize use of all our scanners and maintain the tat, we had dedicated time slots to perform covid- confirmed cases as follows: . covid- confirmed inpatient/outpatient cases to be performed in one of the main ddr scanners during a dedicated h time slot at the end of the day. . covid- confirmed cases in ed coming from the esw or arw to be scanned in ed ct scanner if the ed is not performing any urgent ed scan or backlog is not high. however, if ed scanner is busy and the covid- positive scan is deemed urgent, it can be performed in main ddr, if slot available. figure . photograph of the expanded screening wing (esw) (or "fever tent") set up in the lobby outside the ed to decant patients more effectively and reduce congestion within the ed figure . photograph of the temporary x-ray cubicle within the esw shows a portable dr x-ray machine and adjacent lead shield. the x-ray detector is covered with disposable plastic and cleaned after every patient a caveat is that any emergency case takes priority and is scanned as soon as possible in whichever ct scanner is available followed by terminal cleaning of the room. this was achieved by using diluted bleach solution ( mg chlorine-releasing disinfectant tablet added to ml of water) to wipe down the machine, floor and walls of the scan room. for covid- positive patients who needed imaging for other clinical conditions, similar principles of infection control were applied for subspeciality scanning such as ultrasound, ct, nuclear medicine and magnetic resonance imaging (mri), as well as for interventional procedures. for ultrasound and mri, we reserved dedicated slots at the end of each afternoon for covid- positive cases following which the machines and room underwent terminal cleaning. sonographers performing the scan follow standard infection control protocol and don full personal protective equipment (ppe). within the department, we ensured that safe distancing measures were put in place, such as minimum m distancing between chairs in the waiting areas. only one family member or caregiver was allowed to accompany each patient with special needs entering the department. all patients and visitors entering the hospital premises and the radiology department had to undergo mandatory temperature screening and fill up a screening form providing standard information mandated by the moh. all group meetings were cancelled, for example public seminars, patient focus groups and patient family conferences. a two-pronged approach was employed for infection control and staff protection. staff self-hygiene had always been continuously emphasized as part of our hospital culture. all staff underwent regular audits of hand hygiene, with compliance data for each department published as one of the items for the hospital's quality indicators. this has ensured a heightened sense of the importance of personal hygiene, particularly hand washing, among all staff. secondly, the availability of ppe, such as fluid-resistant surgical masks, n respirators and surgical gowns was crucial. since the sars outbreak, the national stockpile of ppe is sufficient to sustain frontline staff for months, in line with the pandemic response plan published in by our moh. there were regular mask-fitting exercises held for all staff, so that updated staff records of n mask sizes and types could be maintained. all staff were fitted for at least two different brands of n masks so that if supply of one brand is limited, our hcws were not left without protection. from the start of the covid- outbreak, both fluid resistant surgical and n masks were distributed to staff daily at designated sites to ensure accountability and prevent misuse or wastage of resources. staff were required to complete e-learning modules on handling of droplet infections, suspected patients and ppe donning/doffing procedures. regular update e-mails from the hospital infection control unit and the hospital intranet were other sources of vital information. it was mandatory for all staff to wear fluid-resistant surgical masks when performing their duties in clinical areas. the use of n respirators, disposable gloves with over gown cuffs, eye protection (such as face shields or goggles), hair nets and shoe covers was required when caring for suspected or confirmed covid- patients. mandatory bd temperature screening and recording were implemented among hcws, regardless of whether they were on or off duty. as part of moh guidelines, everyone (including hcws) with acute respiratory infection symptoms presenting to general practitioners or family physicians were given a mandatory days of medical leave and instructed to stay home. for unwell staff with higher risk to possible covid- exposure, they were to report to our hospital ed so that swab testing can be performed. these measures aimed to detect disease early so that the affected staff can be isolated and managed separately, without infecting other hcws and patients. there was added stress on existing radiology workforce with the increased demand for imaging during the covid- pandemic. multiple factors contributed to the situation: (a) additional workload of screening chest radiographs in the ed (esw and arw), as well as the isolation wards; (b) increased time required to perform cross-sectional imaging on covid- positive or suspected cases due to additional infection control measures; (c) less available workforce due to segregation strategies to protect staff providing essential services and redeployment of staff to other areas of need; both within our hospital and at other institutions, for example, ncid and (d) limited hospital beds. as the disease spread and number of suspected covid- patients increased, our hospital had to rapidly respond and adapt to the situation. there was an urgent need to diagnose and discharge non-covid- patients to free-up bed capacity. the hospital took certain decisive steps to mitigate the issue: (a) almost % of the existing hospital beds and the adjoining community hospital were converted to covid- ready wards; (b) the ed p area patients (stable patients who were deemed "cold" after triaging) were moved to the specialist outpatient clinic (soc) block, labelled as ambulatory emergency clinic (ae clinic) to increase holding capacity for acute and "'hot" cases in the main ed; (c) outpatient attendance at our soc was drastically reduced by non-acceptance of external referrals (except for those deemed urgent) and cancelling/postponing appointments and use of teleconsultations for existing outpatients; (d) cancellation and postponement of elective surgical and interventional procedures, and (e) converting operating theatres to temporary icu. from end january , all hcws were heavily encouraged to cancel or defer non-essential overseas travel by our hospital. as the number of cases increased across the region by mid-february , moh initially froze all leave for hcws till the end of march , which was extended further till the end of the year as of mid-march . cancellation of leave was intended to ensure the availability of hcws. this also reduced the potential risk of exposure to the disease during overseas travel. the staff were given the option to either carry forward their leave to next financial year or get a one-off encashment at the end of the year. local leave was however allowed, so that staff could be recalled to work if required by service needs. the hospital considered reimbursement of costs incurred as a result of travel cancellation on a case-by-case basis. staff who were currently on overseas fellowship training, study trips or group training were recalled before international travel embargoes took effect. working with our clinical colleagues, postponement and cancellation of non-urgent outpatient imaging helped reduce the workload for radiology staff. this was also in line with the national approach to restrict non-essential local travel for the public. essential imaging and procedures continued, including urgent or emergency procedures performed for ed patients as well as inpatients; and urgent outpatient procedures, such as those performed for cancer diagnosis, treatment and follow-up. we anticipated a steep increase of these non-urgent procedures once the pandemic situation is controlled, resulting in longer wait time for imaging/procedures. hence, during the earlier phases of the outbreak, we managed to expedite completion of most of these outpatient scans scheduled within a -week period. additional staff (radiologists, radiographers, nurses and other radiology department support staff) were rostered over the weekends to clear the extra workload. we introduced some workforce practices to enhance safety for our staff. in the esw, a single radiographer, with full ppe and a portable x-ray machine, performed all the radiographs for a cohort of patients and processed the radiographs. in this way, we did not risk exposing multiple radiographers over a certain time period and at the same time also saved on ppe usage. for cross-sectional imaging, the scans were performed by two radiographers. the radiographer who had direct contact with the patient was deemed to have a higher potential risk of contamination and/or exposure to the virus. this radiographer donned the full ppe, adjusted patient positioning before scan, and moved the patient out of the scan room after the scan completion. subsequently, this radiographer also cleaned the machine and related equipment. the second radiographer, who was inside the control room, was not directly exposed and the control room remained clean. the two radiographers swapped roles for alternate patients. for suspected or covid-positive cases, single-use disposable plastic sheets were used to cover the portable x-ray machine or ct scanner. after imaging was performed, the machines were wiped down with % isopropyl alcohol wipes. terminal cleaning of the ct scan room was usually done by our housekeeping staff, using diluted bleach solution ( mg chlorine-releasing disinfectant tablet to ml of water) to wipe down the walls and floor. after this, the scan room was left to dry for - min before the next patient could be scanned. terminal cleaning had to be performed as we do not have a negative pressure ct scan room. the protocol for machine disinfection was according to recommendations by the respective vendors, and further approved by the hospital infection prevention committee. cohorting strategies for all radiology department staff were put in place to reduce the risk of human-to-human transmission among staff and to preserve the department's capability to meet the hospital's radiology needs, should one team/group be required to be quarantined. cohorting could be temporal (by time) or spatial (by physical location). the differences between the two is beyond the scope of this article and has been described by others. during the initial stages of the outbreak, almost all suspect cases underwent a chest radiograph with very few cases requiring ct to exclude other pathologies like pulmonary embolism. however, as the pandemic worsened and the number of confirmed cases increased markedly as shown in figure , large numbers of patients were housed in temporary community care isolation facilities. as of may , there were , active cases, of which , cases had mild symptoms or were clinically well and were being isolated at these community care facilities. we started to get more requests for ct from the ed for covid- unrelated conditions for this group of patients, which are otherwise deemed routine requests from ed during non-pandemic period such as ct abdomen and pelvis scan to rule out acute cholecystitis or acute appendicitis, ct/ mr brain for stroke or us testis to exclude torsion. as we adapted to this sudden change in ed requests for speciality modality imaging, we realized that there was a concomitant increase in the request for non-urgent inpatient scans as well. this was mainly to expedite discharge of inpatients who are relatively stable and create bed space for covid- cases who were moderately or severely ill. in anticipation of disease progression, our department implemented staff cohorting on march . at that time, there was still a heavy outpatient and elective inpatient workload. we opted for a hybrid system with the department, due to staffing constraints. the diagnostic radiologists were spatially cohorted into two equal teams, each led by a senior radiologist. both teams had equal division of workforce with regard to subspecialty skillsets and distribution of seniors and juniors. due to physical space limitations, one "away team" were located outside the main radiology department, occupying the satellite radiology sections at the ed, specialist outpatient clinic (soc) block, adjacent community hospital and a large central reporting room that opened onto a staff corridor leading to a staff entry door to the main radiology department. a . m high wooden wall with an internal door was installed within the department to separate the central reporting room from the rest of the main department(- figure ). the internal door was permanently closed but could be opened in an emergency to enable rapid and urgent movement of staff in or out of the department, in case of any patient emergencies, for example, code blue collapse or general emergencies, for example, fire alarms. the "home team" were stationed in the rest of the main department, with access either through the main department entrance or the other staff entry door at the other end of the staff corridor. some reporting workstations had to be relocated to ensure an equal distribution between the two teams of diagnostic radiologists. the rest of our department was cohorted temporally. the diagnostic radiographers at ed were divided into four teams, each team working two consecutive h shifts ( am- pm or pm- am), followed by two rest days each. the radiographers in the ct and mri scanning rooms were split into two teams, each working for two days ( am- pm, with extension to pm daily if needed), followed by two rest days. the two interventional radiology teams (each consisting of interventional radiologists, radiographers, nurses and healthcare assistants) covered all interventional radiology work for h ( am- am) for two consecutive days, followed by two rest days. the remaining radiographers (ultrasound, nuclear medicine) and administrative staff were deemed at low risk of exposure and were not segregated. with markedly worsening of the covid- outbreak at the beginning of april, the singapore government implemented a partial lockdown, called "circuit breaker" measures, initially from april for a month till may and recently further extended to june . with marked decrease in both elective outpatient and inpatient imaging, in particular musculoskeletal mris, and increase in available radiologists due to cancellation of leave, and return of our radiologists who have served their post-overseas travel day stay home notices, our diagnostic radiologists were able to move to a partial temporal segregation timetable starting from may . our diagnostic radiologists were split into three teams: one small permanent daytime team and two shift teams. the small permanent daytime team consisted of three senior radiologists covering three main subspecialty areas of neuroradiology, body imaging and musculoskeletal radiology; and four breast radiologists and nuclear medicine specialists, as breast and nuclear medicine imaging were all done during regular office hours. the daytime team (working - pm daily) were separated by physical location from the two shift teams. the two shift teams were separated temporally, and each worked h shifts ( am- pm daily) for days, followed by days of rest. each shift team had equal division of workforce with regard to subspecialty skillsets and distribution of seniors and juniors. to cover overnight work ( pm- am) daily, there was a small on-call team comprising three radiologists from all teams, with all individuals separated physically when on duty. the option of working from home (wfh), in short teleradiology, was not mandated by hospital management in public healthcare institutions. this was following termination of direct access to the internet from hospital's internal systems by the singapore government following previous cyber-attacks. however, it was still possible for our radiologists to access images using their personal computers via virtual private network (vpn). following extensive discussion among our senior radiologists, most preferred to come to the radiology department to work and report. there are however inherent advantages of wfh, for example, personal protection of individual staff and increased segregation. we have kept the option to report from home open for those who wanted to try it out, although there are currently no volunteers. there were however multiple considerations and limitations to take note of. the table lists the requirements and limitations of wfh and ways of mitigating them. figure . photograph shows the newly constructed . m high wooden wall to cohort radiologists into "home" and "away" teams. this wall separated the central reporting room from the rest of the main department. the "away team" gained entry via the glass staff entry door at the end of the corridor. the internal door built within the wall was permanently closed but could be opened (shown in second image) in an emergency to enable rapid and urgent movement of staff in or out of the department, in case of any patient emergencies e.g. code blue collapse or general emergencies e.g. fire alarms. the second image also shows the other staff entry door (black arrow) at the other end of the corridor for the "home team" the interhospital visiting consultant scheme had been suspended since february . transfer of residents in training between institutions have also been suspended. to cater for their training needs, we leveraged on teleconferencing technology for intradepartment learning sessions as well as webinars. we also tried to provide as much teaching and training as possible within the segregated teams, with rostering being tailored to their subspecialty areas of residency rotation. interdepartment interactions between radiologists, radiographers and other staff of the department were minimized, and restricted to non-physical forms of communication as much as possible, for example, sharing of messages and scanned request forms through electronic notes on ris and annotated images on pacs. each team leader disseminated the information to the rest of the team via group messages or emails. regular face-to-face department meetings were suspended and if a physical meeting was necessary, standard social distancing policy was strictly complied with. we have made use of the zoom application for department meetings and for intrainstitutional and interinstitutional meetings, as well as conducting job interviews. in these challenging and unpredictable times, our staff were faced with tremendous physical and mental burden. many of our international staff have not had physical contact with their families residing overseas for months. to boost staff morale, the department and the hospital have taken up many initiatives, such as providing lunch and dinner to all frontline staff, including our radiographers and nurses, working over the weekends and on public holidays. the hospital has tried to help staff in various ways, for example arranging childcare for staff with small children that have lost their normal caregivers because of movement restrictions between households, refunds for cancelled overseas trips, arranging for alternative local living quarters for our malaysian staff who previously commuted daily from our neighbouring country. the psychological medicine department has a psychological support program called peers around lending support (pals), available to all staff to address any psychological issues and provide counselling services. staff members were regularly reminded of the availability of pals. the current pandemic had taught us some important lessons that made us rethink the design layout of the radiology department. disaster planning and business continuity contingency plans should be incorporated in department design and layout. in a new department, the workforce is expected to be modest. for a lean team, temporal cohorting is extremely difficult to implement without compromise on radiology service coverage. keeping in mind the option of spatial cohorting, the department needs to be planned such that in the event of any future outbreak or pandemic, it is easy to divide the reporting areas into teams. satellite reporting rooms in outpatient, inpatient as well as ed, administrative areas, conference rooms and meeting rooms, should have provisions for installing additional reporting workstations. during spatial cohorting, reporting stations that are near high patient flow, high acuity and emergency areas should be designated as "high risk" areas. the other workstations can be designated as "low risk. " at-risk radiologists (pregnant or older than years old) should work in the "low risk" areas as far as possible. the ability to report remotely is useful not just during pandemics but also in non-pandemic periods, when subspecialty opinions can be sought after office hours. however, there are some intrinsic issues pertaining to remote reporting. firstly, cybersecurity is a growing problem in healthcare and past security breaches, both locally and globally, have led to leakage of sensitive patient data. even if we can get around the cybersecurity issues, there are still cost, maintenance and support issues that come with installing workstations at home. leasing of these equipment may be an option to consider. negative pressure procedure rooms should be planned for imaging modalities such as ct and mri, as well as the angiography suites. a dedicated ultrasound unit should be set aside to perform portable bedside ultrasound for isolated patients. timely and accurate information dissemination is critical during outbreaks and times of crisis. misinformation leads to low staff morale and can also put our healthcare professionals at risk. a monitor can be put up in key areas like the ed reporting room and inpatient ct room, which can serve as a live dashboard notifying staff about confirmed or suspected cases been scheduled for procedures. similar dashboard features have already been in place within ed. innovative ways of performing portable radiographs should be considered and implemented if deemed safe. one option is to utilize a robotic-assisted mobile x-ray unit for intensive care and isolation cases. the nurses in the ward, who are already donning ppe can help in positioning of the patient while the radiographer remains outside the room. this avoids direct contact between the radiographer and the patient, as well as reduces usage of ppe. in the usa, penn state health medical center has installed drive through portable x-ray units at the entry gate. frontloading of the screening chest radiograph has multiple advantages. firstly, it helps in further triaging patients based on the radiographical findings, for example, patients with positive radiographical findings get isolated and swabbed earlier than the asymptomatic cases. secondly, it saves workforce and other resources such as ppe, as all one needs is a sole radiographer manning the unit donned in ppe. there is less time and resources spent on decontaminating a portable unit as there is less patient contact and time is saved in doing air exchange and wipe down. thirdly, regular mobilization of the unit causes significant lowgrade blunt injury to the radiographers like backache which can be avoided with a drive through unit. lastly, during nonpandemic times, this unit can be used to frontload many of the radiographs done in ed. conclusion during a pandemic, key factors are sustainability of mitigating measures and the ability of a radiology department to adapt quickly. the department must protect its staff and the vulnerable population while promptly providing essential services. what may seem like the correct strategy today may be superseded by another course of action in an ever-changing scenario. we described how our department shifted from an initial spatial cohorting plan to a temporal cohorting plan with hybrid elements, as the outbreak progressed. this was achieved without compromise to patient and staff safety. the aforementioned strategies and workflows are gleaned from our experience as a radiology department in a medium-sized regional hospital with space constraints. we acknowledge that some of these measures may not be applicable or appropriate in other departments due to inherent differences. however, we believe that the underlying basic principles are uniform and if implemented, or adopted in a modified manner, can still be relevant to many radiology departments during the current covid- pandemic, particularly in small-sized and medium-sized hospitals. we thank mr michael chin sze min, our department manager and principal radiographer, for his valuable inputs. covid- coronavirus pandemic severe acute respiratory syndrome (sars) outbreak delivery of infection from asymptomatic carriers of covid- in a familial cluster the time scale of asymptomatic transmission affects estimates of epidemic potential in the covid- outbreak the role of chest imaging in patient management during the covid- pandemic: a multinational consensus statement from the fleischner society of birpublications.org/bjro bjr open bjr|open practice and policy: radiology department's adaptation and operational responsiveness to covid- pandemic doi coronavirus disease (covid- ): a perspective from china radiologic findings of coronavirus disease (covid- ): clinical correlation is recommended covid- ) outbreak: what the department of radiology should know outbreak of novel coronavirus (covid- ): what is the role of radiologists? acr recommendations for the use of chest radiography and computed tomography (ct) for suspected covid- infection org/ advocacy-and-economics/ acr-position-statements/ recommendations-for-chest-radiography-and-ct-for-suspected-covid -infection amazon is powering the coronavirus diagnostics of the future singapore ministry of health singapore ministry of health. news highlights singapore ministry of health. moh pandemic readiness and response plan for influenza and other acute respiratory diseases singapore ministry of health. the national infection prevention and control guidelines for acute healthcare facilities planning and coordination of the radiological response to the coronavirus disease (covid- ) pandemic: the singapore experience singapore makes 'decisive move' to close most workplaces and impose full home-based learning for schools, says pm lee singapore health system hit by "most serious breach of personal data" in cyberattack; pm lee's data targeted singapore ministry of healthupdated guidance on the movement of healthcare workers, patients and visitors in healthcare institutions at dorscon orange.internet walk-up x-ray booth offers quick scans to covid- patients key: cord- -id jg v authors: fouda, ayman; mahmoudi, nader; moy, naomi; paolucci, francesco title: the covid- pandemic in greece, iceland, new zealand, and singapore: health policies and lessons learned date: - - journal: health policy technol doi: . /j.hlpt. . . sha: doc_id: cord_uid: id jg v objective(s): this paper aims at providing an overview of the covid- situation, health policies, and economic impact in greece, iceland, new zealand, and singapore. the four countries were chosen due to their ability to contain the spread and mitigate the effects of covid- on their societies. method(s): we use document analysis based on the available national reports, media announcements, official coronavirus websites and governmental decrees in each of the four countries starting from the (st) of january o the th of august announcements. we apply a policy gradient to compare and examine the policies implemented in the four countries. finding(s): the four countries have different demographic, epidemiological, socioeconomic profiles but managed to control the pandemic at an early stage in terms of total number of positive cases. the four countries managed to absorb the health system shock and decrease the case fatality ratio of covid- . early interventions were crucial to avoid expected life lost in case of no early lockdown. the pandemic triggered several economic stimulus and relief measures in the four countries; the impact or the economic rebound is yet to be fully observed. conclusion(s): we conclude that early, proactive and strict interventions along with leveraging previous experience on communicable diseases and the evolution of testing strategies are key lessons that can be synthesized from the interventions of the four countries and that could be useful for a potential second wave or similar pandemics. in a space of three months, the world has changed quickly as a result of the spread of the severe acute respiratory syndrome coronavirus (sars-cov- ) virus reported in the final days of . to date, only a few countries reported no positive cases within their borders. due to rapid spread and the uncertainty regarding the nature, pathology, prognosis, spread of the virus, and day of confirmed positive cases between different countries, there was no unified regimen to deal with the pandemic on a clinical, social, or economical scale. different countries adopted different measures for detection, treatment, mitigation, and elimination of the virus within their borders. a number of the measures taken are influenced by the existing health care system and its ability to respond to an influx of covid- cases. as a respiratory disease, patients with severe covid- are likely to require intensive care and use ventilators. in addition to focusing on the virus, many countries have considered the societal and economic repercussions of the pandemic and therefore, have provided several economic initiatives to relieve those who are affected and to stimulate the affected sectors. in this paper, we document and compare four countries with different demographic characteristics, health systems, and different varying timelines to combat covid- . the countries greece, iceland, new zealand and singapore have been chosen due to their ability to mitigate the effects of covid- at an early stage and, in the case of one, eliminate community transmission of sars-cov- ; their similar geographic nature as islands and peninsulas; and their economies which mainly rely on service producing industries. the first confirmed cases of covid- in all four countries have varied, singapore reported its first case on the rd of january, whereas the first confirmed cases were almost a month later for new zealand ( th of february), greece ( th of february), and iceland ( th of february). the main objective of this paper is to investigate the health policies implemented by the four countries and to provide insights on the resulted health outcomes and the economic and fiscal impact. we explore the footprints of escalation and de-escalation of measures and policies to contain the pandemic in financial markets as well as macroeconomic indicators. after this brief introduction, the second section provides a country description for the four countries in hand where we look at the demographic profile, health system, healthcare resources, and potential risk factors associated with covid- . the third section describes the methods. the fourth section delves into the results and findings divided as the different trends of covid- in the four countries and policy; technology roadmap based on the available data till the th of august ; the healthcare response data; and the economic and financial indicators and measures. the fifth section is the discussion and conclusion. not only are each of the countries geographically different, but they differ culturally, economically and on a health system level. all of which are likely to have had an influence on how well its population has responded to the spread of sars-cov- . out of the four countries, iceland has the smallest population ( , citizens), whilst greece is the largest ( , , citizens) [ ] . in terms of population size, none of these countries reach the top in the world [ ] . referring to table , greece has the highest population density and old age dependency percentage, the greek population also has the lowest life expectancy at birth however it is above the european average [ , ] . on the other hand, iceland has the smallest population and density with people per km of land, as well as the highest life expectancy at birth. compared to the other countries, singapore has the lowest percentage of old age dependency and the highest population density per km [ ] . . . [ ] . [ ] . [ ] population there are different typologies of health systems between the four countries. for instance, the greek system is a mixed system that includes a predominant social health insurance (shi) system and a supplementary voluntary health insurance (vhi) market. on the other hand, both the new zealand and the icelandic systems are tax-based systems. table shows that new zealand has the highest percentage of health expenditure as a percentage of gdp ( . %) while iceland and greece have a similar percentage, they differ in terms of health expenditure per capita. singapore has the least health expenditure percentage ( %). greece has the highest out of pocket percentage expenditure and the lowest percentage of insured population ( %). service provision in the four countries are mainly from public and also private providers. evidence from countries who have experienced the sars-cov- outbreak for longer suggests that those who have chronic conditions or engage in riskier health behaviors are more at risk from severe consequences of covid- [ ] . in terms of risk factors that might be correlated with the prognosis of the covid- active cases, we look at the prevalence of chronic conditions, tobacco use and alcohol consumption. table shows that greece has the highest percentage of + -year-old population who are daily smokers ( %), while iceland has the least ( . %). as for alcohol consumption, new zealand has the highest number of yearly liters per capita consumed ( . ) . [ , ] tobacco use % . % . % % [ ] percentage of obesity in adults [ ] . % . % . % . % top three conditions as proportion of mortality [ , ] sources: ( )- ( ) containing the spread of sars-cov- has meant implementing a number of initiatives that support the existing healthcare systems within a country. in terms of pre-existing healthcare resources, table shows different parameters to compare the four countries. for example, in terms of number of beds per , of the population, greece has the highest number of hospital beds ( . ). the severity of covid- will mean that a number of intensive care unit beds will be required, out of the four nations iceland has the highest number of beds with . per , people and the highest number of icu beds/ , populations. new zealand has the highest ratio of general practitioners compared to specialists, while greece is the opposite. iceland has the highest number of nurses per , populations. greece has an understaffing issue; the lowest number of nurses per population and the highest number of physicians per , populations; while singapore has the least number of physicians per , populations ( . / , ). [ ] gps to specialist ratio : : : : . [ ] no. of nurses (per , people) approx. . lowest in eu approx. . . . [ ] no. of physicians around . / population highest in eu around . / population . / population . [ ] no. of icu beds / k population in lower than average . / k . / k [ ] . / k [ ] sources: ( )-( ), ( ) . methods the case definition for covid- in new zealand is a person who is unwell with an acute respiratory infection and has at least one symptom of coughing, sore throat, head cold or a loss of the sense of smell. while in iceland, symptoms of covid- are described to be cough, fever, cold-like symptoms, muscle pain, fatigue or sore throats, there have been some instances of abdominal pain and loss of smell and taste. in greece, a case definition for testing if someone shows symptoms such as a fever, cough and difficulty breathing. it is also advised that covid- can present with symptoms of muscle pain, fatigue, and difficulty breathing. at the current stage, testing in greece is restricted to patients with severe acute respiratory illness who are or need hospitalization, as well as patients in hospitals, elderly (> ) care or chronic care, and health staff who develop respiratory infections with fever, coughs or dyspnea [ ] . testing in new zealand can occur through a septum test or nasal swab, and all are expected to self-isolate until the results are confirmed. it is possible that a small number may not be tested and those that are not are still expected to self-isolate. in iceland, initially testing was conducted on residents returning from high risk areas and contacts of confirmed cases. this was widened to include the general community who presented with symptoms, in addition a private testing agency has collaborated with the directorate of health to randomly sample the population. singapore has not released detailed information about the country's testing strategy, in fact the number of tests were released twice in april and have since been reported on a weekly basis. none of the nations have reported an overview of the epidemiology data related to covid- deaths, some of this information is provided in respective nation's media releases however comorbidity information is not included. new zealand, singapore, greece and iceland report information on whether the confirmed cases are in the community or were imported (contracted overseas). new zealand provides information on the flights that the individuals came on, while singapore reports the residency status of confirmed cases. all but singapore are currently reporting information on confirmed cases at a regional level, while confirmed deaths are reported at a national level. there are four periods where greece does not report the daily testing information, the th of march, th of april, rd of june, th to th of june and th of july. the next reported day includes the data for the missing period, for example the th of june reports a , new test increase. to examine the impact of policy interventions on covid- related outcomes, we use the policy categorization process and gradient proposed by moy et al. ( ) . [ ] this categorization process groups policy interventions for those that contain the spread of a virus, interventions for the prevention and care, policies to reduce the economic impact, as well as a categorization for measures taken by private sectors without government intervention and health technology interventions used for treating, testing and tracing cases of a virus. from these categorizations, it is possible to apply a gradient that represents the strictest or most dominant policy being used. to examine the impact of the most dominant policy on outcomes such as the daily rate of cases, we incorporate the gradients into each of the figures in the following sections. . . . daily data covid- cases, deaths, recoveries as of the th of august , greece, iceland, new zealand and singapore had reported , laboratory confirmed cases of sars-cov- between them, accounting for . % of the world's confirmed cases [ ] . out of the four nations, singapore has the most cases with , , whilst new zealand had reported the least with , (see table ). whilst iceland has reported the lowest number of deaths ( ), and greece the highest with covid- related deaths. however, there are numerous differences between the four countries, such as the health systems, interventions put in place and size of the country, that may influence the overall rate and impact of sars-cov- . in order to compare the rates of growth of sars-cov- , and the daily and cumulative trend over the course of the pandemic we revert the date of the first confirmed case to day one. as such we observe that greece, new zealand and iceland are at and days, whilst singapore has reached its th day. the daily number of cases in greece, new zealand and iceland show a fairly normal distribution (see figure ), indicating that the nations are past the peak. in fact, new zealand has announced that it has eradicated the virus from its shores. however, the daily confirmed cases of singapore show a left skewed distribution, as the country had maintained a low number of cases for the majority of the period observed but the number of cases has recently increased. all four countries implemented medium level interventions to contain the spread relatively soon after the first case. containment measures increased in strictness for new zealand at the peak of daily cases, while singapore escalated measures as the daily cases began to increase. economic interventions began to be introduced approximately days after the first case for new zealand, greece, iceland and singapore. it is evident that all countries were experiencing a different daily rate of the virus as the pandemic progresses. to determine the daily rate of change in cases, we divided the daily new cases by the daily new cases from the day before. if the growth rate is higher than one, then the number of cases is increasing and if the rate of growth continues to increase then it could indicate that the policy interventions are not mitigating the spread of sars-cov- . in figure , it is clear that each of the four countries has maintained relatively low daily growth rates, with the biggest spikes in growth occurring in greece towards the beginning of the pandemic, and most recently at the th day. these spikes in greece are likely to be driven by clusters of covid- being discovered. both singapore and iceland have maintained growth rates between zero and three for the duration of pandemic so far. for the last seven days, the average rate of growth for greece, table ). the country with the lowest number of confirmed cases per , was new zealand with per , , however greece also reported cases per , . as observed in figure , the majority of iceland's daily cases were in its fifteenth to fortieth days, whereas singapore's picked up pace towards the seventy-fifth day. despite delaying the number of cases in the wider community in singapore, there was a breakout of cases in the dormitories that house migrant workers. as a result, authorities increased testing in the dormitories and implemented dormitory wide quarantine to stem the spread. note: singapore does not report the daily testing numbers. hospitalization information provides an overview of how note: around the th day singapore reclassified its categorization of hospitals, and a number were moved into isolation. although sars-cov- virus is indiscriminate in those that can catch it, covid- appears to severely affect those over the age of more than other age groups, whilst children seem less likely to catch the virus. each of the four countries provide data on the distribution of covid- by different age groups and gender, although singapore stopped providing age and gender for confirmed cases from the th of april. as of the th of august (see table ), more females (males) were confirmed with sars-cov- than males (females) in new zealand (greece). this equates to male confirmed cases per , , with and confirmed male cases per , and and confirmed female cases per , in new zealand and greece, respectively. [ ] in terms of the distribution of laboratory confirmed cases by age group, all but singapore have released up to date information. however, as each country uses different age group scales the following section reports the total counts for the th of june and does not convert to a comparable population level. referring to figure , the majority of cases in all three countries are in the working population (considered the - age group). whilst the least number of confirmed cases appears to be in children and youth. each nation has reported a number of cases in the over age group, who are considered to be the most at risk. note: singapore has not released a breakdown of deaths, although some information is released in the singapore government's daily media releases. this figure demonstrates the associated deaths, as such this figure refers to the associated deaths and reports more for iceland. all four countries have reported information on the number of deaths and the corresponding ages of the deceased. whilst this is not necessarily released on the dashboards, government media releases specify the ages (or age group) of those who have passed and tested positive for finally, whilst research has indicated that pre-existing morbidities are related to increased severity of symptoms and higher probabilities of death, limited information has been reported by each country on the pre-existing health status of those who test positive for covid- . a limited amount of health-related information is available on the deceased based on media announcements by the ministry of health in singapore. it was reported that ten of the covid- related deaths had pre-existing conditions that were related to cancer, chronic heart disease, diabetes, hypertension, hyperlipidemia, isometric heart disease and kidney disease. seven of the associated cases had multiple morbidities [ ] . in order to estimate changes in mortality risk determine the benefits of public health and environments policies, the estimates of life-years saved by these policies is used as a measure of mortality risk. [ [ ] . in panel b of figure , we see the distribution of government intervention based on the government response index created by [ ] . both demonstrate the increased government activity used to control or stop the spread of the virus. referring to panel a, we see that a majority of interventions are observed after the th case for new zealand, greece and iceland. however, singapore implemented hygiene and border control measures swiftly, before focusing on tracing contacts of confirmed cases. in addition, singapore implemented fines up to $ , and months in prison for breaking quarantine. in comparison to the other three nations, singapore has focused on the use of technology to help manage the spread and increase citizens' awareness of crowded places and social distancing measures. whilst new zealand and greece locked down earlier than most nations relative to the amount of cases (see figure ) , iceland never declared a full lockdown instead the number of people able to meet was restricted (maximum of ). rather there was a focus on containment and protecting health systems before implementing stimulus packages. iceland utilized private industry and created a testing policy for anyone to be tested free of charge, providing the most detailed spread of the disease outside of the diamond princess case study [ , ] . in all nations, the number of hospitalized cases has not overwhelmed the existing health care system, however there are a number of healthcare workers being affected by the virus in terms of confirmed cases and self-isolation as a result of being in contact with confirmed cases. singapore has reported a number of confirmed cases of healthcare staff through their media announcements, with confirmed cases amongst their health staff as of the th of april [ ] . new zealand reported on the th of april that healthcare staff members were isolating and a further had recovered. however, iceland is the only country out of the four that has provided daily updates on the number of staffs in self-isolation and quarantine (see figure ) [ ] . whilst all four countries' health systems have responded well to the virus, all are preparing for potential increases in cases that are beyond their existing health systems capacity. in fact, in response to the covid- outbreak, the greek government announced an increase in the number of permanent medical staff and the intention to reach intensive care unit beds per , of the population [ ] . the government has aided this goal by providing million euros for health resources, and an additional million euros to hire additional health staff. since then, almost , medical staff have been made permanent [ ] . greece has also begun to reduce the lockdown measures and allow certain systems to reopen, at the same time the nation is also preparing resources for an eventual surge of covid- and influenza cases in the fall of . in singapore, the government is increasing its ability to bring online additional icu beds if they become needed. at present, singapore has vacant icu beds, with an additional able to be brought online. there are additional plans in place to bring another online within the next few weeks [ ] . in addition, general isolation beds have increased from to , beds since january and the national centre for infectious diseases has increased their negative pressure isolation beds from to over [ ] . to increase the health staff capacity of the public health system, the government launched the sg healthcare corps on april th for private healthcare professionals to sign up. as of the th of april, an additional , health care professionals had registered [ , ] . those who show milder symptoms and are on the path of recovery from more severe symptoms of covid- are placed in community care facilities in singapore. to care for these individuals, singapore created , beds in a number of facilities across the country. for those individuals who are recovering well and are healthy at the -day mark of the course of covid- , they are moved to a community recovery facility to stay where they are then assessed for discharge [ ] . singapore has , recovery beds and will be expanding it to more than , beds by the end of june [ ] . as well as these facilities, singapore has created swab isolation facilities (totaling , beds) where those who are unable to self-isolate can stay whilst they wait for their test results to come back [ ] . other measures have been taken by the four countries to help facilitate the movement of medical resources, such as the easing of importers licenses for medical protective gear in singapore [ - ]. we can also observe that the consumer confidence indices in these countries have hit their lowest since the beginning of . similarly, business confidence indices in these countries decreased during the pandemic given the covid- outbreak has brought the economy across the four countries to a standstill. in figure , we see the impact that the pandemic has had on the retail and tourism industries. except supermarkets and consumable sectors, the turnover in other sectors has fallen since february . this is explained by the majority when it comes to discretionary spending, it is clear that individuals have reduced their purchases throughout the pandemic as a result of the high level of uncertainty and unemployment rate. tourism has been heavily impacted by government interventions causing an incredibly low number of foreign visitors, with more than % decrease compared to the same period in . such a drop in a sector clearly indicates there is a need for continuous support for the workers and business in the tourism industry. as a part of this, job keeper and job seeker support packages should be fairly distributed among the hardest hit businesses such as the tourism industry. figure demonstrates weekly job seeker support or the cumulative wage subsidy as well as the community activity of new zealand. due to the easing in the restrictions, where the majority of businesses have started opening, we see that the subsidies provided by the new zealand government flatten during may . in addition, we can see that various activity indices, including card transaction spending, electricity grid demand, and traffic indices, have been normal after re-opening the economy. the only noticeable exception is in singapore where the curve of the total positive cases showed an exponential pattern from day onwards. this is due to the outbreaks in the country's migrant dormitories, which are densely populated and difficult to socially distance in. in addition, greece has seen a steady although small increase in numbers which may be due to the increase in testing and a more widespread testing strategy. iceland also announced plans to implement nationwide testing which is easier to implement in iceland due to the small population number. the four countries maintained a low case fatality ratio (cfr) with singapore having the lowest cfr of . %. it is noticeable how singapore has the lowest cfr and the lowest deaths per , regardless of the fact that it has the least health expenditure as percentage of gdp. this might be primarily attributed to the readiness of the health system for such events based on the experience with previous pandemics like sars and h n . additionally, this low cfr could be attributed to early intervention by the singaporean government. as shown in figure , singapore initiated its response days prior to the detection of the first positive case; the response included advice for wuhan-bound travels and a temperature check in sea checkpoints and airports. greece has the highest cfr with . % but compared to other european mediterranean countries such as italy, spain, france, and turkey, the greek cfr remains relatively lower. compared to the four countries, the high cfr could reflect the high old age dependency as shown in table and could also reflect the fact that the positive cases are higher in older age groups compared to the other three countries as shown in figure . additionally, the high cfr in greece could be related to the testing strategy, which focuses on severe cases. iceland has the highest number of deaths per , populations among the four countries and this is mainly due to the small population number and the fact that the number of confirmed cases is concentrated in the younger age groups as shown in figure . the mitigation policy interventions as shown in table and figures , , , and , show that the early policy interventions as seen in singapore and the strict early policies as seen in greece, iceland and new zealand might also be correlated to the relative low number of positive cases and deceased cases at early stage of covid- . this is also reflected in the low number of hospitalizations and icu admissions in the four countries in figure . this indicates that the health systems of the respective countries managed to absorb the influx of new cases without reaching full capacity/saturation. in addition to the pandemic's impacts on health systems, the economic and financial impact in the four countries is ostensible. several measures and policies implemented by the four countries along with their economic and fiscal responses in order to contain the pandemic. the economic and fiscal measures implemented by the four countries resulted in immediate relief for relevant stakeholders however, the assessment of the full effect will need a longer time period to observe amidst the covid- -related economic hardships. despite all economic and fiscal support packages provided by these countries, we can observe that the major market indices have recently started moving smoothly across four countries. however, we see a significant drop in exports and imports by the four countries that signals the break in the global supply chain. if this continuously happens, we will ultimately see the increase in unemployment and inflation rates and gdp will collapse. the covid- pandemic has also hit the consumer and business confidence indices, thus, neither consumers nor businesses feel safe during such a tough period. due to the high level of uncertainty amid the covid- pandemic, the local exchanges have depreciated compared to the us$ dollar, which can be related to the boost in the demand for us$ given its safe-haven status. on the other hand, short-and long-term government bond yields have hit their lowest in spite of their lower risk compared to other securities such as equity stocks. however, these countries hope to recover the damage by providing continuous support and implementing existing policies. these measures will get employees back to their jobs, guarantee their wages and salaries, and boost the economy. important lessons can be learned from the management of the covid- pandemic in the four countries. firstly, building upon previous experience and capacity to respond to future pandemics as shown in the singaporean experience. secondly, the early and strict policy interventions to combat the spread of the pandemic within borders as seen in the greek and new zealand case. thirdly, the proactive and responsive policy intervention since day one of the infection globally as seen in singapore. fourthly, the evolution of the testing strategy to a nationwide approach to detect cases at an earlier stage and prevent serious complications. regardless of the differences in the demographic, epidemiological, health system profile, some of these lessons can be applied even in countries with larger borders, bigger populations, or less stable economy. as the four countries have unfolded their exit strategy to the new normal, ongoing/future research should observe the developments and the indicators for a potential second wave and the concurrent health system and economy performance. world health organisation. who director-general's opening remarks at the media briefing on covid- - world health organisation -speeches health system review statistics iceland. population by municipality, sex, citizenship and quarters population department of statistics singapore. population and population structure the world bank open data population (live) european commission. country health profiles european union the struggle for intensive care coverage after hepatic resections: the greek reality. the lancet observatory on health systems and policies. greece. country health profile intensive care and ventilator capacity in district health boards new zealand health system review. health systems in transition sustainable health care financing: the singapore experience. global policy ministry of health singapore. health manpower critical care bed capacity in asian countries and regions. read online: critical care medicine| society of critical care medicine world health organisation. management of substance abuse -country profiles -singapore prevalence of comorbidities in the novel wuhan coronavirus (covid- ) infection: a systematic review and meta-analysis progress in tobacco control in singapore: lessons and challenges in the implementation of the framework convention on tobacco control. asia & the pacific studies world health organization. global health observatory (gho) data: overweight and obesity: prevalence of obesity among adults world health organization. noncommunicable diseases (ncd) country profiles: greece world health organization. noncommunicable diseases (ncd) country profiles: iceland world health organization. noncommunicable diseases (ncd) country profiles: new zealand world health organization. noncommunicable diseases (ncd) country profiles australian and new zealand intensive care society. centre for outcome and resource evaluation (core) infection with the new coronavirus covid- -criteria for laboratory testing categorising policy & technology interventions for a pandemic: a comparative and conceptual framework hellenic statistical authority qalys vs dalys vs lys gained: what are the differences, and what difference do they make for health care priority setting the importance of (shared) human values for containing the covid- pandemic report : impact of non-pharmaceutical interventions (npis) to reduce covid mortality and healthcare demand valuing changes in mortality risk: lives saved versus life years saved oxford covid- government response tracker, blavatnik school of government. data use policy: creative commons attribution cc by standard -restrictive-measures-introductory-presentation- . . _en.pdf . government of iceland. iceland's response: government objectives and actions ministry of health singapore ministry of health singapore. easing the tighter circuit breaker measures, preparing for gradual resumption of activity after past updates on covid- local situation spread of sars-cov- in the icelandic population kikilias: next day with icu beds - , permanent recruitment of doctors and nurses at the nss hellenic national public health organization import of hand sanitizers, masks, thermometers and protective gear key: cord- -gm s a authors: teo, wan-yee title: implications for border containment strategies when covid- presents atypically date: - - journal: public health doi: . /j.puhe. . . sha: doc_id: cord_uid: gm s a abstract objectives for a large part of covid- pandemic, singapore had managed to keep local cases in the single digits daily, with decisive measures. yet we saw this critical time point when the imported cases surged through our borders. the gaps which we can and have efficiently closed, using a public health approach and global border containment strategies, are aptly illustrated through this case. this critical point of imported case surge, has resulted in large spike of daily local cases sustained through community transmission, up to /day within a very short time frame. we were able to rapidly bring this under control. study design this is a case study of a patient who passed through our borders, with covid- masquerading as a resolved sore throat. methods the events were prospectively documented. results we present a case of a year-old student returning from nottingham. he presented with sore throat as the only symptom the few days prior his return, and on arrival at our border (day from initial symptoms), his sore throat had already resolved. the events leading up to his covid- diagnosis highlight the gaps of the international screening processes at the global border entry, and the potential consequences of community chain transmission through imported covid- cases. conclusions an important global border control measure to implement quickly, will be to expand the symptom list to isolated sore throat, and/or a prior history of recent symptoms (resolved). this may capture a larger proportion of imported cases at border entry point, for more effective containment. this piece will be equally relevant to the general physicians, emergency care physicians, otolaryngologists and anaesthetists, who are at higher risk of encountering a throat visualization during intubation and routine examination. this information can be useful to countries with low resources or insufficient covid- testing kits. in the early months of the covid- pandemic, singapore had managed to keep the number of local cases down to single figures daily through decisive measures. we identified a critical time point when the number of imported cases surged through our borders that resulted in a large spike of daily local cases, up to /day within a very short time frame, that was further sustained through community transmission. using a public health approach and global border containment strategies, we were able to rapidly bring this under control. this short communication highlights how an atypical presentation of covid- (sore throat) could breach border containment. we present some effective strategies for covid- screening at border entry. a year old student returning from nottingham presented with sore throat as the only symptom a few days prior his return. on arrival at our border (day from initial symptoms), his sore throat had already resolved. self-taken photographs by the patient during the initial symptomatic phase (day ) with the sensation of sore throat, and on day and , when the sensation of sore throat had resolved, revealed persistent pharyngitis. the patient had no fever during his symptomatic phase and had performed temperature checks twice-a-day with a thermometer. he had experienced some nasal congestion initially which was attributed to his underlying allergic rhinitis. at border entry, this patient had declared his symptom of sore throat, which had resolved. the patient directly moved from the airport to his stay home notice (shn) hotel to stay in isolation. following the instructions on the information sheet from singapore global network (a division in the singapore economic development board which broadens and deepens the overseas network of singapore citizens) available online, the patient and his family contacted the people's association (a government-supported statutory board to promote racial harmony and social cohesion in singapore) to clarify the symptom of a resolved sore throat, and highlighted patient's contact history with an italy-returning medical student during a fencing sparring. italy, at that point, had the most covid- cases globally. staff at people's association rapidly facilitated the patient to be picked up in a dedicated ambulance to national center of infection disease, singapore, where a chest x-ray done was normal, and the swab test was positive for covid- (day of initial symptoms). this patient's parents transported him from the airport to his shn hotel. all individuals (patient and patient's parents) were wearing surgical masks in the enclosed air-conditioned car space (windows were not wound down). the duration of transport was around hour or less. the patient had changed to a new surgical mask, wiped down his suitcase and personal belongings with disinfecting wipes, and washed his hands before meeting his parents and getting into the car. about hours later, the father started experiencing dry throat, dry cough and runny nose. patient's mother experienced dry throat. patient's brother (whom did not have any direct contact with the patient, was picked up in the same car but separately from the patient about . hours after) developed fever of . ᵒc, bodyache, nasal congestion and throat discomfort ~ hours later from the car ride. it is unclear if a chain transmission occurred through parents at home, to the patient's brother who did not come into contact with the patient, or through the consecutive use of a common transport vehicle. swab test results were however negative for the rest of the family*. in retrospect, patient recalled unusual/impaired sense of smell for the first days during initial symptoms. the events leading up to his covid- diagnosis highlight the gaps of the international screening processes at the global border entry, and the potential consequences of community chain transmission through imported covid- cases. here, we emphasize some effective strategies for covid- screening at the global border entry. fever and/or other respiratory symptoms are frequently highlighted at the global border entry as indications for swab tests. however, sore throat alone may be an unclear symptom for individuals to declare. this is a case of covid- with isolated sore throat, which has recovered. we will suggest a detailed breakdown of the symptoms/education posters placed at global border entry points to facilitate declarations and diagnosis. this patient had declared his symptom of sore throat, which had resolved. overseas returning persons to singapore have been placed on a mandatory -day stay home notice (shn) since march h. the availability of the instructions on the information sheet online from singapore global network, and the provision of a hotline assistance from the people's association (government-supported), were the key factors and contact point which allowed the patient to be identified and rapidly facilitated to be picked up while isolated in his shn hotel, in a dedicated ambulance to national center of infection disease, singapore. we highlight the importance and efficiency of a national online covid- network resource for overseas returning persons, facilitation through government agency and a closed loop transportation in the containment of covid- spread. this patient's parents who transported him from the airport to his shn hotel, and patient's brother (whom did not have direct contact with the patient, but was picked up in a common transport vehicle afterwards) developed symptoms despite negative swab test results*. a study on environmental contamination by symptomatic covid- patients in airborne infection isolation rooms, demonstrated that air samples were negative despite the extent of environmental contamination. however, swabs taken from the air exhaust outlets tested positive, suggesting that small virus-laden droplets may be displaced by airflows and deposited on vents. in retrospect, patient recalled unusual/impaired sense of smell for the first days during initial symptoms. some new reports suggest loss of smell or taste as covid- symptoms. [ ] [ ] [ ] loss of smell and loss of taste occurred between - . %, and - % respectively in two european cohorts reported very recently. [ ] [ ] but this knowledge was not available at the earlier phase of the covid- pandemic when the patient was symptomatic, and these symptoms may not be readily offered by a non-suspecting patient. physicians need to actively probe for this history. our frontline physicians worldwide also need a high index of suspicion encountering at least geographic variants of covid- that have been reported so far. while loss of smell and taste were reported in two large european cohorts, - a report published mid-april on patients in new york city indicated gastrointestinal symptoms of diarrhea ( . %), nausea and vomiting ( . %) appeared to be more common than in china (where these symptoms occurred in to % of patients). coupled with the knowledge that covid- can spread asymptomatically, these unusual symptoms may be the initial manifestation of the illness. we hope that global collaborative efforts at border screening can contain and slow down the rapid spread of covid- internationally. availability of a government-supported go-to online resource can unite efforts between returning persons and national directions in containing this pandemic. another strategy to ease the border point screening and declaration logistics, can be to set up an online pre-arrival declaration by government agency, where returning persons/students can selfreport any symptoms or resolution of symptoms, contact history, which can be reviewed prior arrival. returning individuals can then be pre-issued an electronic qr code/tagged queue number through email, which allows the suspect cases to be channelled to a separate queue or screening area with physical distancing precautions. this will allow suspect cases to be effectively prioritized during declaration screening. as of march , our ministry of foreign affairs in singapore has issued a statement to encourage singaporean students studying overseas to consider returning home soon. we will expect an increase in the number of imported cases from this group. a high index of suspicion for covid- when identifying an isolated sore throat on clinical examination, will be equally relevant to the general physicians, emergency care physicians, otolaryngologists and anaesthetists, who are at higher risk of encountering a throat visualization during intubation and routine examination (fig. ) . this information can be useful to countries with low resources or insufficient covid- testing kits. our ministry of health released the figures - % of singapore's imported cases over days ( - march) did not show any symptoms at border entry. an important global border control measure to implement quickly, will be to expand the symptom list to isolated sore throat, and/or a prior history of recent symptoms (resolved). this may capture a larger proportion of imported cases at border entry point, for more effective containment. majority . % ( / ) imported cases (cohort from march, fig. ) were returning from the united kingdom. this is an important message to deliver to the larger global community in our efforts to control the rapidly escalating pandemic. china medical treatment expert group for covid- . clinical characteristics of coronavirus disease in china surface environmental, and personal protective equipment contamination by severe acute respiratory syndrome coronavirus from a symptomatic patient practice management -anosmia, hyposmia, and dysgeusia symptoms of coronavirus disease association of chemosensory dysfunction and covid- in patients presenting with influenza-like symptoms. int forum allergy rhinol olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (covid- ): a multicenter european study clinical characteristics of covid- in new york city advisory for singaporean students studying overseas covid- -what should anaethesiologists and intensivists know about it? anaesthesiol intensive ther recent-days-did-not-show-symptomsat?utm_source=stsmartphone&utm_medium=share&utm_term= - - + % a % a the author thanks the patient and his family for providing the information, case history and images. key: cord- -vksombro authors: teo, leng woon; pang, tanya; ong, yong jin; lai, christopher title: "coping with covid- : perspectives of student radiographers" date: - - journal: j med imaging radiat sci doi: . /j.jmir. . . sha: doc_id: cord_uid: vksombro nan publications about the impacts of covid- on the modifications and precaution measures in clinical practice (as well as the concern/challenges about online teaching methods in radiography teaching) are widely available, yet writings on the radiography students' perspective are lacking. in this commentary, our radiography students share their insights as key players in radiography profession, which should be of interest to radiography educators around the world. with the rising number of unlinked cases of covid- in singapore, the disease outbreak response system condition (dorscon) level was raised to orange on february , . as such, precautionary measures were taken; for example, travel restrictions for new visitors with recent travel history to mainland china, suspension of school activities, and temperature screening and deferment of large-scale events ( ) . later, to further reduce the spread of covid- transmission, the singapore government introduced the circuit breaker on april . the circuit breaker, initially scheduled to end on may , was subsequently extended to june due to the sharp increase in the number of cases, especially among the migrant workers in the dormitories ( ) . as of may , , there are over , cases of covid- infection in singapore ( ). during this period, everyone in singapore has been advised to stay at home as much as possible. the covid- (temporary measures) act was also passed in the parliament in conjunction with the circuit breaker, which bans individuals from gathering with anyone not living in the same residence and public spaces ( , ) . similarly, the new law requires all citizens to wear a mask when outside of home except when engaging in strenuous activity ( ) . recreational facilities such as gyms and swimming pools and non-essential retail outlets were closed, while food and beverage outlets remained open for takeaways and deliveries only ( ) . people in singapore are required to adhere to the regulations or face a hefty fine, with any subsequent breaches possibly incurring a jail sentence. under these temporary measures in place till june , we are only allowed to leave our homes to perform essential tasks such as buying groceries, visiting a doctor, or accompanying the elderly or children to complete certain tasks ( ) . other stringent regulations include compulsory compliance to safe distancing measures of at least metre when queuing, no eating and drinking in eating places, and no loitering or gathering in public ( ) . to ensure that everyone complies to the safe distancing measures, enforcement officers were deployed to various locations. as part of the safe distancing measures, crowd control measures were implemented in premises to prevent overcrowding ( ) . these include shopping malls and supermarkets where we are required to queue and have our temperature taken before entering. likewise, we are also required to register our entry into these premises by producing our identification card for contact tracing purposes ( ) . as schools were closed, our classes have been shifted to full home-based learning and examinations were administered with the use of online software. with the advent of covid- , it became untenable for traditional classroom lectures and tutorials to continue. lessons were instead delivered online via pre-recorded videos, web conferences and discussion boards. practical lessons were removed from the curriculum, while quizzes and exams were administered remotely. clinical placements were also shortened from six weeks to three weeks during may and june. the aforementioned changes impacted radiography students to a large extent. firstly, the transition from fixed, timetable-based lessons to flexible, home-based learning was a challenge. since lessons and slides were now pre-recorded and uploaded for self-study, we no longer had a rigid schedule to adhere to. suddenly, it fell to each individual student to plan their own study schedule. adequate pacing was required to ensure we did not burn out from trying to study too much too fast or become overwhelmed at the end because we did not study enough in the earlier weeks. moreover, not everyone had a conducive environment for home-based learning. compared to the school facilities that were optimized for studying, there were myriad distractions at home that detracted us from our learning. the lack of physical lessons presented difficulties as well. studies have shown the efficacy of combining e-learning with lecture-based curriculums, with increases in student satisfaction and learning rates ( , ) . however, the current situation removed lectures entirely. with classroom-based learning, we could easily bounce ideas off each other and engage in smallgroup discussions while the lesson materials were still fresh in our heads. everyone would be studying at the same pace, thus allowing for constructive engagement with peers. with home-based learning, everyone was studying at a different pace. furthermore, each of us consumed online content differently. there was now a dissonance between students' comprehension of the lessons, despite being provided the same source material. group discussions with peers became more challenging and provided less output. while our lecturers were proactive and very responsive in replying to online queries, it still lacked the immediacy of face-to-face consultations, whereby the conversation flow could lead to us establishing a better linkage between the theories taught and therefore better understanding of the material. as everyone would agree, radiography is a hands-on profession. therefore, the removal of practical lessons and shortening of clinical placements delivered a huge blow to our learning. we were unable to put theories into practice and bridge the gap between the two. in a study by bell et al ( ) , much of the knowledge gained from online tutorials were lost to recall in the following weeks. without practicums for us to supplement and augment our learning, the results were sub-optimal. the shortening of clinical placements meant that we had less time and experience in the real world of radiography. inarguably, the practice of radiography must be the focus of the curriculum ( ) . yet, in this case, it was wrenched from us due to situations beyond our control. overall, we were all confused and frustrated with this sudden change in circumstances. adapting to the new system was not easy and we had to develop new learning strategies to stimulate our own learning, since our old styles were more suitable for physical lectures. however, there was a silver lining in thoroughly stress-testing the limits of remote learning for radiography, and we feel hopeful that, with this experience, e-learning can be more seamlessly integrated with traditional lectures to deliver more value-added teaching for future cohorts. regarding the clinical placement, there is the inevitable worry of encountering a covid- patient during work, and possibly contracting the virus and infecting our family members. however, there are measures in place by the government, the university, and the respective healthcare institutions to ensure our safety during clinical placements. singapore learnt a lot from the sars outbreak in . hospitals are now quick to implement infection control protocols and have improved patient management in fever areas ( ) . staff are also required to be mask-fitted and have daily temperature checks to detect cases early ( ) . additionally, the university introduced an infection control refresher course that focused on procedures such as handwashing, alcohol-based hand rub, and donning and doffing of personal protective equipment. proficiency in these areas will minimize any cross-infection risk, thereby protecting the health of patients, colleagues, and oneself. the university is also working closely with the guidelines of the ministry of health (moh) and healthcare institutions (hcis) to ensure strict compliance to protocols, including travel advisory, movement restrictions, segregation plans, and health monitoring and reporting. these protocols were clearly articulated to us and understanding the emphasis that the institutions are placing on our safety has helped to ease our worries regarding the placement. that being said, it is important to be mentally prepared. we as student radiographers will be exposed to the stresses associated with a pandemic, including fear and worry about one's health, as well as possible anxiety. a study has highlighted that relaxation and exercises such as meditation and deep breathing are effective in reducing stress among students ( ) . other beneficial exercises to cope with stress include journal writing therapy. research has shown its effectiveness in reducing stress and identifying and accepting emotions and should be considered as a tool to de-stress ( , ) . moving on, there is a possible reduction of non-urgent cases in some departments and hospitals since they are being rescheduled or cancelled by the patients or requesting doctors. this may decrease the quantity and variety of cases to choose from for our case report assignments. the lack of cases may also signify lesser hands-on experience. it would be great for the university to reduce the workload of students, especially during difficult times. one should be inquisitive, observe, and participate actively whenever receiving a patient to maximise their learning experience. on the other hand, some departments and hospitals may be understaffed due to the days compulsory medical leaves implemented by the government, or they may be tasked to help out at the various covid- sites. staff may not have the time to teach students, resulting in a rushed learning environment. however, we understand that this circumstance is unavoidable, and it is a great opportunity to learn while under such unprecedented pressure. in fact, this is the best opportunity to take responsibility and be proactive to help out in the department. in conclusion, covid- has left its mark worldwide, but its implications for healthcare professionals are on a totally different level. as student radiographers, it is a poignant glimpse into our future lives as healthcare professionals. the disruptions to our studies have also been numerous and significant. however, we have successfully demonstrated tenacity, discipline, adaptability, and professionalism in the face of this ongoing ordeal, so a silver lining does exist. with the prompt changes in the modes of radiography teaching due to covid- , we believe much has been learnt by both the students and administration regarding the viability and shortfalls of e-learning. looking forward, we hope to see better synergy between traditional lectures and e-learning in the curriculum, allowing for maximised efficiency in terms of content delivery, practical experience and student learning. this will ensure that student radiographers receive the best education possible and, upon graduation, can contribute significantly to the fields of radiography and healthcare. coronavirus outbreak: singapore raises dorscon level to orange; schools to suspend inter-school, external activities. channel news asia pm lee hsien loong's remarks in english, malay and chinese on the coronavirus disease (covid- ) situation in singapore what you can and cannot do during the circuit breaker period covid- (coronavirus disease man charged with going to social gathering at circuit road flat during circuit breaker. today online covid- : what the law says about having to wear a mask when outside your home. channel news asia tightened circuit breaker measures extended for another week; some activities allowed to resume from may . straits times press release for enforcement of safe distancing measures in public spaces in hdb estates to curb covid- transmission crowd-limiting measures at malls, public venues as new safe distancing rules kick in. straits times customers advised to bring nric to enter shopping malls, supermarkets: enterprise singapore. channel news asia comparison of the effect of lecture and blended teaching methods on students' learning and satisfaction e-learning for medical imaging specialists: introducing blended learning in a nuclear medicine specialist course knowledge retention after an online tutorial: a randomized educational experiment among resident physicians towards the development of a reflective radiographer: challenges and constraints outbreak of severe acute respiratory syndrome in a tertiary hospital in singapore, linked to an index patient with atypical presentation: epidemiological study sars transmission and hospital containment stress management techniques for students the effects of expressive writing on pain, depression and posttraumatic stress disorder symptoms in survivors of intimate partner violence an everyday activity as a treatment for depression: the benefits of expressive writing for people diagnosed with major depressive disorder key: cord- -tnik sd authors: tey, jeremy; ho, shaun; choo, bok ai; ho, francis; yap, swee peng; tuan, jeffrey k.l.; leong, cheng nang; cheo, timothy; sommat, kiattisa; wang, michael l.c. title: navigating the challenges of the covid- outbreak: perspectives from the radiation oncology service in singapore date: - - journal: radiother oncol doi: . /j.radonc. . . sha: doc_id: cord_uid: tnik sd in december , pneumonia of unknown cause was reported by china to who. the outbreak was found to be caused by a coronavirus which was officially named “severe acute respiratory syndrome coronavirus ” (sars-cov- ), and the disease caused by it was named ‘covid- ’. the first case in singapore was confirmed on (rd) january . with lessons learnt from the sars epidemic in and the h n flu pandemic in , singapore was much better prepared to deal with the virus outbreak. the government has taken swift measures to contain and break the chain of transmission. healthcare workers face the challenge of keeping patients and staff safe from the disease. there is a higher risk of mortality of covid- in cancer patients and hence unique considerations for a radiation oncology department operating in an infectious disease outbreak. this article is the recommendations and adapted workflow from the two national cancer centres in singapore with the endorsement by the working committee of the chapter of radiation oncology, academy of medicine, singapore. it highlights the challenges that radiation oncology departments in singapore face and the appropriate recommended responses. this includes interventions, business continuity plans and workflow in managing a covid- positive patient on radiotherapy. title: navigating the challenges of the covid- outbreak: perspectives from the radiation oncology service in singapore. in december , pneumonia of unknown cause was reported by china to who. the outbreak was found to be caused by a coronavirus which was officially named "severe acute respiratory syndrome coronavirus " (sars-cov- ), and the disease caused by it was named 'covid- '. the first case in singapore was confirmed on rd january . with lessons learnt from the sars epidemic in and the h n flu pandemic in , singapore was much better prepared to deal with the virus outbreak. the government has taken swift measures to contain and break the chain of transmission. healthcare workers face the challenge of keeping patients and staff safe from the disease. there is a higher risk of mortality of covid- in cancer patients and hence unique considerations for a radiation oncology department operating in an infectious disease outbreak. this article is the recommendations and adapted workflow from the two national cancer centres in singapore with the endorsement by the working committee of the chapter of radiation oncology, academy of medicine, singapore. it highlights the challenges that radiation oncology departments in singapore face and the appropriate recommended responses. this includes interventions, business continuity plans and workflow in managing a covid- positive patient on radiotherapy. on st december , a pneumonia of unknown cause was reported to the who country office in wuhan. this signaled the beginning of the covid- outbreak. the first case in singapore was confirmed on rd january . this was a -year-old chinese male national from wuhan. he had arrived in singapore with his family on th january . within a month, new cases were reported in singapore. as of th march , there have been new cases of covid- cases confirmed in singapore with deaths and , cases of covid- diagnosed worldwide with , deaths in total. with lessons learnt from the sars epidemic and h n flu pandemic, singapore was much better prepared to deal with the virus. , , the singapore government responded swiftly. aggressive contact tracing was initiated for confirmed cases, and close contacts were quarantined for days. a multi-ministry taskforce was also formed on th january with the aim of coordinating national and international responses to the outbreak. the outbreak was then declared a public health emergency of international concern on the th january by the who. in singapore, the risk assessment of the covid- virus from disease outbreak response system condition (dorscon) was raised from green to yellow on rd january , and from dorscon yellow to orange on th february (supplementary table) . multiple measures followed as the number of cases continued to increase in singapore and worldwide. these measures included border restrictions on visitors arriving from hubei, and on people who had travelled to china in the preceding days. thermal screening was implemented at immigration, and a days mandatory leave of absence was implemented for singapore residents returning from china. as the situation continued to escalate in multiple countries, broader border restrictions were placed on new visitors with recent travel history to countries heavily affected by covid- . singaporean residents and long-term pass holders returning from these countries were issued stay-home notices for days upon their return. individuals who are suspect patients are sent to the national centre of infectious diseases (ncid) for further management. in an infectious disease outbreak, there are additional challenges that are unique to a radiation oncology department and must be considered: . time sensitive nature of oncology treatment. radiotherapy patients typically require a multi-fraction course of treatment entailing daily visits to the department. treatments cannot be postponed like elective surgeries without the risk of adverse clinical consequences. for example, in a patient with squamous cell head and neck cancer, fractions of radiation is delivered over . week. each week of delay translates to % lesser cancer control. . radiation oncology side effects mimicking covid- symptoms. the typical presentation of covid- is nonspecific. early symptoms may include low grade fever, cough, sore throat, running nose. many cancer patients on chemotherapy have low grade fever. a sore throat may be due to mucositis from head and neck radiotherapy. many lung cancer patients may have respiratory symptoms of varying degrees. . unique fractionated nature of radiotherapy. the reduction of clinical workload will take time. even without taking on new patients, existing patients must finish their course of treatment before workload decreases. . many oncology centres have satellite centres and satellite clinics with reduced capability due to the high cost of linear accelerators. the radiation oncology departments may have to cover satellite centers, with staff working across multiple hospitals. this poses a risk of possible cross infection if a staff becomes infected. . patients with fever should be isolated in a separate room. however, it is not practical to designate a dedicated linear accelerator, ct simulation room for patients at risk . many patients are seen in the department daily and can be grouped into outpatient followups, on treatment reviews and hospital inpatient referrals. considerations must be made to minimize contact between different patient groups. . careful manpower planning of doctors, allied health and nurses is required for continued provision of the service, to keep them safe from the disease, and to prevent burn out. additional staff are also required to help with additional duties, such as temperature screening, triage and contact tracing. . infrastructure considerations within the department for staff physical segregation from an organizational point of view, oncology is considered a critical service in a tertiary hospital and is expected to continue operations even in an infectious disease outbreak. this is also true from the perspective of the individual patient, who expects his or her oncological treatment not to be disrupted. to ensure such continuity of services, the following measures were implemented. to minimize risks of infection, a strict visitor policy was implemented. patients coming for outpatient radiation oncology appointments were limited to one accompanying person at any one time. children below years of age were not allowed to enter the department. the exception was when the child is the patient. patients were triaged in a dedicated area and had to fill up a screening questionnaire and have their temperature taken. the questionnaire includes the following: . whether they had fever or cough or shortness of breath . whether they were in mainland china (thereafter expanded to include iran, northern italy and south korea in the last days) . whether they had close contact with someone with covid- . patients with respiratory symptoms and a positive contact or travel history would be isolated for further assessment. an infectious diseases specialist would also be consulted if further diagnostic tests or admission was required. if the patient's symptoms were assessed not to be due to an infectious cause, such as a sore throat from radiation to the neck, the patient would be allowed to proceed with his appointment. patients who are attending daily radiotherapy treatments will have their temperature taken at triage prior to proceeding to the radiotherapy treatment area. all patients and accompanying persons were issued surgical masks. as part of the staff illness surveillance system, mandatory twice daily monitoring for all staff working in the department was implemented. the information is updated electronically, and any medical leave is reported daily. the lead of each section (radiation therapist, nurses, radiation oncologist, physics, patient service associates) is accountable for surveillance, and must investigate any cluster of or more staff who develop fever or are on medical leave for acute respiratory illnesses. education materials and information are placed in patient care areas such as the nurses' stations and clinic rooms to educate and remind patients and staff on good personal hygiene, importance of hand washing and the correct way to wear masks. as frontline workers, we must ensure adequate medical supplies for patients coming for treatment, and for healthcare workers in the department. weekly checks of medical supplies including personal protective equipment such as masks (surgical, n ), gowns, goggles and gloves was implemented. as part of an internal communications plan, there must be continuous communication of information from the senior administration to the rest of the radiation oncology team. these included electronic messaging systems, emails and meetings using video or web conferencing. the need for video conferencing to minimize face to face meetings have highlighted the need to plan for and maintain both hardware (including web cams, microphones, speakers) and software (video/web conferencing software) requirements. there is also a need for a fast internet connection. with the evolving covid- outbreak, there needs to be provisions and policies to ensure continuity of radiation oncology services. senior management needs to plan for adequate manpower should staff fall sick or need to be quarantined as a result of contact with patients with covid- . it is worth noting that the threat of staff catching covid- is more likely to come from social rather than medical interactions. it is important, therefore, that staff exercise social distancing after work hours where possible. furthermore, the parent institution may redeploy radiotherapy department staff to other sectors helping to manage an outbreak, further depleting already scarce manpower resources. depending on individual departments, manpower may be augmented by cancellation of conference leave or overseas leave. having a policy in place will facilitate claims and reimbursements for leave cancellation. patients already started on radiotherapy treatment cannot have their treatment stopped or postponed without significant clinical consequences. these patients would need to complete their treatment. the focus would be on reducing elective new cases starting radiotherapy. new starts on high maintenance services such as brachytherapy were reduced and alternatives to brachytherapy considered. new cases for specialized services such as stereotactic body radiotherapy and stereotactic radiosurgery would be reduced. a review of current radiotherapy treatment protocols was undertaken with a view to hypofractionate treatment where possible to reduce treatment time. a review of all outpatient clinic appointments was done, and follow-up appointments were postponed or delayed if deemed appropriate. new cases referred to the radiation oncology department were screened, and all non-urgent cases were postponed. business continuity is of key importance. there should be provisions within the department such that continuity of radiation oncology services will not be impacted as there is possibility of staff managing confirmed cases and therefore needs to be self-quarantined at home. physical segregation of staff was implemented. movement restrictions were in place such that radiation oncology workers were limited only to one hospital or healthcare campus. radiation oncologists, physicists and radiation therapists who were working across multiple hospitals were separated across hospitals to maintain no crossover and minimize infection risk physical segregation of patients coming for outpatient visits was important. outpatients visits are grouped into two categories: patients coming for follow-up consultations or new patient consultations and patients coming for daily visits for radiotherapy. the patient journey for each category was reviewed. dedicated patient care areas were relooked, and specific areas were allocated for patient waiting, patient triage, patient consultation. within each hospital/centre, the radiation oncology department was separated into teams (e.g. teams and ) . this is so that if one team could provide continuity of service should the other team need to be quarantined. each team lead by a team leader consisted of specialists, non-specialist doctors (trainees, residents, fellows), operations personnel, radiation therapists, patient service associates, nurses, physicists, research staff. each team would take turns to be the 'clean' and 'dirty' team. the 'dirty team' would be responsible for inpatient consults, assessment of patients with fever, upper respiratory tract infection, pneumonia or suspect covid- patients. within the workplace, care teams will have dedicated workspaces. for contact tracing, a close contact was defined as being physically within metres for more than minutes at any time. within the workplace, the workspace between individuals is at least metres apart. additional rooms or workspaces would be used if required. within each team, there were separate allocated locations for meals for different groups of staff (physics, nurses, radiation therapists) to prevent mixing. in some large centres, there may be more than one cluster of consultation, planning and treatment rooms. this would serve as an ideal way of physical separation. where this is not possible in small centres, every effort should be made to temporally segregate staff through shift rotations or staggering of mealtimes to minimize possible cross-contamination. special attention needs to be given to certain sections of the multidisciplinary teams which are small but essential, for instance physicists. these staff are required to observe strict segregation to ensure that there is no cross-contamination that may bring radiotherapy services to a stop. some centers have implemented remote planning. the radiation oncologist can remotely dial into the hospital server (with dual security password protection and mobile phone verification) to contour the treatment target volume and organ at risk. the physicist or radiation therapist who is involved in treatment planning can also do so remotely via a laptop at home. this will support staff segregation to ensure two teams working at separate sites. as covid- is transmitted by droplets , patients and visitors to the center are provided with hand sanitiser at the counter and outside the lifts and along common corridors. patients with respiratory symptoms are offered a mask. all healthcare professionals on the frontline are to wear surgical masks and gloves when examining patients. additional personal protective equipment such as an n mask, eye protection, and gown is required when attending to a positive or suspect case of covid- , or when performing aerosol generating procedures such as insertion of a nasogastric tube or performing a nasoendoscopy. it is also mandatory to wash hands after every single patient contact. high touch areas like the visitor toilets, lifts, escalators, front counter desks, doctors and nurses tables and chairs are cleaned and wiped down several times a day with alcohol based sanitizers. patient changing rooms are cleaned and the patient linen basket is emptied every hour. the whole area is mopped three times a day with chlorine. used surgical masks, n , gowns and gloves and other clinical waste are carefully put into biohazard bags and disposed in a proper manner. regular safety check is implemented to ensure adherence. amid the challenges of the evolving covid- crisis, we must not overlook staff morale. support for colleagues in the department can be in the form of provision of basic amenities such as thermometers and personal hand sanitisers. leaders must inspire by leading by example. there must be easily accessible channels for staff feedback and concerns. constant communication and updates allay fears and clarify misconceptions. we need to continue to improve and upgrade our professional knowledge to enable us to provide our patients with the best management. cmes and peer review learning (prl) are continued by video conferencing between radiotherapy staff working in different hospitals. the academy of medicine, singapore organises cme on covid- management by infectious disease experts to update via video conferencing to ensure all doctors are constantly updated. with the current ease of contracting covid- and increasing number of cases, it is inevitable that a current patient undergoing radiation treatment may contract the disease halfway through treatment, or just prior to planned treatment. each department should have a written protocol on the management should the need arise to address this issue. we recommend: . delaying the start of radiotherapy and stopping ongoing treatment temporarily until the patient is no longer infectious if possible. as the mortality rate of covid- is currently estimated by the who to be around . %, it is important to consider a real risk diminished cancer control if radiation treatment is stopped, especially when the radiation is of curative intent. however, if the intent is palliation, other alternative palliative treatments can be explored, and radiation can either be discontinued or resumed only after the patient recovers from covid- . each case should be discussed with the infectious disease specialist to weigh the specific risk and benefits of stopping or proceeding with radiotherapy. . when treatment needs to be continued, to consider replanning with a hypofractionated regime in order to complete treatment at the earliest time . to treat the patient as the last case of the day with the staff on full ppe protection. subsequently, the patient to be transferred back to an isolated room as an inpatient. during treatment, the patient and involved staff will need to don appropriate personal protective equipment (ppe). these may include n respirators, surgical masks and gloves depending on institutional policy, available resources and procedural risks. appropriate high dusting cleaning of the linac room is done on completion of treatment. (table ) . be proactive in anticipating and planning for the impact of covid- . engage and coordinate with the parent institution in formulating policies for identifying patients at risk or who are already infected and contextualizing these to the department during implementation . reduce clinical load where possible in anticipation of depletion of resources. this may involve temporarily reducing frequency of follow-up appointments, reducing fractionation schedules where possible, and considering alternative treatment modalities apart from radiotherapy that achieves the same therapeutic goals. . employ staff segregation either spatially or temporally to reduce risk of the entire service succumbing to infection or quarantine. special attention needs to be paid to "bottleneck" personnel (e.g. physicists) where redundancy cannot be built in. . prepare for the possibility of a covid- patient requiring treatment. plan in advance which indications warrant emergency radiotherapy treatment when proven infectious or merely suspected, what personal protective equipment is required, and how to decontaminate the facility after treatment. the greatest threat to the sustained delivery of essential radiotherapy service is being overwhelmed by a deluge of covid- cases such that the healthcare institution is paralyzed. this can only be mitigated by national and institutional policy. nonetheless, radiation oncology departments can act to better position themselves to continue radiotherapy services in the face of resource limitations brought on by the outbreak, as well as to protect staff and patients. we must continue to learn and adapt to the constantly evolving covid- outbreak. we hope that other radiation oncology departments worldwide will benefit from our experience in dealing with the covid- threat. who coronavirus disease (covid- ) situation report severe acute respiratory syndrome: lessons from singapore hiding in the bunker: challenges for a radiation oncology department operating in the severe acute respiratory syndrome outbreak influenza a (h n - ) pandemic in singaporepublic health control measures implemented and lessons learnt wuhan virus: moh sets up multi-ministry taskforce, advises against nonessential trips to wuhan novel coronavirus: s'pore moves to dorscon orange, as new cases confirmed with no apparent link to previous cases or recent travel to china coronavirus: recent travellers to s. korea, northern italy and iran barred from s'pore; testing for all symptomatic travellers at entry loss of local control with prolongation in radiotherapy covid- ): protecting hospitals from the invisible timely delivery of radical radiotherapy; guidelines for management of unscheduled interruptions the transmission and diagnosis of novel coronavirus infection disease (covid- ): a chinese perspective title: navigating the challenges of the covid- outbreak: perspectives from the radiation oncology service in singapore. .unique considerations for radiation department operating during covid- outbreak. . highlights the challenges of radiation departments providing care during a pandemic in singapore. key: cord- -prizmksg authors: lateef, fatimah; lim, swee han; tan, eng hoe title: new paradigm for protection:: the emergency ambulance services in the time of severe acute respiratory syndrome date: - - journal: prehosp emerg care doi: . /j.prehos. . . sha: doc_id: cord_uid: prizmksg severe acute respiratory syndrome (sars) is a newly emerging and highly infectious form of atypical pneumonia with a high rate of transmission, especially among health care workers. with sars, certain policies had to be implemented rapidly by the emergency ambulance services and the ministry of health to support and protect all personnel adequately. the authors discuss the changes in policies and personnel behavior, the training and education that had to be disseminated widely, and certain alternatives in policies such as transportation. the authors hope to share their experience in the implementation of these strategies by the singapore civil defence force and stress the importance of the psychological preparedness of the paramedics and prehospital care providers worldwide in this era of sars. singapore is a cosmopolitan city at the crossroads of asia, with a land area of km and a population of million. the emergency ambulance service (eas) is run by the singapore civil defence force (scdf) and has a fleet of ambulances. it is a single-tier system, which serves the whole country and handles approximately , calls annually. , the paramedics on the eas perform basic life support skills and are trained to defibrillate with the use of automated external defibrillators (aeds). they also start intravenous lines and administer certain drugs (e.g., adrenaline, dextrose). the complete ambulance crew comprises of a driver (trained in first aid and basic life support), a qualified paramedic, and a paramedic assistant who is a trained medical orderly. in response to road traffic accidents and certain medical emergencies such as cardiac arrest, a first line of response is dispatched before the ambulances. this represents the fast response paramedics (frps). they are paramedics with the same qualifications as the ambulance paramedics but they have in addition to this, training in riding motorcycles, which includes defensive riding. they carry an aed as well as essential first-response equipment on their motorcycles. these frps work alone and will usually hand over the cases they have attended to the ambulance paramedics for transport and further management. severe acute respiratory syndrome (sars) is a form of atypical pneumonia, which was first seen in november in the guangdong province of china. it is a newly emerging and highly infectious disease with a high rate of transmission, especially among health care workers. as the world has become a ''global village,'' sars has become a problem of the ''village.'' the sars outbreak in singapore begun in march and was traced to a traveler returning from hong kong. since then, several index cases and their clusters have been identified and traced. the social and economic impact of sars has been tremendous. up to june , , there have been a total of cases and deaths ( . %) in singapore. on march , , the world heath organization (who) issued a global alert on sars. who defines a suspected case of sars as one with documented fever (temperature c), lower respiratory tract symptoms, and contact with a person who has sars with a history of traveling to an area of documented transmission. a probable case of sars, on the other hand, is similar to a suspected case but has chest x-ray findings of pneumonia, acute respiratory distress syndrome (ards), or an unexplained respiratory illness resulting in death with autopsy findings of ards without any other identifiable causes. , with the outbreak of sars, the eas, an integral component of the overall health care system, had to implement certain practices rapidly. the coordinated efforts of the scdf with the ministry of health were extremely important in this respect. mandatory steps from the preparatory phase to the initial point of contact and subsequent disposition of patients were highlighted and taught to all personnel. the best strategy was to have a high index of suspicion and be vigilant at all times for every patient. prevention is best in the management of any infectious disease and, hence, for sars, it behooves the system to prevent its spread. because it would take up to one week before a diagnosis of sars could be confirmed, universal precautions had to be undertaken for every patient being treated. this entails the adoption of full protection for every ambulance crewmember. to date, a total of seven probable and five suspected cases were conveyed by the eas out of a total of patients with sars-like signs and symptoms. it was compulsory for all ambulance crewmembers to use personal protective equipment (impervious gowns over their uniforms, n masks,* eye goggles, head covers, and disposable gloves) when attending to all cases. the gowns and gloves were changed after every case. the impervious gowns served as protective apparel, which provided a barrier to prevent contamination of the uniform and skin. goggles, or face shields, helped to avoid splashes or sprays of body fluids or secretions to the mucous membranes of the eyes. the gloves provided a protective barrier and prevented gross contamination of the hands, reducing the likelihood of spread of microorganisms from person to person or from fomites (surface or equipment) to person. hand hygiene was also stressed to all. because sars appears to be spread by direct contact with respiratory secretions, touching of contaminated objects was a potential source of transmission. hand hygiene (either by handwashing or the use of hand rub solution) was critical before and after contact with every patient. once worn in the presence of a patient who was suspected of having sars, the mask was considered potentially contaminated with infectious material (even if not visible), and touching of the mask was avoided. reusable equipment such as stethoscopes was disinfected with alcohol-impregnated wipes after every patient. special disposable mechanical filters were fitted for the bag-valve-mask and suction units to filter expired air from possible patients suspected of having sars. because nebulization for severe asthmatics was not allowed to prevent reaerosolization of any organism, spacers for metered-dose inhalers (mdis) had to be used. surveillance of all the eas personnel was also carried out. temperature checks were done regularly three to four times a day, even for those on their off-duty days. those who had contact or had transported any suspected sars or high-risk cases were also monitored closely. they had to report their temperatures and any sars-like symptoms to a central monitoring station in the medical department of scdf. contingency plans were also in place to isolate the contacts of these ambulance crews should they be considered sars suspects. with the sars outbreak, infection control training had to be stepped up immediately. the training sessions were carried out using a variety of teaching methods such as small-group classroom teaching, demonstration sessions, use of videotapes to highlight techniques (such as the donning of personal protective gear and effective handwashing), and hands-on practical sessions for mask fitting. mask-fitting sessions had to be carried out for all staff to ascertain the best-sized mask for each. hand hygiene practical sessions were supervised to ensure it was performed correctly. the infection control officer gave briefings to everyone and all this had to be carried out rapidly, over a short period, to ensure all personnel had the necessary skills and knowledge early. those who failed to comply were given warnings and counseled accordingly. their conduct and practices were then monitored by their supervisor. the compliance rate was observed to be high among all staff. the rate was not objectively measured or analyzed but feedback was obtained from training supervisors, senior paramedics from the medical department at scdf, and also from staff of the emergency departments who were in contact with these paramedics. *n masks: health care particulate respirator and surgical masks designed to provide protection for the user. there is filter efficiency level of % or greater against particulate aerosols free of oil. they are fluid-resistant and disposable and satisfy the centers for disease control and prevention criteria for mycobacterium tuberculosis exposure control. they reduce the exposure to airborne particles ranging from . to > . mm. n masks provide > % bacterial filtration efficacy (bfe) against user-generated microorganisms. there were also frequent updates on the sars situation locally, as well as in the region. updates from the hospitals were also given on some of the cases transported and suspected to be sars. this was part of the hospital contact tracing procedure for every suspected or probable sars case. sars was also highlighted during the continuing education sessions for the paramedics, where the clinical presentations, the rapidly changing epidemiology, definitions, and risk factors were discussed. the history taking by paramedics now had to incorporate certain questions pertaining to risk for sars, overseas travel, and fever. this was also performed by the emergency medical dispatcher (emd) whenever possible. the reason for this was because the high-risk status could be identified early. because the initial clinical features of sars were not specific and physical signs on chest examination were minimal, they were cautioned that every patient could be a potential suspected sars case. the paramedics also helped to educate the public by imparting relevant and accurate information whenever the opportunity was present because, with any public health outbreak such as this, there was bound to be misconceptions with some members of the public. they also helped to stress the importance of making an honest declaration when completing the sars health questionnaires. with the declaration of the sars outbreak in singapore, the ministry of health designated tan tock seng hospital (ttsh), one of the public hospitals, as the ''sars hospital.'' all suspected and probable cases were sent and managed there. with this, ttsh closed its emergency department to all other cases, and cases conveyed by the eas had to be diverted to the other five public hospitals. the patient load at these other hospitals thus increased. during this period, security at all hospital entrances was stepped up to ensure no lapses in patient screening and entry into health care institutions. if patients ''walked in'' to the emergency department at ttsh, they would be screened, assessed, and the appropriate advice/treatment would be given. if they required admission, they would be transferred to one of the other hospitals for further management. the paramedics had to bear this diversion rule in mind when they made decisions about transporting patients to the nearest or most appropriate hospital. based on history and rapid examination, if there were any suspected cases of sars, these patients were sent to ttsh. the rule of having only one relative accompany the patient in the ambulance was discontinued except for pediatric patients. if so, the relative was to be seated in the front of the ambulance and seatbelted. when transporting any patient, the windows of the ambulance should be kept open with the air conditioner off. this helped with ventilation within the ambulance cabin. preventive measures were taken to reduce the heat load on the crew with their full protective clothing. this including wearing of t-shirts instead of uniforms and ensuring adequate fluid intake. these practices were essential with the hot and humid climate in singapore. after the patient had been sent to the receiving hospital, the paramedics had to clean all equipment and trolleys in the ambulance with antiseptic wipes and mop the floor of the ambulance with antiseptic solution. the vehicle was then aired, with all its windows and doors opened, for minutes. on arrival at the hospitals, the paramedics had to comply with temperature checks and health declaration for themselves before being allowed entry into the emergency departments. when there were uncertainties about the history, especially of a possible sars contact, or which hospital to send the patient to, paramedics could clarify with the personnel at the control center in scdf or the emergency physician at the receiving hospital. checks were also made with the sars hotline set up by the ministry of health through the control room, which had access to patients who were on home quarantine orders (hqo). during this outbreak, a separate dedicated sars ambulance service was set up to transport all nonemergency suspected and probable cases to ttsh. this was a free service with a simple single access number, . however, patients, irrespective of whether they were suspected to have sars or not, continued to be treated and conveyed by the eas when they developed any emergency medical conditions. this ''ring fence'' strategy was in place to reduce the likelihood of cross-infection, and it also depended on vigilant screening of all potential sars cases by primary care physicians, paramedics, and emergency department staff. the patients on hqo also used the sars ambulance service when they had to seek medical attention for any reason. these people had been advised not to use public transportation or to drive themselves to the hospitals to reduce any chance of infecting others. with the mandatory practices implemented by scdf, there was high compliance among the paramedics and eas staff. as a result, there were no eas personnel who were affected by sars during the outbreak. in a situation such as this, it is important to put forth sufficient information to gain support and allay fears of the staff. these health care workers at the frontline also have concerns about spreading any likely infection to their families and loved ones. sars is a newly emerging infectious disease, but there are a whole range of other diseases such as tuberculosis, hiv/aids, and meningitis that frontline health care workers need to be aware of. ems staff should continually be updated on relevant information pertaining to these. , the communicative strategy of the scdf is commendable, and it helps that the paramedics were psychologically prepared for the risks ahead. they also know that they have the support of their organization in ensuring they have been given the best protection available. bystander cpr in prehospital cardiac arrest in singapore singapore: ministry of health severe acute respiratory syndrome (sars) in singapore: clinical features of index patient and initial contacts world health organization. who issues emergency travel advisory: sars spread worldwide emts' knowledge regarding transmission of infectious diseases occupational infectious disease exposure in ems personnel the case conference format may be used for the presentation of interesting or unusual ems encounters. this format can illustrate specific medical entities, unusual approaches to field management, or complex administrative issues that a field scenario may present. authors should pay particular attention to the educational value of the manuscript, and avoid a purely descriptive approach. features such as a team approach and innovative solutions to atypical problems should be stressed. while an abstract and specific section headings are not required, the following sections should be considered: . overall description of the scene, types of responding agencies and personnel, etc. . specific challenges encountered . solutions developed to address the challenges . discussion of medical issues involved, with review of the literature where appropriate . discussion of logistic and administrative issues title page, group authorship and acknowledgments page, references, and tables and figures (where appropriate) should follow the same format as for general manuscripts (see the ''manuscript preparation'' section of the ''instructions for authors'' following the text of most issues of prehospital emergency care). key: cord- -j o m ck authors: ng, jun jie; gan, tiffany r.x.; niam, jen yong; menon, raj k.; ho, pei; dharmaraj, rajesh b.; wong, julian c.l.; choong, andrew m.t.l. title: experience from a singapore tertiary hospital with restructuring a vascular surgery practice in response to national and institutional policies during the covid- pandemic date: - - journal: j vasc surg doi: . /j.jvs. . . sha: doc_id: cord_uid: j o m ck singapore was one of the first countries to be affected by covid- , with the index patient diagnosed on january . for two weeks in february, we had the highest number of covid- cases behind china. in this article, we summarize the key national and institutional policies that were implemented in response to covid- . we also describe in detail, with relevant data, how our vascular surgery practice has changed due to these policies and covid- . we show that with a segregated team model, the vascular surgery unit can still function whilst reducing risk of cross-contamination. we explain the various strategies adopted to reduce outpatient and inpatient volume. we provide a detailed breakdown of the type of vascular surgical cases that were performed during the covid- pandemic and compared it to preceding months. we discuss our operating room and personal protective equipment protocols when managing a covid- patient and share how we continue surgical training amidst the pandemic. we also discuss the challenges we might face in the future as covid- regresses. the statistics speak for themselves. as of april , an astounding . million people around the world have been diagnosed with coronavirus disease , resulting in nearly , deaths . singapore was one of the first countries to have been affected by covid- , having diagnosed the first case on january . the index patient was a chinese national from wuhan, china, who arrived in singapore with his family on january . since then, as of april , a total of cases of covid- have been diagnosed. of these cases, ( . %) of patients remain hospitalized, with ( . %) patients requiring intensive care. nine patients ( . %) have, unfortunately died from complications arising from covid- . the sustained rise of covid- cases in singapore can be described by three distinct waves of disease influx and propagation . the initial surge in covid- cases in late january and february can be attributed to travellers from china visiting singapore and causing limited local transmission. this resulted in singapore having the highest number of covid- cases outside mainland china for approximately two weeks in mid-february . from march onwards, the number of covid- cases rose steeply again as singapore citizens based abroad returned home. currently, in april, covid- case numbers are surging again due to widespread local transmission . preparation for covid- in our unit begun in late january after singapore announced its index case of covid- infection. in this narrative, we aim to describe the various governmental and hospital policies that were implemented as a response to covid- . we also aim to describe and discuss the aftereffect these policies had on vascular surgery services in our unit. national policies equipped with lessons learnt from the severe acute respiratory syndrome (sars) outbreak in , the government was quick to respond to the evolving covid- situation weeks before covid- reached our shores , . in january , the government expeditiously instituted measures such as mandatory temperature screening for all travellers, advising citizens to defer all non-essential travel to china, and implemented compulsory quarantine measures for all returning residents with recent travel history to china. new visitors with recent travel history to china were also barred from entry or transit into singapore . on february , as cases of covid- continued to rise, and cases of with no prior travel history or traceable link to prior cases were discovered, the "disease outbreak response system condition" (dorscon) alert level was raised from yellow to orange, signifying more severe disease and easier community transmission . the dorscon alert level system is a systematic outbreak response system with a colour-coded framework (green, yellow, orange and red) that reflects the severity of the outbreak (figure ) . on march , the world health organization declared covid- as a pandemic . the travel entry ban into singapore was extended to include new visitors from italy, france, spain and germany on march . by march , singapore citizens or residents that returned home had to serve a -day stay-at-home requirement with the surge of covid- cases in early april , more stringent measures such as the closure of all non-essential businesses and schools were enforced by the government in an attempt to curb local transmission. public gatherings were prohibited by law. all singapore residents were strongly advised to stay and work from home whenever possible, unless for specific reasons such as seeking medical attention or buying groceries . the national university hospital is an academic tertiary hospital located in the southwest of singapore with a total of beds. before covid- , bed occupancy rates were commonly in excess of %. crucial institutional policies had to be implemented to increase resources for the potential influx of covid- patients. from late january onwards, the listing of non-urgent elective surgeries was prohibited, except for "time-sensitive cases" such as oncological cases or limb salvage procedures. departments were also urged to plan for a segregated team model for both clinical and non- the clear and concise flow of information to ground staff was paramount to ensure compliance with implemented policies. this was achieved by daily emails and text messages from the hospital's leadership. these messages also served to boost the morale of healthcare workers and augment organizational loyalty. as the number of covid- cases continued to rise, arrangements were made for administrative staff to work from home from april onwards. segregated team model after the dorscon alert level system was raised to orange on february , our vascular surgery unit immediately adopted a segregated team model as part of its business continuity plan. our unit comprised primarily of four attending surgeons and four senior residents or fellows. each attending surgeon was paired to a senior resident or fellow to form a pair. the roster was planned in a cyclical fashion such that each pair would move through four sequential -day phases (inpatient, outpatient, back-up and rest). the inpatient team covered ward patients and performed surgery, while the outpatient team ran the outpatient clinics. if additional manpower was required, the team in the back-up phase could be mobilized to help. the segregated team model would prevent cross-contamination and ensure that the entire vascular surgery unit would not be infected or quarantined in the event of covid- exposure. it also allowed each team to have a to day wash-out period from their last patient contact before embarking on patient contact again. the wash-out period allowed sufficient time for symptom manifestation if a team member had contracted covid- before returning to patient care. a to day wash-out period was more than adequate after taking into consideration the mean incubation time of covid- . besides segregating within the unit, inter-departmental segregation was practised. all face-to-face multidisciplinary team meetings were suspended and replaced by virtual meetings. as our unit provided consultative services to a rehabilitation-focused subsidiary hospital, these consultations were also conducted in a virtual fashion. outpatient clinics vascular surgery outpatient clinics were immediately scaled down when the dorscon alert level was escalated to orange on february ( figure ) . we reduced the number of scheduled outpatient clinic sessions from half-day to half-day sessions per week. although we kept our outpatient clinic open from a.m. to p.m. to accommodate any possible patient that might require an urgent ad-hoc review, scheduled patients were only reviewed in the morning session from a.m. to noon. we aggressively reduced the number of patients that required scheduled on-site visits by conducting teleconsultations and reviewing electronic medical records. as per the segregated team model, an attending surgeon paired to a senior resident or fellow would run the outpatient services for -days before another pair takes over. the other segregated pairs that were on non-clinical duties would remotely review new clinic referrals and conduct telephone interviews with patients that were scheduled for upcoming clinic visits. non-urgent new clinic referrals such as varicose veins without ulceration, asymptomatic peripheral arterial disease or pre-emptive dialysis access creation were postponed. patients that were on active follow-up were screened carefully via a combination of several measures have also been instituted to facilitate the discharge of patients that are currently admitted. expedited pathways were set up to accelerate the administrative processes required to discharge stable patients to subacute facilities for continued wound care and rehabilitation. virtual meetings were held regularly between medical social workers, therapists and the medical team to discuss and formulate discharge plans for patients with complex social issues. the reduction in our bed occupancy rate meant that more bed space could be used to treat incoming covid- patients. as part of our inpatient services, we provide an emergency vascular surgical consult service to medical teams that are managing covid- patients. thus far, we have not however, due to the various institutional policies implemented for covid- , the amount of elective vascular surgery cases such as pre-emptive dialysis access creation, and venous surgery have fallen. the amount of aortic-related cases have also decreased as we now tend to postpone patients with abdominal aortic aneurysms who are asymptomatic. interestingly, the number of major amputations have risen considerably compared to . this is primarily due to a lower threshold in offering either primary major amputation for patients with a low chance of successful limb salvage, such as those who present with severe infection or extensive tissue loss, or early major amputation for patients who have not improved despite maximal revascularization. as such, these patients can be discharged earlier to a subacute facility or directly home to free vital bed space in the hospital. we have also created and implemented an in-house scoring system to triage patients who require arteriovenous dialysis access creation. this scoring system consists of variables such as prior catheter-related blood stream infection, extended tunnelled catheter time of months or more, access concerns such as limited catheter options, or history of catheter malfunction. currently, we still selectively perform arteriovenous dialysis access creation only for patients who have two or more of the abovementioned variables. when covid- subsides, this scoring system can also be used as a tool to prioritize patients who require dialysis access creation earlier. in response to this inevitable paradigm shift in surgical training, we implemented several measures to ensure continued training for our trainees. we curated surgical or procedural videos from the various online sources for our trainees to view. for example, we found that the "houston methodist debakey cv education" channel on youtube contained multiple highly educational surgical videos and didactic lectures that were immensely useful to our trainees. we also encouraged our trainees to listen to the "audible bleeding" podcast and participate in the interactive online symposiums organized by vascupedia. we found that a large myriad of tools for vascular surgery education had already existed prior to covid- and we aim to continue using these tools to facilitate and augment surgical training in the foreseeable future. educational activities that were previously conducted in a face-to-face manner such as journal clubs or case discussions have now been transitioned to a virtual platform. virtual preparing for the future we need to start preparing for the future. technologies that have flourished during covid- such as telemedicine or remote monitoring technologies should be harnessed for our future practice , . we will face a large backlog of cases once covid- dwindles. sensible triaging still applies, such that more essential cases are operated on first. as we gradually increase our outpatient and inpatient services to pre-covid- levels, we must continue to screen for patients with potential covid- and be vigilant in maintaining a high level of hygiene. once covid- subsides, we plan to transition from the current four-phase segregated model back to the pre-covid- state by reducing the number of phases and simultaneously increasing the number of medical staff in each phase gradually. this cautious approach is adopted in anticipation of a second covid- wave. conclusion covid- has affected our vascular surgery unit in multiple ways. most of these changes are invariably due to national and institutional policies made to preserve hospital resources. these policies are essential and crucial, especially in a resource-constrained country like singapore. however, we are not alone as multiple vascular surgery units around the world are experiencing the same changes . as the number of covid- cases in singapore continues to rise due to local transmission within several foreign labour communities, we must continue to prepare for a sudden influx of patients. as vascular surgeons, we will have to remain dynamic and tailor our vascular surgery services accordingly based on available resources. in the extreme situation, challenging decisions like declining surgery for an elderly patient with a ruptured abdominal aortic aneurysm to preserve intensive care unit capacity might have to be made. covid- ) situation report - organisation (who) web site confirmed imported case of novel coronavirus infection in singapore ministry of health singapore's strategy in fighting covid- . the straits times, singapore. . coronavirus disease (covid- ) situation report - organisation (who) web site commentary: why singapore is better prepared to handle covid- than sars channel news asia, singapore. . extension of precautionary measures to minimize risk of community spread in singapore. [ministry of health risk assessment raised to dorscon orange what do the different dorscon levels mean additional border control measures to reduce further importation of covid- cases. [ministry of health covid- : mccy advisory on religious activities circuit breaker to minimise further spread of covid- early transmission dynamics in wuhan, china characteristics of and important lessons from the coronavirus disease (covid- ) outbreak in china: summary of a report of cases from the chinese center for disease control and prevention clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study lower risk of venous thromboembolism in multiple asian ethnic groups covid- guidelines for triage of vascular surgery patients what we do when a covid- patient needs an operation: operating room preparation and guidance robots may become heroes in war against covid- the global impact of covid- on vascular surgical key: cord- - r t yxv authors: tay, yi xiang; cai, sihui; chow, hwei chuin; lai, christopher title: the needs and concerns of clinical educators in radiography education in the face of covid- pandemic date: - - journal: j med imaging radiat sci doi: . /j.jmir. . . sha: doc_id: cord_uid: r t yxv nan it has been more than months since singapore reported its first covid- case on january rd , . since then, there have been more than , cases and have resulted in deaths in singapore from the severe acute respiratory syndrome coronavirus (sars-cov- ), which was first detected in wuhan, china . having experienced sars outbreak in which resulted in deaths including healthcare worker, the feeling of déjà vu was vivid . risk measures were implemented and strengthened progressively as the situation escalated, both globally and in singapore. initially, public health interventions were raised to contain the first covid- wave, allowing schools and most businesses in singapore to remain open . however, despite the measures to contain the outbreak, community cases increased, and infections began to surface in the population of foreign workers housed in dormitories across the island . in response, nationwide strict restrictions in the form of a "circuit breaker" was instituted by the singapore government -resulting in closure of schools and all non-essential businesses, forcing majority of the population to be confined to their homes . in tandem, education of healthcare professionals was also affected, including the clinical training of radiographers . like nursing, midwifery and many allied health education programmes, clinical training is an important cornerstone of radiographer education -equipping students to safely and competently transit into complex healthcare environments , . during clinical training, students are supported by clinical educators who are usually registered professionals who facilitate clinical education alongside clinical and j o u r n a l p r e -p r o o f academic colleagues . collectively in singapore, a clinical educator may be a radiographer formally appointed by an academic institution or have education and training role recognised within their job role. formal appointed clinical educators differ from the latter as they are primarily responsible for signing off competency and evaluation, based upon standards provided by academic institutions. nonetheless, all clinical educators are expected to support students in the workplace to gain appropriate experience and skills. similar to singapore, many countries have undertaken drastic measures to prevent further spread of the virus. this has substantially affected clinical training where clinical placement are suspended or clinical exposure has significantly reduced . thus, it is important to ensure that clinical educators are successful at responding to this challenge of maintaining high-quality clinical training amid the pandemic. this paper aims to provides insights on the needs and concerns of clinical educators in the face of the covid- pandemic. drawn from the first-hand experiences as clinical educators from one of the tertiary hospitals in singapore, this paper examined the ways in which clinical educators faced during the health crisis while facilitating the clinical radiography teaching. this will serve as a springboard for other educators who must overcome the massive and rapid change made during this period to continue to facilitate and improve clinical training. the sars epidemic posed many challenges in radiography service, but valuable lessons learnt enabled progression in many areas, including clinical education . lessons from sars could be translated to covid- -innovations and contingency j o u r n a l p r e -p r o o f plans that allowed clinical teaching to continue without actual patient contact . as majority of the young clinical educators did not experience the uncertainties and damaged caused by the sars outbreak, many could not relate to the painful chapter of the outbreak. inevitably, it was difficult for some to stay calm when this new and unknown bug emerged in wuhan and subsequently imported into singapore. the clinical educators' ability to deal with disruptions were first tested at our hospital when international students' clinical training was disrupted at the onset of the outbreak. such a decision not only cause the students to suffer financial losses, but also loss of opportunities of acquiring additional competencies gained in a foreign healthcare system . nevertheless, it was clear that such decisions were deliberated and never made lightly with priority and emphasis on the health and well-being of all students, staff and patients. however, as all the overseas students were selffinanced, the potential of additional emotional and psychological challenges had to be considered one of the ways of support for the clinical educators came in the form of encouragement from notes of appreciation and gifts from the public, and the hospital senior managements to all frontline heroes -showing how much their efforts were valued through these gestures of care and appreciation. moreover, as highlighted in the editorial by gibbs , the pandemic has driven teamworking of radiographers, supports motivation and improves psychological well-being. coupled with encouragement among colleagues, there was a sense of safety and togetherness . this provided much-needed encouragement for the clinical educators to work even harder, to remain unfazed and to press on for the education of the future radiography profession. as the clinical educators prepared to welcome the return of radiography students in their penultimate year, it was essential to understand the perspectives from these students who had to recover lost ground after missing months of clinical experience while dealing with the threat of delayed graduation in fact, many covid- era publications surfaced, advocating the importance on reporting students' perspectives , [ ] [ ] [ ] . these publications were also timely as many of our current students were generation z (born in or later), and educators (baby boomer/generation x and millennial); preventing a "culture clash" as a result of generational difference in medical education . generation z consists of active problem solvers, independent learners and learners who are better technological integrated, but with increased risk of suffering from psychological distress . indeed, these characteristics of generation z students will certainly affect how clinical educators provide education in the covid- pandemic. in the radiography profession, clinical placement is crucial to develop knowledge and skills acquired theoretically -allowing students to consolidate knowledge, socialising into the radiographer role and acquiring values . in a commentary on the perspectives of student radiographers in singapore, the students highlighted their need to put theories into practice to bridge the gap between the two . this phenomenon of theory-practice gap had been identified across multiple healthcare disciplines and might have implications on professional competence and future progression from student to novice professional while clinical placements had resumed, the duration, movement and rotation were reduced. the return of students for clinical placement was also staggered and numbers of students kept to minimal. this was in line with the practices in the united kingdom (uk), australia, and north america where students were to learn in much smaller and stable social bubbles . modification was also made to the clinical assessment -previous summative clinical examination conducted by academic institution appointed examiner had been replaced with multiple formative assessments throughout the duration of the clinical placement. like the medical students, radiography students must comply with strict personal hygiene, physical distancing and were not allowed to enter high-risk areas nor participate in risky, aerosol-generating procedures . clinical educators were instituted to ensure that students comply with the risk control measures, while focusing on the students' core clinical learning outcomes and competencies . these made teaching and supervising students in clinical settings more challenging than pre-covid. in similar vein, midwifery educators who shared comparable workplace characteristics with the radiographers -mainly not possible to maintain physical distancing in the line of work but had to deliver effective education safely, echoed similar concern . it was undeniable that academic institution had tried to reduce demands on the learning can take place everywhere and covid- has forced us to rethink the educational strategies for the generation z students. as the covid- situation evolved, all non-essential appointments and elective procedures had to be deferred as part of enhanced safe-distancing measures. radiographic examinations were reduced and impacted on the students' hands-on opportunity. their movement were restricted, and they could only have placement in low risk areas. these posed a potential challenge to the generation z students who preferred hands-on experience and on-the-job-learning . as clinical educators, they had to mitigate the loss in learning opportunity based on the profile of the students. the student to educator ratio of : was reduced to : , and it allowed an increased direct observation of the assigned student and other teaching opportunities such as self-reflection and roleplaying . with the new ratio, clinical educators were able to provide the students with more guidance, frequent immediate feedback and encouragement to learn from their mistakes -meeting the generation z students' learner perspectives [ ] [ ] . since it was emphasis to all clinical educators at the onset that they had to jointly teach and meet service requirements, clinical educators were more prepared. with the youngest generation now entering clinical placement, clinical educators had to modify their teaching strategies to account for the learner perspectives. transformation includes strong mentoring relationships, collaborative work with ground radiographers, reflective activities, real-time feedback, frequent interactions, case-based learning and more importantly technology in education [ ] [ ] [ ] . the pandemic had caught the clinical educators unprepared in the incorporation of technology into teaching, and presented a diversion from the traditional methods of teaching. perhaps, it would be timely for clinical educators to consider creative ways such as interactive tutorials and the use of social media sites , , . in times of uncertainty, it was crucial for clinical educators to actively manage the well-being of students. the covid pandemic would likely lead to increased distress and burnout of the students given the dramatic changes to their learning environment and plans , . the negative well-being could lead to depression, burnout and anxiety . this was of great concern as generation z was shown to be more prone to psychological distress than earlier generations . when a radiographer working at the community care facility was reported to have tested positive for covid- , there was fear that the student's psychological well-being would be affected . in concordance with the approaches adopted by the medical educators, j o u r n a l p r e -p r o o f clinical educators checked-in with the students through electronic communication and provided reassurance on the risk measures in the clinical environment , . it was crucial for the clinical educators to be available on demand while providing support to normalise stress. in addition, clinical educators worked to develop a sense of belonging and safety for the students . routine instructions from the hospital disease outbreak taskforce were disseminated regularly to the students. students were also invited to attend radiographers' continuing professional development sessions and radiographers' led tutorials -creating a community for the students in the face of physical distancing . in addition, like the radiographers, students were also issued tokens of appreciation -recognising them for their dedication and hard work, supporting their esteem and well-being needs . with no silver bullet in sight to the end of covid- , clinical education would be subjected to further circumstances beyond our control. however, regardless of the circumstances, it is still fundamental that students need the opportunity, under supervision, to experience and learn to practice safely in a pandemic work environment. moreover, clinical educators must now consider the new generation learners' perspective and help support their learning. the battle may be long but with creativity, resiliency and perseverance, clinical educators can adopt clinical teaching practices to meet dynamic and complex student demands complicated by the evolving pandemic. this will future proof the radiography workforce in preparation for the next global challenge, lest not having radiographers ready to meet singapore's evolving healthcare demands. j o u r n a l p r e -p r o o f 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doi: . /fpsyt. . sha: doc_id: cord_uid: ke iktly nan the coronavirus disease (covid- ) pandemic has had an immense impact infecting million individuals and claiming , lives globally as of july ( ) . the rapid spread was largely enabled by the onset of the outbreak in wuhan city just prior to the lunar new year season, a peak period in travel to and from china ( ) . fortunately, many regions have controlled initial outbreaks and shared their experiences. these have been recently summarized by the world health organization (who), highlighting the importance of developing targeted responses and enhancing communication to address the pandemic's impact ( , ) . notably, emotionally driven sharing of misinformation has featured prominently in this crisis, fueling both confusion and irrational anxiety among the public ( , ) . termed an "infodemic", this has far-reaching consequences on population health with a direct impact on overloaded health systems and an indirect impact on mental health, resulting in paranoia and behavioral responses like stock-piling due to disproportionate fear ( ) . the impact of misinformation in the media on public emotion and fear has been illustrated with the middle-east respiratory syndrome (mers), whereby it led to a surge in fear and sustained economic consequences ( ) . the psychosocial impact of large-scale disasters and previous outbreaks have been described, including increased incidence of mental health disorders ( ) . similarly, covid- has had a twofold detrimental impact on the mental health of populations subject to the psychosocial consequences of the pandemic, including the incidence of new onset mental health disorders as well as deterioration in the condition of patients with existing mental health disorders ( , ) . this impact is on the rise given the protracted lock downs, social isolation, and concomitant occupational stressors in the context of the weakened global economy ( ) ( ) ( ) . these factors highlight the urgent need to scale-up and decentralize mental health services to attain a multiplier effect in the provision and accessibility of these services to combat the pandemic-driven surge in mental health disorders ( , ) . fortunately, several reports have demonstrated the effectiveness of digital health solutions for various applications, including addressing gaps in mental health services ( ) . these solutions include cloud-based big data systems, artificial intelligence (ai)based chatbots, online health communities (ohcs), and telehealth platforms. several have already been extensively applied for the pandemic's direct impact on health, such as big data systems and telehealth for remote consultations ( , ) . this review summarizes relevant applications of digital health that can help address the indirect impact of the pandemic on population mental health. cloud-based big data systems have been successfully applied in previous infectious disease outbreaks by aggregating data from numerous possible sources including weather surveillance systems ( ) , queries in online search engines ( ) , and even connected devices among the internet of things (iot) such as mobile phones and drones ( , ) . applications of these systems range from early detection of outbreaks to facilitating global digital epidemiology collaborations that address unresolved clinical uncertainties, such as ocular findings for early detection of latent tuberculosis ( , ) . successful applications include monitoring dengue outbreaks using data on mobility from mobile phones ( ) or queries in search engines such as baidu in china ( ) . evidence is emerging for the value of these platforms beyond retrospective or real-time surveillance applications, to prospective projections of disease trends and clinical need. in the context of the ongoing pandemic, several potential applications of these tools have emerged, such as predicting outbreaks of covid- based on historic travel data and public health capacity ( ) . also, cornelia betsch and the covid- snapshot monitoring (cosmo) group evaluated methods for surveillance of behavioral responses to the pandemic ( ). these applications enable evidence-based approaches to localize public health responses and monitor their effectiveness, in accordance with who recommendations ( ) . related applications for mental health include the prediction of disorders such as depression, stress and anxiety, using publicly available data from websites like twitter ( ) . these applications are gaining traction in academic consciousness as digital data becomes more ubiquitous, as exemplified by the development of recommendations for evidence-based research using tools like google search to predict mental disorders ( , ) . there are also validated individual-level applications of big data, such as the use of ecological momentary assessment (ema) from passive behavioral monitoring of mobile data, that have been used to detect and monitor severity for a spectrum of mood and behavioral disorders ( ) . this ushers in the possibility of precision digital mental health with tailored recommendations to the individual, as recently described for panic disorder ( ) . these methods can be leveraged for useful applications during lockdowns, such as early detection of mental health disease onset or progression. however, unresolved barriers to implementation include ethical and privacy issues of populationlevel monitoring such as with big data systems for contact tracing, that would similarly apply to systems for mental health surveillance ( ) . measures to facilitate implementation include the use of high quality input data and clinical validation using formal diagnostic criteria, robust methodology, and actionable outcomes ( ) . nonetheless, these systems can contribute to responses to the pandemic and address the needs of the vulnerable groups during the recurrent lockdowns in response to local outbreaks, such as potential victims of domestic violence ( ) . ai chatbots utilize pre-programmed content and decision-trees for automated conversations using techniques such as natural language processing (nlp). these are more interactive than static digital repositories leading to higher engagement for patients ( ) . preliminary reports of ai chatbots that have been developed for mental health include solutions providing counseling for well individuals to improve psychological wellbeing ( ) . others include ai chatbots such as wysa for digital mental well-being with demonstrated effectiveness in patients with depression ( ), and woebot for cognitive behavioral therapy (cbt) in young adults with depression/anxiety symptoms ( ) . these tools have potential applications in the current pandemic and beyond for preventive care and mental health promotion. they also function as contingency solutions to expand surge capacity in the event of overwhelming clinical need ( ) . however, their applications needs to be supervised given limited clinical validation with robust experimental design ( ) . other challenges clinical ai have also been described in various specialities, including practical, technical, and sociocultural barriers to implementation ( , ) . particularly given the conversational nature of chatbots and linguistic variations in different populations, acculturation is needed to facilitate the implementation of chatbots in new populations, as demonstrated with ai chatbots for health professional training to address colloquialisms such as "singlish" in singapore ( ) . this is crucial to ensure emotional support or triage advice are perceived accurately by patients, and piloting messages will help ascertain effectiveness ( ) . validated community mental health assessment tools could be incorporated in future conversational ai chatbots to prompt regular self-reporting by patients of wellness and social inclusion for active population monitoring. these include the various iterations of the social and communities opportunities profile (scope) scale validated in the united kingdom and hong kong, as well as the mini-scope in singapore ( ) . applying ai chatbots in this manner using a "sorting conveyor" operational model could be transformative, whereby the ai solutions built with predefined criteria can re-direct individuals requiring more comprehensive psychological support to appropriate services within a stepped-care mental health service ( ) . open digital patient engagement platforms that allow any visitor to a website or application to view interactions between patients and/or healthcare providers are called online health communities (ohcs). ohcs could be the silver bullet to the "infodemic", which is largely attributed to the unfettered spread of viral misinformation in unverified sources or platforms like social media, crowding out official communication ( , ) . in the earlier example of the impact of misinformation on fear during mers, choi et al. found that it created a positive feedback loop leading to a spiral of growing misinformation and paranoia, with the publication of more inaccurate information by the media in a bid to capitalize on public interest ( ) . big data systems such as the aforementioned cosmo for behavioral surveillance provide measures of these phenomena to develop targeted public health communication messages-an essential first step to combat this problem ( ) . however, due to the speed of misinformation propagated online, there is increasingly a need to implement a digital effector arm for our monitoring systems ( ), one that amplifies reputable sources to directly combat misinformation in a transparent, scalable manner by addressing myths and promoting reputable sources of information ( ) . in singapore, such a solution was developed by askdr through needs-finding surveys and ideation with frontline providers (figure ). it combines network effects of social media with behavioral gamification to give registered medical professionals digital tools to crowd-source a coherent counter-narrative to misinformation ( ) . public health agencies should similarly develop or adopt such tools for the "last mile" of public health communication. in the context of the ongoing pandemic, key applications include promoting reliable information and directly breaking the "spiral of misinformation". direct potential applications of ohcs for patients at-risk of mental health disorders include lowering the barrier to access care and support for stigmatized illnesses such as anxiety and depression, by allowing patients to seek initial medical advice anonymously ( ) . apart from the provision of basic demographic information such as gender and age that are required to contextualize medical advice; otherwise, anonymous engagement also helps to address limitations such as privacy issues similar to those with big data systems ( ) . other applications of ohcs that can enhance public health responses to the pandemic include provision of triage advice to optimize right-siting of patients and reduce unnecessary healthcare presentations where appropriate. this "tele-support" can be used long-term for fundamental illness-related concerns that may not require formal consultation, such as questions about potential interactions of chronic medications with overthe-counter (otc) medications or other health products ( ) . finally, they provide an avenue for asynchronous patient engagement between outpatient appointments while protecting the privacy of healthcare providers, creating opportunities for patient support and early identification of at-risk individuals needing to be re-directed to formal mental health services online or in-person ( ). digital telehealth services have numerous embodiments including video-conferencing, store-and-forward technology, remote tele-monitoring with connected devices, and mobile health applications, all of which are increasingly applied in large-scale disasters ( ) . these can be used for either asynchronous or synchronous consultations with private discussions between patients and healthcare providers ( ) . existing descriptions of tele-mental health services indicate the importance of human support and interaction regardless of the embodiment of telehealth used ( , ) . although its application in covid- for mental health services has been greatly enabled by legislative changes ( ), the barriers to telehealth adoption that have kept it from becoming mainstream to date still remain ( ) . ensuring successful, sustained adoption requires active alignment with clinical needs when deploying services ( ) . nonetheless, tele-mental health services are critical to maintain the continuity of care for patients with mental health disorders by providing avenues for remote review and prescription re-fills ( ) . other avenues with long-term value to health systems include co-ordinated avenues for health professionals to engage patients with mental health disorders more frequently, facilitate early detection of those at-risk of selfharm, and enable preventive interventions such as motivational interviewing that reduce hospitalizations ( , , ) . apart from the traditional two-way teleconsultation between doctor and patient, multi-way conferencing or tele-collaboration by allied professionals remotely supported by clinicians has been described ( ) and is mainstreamed in countries like singapore to project tertiary care to nursing homes and intermediate and long-term care (iltc) facilities. covid- is the first "viral" pandemic that threatens to overwhelm mental health services in coming months as a result of fear perpetuated by misinformation alongside social isolation during lockdowns ( , ) these unprecedented challenges highlight the need to develop creative solutions to address the impending surge in mental health disorders ( , ) . the four technologies discussed in this review are potential avenues to expand the capacity and penetration of existing mental health services to address this indirect health impact of the pandemic. hybrid strategies combing various solutions in an overarching "pyramid" operational model may be required to rapidly scale-up stepped mental health services. this was illustrated in the saved study operationalizing telehealth for complexed emergency services ( ) . digital operationalization of mental health services can be similarly achieved using combinations of digital tools in comprehensive services such as illness management and recovery (imr) programs ( ) . imrs are structured mental health services incorporating multi-modal mental health interventions to promote self-management and optimize treatment. pioneered in america, they were externally validated and demonstrated to reduce readmissions and the post-illness recovery period of asian patients after discharge from in-patient psychiatric services ( ) . the pyramid base catering to the needs of the general population could include screening tools such as big data systems and/or ohcs to actively identify and/or engage at-risk individuals without pre-existing mental health disorders, as well as provide tele-support services to reduce risk of progression in patients with mental health disorders ( ) . as countries re-open, at-risk individuals can be directed to ai-based chatbots providing automated support as well as triage in a "sorting conveyor" operational model to further escalate care as appropriate to inperson or telehealth mental health services based on patient risk profile ( , ) . these requires modifications to traditional practice as described for telehealth cognitive processing therapy (cpt) services to treat post-traumatic stress disorder (ptsd), a condition likely to increase in coming months even among healthcare professionals due to the prolonged stress of frontline services or rationalizing care in some regions ( , ) . ultimately, the effective deployment of digital mental health services is greatly dependant on successful assimilation within existing health systems. patient willingness to use, provider acceptance, and even the quality of digital and hardware infrastructure are fundamental considerations that need to be addressed. this has been recently illustrated based on the challenges of implementing ai solutions for ophthalmology despite maturity of the technology ( , ) . deployment of digital health thereby needs to be driven by the needs of the target patient population, clinical acceptance, and validated effective applications ( ) . these considerations dictate the likely effective form of deployment for these digital tools. designing effective digital mental health care requires taking into account the wide range of patient needs determined by the severity of mental health disorder(s), social determinants of health (sdh), access to technology, and cultural acceptance, among others ( , ) . there is no "one size fits all" solution, and research in telehealth has demonstrated that individualized design considerations are critical to maximize acceptance, ensure effectiveness, and sustain adoption with recurrent use ( ) . meeting the needs of patients in a timely and cost-effective manner ensures sustained adoption beyond the covid- crisis. for provider adoption, stakeholder engagement methods have been advocated to map out clinical processes, participants, and individual responsibilities to actively plan deployment for telehealth ( ) and are just as important for other forms of digital health ( ) . firstly, this requires detailed mapping of the needs, roles, and incentives of stakeholders such as healthcare workers, logistic procurement teams, and chief medical informatics officers. they are prioritized into primary and secondary stakeholders based on their capacity to make or influence decisions about adoption of digital tools. subsequently, a deployment strategy is developed to maximize stakeholder alignment while minimizing disruption to existing processes or new responsibilities that may overburden stakeholders. this also yields crucial insights for communication strategies to engage individual stakeholder groups effectively. participatory approaches like these with design-thinking have been used to operationalize tele-health in complexed emergency services ( ), as well as develop solutions with targeted applications such as ai chatbots for automated adolescent mental health coaching ( ) . in tandem, it is important to address the needs of vulnerable populations that may fail to seek care, such as potential domestic violence or child abuse victims ( ) . they may require tailored solutions such as targeted deployment of mobile mental health services provided by allied mental health professionals that could be remotely advised by psychiatrists using "hub-and-spoke" telehealth to project services into these pockets of society. in conclusion, the massive health impact of the first "viral" pandemic has been fueled by global travel, social isolation, rampant misinformation in social media, and other intricacies of modern life. however, digital mental health tools are the silver lining we are fortunate to have, as they can empower responses to the covid- outbreak at a scale that was never before possible in human history. responding effectively to the mounting impact of this pandemic on population mental health may ultimately require us to leverage these digital health solutions to expand the capacity of mental health services and supplement face-to-face care with an intentional approach for successful deployment ( , ) . authors ac and ro are medical students on clinical research attachment with author dg. author h-hl is an adjunct associate professor at the saw swee hock school of public health (sshsph), nus, and concurrently chief executive officer, the american chamber of commerce in singapore. author rm is a tutor in academic english at the center for english language communication (celc), nus. author gk is a senior operational manager at the institute of mental health (imh), singapore. authors sv, df, and jj-yl are senior consultant psychiatrists at imh, singapore. author sv is also a professor at duke-nus, singapore. the author df is also the chairman medical board at imh, singapore, as well as president of the international association of child and adolescent psychiatry. df is concurrently adjunct associate professor at all three medical schools in singapore, nus, duke-nus, and lkc. dg is a senior lecturer and faculty advisor (medical innovation) at the national university of singapore (nus), and physician leader (telemedicine) at raffles medical group. authors ac, ro, and dg conceptualized the manuscript, researched its contents, wrote the manuscript, and edited all revisions. authors h-hl, rm, gk, sv, df, and jj-yl intellectually contributed to the development and writing of the manuscript, added text, and edited all revisions. coronavirus disease (covid- ) situation reports the sars, mers and novel coronavirus 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date: - - journal: eur j clin microbiol infect dis doi: . /s - - - sha: doc_id: cord_uid: wu ygt w the severe acute respiratory syndrome (sars) is an emerging infection caused by a novel coronavirus which first appeared in southern china at the end of . in early , through a single incident, it spread to hong kong, singapore, canada and vietnam. for busy clinicians in large public hospitals, the response to the virus was initially based on ensuring a high level of protection for staff. however, as the epidemic progressed and more information became available about the virus, procedures were rationalized and the virus is currently under control worldwide. there are, however, numerous unanswered questions concerning super-spreading events, the modes of transmission of the virus and, perhaps most importantly, the rapid detection of the virus early in the course of disease. these issues need to be addressed in case the virus becomes more widespread in the near future. the severe acute respiratory syndrome (sars) is a newly recognized coronavirus infection that emerged in southern china [ ] with subsequent global spread to countries [ ] [ ] [ ] [ ] . in countries where local transmission has occurred, hospitals have been the major foci of infection especially in singapore [ ] and canada [ ] . in february , reports began emerging on promed mail of an outbreak of atypical pneumonia in the guangdong province in southern china [ ] . it is now believed that the first cases of sars occurred in the city of foshan in the guangdong province [ ] . however, throughout november until the late part of february, sars was largely confined to the province of guangdong. the global dissemination of sars is believed to have begun on the ninth floor of hotel m in hong kong, where a physician from guangdong stayed for one night on february [ ] . at least individuals who were staying on the ninth floor of the hotel were subsequently infected with sars, although none of them reportedly had direct contact with the ill physician. the newly infected individuals traveled onward to their homes or next destinations in the usa, canada, singapore, hong kong and ireland sparking off epidemics of varying degrees of severity in each of those countries, mainly in hospitals but also in their respective communities. it is striking to realize that the entire global dissemination of this epidemic can probably be traced to this single event of one overnight hotel stay. it has almost become a cliché to report that the sars epidemic, the first emerging infectious disease of the st century, heralded an unprecedented collaboration between researchers across the globe. within weeks of the first cases, electronic publications reviewed the clinical syndromes [ , ] as well as the characteristics of the virus and methods for its detection by the polymerase chain reaction [ , ] . the genome of various strains of the virus were sequenced, which contributed tremendously to knowledge of its molecular epidemiology [ ] . there was an explosion of reports about the sars coronavirus, with more than a thousand publications available on pubmed by the beginning of march , the first anniversary of the global emergence of the virus. it is beyond the scope of this review to cover all of the virological and clinical information contained in these articles and i would refer the reader to the excellent review by peiris et al. [ ] . the present review focuses on the response to this emerging disease and its evolution in light of increasing information. outstanding issues that remain to be resolved are also highlighted. one of the first unusual aspects of this emerging infection was the recognition that healthcare workers (hcw) were uniquely susceptible to the then unknown etiologic agent. in hong kong, the first clue that a new infection had emerged was a cluster of ill hcws. the same was noted in vietnam and led to the world health organization (who) sending a team to vietnam under the leadership of dr carlo urbani, who later died from the virus he helped to define [ ] . as soon as sars was recognized as a nosocomial infection, guidelines were issued by various authorities including the who it is important to recognize that in the beginning of the sars outbreak there was no information about the agent responsible for the infection or its mode of transmission; hence, there was a tendency to "over-protect." as the epidemic evolved, so did the guidelines, which are constantly being updated and might indeed be out of date by the time this report is read. all guidelines are published on the internet [ - ], and the reader is encouraged to review the websites for the latest information. the physician from guangdong who became the source of the global epidemic through his stay at hotel m was admitted to a hospital in hong kong the day after his arrival in the city. he became progressively more ill and died days later. it is striking that although he was critically ill and intubated on a ventilator in the intensive care unit, only one hcw who attended to him in the emergency department became ill [ ] . the reason for this is likely that hong kong hospitals had been on the alert for highly pathogenic avian influenza. in february, there had been a small cluster of cases of avian influenza in a hong kong family that had traveled to mainland china [ ] . a directive had gone out from the hong kong department of health on february to maintain strict infection control with droplet precautions for all cases of "atypical" community-acquired pneumonia because of concerns that highly pathogenic avian influenza might be easily transmissible from person to person. one of the singaporean women who returned from hotel m was indeed isolated as a possible case of avian influenza in one of singapore's large general hospitals, and no secondary cases resulted from her. because of the concerns for possible avian influenza, or some unknown pathogen with an uncertain mode of transmission, most of the initial strategies devised for the prevention and control of sars were directed against a highly contagious airborne pathogen. in [ ] , previously healthy young people were infected and six died from highly pathogenic avian influenza in hong kong. this mortality rate ( %) is much higher than the normal mortality rate for influenza especially among young healthy individuals [ ] . in response to the outbreak, more than one million chickens were slaughtered and the disease was rapidly brought under control. seroepidemiologic studies of hcws done at the time [ ] demonstrated the efficacy of personal protective equipment (ppe) in preventing transmission and identified the risk associated with close personal contact in addition to the virus's lack of efficient humanto-human transmission capability [ ] . fears of a recurrence of a more virulent or easily transmissible form of avian influenza directed the initial efforts against sars. however, sars possessed an unusual quality in that it seemed to be transmitted in the healthcare setting far more efficiently than in households, where measles, varicella and other airborne viruses usually take rapid hold [ ] . this has yet to be explained completely, but it supports the argument that close contact is the major mode of transmission of the sars virus. fomites have been a cause for concern with the sars coronavirus since the initial global dissemination stemming from individuals in hotel m who had no direct contact with the index case but had stayed in the same corridor and probably had occasion to touch elevator buttons or railings that might have been contaminated with the sars virus. in the outbreak of sars in the amoy gardens apartments in hong kong [ ] , more than individuals who had no known direct contact were infected possibly through the aerosolisation of contaminated sewage. the implications of fomite transmission of sars are considerable and would mandate a much greater degree of environmental cleaning than is currently practiced. however, there are many unanswered questions in this arena. for example, why did the individuals staying on the same hotel floor as the index case in hotel m get infected but none of the staff? [ ] . sars has been convincingly demonstrated to be caused by a coronavirus [ ] . certain other characteristics have been ascertained from the previously known coronaviruses, e and oc , including their ability to survive after drying on inanimate surfaces in the hospital environment as well as differences in the viability of the virus at different conditions of temperature and humidity [ , ] . while the sars coronavirus has a certain amount of homology with the other pathogenic human coronaviruses [ ] , too little is known about its behavior under different environmental and atmospheric conditions to make a definitive statement about the role of the environment in nosocomial transmission. there have been reports of the sars coronavirus persisting for prolonged periods of up to days on environmental surfaces [ ] . survival in stool is reported to be even longer at up to days in alkaline diarrheal stools. this would certainly help explain such circumstances as the hotel m outbreak. the attack rates for sars have generally not been high. in singapore, for example, the index case for the national outbreak was nursed in a general ward by staff who were not wearing protective covering of any kind, and the attack rate was only / doctors, / nurses and / fellow patients in the same ward areas [ ] . again, the distribution of infections suggests that close contact is the most important factor leading to the transmission of this pathogen in hospitals. the widespread emphasis on ppe has been seen by some as placing an undue emphasis on hcw protection without adequately considering the protection of other at-risk individuals, such as other patients in the same area. the use of ppe is also not without its own adverse consequences [ ] as reactions to latex are common among hcws, some with serious consequences. it should also be noted that the use of respirators has been associated with fatal adverse events [ ] . costs are also an issue, and in resource-poor settings -ply cotton masks have been used, which have reportedly been effective in preventing the nosocomial transmission of the virus in at least one large public hospital [ ] . in a case-control study, seto et al. [ ] found that surgical masks were also effective in preventing transmission of sars to hcws, which is in line with our understanding of the epidemiology of the virus. in singapore, one of the successes of our approach to the control of sars was the widespread availability of full ppe for any staff member who requested it. this was even before the widespread dissemination of the virus led to the mandatory use of full ppe in all hospitals, and it provided staff the reassurance that their welfare was a high priority in the midst of an epidemic. there have been concerns that the use of n masks alone might not be adequate for preventing the nosocomial transmission of sars since cases have occurred among "fully protected" hcws [ , ] ; these cases possibly resulted from contact transmission. recognition of the role of contact transmission has led to the inclusion of recommendations for the use of gloves and gowns in all guidelines [ ] [ ] [ ] [ ] [ ] [ ] . while these garments have been shown to be effective in preventing the nosocomial transmission of other respiratory viruses [ ] , few data are available for their efficacy regarding sars. travel restrictions were among the more controversial aspects of the sars epidemic. the economies of most affected countries in east asia were devastated by these travel advisories. while other pathogens have been documented as being transmitted on airplanes, most notably influenza [ ] , the number of individuals infected with sars during air travel was remarkably low. according to the who [ ] , there have been flights carrying symptomatic probable sars patients and of those flights did not result in a single secondary infection. overall, cases of secondary infection resulted from symptomatic individuals. one flight alone, ca , which flew from hong kong to beijing on march, is now known to have accounted for of these cases. olson et al. [ ] reported that one flight with four symptomatic individuals with sars was associated with an attack rate (for confirmed sars) of zero while another flight with a single symptomatic individual was associated with an attack rate of %. the singapore experience [ ] was that three flights with symptomatic sars patients resulted in only one transmission. the overall attack rate for the flights into singapore was thus less than % despite one symptomatic individual being a so-called "superspreader" and another being critically ill at the time of the flight, requiring intubation soon after arrival. interestingly, olson et al. [ ] point out that fully % of the fellow passengers who became infected with sars had no direct contact, as defined by the who, with the index patient on their ill-fated flight. they do not offer any explanation for the differing attack rates, although a careful reader would realize that among the individuals allegedly infected on the flight, ten were traveling together as part of a tour group. also, the flight with the four symptomatic individuals was much shorter than the flight that was associated with widespread transmission. this is supported by icu data from canada [ ] that showed time of exposure to be a major risk factor. overall, however, what these reports demonstrate is that a much more detailed analysis is required in order to truly understand the epidemiology of this unusual virus. during the peak of the sars epidemic in china ( - april ), when the who had travel advisories and alerts in place, there were more than , visitors from china and hong kong [ ] who entered singapore and not a single case of transmission was recorded from any of these individuals. in taiwan, a strict -day quarantine [ ] was placed on all individuals returning from countries that were on the who list of sars-affected countries. a total of , individuals were quarantined, among whom had probable sars and only one of whom had laboratory-confirmed sars. thus, the detection rate was . % for probable sars and . % for laboratoryconfirmed sars. these figures have to be balanced against the costs and psychological impact of quarantine for more than , individuals who were perfectly well. thanks to excellent isolation and case finding with contact tracing, the number of people infected with sars with each successive generation of the outbreak was progressively reaching extinction levels [ ] in the sarsaffected countries. with the re-emergence of sars at the beginning of , drastic travel restrictions have fortunately not been instituted to date since there is no evidence yet of widespread dissemination of the virus across international air routes by travelers. it could also be argued that since we now have much better knowledge of the epidemiology of the virus, travel restrictions might not be necessary the next time around. all of the guidelines agree it would be ideal if patients with sars could be nursed in isolation rooms [ - ]. there are differences, however, in the recommendations for negative pressure with separate ventilation systems, and these perhaps reflect the differences in resources available for healthcare. one drawback of isolation rooms is that unless there are adequate nursing or medical resources, the degree of attention that the patient will receive in a single isolation room is obviously lower than in an open well-ventilated area. patients isolated for infection control purposes are known to be at risk for adverse events in hospital [ ] and this again has to be balanced against the benefits in terms of reduced nosocomial transmission. while all of the available evidence points to droplet and contact transmission, there is a possibility that the virus might be aerosolized during such procedures as high-flow oxygen therapy or possibly via the use of extractor fans, which were blamed for the aerosolisation of contaminated sewage during the amoy gardens outbreak [ ] . therefore, n respirators or higher should be used. this is a cause for concern as in many countries, including singapore, without adequate pre-prepared negative-pressure rooms, powerful extractor fans similar to the ones used in the bathrooms at the amoy gardens apartments are used to create a form of laminar uni-directional airflow. while these may serve to direct the flow of air away from areas of heavy traffic, it is possible that they might be hazardous by facilitating the aerosolisation of infectious droplets. in singapore [ ] and canada [ ] , transmission of the sars virus has been noted in crowded emergency rooms where patients routinely wait for hours for a hospital bed. in singapore, sars was documented as being transmitted to a patient's visitor who was waiting in a corridor during the patient's radiological procedure [ ] , again a common occurrence in many healthcare settings. in our own hospital, the national university hospital, the largest cluster of sars cases occurred in one of our eight-bed wards [ ] where patients are deliberately placed eight to a cubicle in order to support the philosophy of healthcare financing in singapore. the sars outbreak has clearly been a wake-up call for health authorities worldwide [ ] as they try to adjust health systems primarily designed to minimize costs into systems designed to protect staff and patients. the isolation and segregation of patients with suspect and probable sars has been credited with markedly reducing the transmission of the virus [ ] . lipsitch et al. [ ] reported a reduction in the time to isolation of patients with sars as the epidemic progressed with a corresponding decline in the number of secondary cases as knowledge of the virus increased. the majority of individuals with sars have not transmitted the virus to anyone [ ] . while it is tempting to ascribe this to infection control measures, many of these individuals were infected and hospitalized long before the institution of infection control methods. this has given rise to the concept of "super-spreaders." it is known that the presence of common viral upper respiratory tract infections can turn some hcws into so-called "cloud hcws" [ ] . these individuals have been linked with the airborne dispersal of agents that are normally only spread through contact, such as group a streptococci or staphylococcus aureus. the hypothesis is that the presence of upper respiratory tract infections transforms these individuals into efficient transmitters of pathogens through increased coughing, sneezing or nose rubbing. alternatively, airborne dispersal could result from the use of various respiratory therapies. the index patient for the singapore epidemic was not isolated, and hcws, visitors and fellow patients were infected [ ] . the second generation of cases associated with this cluster, before the institution of infection control practices or strict isolation, included only cases. the situation in canada was similar, with cases in the second generation occurring preisolation [ ] . it is quite clear, however, that non-isolated patients are hazardous to staff, visitors and other patients. single non-isolated patients have led to well-documented outbreaks in hospitals in singapore [ ] , taiwan [ ], canada [ ] and hong kong [ ] . the phenomenon of "super-spreaders" has been invoked to explain why so few transmissions resulted from the majority of non-isolated individuals while a few rare cases were associated with the vast majority of transmissions [ ] . the jury is still out as to whether these are indeed individuals who are for some reason more able to transmit infection or whether events, such as the use of high-flow oxygen therapy, are more responsible for what are probably more accurately described as "super-spreading events." until we have more virologic information, we have to assume that all individuals with sars are "super-spreaders" until proven otherwise and we have to take all the necessary precautions. again, because of the concern that an undiagnosed patient might turn out to be a "super-spreader," the threshold to isolation has become progressively lower. initially, hospitals and clinics were using the who case definitions of suspect and probable sars cases to determine which cases to isolate. as we, and others, have pointed out, atypical presentations [ ] are the achilles heel of such a strategy and these have been associated with significant nosocomial transmission. in a very important report from a sars screening clinic, rainer et al. [ ] pointed out that the who criteria, which were actually designed for epidemiologic purposes, while relatively specific, have a sensitivity of only about % in predicting which individuals will turn out to have sars. the implications are that a large number of individuals will need to be isolated and monitored very closely until their clinical course becomes evident. in practice in singapore, this resulted in the conversion of large numbers of hospital wards to isolation facilities, cancellation of elective surgeries and an overall paralysis of the healthcare system. we used a regime of -hourly temperature monitoring without any use at all of antipyretics together with daily serial chest radiographs and blood counts and comprehensive chemistry work ups. with this regime, we found a sensitivity of %, specificity of %, positive predictive value of % and negative predictive value of % for the who criteria at patient presentation [ ] . it is clear that an accurate rapid diagnostic test is urgently needed to allow us to filter out individuals who are at low risk of sars or, better still, at lower risk of transmitting the virus should they not be isolated. current diagnostic tests [ ] , which are based on either molecular methods or serological diagnosis, are severely limited not predominantly by sensitivity or specificity but by the fact that they take awhile to become positive, during which time widespread dissemination of the virus could have occurred from a single non-isolated "super-spreader." fever screening is widely practiced as a sars-prevention measure. there was even a period when the who called for fever screening at airports to prevent the global spread of sars. unfortunately, fever is a non-specific and insensitive screening tool for sars [ ] . atypical presentations of sars without fever have been reported especially in older and immunocompromised patients [ ] . one case is particularly illustrative [ ] . a -year-old man cleared a fever triage area in an emergency room as he was afebrile; he was then admitted to a general ward (not a "fever ward") as a case of heart failure, and he remained afebrile until he developed a lowgrade temperature after being transferred to the medical intensive care unit for progressive shortness of breath. two other patients, one visitor and one nurse who had been in the same emergency department area as this patient were infected with sars. the visitor, a previously healthy -year-old woman, died and her husband and son were subsequently infected. in the brief period the index patient was in the general ward, two other patients and the entire shift of nurses working in the ward at the time, who were only wearing n masks, were infected. by the time the patient became febrile in the intensive care unit, staff were wearing full ppe and no further infections resulted. thus, a single patient who "passed" two strict fever screens managed to be the source of at least nine infections in less than h. this patient was critically ill and died days later; thus, he may have had a very high viral load. this case illustrates the limitations of "cookbook screening" by using fever protocols without paying attention to a careful clinical history and physical examination. in this case, an alert cardiology team who re-did the patient's history and examination and performed a bedside echocardiograph to prove that he was suffering from pneumonia not heart failure made the diagnosis. during the sars outbreak, the inter-hospital transfer of patients in canada [ ] , taiwan [ ] and singapore [ ] was a very efficient means of dissemination of the sars virus. in singapore, on march, the decision was made to close one hospital to new admissions and to concentrate all sars patients there [ ] . this unfortunately led to patients recently discharged from this hospital being shunted to other hospitals and starting off epidemics there. now, in singapore, once a cluster of cases with even a low degree of suspicion is identified, the unit is "locked down" with no admissions, transfers or discharges in order to prevent a recurrence of the former situation. this strategy was also used successfully in vietnam to contain the sars virus, which led to vietnam being the first country to be declared free of local transmission of sars [ ] . while we have learned a tremendous amount in the brief period since sars first emerged in november , there are still a number of unresolved issues for practicing clinicians. the cases of sars in early have quashed hopes that the virus was "put back in the box," and in the formerly affected countries many clinicians are deeply worried about dealing with a devastating resurgence of the virus. i have a personal "wish list" of questions that i would like answered before too long. these include: what are the conditions required for the airborne transmission of the sars coronavirus? when can we be sure that transmission does not occur? when can we get a good rapid diagnostic test that is positive early in the course of the illness? what makes a super-spreading event? is quarantine really necessary? i can only hope that the answers to these and numerous other questions raised by infection control practitioners, hospital epidemiologists, infectious disease clinicians and researchers can be answered before we face the next sars outbreak or something worse! even as this is being written, avian influenza rampages across east asia affecting primarily birds, but also claiming the lives of more than individuals. if this becomes a pandemic form of influenza, sars will pale in comparison. epidemiology and cause of severe acute respiratory syndrome (sars) in people's republic of china a novel coronavirus associated with severe acute respiratory syndrome identification of a novel coronavirus in patients with severe acute respiratory syndrome a major outbreak of severe acute respiratory syndrome in hong kong identification of severe acute respiratory syndrome in canada 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procedures to prevent nosocomial infection with respiratory syncytial virus an outbreak of influenza aboard a commercial airliner global surveillance for severe acute respiratory syndrome transmission of the severe acute respiratory syndrome on aircraft low risk of transmission of severe acute respiratory syndrome on airplanes: the singapore experience accessed use of quarantine to prevent transmission of severe acute respiratory syndrome-taiwan transmission dynamics and control of severe acute respiratory syndrome safety of patients isolated for infection control preventing local transmission of sars: lessons from singapore identification and containment of an outbreak of sars in a community hospital update: severe acute respiratory syndrome-singapore the sars outbreak: how many reminders do we need? cloud" healthcare workers update: severe acute respiratory syndrome-taiwan update: severe acute respiratory syndrome-toronto, canada sars experience at prince of wales hospital, hong kong atypical presentations of sars evaluation of who criteria for identifying patients with severe acute respiratory syndrome out of hospital accuracy of who criteria for sars was similar in a non-sars hospital in singapore crouching tiger, hidden dragon: the laboratory diagnosis of severe acute respiratory syndrome atypical sars in a geriatric patient vietnam-sars free key: cord- -jnmogy s authors: yang, lin; ma, stefan; chen, ping yan; he, jian feng; chan, king pan; chow, angela; ou, chun quan; deng, ai ping; hedley, anthony j.; wong, chit ming; peiris, j.s. malik title: influenza associated mortality in the subtropics and tropics: results from three asian cities date: - - journal: vaccine doi: . /j.vaccine. . . sha: doc_id: cord_uid: jnmogy s influenza has been well documented to significantly contribute to winter increase of mortality in the temperate countries, but its severity in the subtropics and tropics was not recognized until recently and geographical variations of disease burden in these regions remain poorly understood. in this study, we applied a standardized modeling strategy to the mortality and virology data from three asian cities: subtropical guangzhou and hong kong, and tropical singapore, to estimate the disease burden of influenza in these cities. we found that influenza was associated with . , . and . deaths per , population in guangzhou, hong kong and singapore, respectively. the annual rates of excess deaths in the elders were estimated highest in guangzhou and lowest in singapore. the excess death rate attributable to a/h n subtype was found slightly higher than the rates attributable to a/h n during the study period of – based on the data from hong kong and guangzhou. our study revealed a geographical variation in the disease burden of influenza in these subtropical and tropical cities. these results highlight a need to explore the determinants for severity of seasonal influenza. influenza is one of the respiratory pathogens that can cause serious health problems in both mortality and morbidity worldwide. however, unspecific presenting symptoms of influenza, absence of timely laboratory tests in clinical practice and frequent secondary bacterial pneumonia make it difficult to estimate the disease burden of influenza directly from the clinical diagnosed cases [ , ] . it is therefore necessary to assess influenza associated excess mortality or hospitalization by statistical modeling and use the estimate as a measurement for severity of influenza epidemics [ ] . some studies reported that the disease burden of influenza was nearly equivalent across some temperate countries [ ] , but others noticed that abbreviations: ili, influenza-like illness; icd, international classification of diseases; crd, cardiorespiratory diseases; p&i, pneumonia and influenza; copd, chronic obstructive pulmonary diseases; ihd, ischemic heart diseases. effects of influenza occasionally exhibited disparities between geographical areas even in the same influenza season [ ] . it has been proposed that socioeconomic factors and various circulating virus strains could play an important role in determining the severity of influenza epidemics [ ] [ ] [ ] . some environmental factors that are critical for survival and transmission of viruses, such as temperature and humidity, could also be involved as effect modifiers [ ] . however, geographical variations in influenza associated disease burden in the tropics and subtropics have not been explored. a recent large-scale phylogenetic study postulated that novel influenza viruses first emerge in the tropics and subsequently spread into the temperate when environmental factors favor virus transmissions [ ] . particularly, east and southeast asian countries are proposed as the potential reservoirs for dormant influenza viruses, although the mechanism remains unclear [ ] . unfortunately, there are few disease burden studies in this region to provide the evidence for or against the postulation, largely due to a lack of data from well-designed long-standing surveillance. this situation was further complicated by the unpredictable influenza seasonality in these regions. in this study we applied a standardized modeling strategy to three metropolitan cities in east and southeast asia: guangzhou, hong kong and singapore, all of which have well-organized surveillance networks for influenza for several years. guangzhou and hong kong, both located at southern china, share a similar subtropical climate with a mean temperature around • c, but the latter is more economically developed with a higher gdp per capita of $ , in hong kong as compared with that of $ in guangzhou in [ , ] . singapore is a tropical city with a higher mean temperature of . • c than guangzhou and hong kong. the socioeconomic level of singapore is comparable to hong kong, with a gdp per capita of $ , in [ ] . the difference and similarity between these cities, in terms of socioeconomic status and environmental factors, provide us a good opportunity to explore the factors that may affect the disparity or similarity across geographical areas. the influenza virology data in guangzhou, hong kong and singapore during - were obtained from the guang dong provincial center for disease control and prevention (gdcdc), the hong kong department of health (dh) and the singapore ministry of health (moh), respectively. the nasopharyngeal aspirate specimens were collected from the outpatients or inpatients presenting influenza-like illness (ili) symptoms of fever (≥ • c), cough or sore throat and then were tested for influenza by direct immunofluorescence or cell culture. positive samples were later typed or subtyped into a/h n , a/h n and b by haemagglutination inhibition (hi) test with strain-specific antiserum provided by the world health organization (who). mortality data for each city were obtained from hong kong census and statistics department (coded according to the international classification of diseases tenth revision, icd- ), guangzhou department of health (coded in icd- ) and singapore registry of births and deaths (coded in icd- ), respectively. we aggregated the weekly numbers of deaths with underlying cause of cardiorespiratory diseases (crd, icd- - ; icd- i -i , j -j ), pneumonia and influenza (p&i, icd- - ; icd- j -j ), chronic obstructive pulmonary diseases (copd, icd- - ; icd- j -j ), ischemic heart diseases (ihd, icd- - ; icd- i -i ) and all causes (icd- - ; icd- a -t ). two age groups were considered: all-ages and the elders aged years or over. we obtained the weekly mean temperature and humidity for three cities, from the national meteorological information center in china, hong kong observatory and singapore national environment agency, respectively. we fitted a poisson regression model to weekly numbers of mortality with the aim to assess the percentage of excess mortality associated with increased influenza activity in the population, as described in our previous studies [ , ] . briefly, long-term trends and seasonal patterns of mortality counts, as well as weekly average temperature and relative humidity, were added as confounders into the core models with their natural cubic spline smoothing functions. both temperature and humidity have been found to affect influenza virus transmission [ ] and also been associated with mortality in previous studies [ , ] . a typical form of core model is where yt denotes the death numbers at week t; ns(t), ns(temp t ) and ns(humd t ) denote the natural spline smoothing functions of time, temperature and relative humidity, respectively. auto-regressive terms in the residuals may be added to remove significant autocorrelations of residuals in first four weeks, so that time varying confounding could be adequately controlled. the weekly proportions of specimens positive for specific influenza types/subtypes (named as influenza proportions, flu t ) were simultaneously entered into the core model, to estimate influenza effects: the annual effects of influenza on mortality for each year were measured by excess mortality associated with influenza, which is defined as the sum of differences between the observed and expected death numbers when influenza proportions were assumed to be zero during that entire year [ ] . the % confidence intervals (ci) for estimates were derived by bootstrapping the scaled pearson residuals for times. we further derived the excess death rates associated with influenza per , population to render influenza effects comparable between cities. the percentage of excess deaths was calculated as the excess deaths divided by the total number of observed deaths. all the analyses were performed using the mgcv package of r software (version . . .) [ ] . two subtropical cities guangzhou and hong kong shared similar meteorological conditions, while the tropical city singapore tended to be hotter and more humid with much less variations in both temperature and humidity (table ) . among the three cities, hong kong had the largest population, while singapore had the youngest ( table ). the crude mortality rate of guangzhou was slightly higher than that of hong kong and singapore, respectively. more than % of deaths were in the or older age group in guangzhou and hong kong, whereas this number was only % in singapore. crd was the major cause of death in all three cities, but p&i mortality in guangzhou and copd in singapore was the lowest among the three cities ( table ) . the proportion of specimens positive for influenza a or b in singapore had an average of . %, which was lower than that in guangzhou and hong kong ( . % and . %, respectively) ( table ). this could be due to less stringent diagnosis criteria adopted by singapore for recruitment of patients into its surveillance network, using the case definition of acute respiratory illness instead of ili. influenza seasonality was similar between hong kong and guangzhou, but the winter peak was less pronounced in the latter. there were no clear epidemic periods in singapore, despite one sharp spike around june of (fig. ) influenza was significantly (p < . ) associated with all-cause mortality as well as with underlying cause of crd, p&i, copd and ihd for the all-ages group in all three cities, with the exceptions of copd in guangzhou and singapore, and ihd in singapore (table ) . during the study period of - , hong kong had the highest percentages of excess deaths associated with influenza among the three cities, with the only exception of ihd deaths. for the all-ages group, hong kong had the highest excess deaths for all causes and for underlying causes of p&i and copd, whereas guangzhou had the highest excess deaths due to crd and ihd. the excess death rates for the old population were highest in guangzhou for all-cause and crd death. note: ci, confidence interval; crd, cardiorespiratory diseases; p&i, pneumonia and influenza; copd, chronic obstructive pulmonary diseases; ihd, ischemic heart diseases. the annual death rates attributable to influenza revealed the greatest disease burden of influenza in the year for guangzhou and singapore, but in for hong kong. the year with the lowest disease burden was for hong kong and singapore, and for guangzhou (fig. ) . in guangzhou, an annual rate of . between the two types of influenza virus, influenza a accounted for the majority of excess deaths in all three cities (data not shown). as the denominator of subtype proportion of singapore was not comparable with that of the other two cities, we only estimated deaths attributable to influenza a subtypes, a/h n and a/h n , in guangzhou and hong kong. comparison between the two subtypes showed that a/h n accounted for slightly more excess deaths in the all-ages group for all the disease categories under study in both guangzhou and hong kong (fig. ) . this pattern was also observed for the + age group. to our best knowledge, this is the first comparative study between asian subtropical and tropical cities for influenza disease burden. the surveillance networks for influenza in guangzhou, hong kong and singapore were established under the who global influenza surveillance network [ ] , which allowed us to estimate the disease burdens in a standardized procedure and to compare across cities. here we adopted the poisson regression models to assess the age-disease specific excess mortality rates associated with influenza. allowing for flexible adjustment of seasonal factors, this poisson model has been widely used in many other disease burdens studies and is recommended for the subtropical and tropical regions with unpredictable influenza seasonality in a recently published who guideline [ ] [ ] [ ] [ ] [ ] . our recent validation study using an empirical dataset of laboratory confirmed influenza cases demonstrated that this model was able to provide reliable estimates for disease burden of influenza [ ] . although this approach requires sufficient long-standing year-round surveillance data, such data have become available in many subtropical and tropical regions in recent years. our study may serve as a good example for the disease burden studies across these regions. two previous studies found that the influenza associated mortality rates were nearly equivalent between hong kong and singapore, and singapore even had a higher excess rate for the older population [ , ] . however, these results need careful interpretation as these two studies differed in terms of statistical models, data aggregation and study periods covered. the present study adopted a standardized modeling approach to show that the overall influenza burden was comparable between the two subtropical cities guangzhou and hong kong, but lower in the tropical singapore. this geographical disparity was particularly evident in the elders, with the highest excess mortality rates associated with influenza found in guangzhou, which has a smaller proportion of old population than hong kong but is the least developed among the three cities. cohen et al. also found the mortality impact of seasonal influenza was higher in the elders of south africa than in those of the united states and this difference did not diminish after adjustment for age structures [ ] . together with our findings, it seems that the socioeconomic factors may associate with the mortality burden of influenza, particularly for the elders. another fig. . annual excess all-cause mortality rates associated with influenza (per , population) between guangzhou, hong kong and singapore, all-ages group. important factor that needs to be considered in interpreting our results is the different underlying susceptibility of population to severe outcomes of influenza infection across three cities. for example, the lower overall impact of influenza in singapore may not be due to its tropical climate, but partially due to its younger age structure. this heterogeneity of susceptibility could possibly been adjusted for by calculating age standardized excess mortality rates for each city, as the elders tend to be more fragile and have a higher mortality risk attributable to influenza. however, it is difficult to obtain reliable estimates for younger age groups due to small numbers of deaths. a future study with a longer study period shall be able to provide estimates with proper adjustment for age structures. singapore had the lowest disease burden from influenza among three cities, although fewer people in singapore had received influenza vaccination annually. in , doses of influenza vaccine were distributed for every total population in singapore [ ] , but a corresponding vaccination rate doses/ total population was reported in hong kong [ ] and doses/ total population in guangzhou (he jf, unpublished data). during - the annual distribution doses of seasonal influenza vaccines in singapore were around doses/ total population, less than half of those in hong kong [ ] . however, the effectiveness of influenza vaccines is largely complicated by age structure of population and also by various levels of herd immunity. moreover, the severity of infections could be aggravated by the environmental factors favoring virus transmission, such as air pollution [ ] . it has been widely cited that the disease burden of influenza, in terms of excess p&i mortality and hospitalization, tended to be higher in the a/h n dominant seasons than those with a/h n and b as the dominant virus strains [ ] [ ] [ ] . a/h n is believed to transmit more efficiently in human population than a/h n and antigenic drifts occurred more frequently in this subtype [ , ] . surprisingly, we found that the disease burden attributable to a/h n was slightly lower than the burden attributable to a/h n in guangzhou and hong kong. we noticed that after the outbreak of severe acute respiratory syndrome (sars) viruses in , all the three cities observed dramatically increased vaccination rates for influenza [ ] . we compared the excess mortality attributable to each subtype during the pre-sars period of - in hong kong, and the results showed that h n were associated with significantly more deaths than h n (data not shown). although a new strain a/california/ / -like gradually became prevalent in the late year of , it did not dramatically increase the mortality risks associated with influenza according to our results. some studies have shown that this novel strain mainly attacked the young adults and the vaccine recommended for the northern hemisphere during the - season was still able to provide crossprotection against it [ , ] . as a result, those susceptible people (the elders and chronic patients) might have still been benefited from increased vaccination and exempted from deaths. however, the disease burden of a/h n may have long been neglected, probably owing to its less frequent antigenic drifts compared to a/h n in the human community. recent experimental studies have found that seasonal h n strains can replicate as efficiently as pandemic h n and avian h n strains in ex vivo-infected lung tissues [ , ] . further experimental studies on virulence of different subtypes circulating in - may help to solve this mystery. more epidemiology studies with longer time series data from different climates are also needed to compare the relative severity of a/h n and a/h n strains. our study has potential caveats. firstly, these three cities vary in the organization of their influenza surveillance networks. most specimens in hong kong were mainly from the inpatients and therefore more severe cases of influenza infections were recruited into the surveillance. the sentinel doctors of guangzhou were all from the outpatient sectors, and the virology data exhibited greater variation than the other two cities due to limited numbers of samples taken each week. singapore had the lowest positive rates of influenza specimens, probably due to the fact this city included a mixture of samples from both inpatient and outpatient settings. nonetheless, we standardized the comparison procedure by using the age-specific excess mortality rate as measurement for influenza effects, which could at least partially exclude the bias introduced by different surveillance systems in these cities. secondly, although we carefully controlled for the confounding seasonal factors by building core models a priori, it is possible that there are still many unmeasured confounding factors. moreover, to what extent such confounding factors should be adjusted for was subject to personal judgement and over-fitting of core models cannot be completely avoided, as revealed by the negative estimates in some disease categories. thirdly, all three cities in this study 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be found, in the online version, at doi: . /j.vaccine. . . . key: cord- -j rpvwk authors: leong, hoe nam; lim, hong huay title: sars – my personal battle date: - - journal: travel med infect dis doi: . /j.tmaid. . . sha: doc_id: cord_uid: j rpvwk it isn’t every day that a doctor becomes a patient. it is more peculiar when it occurs with an unknown mysterious epidemic respiratory illness that kills. severe acute respiratory syndrome (sars) gripped the world in , spreading via air-links and throwing the global economy into disarray. as a practicing physician in singapore, one of the first countries affected, i describe my first-hand account of my battle with this illness, how i acquired this illness in singapore, and eventually quarantine in frankfurt am main, germany. summary it isn't every day that a doctor becomes a patient. it is more peculiar when it occurs with an unknown mysterious epidemic respiratory illness that kills. severe acute respiratory syndrome (sars) gripped the world in , spreading via air-links and throwing the global economy into disarray. as a practicing physician in singapore, one of the first countries affected, i describe my first-hand account of my battle with this illness, how i acquired this illness in singapore, and eventually quarantine in frankfurt am main, germany. ª elsevier ltd. all rights reserved. i vividly remember the time when i first saw the index patient with severe acute respiratory syndrome (sars) in singapore. she had just returned from a shopping trip from hong kong. she was unwell on the last day of the trip while her travelling companion had been unwell earlier. upon return, both eventually sought help at two different major hospitals in singapore. the index patient was admitted to tan tock seng hospital (ttsh) on saturday, ( st march ), and an infectious disease consult was sought on the following monday. i was the infectious disease registrar-oncall that day for ttsh. her presentation intrigued me, and with little hesitancy after discussing with my consultant, we assumed the medical management of the patient. the working diagnosis was atypical pneumonia of uncertain etiology. on that day, rd march , the entity of sars-coronavirus was not even coined. at a much later time, i learnt that there were rumours of an 'infectious agent' in guangdong province, and various diagnosis were offered included chlamydia infection to avian influenza. she was nonetheless investigated, and managed as for atypical pneumonia. as a young enthusiastic registrar, i was determined to find the etiology to her infection. not wanting to miss any unusual signs, i examined the patient thoroughly twice daily. we explored and liaised with the various clinical laboratories to investigate the cause of her pneumonia. routine tests from sputum bacterial culture to respiratory viruses immunofluorescence to serology were unyielding. all investigations were fruitless. on the sixth day of her admission, i was referred another patient with atypical pneumonia. and again, i was presented with the same history of a young singaporean woman with atypical pneumonia in a returning traveler from hong kong after shopping. the incredulous similarity unsettled me as i asked the referring consultant if we were talking about the same patient. with this new referral, both patients were immediately isolated and an alert was issued to the ministry of health, singapore. this was to the credit of my consultant. it was an exceedingly busy day for me as i had to attend to new referrals, run an outpatient clinic, and subsequently draft a clinical summary of these two patients by the early evening. needless to say, i didn't go home till it was very late that night. it was subsequently elucidated that these two individuals acquired the disease while staying in the same hotel in hong kong from an ill visitor from guangdong province. the next day was the weekly scheduled infectious disease round in my practicing hospital, ttsh, where infectious disease physicians from the various public hospitals in singapore would gather. each public hospital (singapore general hospital, national university hospital, and ttsh) would take turns to host the event that is held on all most fridays of the month. at this opportunity, we presented our cases, and discussed our findings. as a group of infectious diseases physicians, we had no inkling to the etiological cause. nonetheless, the patients remained isolated. eventually, the patient's fever defervesced on day of illness. i wasn't scheduled to perform the ward round that day, but i returned to visit the patient that sunday morning. my curiosity had the better of me. on hindsight, i should not have, as i developed fever with chills and severe myalgia that very morning while going to work. that spelled the beginning of my own illness. for once, i appreciated what having chills meant. despite driving in hot-weather singapore, with the vehicular heater at its maximum setting, i failed to get any relief. coupled with the severe backbreaking myalgia and the absence of respiratory symptoms, i believed i had dengue fever. i drank plenty of fluids and took plenty of rest. the fever broke eventually on the tuesday morning. this was day three of illness. with this reassurance, i decided to continue on my scheduled trip to new york for a conference. my pregnant wife and my mother-in-law accompanied on this trip. the plans were that we would have a short holiday visiting relatives after the conference. the flight was pleasant but interrupted by the airline staff seeking assistance for a passenger who developed epigastric pain. my paediatrician wife and i rendered assistance. this turned out to be a blessing in disguise later. the next day i remained well and we toured the new york city prior to the start of the meeting that evening. when the lecture began, i felt extremely unwell, and developed severe chills and myalgia again. on returning to my room, i realised that i had broken out with a faint viral looking-like rash. i had a huge sigh of relief with the firm belief that my diagnosis of dengue fever was further reaffirmed. at that point in time, i had yet to develop any respiratory symptoms. my wife and i telephoned a colleague in singapore and we concurred to have a full blood count test done at the clinic the next day. the american physician we referred to by the hotel in new york was a board-certified travel physician. his associate examined me initially, and astutely identified crepitations on my right lung. a chest x ray demonstrated radiographic features of consolidation and a full blood count showed normal white cell count and platelets. the physician immediately made a diagnosis of atypical pneumonia and i was prescribed levofloxacin. he showed professional courtesy and offered me free samples. on my part, i made a decision to return home on the first flight out that evening. the physician tried to dissuade me as he felt i would recover in a few days. just prior to leaving the clinic, i decided to call home to singapore to update my family and a trusted colleague in singapore on this new development. it was easily midnight in singapore time when i woke up my colleague! it turned out that this call was highlighted to the director of medical services, ministry of health, singapore, and a frantic search began for this sick doctor. i was halfway across the atlantic ocean when the ministry eventually found me. the crew servicing the passengers happened to be the same crew that serviced us on the flight out to frankfurt from singapore. naturally, we were identified out easily, like a sore thumb! we were cordoned off to the rear of the plane with three empty rows ahead of us. it was extremely professional of the aircrew to have treated us with dignity and respect. perhaps it was ignorance, but i was not treated as if i had a highly infectious agent. my respiratory symptoms of cough began with this flight, and in retrospect, i wish i had stayed in new york. when we arrived in frankfurt am main germany, the passengers and then the crew were taken off the plane, leaving my pregnant wife, my mother-in-law and myself as the last passengers. eventually, three germans boarded the plane in 'spacesuits'. i was full of admiration for my mother-in-law who took all these sudden news and men in full personal protective equipment (ppe, complete with powered air-purifying respirator) in unbelievable calmness. in a matter-of-fact tone, she told me composedly that she had watched television and knew what to expect e exactly! she had developed a cough by now, which she did not blame me for. the germans were clearly well-prepared for the scenario, having rehearsed this recently for a mock patient at the airport with a viral haemorrhagic fever. the hospital, klinikum der johann wolfgang goethe-universität, and its staff, led by professor hans-reinhard brodt, was exceptional in delivering the best care possible to me. as both my mother-in-law and myself were ill, we were moved to the intensive care unit in this isolation ward. my wife was cordoned off in a separate room. however, the nightmare with my illness has just begun. i became increasing short of breath with an unabating persistent fever. my respiratory symptoms that were nonexistent initially returned with a vengeance, as i had to cope with haggling bouts of cough that resulted in me desaturating on the oxygen monitor. every single attempt to change my posture would result in a severe bout of cough that frightened my mother-in-law. it appeared as if my lungs would be spit out at the next cough. at the end of each bout of coughing, there would be haemoptysis. this was a terrifying sight for a mother whose daughter was pregnant with my child. the thought of a fatherless child, no doubt, crossed her mind. my experience as a patient humbled me. i had no toilet privileges, as i was too unwell to get out of bed. for the love of my life, i was cursed that i couldn't bring myself to empty my bladder supine, but had to stand. it didn't help when it was frequently interspersed with bouts of coughing and haemoptysis every time i tried to position myself! science thus taught me, in cruel fashion, that i could hold l of urine in my bladder. my wife eventually joined me when she developed fever at the end of the second day of arrival. the sense of guilt overcame me as i thought of the illness i had exposed my wife to. in this moment of desperation, i cried to god's help, and i offered my life for the safety of my wife and my unborn daughter. my hopes fell to despair when i became extremely breathless one evening despite being on a full-face oxygen mask of %. the sensation of breathlessness was extremely terrifying as i tried to take in deeper and deeper breaths to satisfy my air hunger, but to no avail. i felt suffocated as if the air had no oxygen. incredulously, i retained some sense of logic. i knew i had to avoid mechanical ventilation if i wanted to keep the odds in my favour. i struggled and prayed, and in the silence, i found peace. the night turned to day, and amazingly my recovery started. my mother-in-law never developed fever. her respiratory symptoms resolved by the evening of admission, and she was up and about, back to her usual spritely self. in jest, we attributed her health to her younger days when she worked in a farm. my wife miraculously had much milder symptoms. there was a fetal ultrasound assessment, which turned out well. the doctor avoided all chest radiographs of my wife to protect my unborn child. intravenous erythromycin, a category b drug, was the only drug prescribed for my wife. the managing physician allowed me to participate in the medical care and we actively discussed the choice of antibiotics. on the first day of admission, there was still no news of sars or any infectious agent. but the news of a new infectious agent (sars) broke out on the second day of admission, and i was given a promed email on this. this was th march . with that news, my days as a patient in isolation continued. regularly thereafter, we were fed information from the promed by the attending healthcare workers. in the study of science, my mother-in-law, wife and myself were subjected to various samplings for viral cultures. it almost became a daily routine that we had daily nasopharyngeal and eye swabs. arterial blood gases (requiring a puncture on the radial artery) were performed regularly. the attending physicians had to do this while in their full ppe in thick industrial grade gloves. to their credit, they managed to perform these tests in those unwieldy suits and gloves. when i was better, i performed the blood sampling for my wife and mother-inlaw instead. for the benefit of science, i agreed to a bronchoscopic examination. they obtained an old scope and a respiratory physician was flown in for the procedure. the bronchoscopist was accomplished, but the experience was far from pleasant, but it gave me the moral authority to advise my subsequent patients when i submitted them for endoscopic examinations. a computer scan of the chest was performed when i was much better. the record of my stay and the findings was eventually published. we all eventually recovered, and during the obligatory isolation, we had the chance to sample hospital german cuisine, and ordered in chinese takeaways and pizzas. indeed, frankfurt should be the place to eat frankfurters! the only recreation was the ice figure skating championship that was broadcasted during that period. the doctors were fantastic, and the nurses were unbelievably warm and understanding. we couldn't have received better care from anyone else. the solitude in isolation was deafening as the days wore on. my initial reading was with the only english book my wife asked from our german caregivers, the bible. it was through this episode that i first read the whole gospel according to luke. our friends and family took turns to call us to keep us entertained. we were regularly updated by colleagues fighting the battle in ttsh. without these friends, we would have clearly lost our sanity. the best gift came when dr asok kurup, my colleague in the singapore general hospital (sgh) came to visit me. he brought well wishes from my department; get well cards and an english novel. i felt 'loved' by my friends. i was a staff of sgh, and was rotated to ttsh as part of the infectious diseases training programme. despite the fact that i acquired the disease from another hospital, the ceo of singhealth, the administrative group for sgh, professor ser kiat tan, announced publicly that he would pay the entire hospital bill. this settled my worries. some time after my discharge, my employer was billed for my entire stay, including the quarantine charges. it was a large bill that i would never have been able to pay in a lifetime. professor tan made calls to me either personally or through his secretary. that offered a lot of hope for this patient. even singapore airlines offered my wife a bouquet of flowers, despite the trouble we created for them. they truly exemplified their motto e "a great way to fly". i am still grateful to their staff till this day. a lady approached our isolation unit one day, with magazines in english. she introduced herself in spattering bits of english and gesticulations as the matron of the hospital. she represented the hospital and felt for sorry our solitude. we were very grateful for this unusual warmth in the cold early spring in frankfurt am main. in return, we gesticulated wildly back at her, acknowledging her kindness. eventually we were discharged when our period of isolation was over. we were whisked off in a private car and quietly into the airport. we never went through immigration when we first arrived, and hence, technically, illegal immigrants! the flight back was uneventful. the crew knew of our special status but remained professional. on arrival in singapore, we were whisked into a waiting taxi and sent home. the journalists never got to me. we returned home to welcoming family, colleagues and friends, intermixed with hugs, kisses and warm handshakes. they were clearly relieved that we have survived this episode. this came amidst further news of infection and death caused by the virus. for me, it was great to be home. i visited sgh on the monday after, and greeted my colleagues. this was just when sars was identified in sgh. i was roped in to help with the transfer of patients from sgh to ttsh. thereafter, i started working in ttsh, working hand-in-hand with my colleagues in battling sars. my wife joined me subsequently on secondment from kk women's and children's hospital. together with other sars survivors, we formed a team, collecting respiratory samples from individuals suspected to have sars. my wife and i worked with various doctors. the camaraderie was amazing to say the least, and we made long lasting friendships with many people. sars was eventually controlled, and we returned to our previous positions. my daughter, was born in early september, full term with no apparent birth defect. we have survived an epidemic, and in , the world was thrown into another epidemic of swine-origin h n influenza. as a physician, this experience has allowed me to better appreciate what a patient experiences. that solitude and isolation, is a horrific tragedy for both the physician and patient. and yet, as an infectious diseases physician, i have sadly implemented this order on many individuals. sometimes, these individuals die, alone, in desolation. the fear of an unknown mysterious illness is overbearing. coupled with isolation, this becomes defeatist. the impetus is thus with us physicians as we remember the aphorism by dr edward trudeau, "to cure sometimes, to relieve often, to comfort always". we all can always comfort patients, even in isolation. since , we have been blessed with two other children, vivianne and lucas. marianne, who is now six years old, is starting first grade this year. though tumultuous, the sars experience has taught us valuable lessons as doctors not otherwise taught in medical school. outbreak of severe acute respiratory syndrome e worldwide identification of a novel coronavirus in patients with severe acute respiratory syndrome no conflict of interest. key: cord- -kj zi authors: coleman, kristen k.; nguyen, tham t.; yadana, su; hansen-estruch, christophe; lindsley, william g.; gray, gregory c. title: bioaerosol sampling for respiratory viruses in singapore’s mass rapid transit network date: - - journal: sci rep doi: . /s - - - sha: doc_id: cord_uid: kj zi as a leading global city with a high population density, singapore is at risk for the introduction of novel biological threats. this risk has been recently reinforced by human epidemics in singapore of sars coronavirus, pandemic h n influenza a virus, and enterovirus . other major threats to singapore include mers-coronavirus and various avian and swine influenza viruses. the ability to quickly identify and robustly track such threats to initiate an early emergency response remains a significant challenge. in an effort to enhance respiratory virus surveillance in singapore, our team conducted a pilot study employing a noninvasive bioaerosol sampling method to detect respiratory viruses in singapore’s mass rapid transit (mrt) network. over a period of weeks, aerosol samples were collected during peak mrt ridership hours. nine ( %) tested positive for adenovirus, four ( . %) tested positive for respiratory syncytial virus type a, and one ( %) tested positive for influenza a virus using real-time rt-pcr/pcr. to our knowledge, this is the first time molecular evidence for any infectious respiratory agent has been collected from singapore’s mrt. our pilot study data support the possibility of employing bioaerosol samplers in crowded public spaces to noninvasively monitor for respiratory viruses circulating in communities. a high population density, international tourism and trade traffic puts singapore at a high risk of novel emerging respiratory epidemics. this risk has been recently reinforced by human epidemics in singapore of severe acute respiratory syndrome-associated coronavirus (sars-cov) , pandemic h n influenza a virus , and enterovirus , (which causes hand, foot and mouth disease). other major threats to singapore include middle east respiratory syndrome-related coronavirus (mers-cov) , and various avian (h n , h n , h n , h n , etc.) and swine (h n , h n , h n ) influenza a viruses, especially if they become highly transmissible between humans. for instance, the first human case of a(h n ) was confirmed in february , and a total of , human cases of a(h n ) have been reported since , with % ( ) in the th wave of the epidemic from october to september . compared to the estimated . % case fatality rate for the global pandemic h n virus , a(h n ) (including both high and low pathogenic strains) has an alarming % case fatality rate, which has resulted in known deaths since its emergence in , , . international travel can play a significant role in the spread of infectious diseases. for example, during the influenza h n pandemic, countries receiving the highest volume of passengers (> , in two months) from mexico (the country of origin of the h n virus), had a significantly higher risk of virus importation associated with travel to mexico . china (the country of origin of a(h n ) and a(h n ) viruses) is the third largest market of travelers for singapore changi airport, which receives ~ , passengers from china per week. with singapore's close connection to china, and recent evidence suggesting the potential for airborne transmission of highly pathogenic avian influenza a(h n ) , it is prudent for singapore to ramp up disease surveillance. the ability to quickly identify and robustly track respiratory threats is fundamentally important for an early emergency response. to better understand the dynamics of microbes in cities in relation to human health, and to create healthier environments in areas where people frequently visit, researchers have begun studying the microbiome in and around public transportation vehicles , . an international project named metasub was launched to map the microbiome of transit networks in the world's largest cities. over cities, including singapore, boston, shanghai, paris, stockholm, and são paolo are participating in the project to improve city planning and public health. although baseline metagenomic maps created from these studies are said to be useful for mitigating bioterrorism and infectious disease outbreaks, most of them focus largely on mapping surface-borne bacterial dna and neglect to address the threat of weaponized or global catastrophic biological risk-level (gcbr-level) agents, both of which would likely be aerosolized or respiratory-borne rna viruses . bioaerosol studies have demonstrated that concentrations of airborne bacteria in underground subway systems tend to fluctuate seasonally and are linked to human presence and activities , . such information demonstrates the possible role of public transportation in disease transmission, but again, only few studies have focused on the existence of airborne viruses in public transportation systems [ ] [ ] [ ] [ ] . mathematical models have been developed to assess the risk of airborne and droplet transmission of respiratory viruses in buses, airline cabins and cities [ ] [ ] [ ] , and although these simulation data are useful, we have sparse field data to support them. in this study, we sought to monitor for respiratory viruses in singapore's mass rapid transit (mrt) network, a likely area of virus incursion as well as a pathway for virus transmission. specifically, we asked, could noninvasive bioaerosol sampling detect respiratory viruses in singapore's mrt network? using real-time polymerase chain reaction (pcr) and real-time reverse transcription pcr (rt-pcr), fourteen ( %) of the aerosol samples collected from the singapore mrt tested positive for one or more respiratory viruses. nine ( %) of the virus-positive aerosol samples were collected from the north east mrt line (nel; purple) and five ( %) from the east west mrt line (ewl; green). nine of the virus-positive aerosol samples ( %) tested positive for adenovirus, four ( %) tested positive for rsv-a, and one ( %) tested positive for influenza a virus. one sample tested positive for both adenovirus and rsv-a. one additional sample with a ct value of was suspected to be positive for influenza a virus. aerosol samples did not test positive for any other target pathogens including influenza b viruses, enteroviruses, coronaviruses, and rsv-b. temperature, relative humidity (rh) and light intensity remained relatively consistent inside the purple and green mrt lines throughout the study, with averages of °c and °c, % rh, and . and . lum/m², respectively (table ). there were no significant differences in these environmental conditions on sampling days yielding virus-positive aerosol samples. adenovirus-positive droplets (> μm in aerodynamic diameter) and droplet nuclei (≤ μm in aerodynamic diameter) were retrieved from six ( %) and four ( %) of the adenovirus-positive samples, respectively. in one instance, adenovirus-positive particles of both size ranges were retrieved from the same sample. rsv-a droplets and droplet nuclei were both retrieved from four ( %) of the rsv-a-positive samples. only influenza a virus-positive droplets (not droplet nuclei) were retrieved from the influenza a virus-positive sample. adenovirus-positive samples were collected in january , and february, march, may, june, september and october . rsv-a-positive samples were collected in february , and the influenza a virus-positive sample was collected in september . the additional sample that was suspected to be positive for influenza a virus was collected in november . see table for a monthly summary of pcr-positive aerosol samples. attempts to culture and subtype adenovirus and influenza a virus from pcr-positive aerosol samples were unsuccessful. insufficient volumes of the original samples were leftover to attempt to culture rsv-a from pcr-positive aerosol samples. to our knowledge, this is the first time molecular evidence for any infectious respiratory agent has been collected from singapore's mrt. our results suggest that bioaerosol sampling might have a practical application for pathogen detection in public areas such as subway systems. bioaerosol sampling in the field provides a noninvasive way to monitor and characterize the community of aerosolized respiratory viruses that regularly infect the public, as well as potentially detect or discover novel pathogens with pandemic potential, such as the influenza a(h n ) virus. additionally, a bioaerosol sampling system is advantageous as it does not require collecting individual samples from human subjects, nor informed consent. although this pilot study provides important qualitative data (i.e., molecular presence of respiratory viruses in the mrt), it is important to note that solely detecting viral dna/rna in the air does not determine that a virus is successfully transmitted through the air. cultures in this study were negative and therefore the viruses detected may have been non-viable. however, studies have demonstrated that upon the first ~ minutes of aerosolization, viruses tend to decay the most rapidly , , and therefore it is possible that the viability of the viruses captured in our study rapidly decreased during sample collection and transport. moreover, temperature and rh have been widely understood to influence the viability of aerosolized viruses . however, novel research has recently demonstrated that the viability of aerosolized influenza virus is independent of rh when the aerosol composition includes human bronchial epithelial (hbe) extracellular material (ecm) , indicating that the influence of rh is more so on the rate of aerosol deposition after expulsion, which in turn, influences the overall concentration of viral aerosols in the environment. aerosols tend to deposit onto surfaces more quickly at higher rh levels (> %), suggesting that greater time spent in controlled environments with lower, more comfortable rh levels, could increase the risk of acquiring a respiratory virus via inhalation and respiration. therefore, the average rh level ( %) on the singapore mrt is not theoretically conducive to heavy airborne transmission of influenza viruses. a likely contributor to the lack of data regarding airborne transmission of viruses is the difficulty of detecting respiratory pathogens in the air. standard detection methods are designed to target viral nucleic acids which are subject to degradation from various environmental stressors (e.g., temperature, humidity, and uv light) as well as physical stress from aerosol sample collection methods, potentially deterring downstream detection. therefore, high rh levels, in addition to sample degradation, could explain the low recovery of virus-positive aerosol samples in our study. additionally, viral bioaerosols have notoriously low airborne concentrations, reducing the sensitivity of bioaerosol sampling. some bioaerosol samplers, such as the niosh sampler used in this study, are compact and require a low flow rate which also may reduce sensitivity. although the air pump flow rate and sample collection times used in our study have been demonstrated to efficiently capture aerosolized influenza virus and rsv rna [ ] [ ] [ ] , it is possible that these parameters are not optimal for capturing the other respiratory virus dna/rna targeted in our study. for example, it is possible that when compared to rna viruses (e.g., influenza virus, rsv), adenovirus (a more durable dna virus) can withstand a higher flow rate and/or longer sampling duration. furthermore, although each of the assays used to detect viral dna/rna in our aerosol samples are highly sensitive, validated, singleplex real-time rt-pcr/pcr assays, specific detection limits (viral copies per volume of air) were not tested in our laboratory. therefore, our dna/rna detections should not be mistaken as a true representation of the prevalence/densities of these viruses circulating in the air of the mrt, but rather a representation of the viruses our bioaerosol sampling technique is capable of detecting in this environment. to improve the sensitivity and specificity of bioaerosol sampling, more virus-specific controlled studies are needed to determine optimal sampling parameters for multiple respiratory viruses. airborne microbial concentrations have been demonstrated to fluctuate seasonally in underground subway systems . however, the singapore mrt is a controlled environment and therefore environmental conditions remained consistent throughout the study and no significant differences were recorded on days yielding virus-positive samples. furthermore, unlike temperate climates with distinct seasons, singapore has a tropical rainforest climate with high temperatures and humidity levels year-round, with little monthly variation. therefore, singapore experiences influenza outbreaks year-round, with two peak periods (april-june and september-december). although we were able to stratify our pilot study data by month, our results are too limited to properly assess a correlation between virus-positive aerosols and singapore's peak influenza periods. however, it is notable that the influenza a virus-positive and suspect-positive aerosol samples were both detected during singapore's second peak influenza period in . additionally, rsv-a-positive aerosols were collected during weeks of increased polyclinic attendances for acute respiratory infections in singapore . adenovirus-positive aerosols were collected during weeks of increased, average and decreased polyclinic attendances for acute respiratory infections . a larger study yielding more aerosol samples over a longer duration would be needed to further characterize the relationship between bioaerosols in the mrt and community health data in singapore. quickly identifying and robustly tracking respiratory threats are fundamental steps in an early emergency response to a pandemic. a bioaerosol sampling system is advantageous in this regard as it does not require the timely acquisition of ethical/irb approvals and informed consent needed to collect individual samples from human subjects. if an outbreak is suspected or underway, bioaerosol samplers can be immediately deployed in high-risk areas, yielding results within a minimum of ~ hours. moreover, if bioaerosol samplers are proactively used to monitor high-risk areas, initial results turnaround times are nearly cut in half, as sample collection time is ~ - hours. proactively monitoring for respiratory viruses also eliminates the risk of missing the time window of exposure to pandemic viruses in high-risk areas and would allow a more robust surveillance, which could be beneficial when the etiologic agent is known but the route of exposure is not fully understood. our bioaerosol sampling method also size-fractionates virus-laden particles, which can help measure the proportion of exposure to droplets versus droplet nuclei (i.e., inhalable versus respirable particles) in multiple environments and climates, which is important when assessing the type or severity of disease (e.g., an upper versus lower respiratory tract infection) that might follow. however, the full extent of exposure cannot be determined without measuring viral load. our study falls short in that we did not quantify the viral load in our aerosol samples, making it difficult to compare our results with quantitative aerosol studies. in the future, we will implement a dilution series of positive controls into our real-time rt-pcr/pcr assay protocols to create a standard curve that can be used to accurately quantify the viral load in each aerosol sample. when compared to a mobile/personal bioaerosol sampling method such as the one used in our study, a stationary sampling method is arguably a more practical approach to conducting disease surveillance. however, the use/installation of stationary samplers on the mrt would likely require permission from governmental authorities. strapping the bioaerosol samplers to our bodies was the least invasive way for our team to recover molecular evidence of aerosolized respiratory viruses on the singapore mrt. as this type of research is new to singapore, the wellbeing of singapore's civilians was carefully considered and therefore, researchers wore their duke-nus employee badges while sampling, and our laboratory's name was stitched onto the sampling backpacks (fig. ) for transparency. similar to a study measuring the risk of exposure to aerosolized influenza virus among healthcare workers in an emergency department during influenza season , strapping the samplers to personal backpacks allowed us to detect personal exposure to aerosolized viruses and provide insight into the efficacy of potential interventions (e.g., air/surface decontamination, and wearing face masks when infectious). moreover, with evidence validating the notion that mrt riders are at risk of exposure to respiratory viruses, we hope to motivate scientists to conduct similar field studies to unveil the true risk of exposure while using public transportation, as data on this topic are scarce. field studies may also inspire bioengineers and scientific instrument companies to design and test improved bioaerosol sampling such that it might be employed in a more widespread fashion to surveil for respiratory threats. in conclusion, our study suggests that when combined with molecular diagnostics, aerosol sampling has promising potential to work as a noninvasive tool to monitor for respiratory pathogens in public areas. additional studies are needed to assess a possible contribution of aerosol sampling to public health surveillance during periods of increased risk. bioaerosol sampling. from january through january , national institute for occupational safety and health (niosh) bc -stage aerosol samplers were used to collect aerosol samples from the following singapore mass rapid transit (mrt) heavy rail lines: east west line (ewl; green), and north east line (nel; purple). mrt lines were selected for their high capacity (~ , passengers per -car train), frequent use, and connection to high-traffic public areas. the ewl was specifically chosen for its connection to changi airport, and the nel for its connection to downtown singapore. aerosol samples were collected weekly, with occasional interruptions, during peak ridership (~ passengers/car or pax/m ) from : - : and : - : on wednesdays. sampling days varied occasionally due to public holidays and the researchers' availability. using a -foot ( cm) long piece of ¼" ( . cm) tygon tubing, niosh samplers were connected to airchek ® touch sample pumps (skc, eighty four, pennsylvania) carried inside personal backpacks worn by the researchers. both straps were tightened around the shoulders to secure the backpack against the researcher's back. niosh samplers were securely fastened to the front of the backpacks (on or above the researcher's heart) using velcro (fig. ) . for each separate mrt line (i.e., green and purple), the same assembled niosh sampler was used for both am and pm sampling sessions. to ensure all researchers followed the same sampling protocol, each researcher sampled one of the middle train-cars and remained standing with intermittent walking throughout each sampling session. between am and pm sampling sessions, sampler inlets were covered with electrical tape and the assembled samplers were refrigerated. all of the material collected by one niosh sampler during hours of sampling was counted as one aerosol sample. before aerosol sampling, air pumps were calibrated to sample at . l min − collecting a total of l of air per mrt line each week. calibration was performed by inserting the sampler into a calibration adaptor (designed for niosh samplers) attached to an skc check-mate calibrator. niosh samplers were engineered to separate collected particles into three size fractions: > μm, - μm, and < μm in diameter . prior to molecular analysis, the particles collected in the - μm and < μm size fractions were combined (see sample processing below). therefore, our study reports molecular results for two particle size fractions (droplets > μm and droplet nuclei ≤ μm). if processed directly, the minimum time duration between the start of sample collection and reporting of assay results (for one, hr aerosol sample) was hours. however, most of the dna/rna extracted from the aerosol samples was stored at − °c and analyzed in monthly batches. niosh samplers were rinsed with deionized water and soaked in % ethanol between each sampling day and a swab sample of the sterilized niosh sampler interior was used as a negative control sample for each sampling day. negative control swabs were transferred to tubes containing ml of . % bsa solution, vortexed for seconds, and discarded. negative control sample solutions were stored at − °c prior to further analyses. environmental data collection. ambient temperature, relative humidity (rh) and light intensity were logged during each sampling session using portable hobo data loggers (onset; bourne, ma, usa) tied to the sampling backpacks worn by the researchers. using bluetooth low energy technology, each hobo data logger wirelessly transmitted data to the researcher's mobile device using the hobomobile application. once sampling was complete, researchers used the application to stop the data logger and convert the data file to an excel file before sending the data to a designated research assistant's email address. data were then recorded onto a master excel file. sample processing. a uv-sterilized biological safety cabinet class ii and sterile consumables and equipment were used to process samples. using a filter-handling kit ( - ; skc), each polytetrafluoroethylene (ptfe) filter was removed from the niosh sampler cassettes and transferred to a ml falcon tube and vortexed while dry for seconds. to minimize cross-contamination, forceps were sterilized with % ethanol in between each filter transfer. one milliliter of . % bsa solution was then added to each ml falcon tube containing a filter and vortexed again for seconds. one milliliter of . % bovine serum albumin (bsa) solution was added to each . ml conical tube from the niosh samplers and vortexed for seconds. using cryotube vials, the bsa solutions from the ml falcon tubes containing filters were pooled together with their respective . ml conical tube sample. two milliliters of bsa solution were added to each ml falcon tube from the niosh samplers, vortexed for seconds, and transferred to cryotube vials. nucleic acid extraction and real-time rt-pcr/pcr. dna/rna was extracted from . ml of each aerosol sample and negative control sample solution using the qiaamp viral rna kit and qiaamp dna blood kit (qiagen) following the manufacturer's instructions. using previously validated probe-based molecular assays [ ] [ ] [ ] [ ] [ ] adapted to the duke-nus laboratory of one health research, extracted rna was tested for the presence/absence of influenza a and b viruses, enteroviruses, coronaviruses, and rsv subtypes a and b using superscript iii one-step real-time rt-pcr with platinum taq polymerase. rsv-a and rsv-b assays were not adapted to our laboratory during the time of sampling and therefore were performed months after the last aerosol sample was collected. extracted dna was tested for the presence/absence of adenoviruses by real-time pcr using a quantinova probe pcr kit (qiagen). three negative control reactions (no template) were included in each real-time rt-pcr/pcr assay. a positive aerosol sample was one in which virus was detected in one or more of the niosh sampler stages, with a ct value < . stage ( . ml tube) and stage (filter) were combined to represent respirable particles (i.e., droplet nuclei ≤ μm in diameter) compared with particles that are only inhalable (i.e., droplets > μm in diameter) collected in stage ( ml tube). cell culture and dna sequencing. virus-positive samples were tested for viability using cell culture. first, μl of each adenovirus-positive aerosol sample was inoculated into a cells (atcc) with dulbecco's modified eagle medium (dmem) % (v/v) fetal bovine serum (fbs) and incubated at °c. mdck cells were used to culture the influenza a virus-positive and suspect-positive aerosol samples. inoculated shell vials were then observed for cytopathic effect hours after inoculation, and daily for ten days afterwards. observation of cytopathic effect was used to score positive or negative cultures. rsv-positive samples were not tested for viability as rsv assays were not performed until after all of the original aerosol sample material had been used for dna/rna extraction, leaving us with no original sample material to perform cell culture on rsv-positive the findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the us centers for disease control and prevention. singapore ministry of health outbreak of pandemic influenza a (h n - communicable diseases surveillance in singapore epidemic hand, foot and mouth disease caused by human enterovirus middle east respiratory syndrome coronavirus (mers-cov). health advisory detection of the middle east respiratory syndrome coronavirus genome in an air sample originating from a camel barn owned by an infected patient a cross-sectional study of primary-care physicians in singapore on their concerns and preparedness for an avian influenza outbreak diagnostic testing for pandemic influenza in 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tests with four viruses the effect of environmental parameters on the survival of airborne infectious agents influenza virus infectivity is retained in aerosols and droplets independent of relative humidity. the journal of infectious diseases measurement of airborne influenza virus in a hospital emergency department development of an improved methodology to detect infectious airborne influenza virus using the niosh bioaerosol sampler distribution of airborne influenza virus and respiratory syncytial virus in an urgent care medical clinic singapore ministry of health healthcare personnel exposure in an emergency department during influenza season. plos one surveillance for respiratory and diarrheal pathogens at the human-pig interface in sarawak, malaysia increased detection of respiratory syncytial virus, influenza viruses, parainfluenza viruses, and adenoviruses with real-time pcr in samples from patients with respiratory symptoms cdc protocol of realtime rt-pcr for influenza h n . world health organization evaluation of three influenza a and b real-time reverse transcription-pcr assays and a new h n assay for detection of influenza viruses performance of different mono-and multiplex nucleic acid amplification tests on a multipathogen external quality assessment panel improved real-time pcr assay for detection and quantification of all known types of human adenoviruses in clinical samples. medical science monitor: international medical journal of experimental and clinical research this study was supported by start-up funding for dr. gregory gray's laboratory of one health research at duke-nus medical school, singapore. the datasets generated and/or analyzed during this study are available from the corresponding author on reasonable request. k.c., t.n., c.h.e., and g.g. designed the study. k.c., t.n., s.y., and c.h.e. performed aerosol sample collection and t.n., s.y., and c.h.e. performed laboratory works. k.c., t.n., s.y., and c.h.e. analyzed and interpreted the data. w.l. provided the niosh aerosol samplers and k.c. and w.l. guided the researchers in their use. k.c. and g.g. supervised the study. k.c. drafted the manuscript and w.l. and g.g. contributed to writing and reviewing the manuscript. all authors read and approved the final manuscript. competing interests: the authors declare no competing interests.publisher's note: springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. license, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the creative commons license, and indicate if changes were made. the images or other third party material in this article are included in the article's creative commons license, unless indicated otherwise in a credit line to the material. if material is not included in the article's creative commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. to view a copy of this license, visit http://creativecommons.org/licenses/by/ . /. key: cord- -hrcf udq authors: dickens, borame l.; koo, joel r.; lim, jue tao; park, minah; quaye, sharon; sun, haoyang; sun, yinxiaohe; pung, rachael; wilder-smith, annelies; chai, louis yi ann; lee, vernon j.; cook, alex r. title: modelling lockdown and exit strategies for covid- in singapore date: - - journal: nan doi: . /j.lanwpc. . sha: doc_id: cord_uid: hrcf udq abstract background with at least countries undergoing or exiting lockdowns for contact suppression to control the covid- outbreak, sustainable and public health-driven exit strategies are required. here we explore the impact of lockdown and exit strategies in singapore for immediate planning. methods we use an agent-based model to examine the impacts of epidemic control over days. a limited control baseline of case isolation and household member quarantining is used. we measure the impact of lockdown duration and start date on final infection attack sizes. we then apply a -month gradual exit strategy, immediately re-opening schools and easing workplace distancing measures, and compare this to long-term social distancing measures. findings at baseline, we estimated total infections ( . % of the population). early lockdown at weeks with no exit strategy averted ( . % of baseline averted), ( . %) and ( . %) infections for , and -week lockdown durations. using the exit strategy averted a corresponding , and total cases, representing . – . % of the total epidemic size under baseline. this diminishes to – for a late -week start time. long-term social distancing at and -week durations are viable but less effective. interpretation gradual release exit strategies are critical to maintain epidemic suppression under a new normal. we present final infection attack sizes assuming the ongoing importation of cases, which require preparation for a potential second epidemic wave due to ongoing epidemics elsewhere. funding singapore ministry of health, singapore population health improvement centre. case importation and the non-elimination of local cases, which parallel economic and social issues from lockdown implementation. sustainable and public-health orientated exit strategies are therefore required. we searched pubmed from database inception to may , , for articles using the search terms "covid- ", "sars-cov- ", "exit strategies" "lockdown" and "control measures". our search yielded three modelling papers of relevance. two articles examined control strategies within wuhan with one focusing on the effects of social mixing and the other on case isolation. another estimated the efficacy of long-term social distancing in the us. we found no articles which modelled the impacts of national lockdown and exit strategies for countries within the western pacific outside of china. in response to the rising number of local coronavirus disease (covid- ) cases, many countries have implemented lockdowns to restrict movement and community interactions and thereby suppress infection. details vary [ ] but measures commonly include the closure of premises such as non-essential workplaces, schools, recreational facilities and places of worship. essential services in healthcare, transport, cleaning, food services and supply chains may remain open to sustain the economy and welfare of the population. most lockdowns have successfully reduced the reproduction number and curtailed epidemic growth, but emerging from a lockdown prematurely without sufficient planning may result in epidemic rebounding [ ] , as the previous suppression of cases may leave a substantial proportion of the population susceptible to infection. intermittent lockdowns have been proposed [ ] through the cycling of initiation and cessation of these interventions-possibly until -to avoid exceeding hospital capacities. concerns exist, however, on the long-term economic disruption, negative consequences on social and mental well-being, and costly administration required to ensure compliance. here, in the context of lockdown and social distancing measures, we explore the impact of a gradual release exit strategy (gres) with a rollback of social distancing interventions operating outside of trigger mechanisms from emergency intermittent lockdown measures. health and isolation facility expansion and preparation will be required during the lockdown phase regardless of control strategy to maintain a high standard of healthcare, which can substantially reduce case fatality rates [ ] . gres can provide timelines to government agencies, services and businesses, and allow society and the economy to return to a new-normal state with continuing extensive education on the importance of safe distancing, hygiene practices and precautionary measures such as mask wearing. we assess gres through an agent-based model of a city, modelled upon the city-state of singapore. the implementation of social distancing measures in singapore has been progressive from march with the rollout of gradually stricter recommendations and regulations [ ] , leading to the implementation of a 'circuit breaker' [ ] , or lockdown, on april in response to rising autochthonous cases. although singapore's lockdown seemingly had no effect on several large outbreaks among foreign worker dormitories that started in early april, it appears to have arrested the epidemic growth in the general population, using school closures and workplace distancing as recognized and effective attack rate reduction measures [ , ] . substantial education and productivity losses are expected with all children tele-learning and an estimated % non-essential employees working from home or unable to work [ ] . in response, a -tier financial support package for businesses and individuals has been released to provide financial assistance for families, support networks, workers and students amounting to ∼$ . billion usd [ ] . on april , the singaporean government announced an extension of social distancing measures to weeks in total with plans to end on june [ ] . we utilise the geographical, demographic and epidemiological model of singapore for respiratory diseases (geodemos-r), an agent-based epidemic simulation model comprising of a synthetic and calibrated population where the impact of interventions can be measured. the model has been previously used to estimate the effects of early epidemic control [ ] and of home versus institutional isolation of cases [ ] , and has been updated and expanded to assess exit strategies. in summary, we investigate the effects of early social distancing, lockdown and gres in days by: ( ) establishing a limited control baseline with case isolation and quarantining of family members only; ( ) measuring the impact of -week (early cessation), -week (planned) and -week (extended) lockdown in duration, at different start dates of , , and weeks, on the final infection attack size, when compared to a no-exit strategy where lockdown is immediately lifted; ( ) estimating the effects of this lockdown with gres which includes the immediate re-opening of schools post lockdown, due to their limited epidemic suppression impact [ ] , with a -month readjustment period. in the first months, % of the workforce returns physically to work, followed by month at %, before full re-opening to pre-epidemic levels; and ( ) comparing lockdown to a no-lockdown strategy with longterm social distancing of differing start times at , , and weeks from the epidemic start date and durations of , , and weeks. during this period, % of the adult population is actively working, schools are closed and active social distancing is being done within the community. the model used is geodemos-r, an agent-based epidemiological model with a synthetic resident population that is heavily calibrated to be representative. full details are explained elsewhere; [ ] here we provide a summary. households were constructed using census tables based on a sample of , households. an heuristic search algorithm was used to create a total of . million singaporeans with the attributes of age, ethnicity and gender. remaining attributes were drawn randomly from the specified attribute's marginal distribution and summary tables of the population comparable to the census tables formed whose fit were assessed using pearson's chi-squared statistic. zero count cells were avoided by setting them to . . each attribute was fitted using a monte carlo swapping algorithm, which swaps two random individuals' data until the improvement in fit becomes negligible ( < . % improvement for , runs). the same process was used to generate partners, allocate children and create multi-generational families for . million households. households were geolocated within discrete areas named subzones according to spatial characteristics outlined in the census, and individuals allocated workplaces and schools appropriately based on distributions of commuting time data from singapore's household inter- view travel study and ez-link data which is a -month record of the majority of the population's public transport activities. in the transmission model, day and night steps exist to differentiate movement behaviour and infection likelihood between individuals within the household, school, workplace and community. during the day, workers interacted with individuals in the same workgroup, and students within their classes. these two groups also interacted with those in the wider area around their workplace and school at community rates. individuals who were not working or studying were modelled to interact with people in the same residential community. in the night step, individuals interacted primarily within their households where children had the highest probability of contact with his or her family members. suppose i and j are two individuals in the synthetic population with j becoming infected, we denote the probability of j infecting i on day t in location type g as ( ) here β g is constant for location type g , defined as the home, workplace or school which both individuals belong to; β g is obtained from a contact rate study (supplementary table , ) for different social group settings in singapore where the contact rates serve as the likelihood for individuals to infect one another at specific group locations and the wider spatial subzone area. overall, the probability of individual i getting infected from location type g on day t is therefore given as, here g is a set of individuals of location type g, g t is the subset of all individuals who belongs to set g and are infectious on day t . we use | . | to denote the size of the set of individuals. hence, | g | is the total number of people in set g . the number of people in set g that would be infected on day t can be denoted by a random variable x g ( t ) and where g r is the subset of g consisting of individuals that have been removed through hospitalisation and subsequent recovery. the total number of people α infected on day t can then be expressed by summing over all the different sets of individuals in the population, for each simulation, the model was run for daysapproximately months-to estimate the number of cases by the end of april ; cases began entering singapore in january . with more epidemiological information available, model parameters that were previously based on the severe acute respiratory syndrome coronavirus (sars-cov) have been updated (a summary of parameters and interventions is provided in supplementary table ). we assumed that the basic reproductive number ( r ) for sars-cov- was . [ ] , the asymptomatic rate was . % [ ] and the incubation cumulative distribution function was modified to have a median incubation period of days [ ] . the r parameter was built with a multiplier γ , which modified the infectiousness parameter of each individual in the simulation [ ] . we first simulate the initial weeks for a selected γ ∈ [ , ]. this γ has a correspondence with r ∈ r , the value of the exponential model exp( rt + b ) that best fits the simulated -week outbreak. this value of r was used in the linearized form of the susceptible-exposed-infectious-removed (seir) model [ ] to compute the corresponding r . through this process we obtained a corresponding value of r for γ . a grid search was performed on γ , with γ that corresponded closest to r = . being selected. for each scenario, we had case importation based on a poisson model with λ = . . to calculate λ, case importation data was used to fit a model on the expected number of daily case importations, where λ was the model's average case importation over time. for this study, we ran simulations for each intervention. there was no limit to isolation capacity as we assumed that the majority of the symptomatic cases will be transferred to hospital or community isolation facilities. our baseline scenario included the isolation of ascertained cases and home quarantine of their household members. all ascertained cases are assumed to have a -h delay before they are no longer infectious to the wider population to accommodate for healthcare facility visitation and testing. we additionally assumed perfect compliance of those under household quarantine as strict punitive measures are in place. for lockdown, a harsher penalisation on the contact rate was implemented with an initial -week period of social distancing, followed by a , or -week period where schools remained closed, and work and community contact rates are further reduced to %. this further reduction is to simulate essential work and economic activity still being carried out by the population during the lockdown period. the starting points were at week , , and of the epidemic. for the post lockdown strategy, two scenarios were modelled. the first assumed conditions went back to a pre-epidemic state with all schools, workplaces and the community at % transmission. the second, labelled as the gradual release exit strategy (gres), assumed a successive restoration of contact rates over a period of three months. in the two months directly after lockdown, schools reopen and contact levels are restored at %, followed by month of % restoration of workplace and community contact levels, and then pre-epidemic contact rates at %. this represents a cautious and planned approach to avoid heavily abnormal contact disruption from the initial lockdown period whilst maintaining a level of epidemic suppression. for a long-term social distancing strategy, school closure occurs and we assume % suppression in contact rates at workplaces and within the wider community. this measure can begin at week , , and where at each starting point, social distancing was implemented for , , and weeks in duration. after the end of the social distancing period, all schools were reopened with contacts restored to pre-intervention levels. the two weeks of social distancing pre lock-down are also assumed to follow the same contact rate reduction levels with school closure. we present the main results using a . % asymptomatic proportion, and the same analysis for % in the supplementary information ( supplementary figs. - ) . for the limited control baseline, the total number of infections by days was (iqr: - ), which represents . % ( . - . %) of the total population ( table ) a delayed post lockdown secondary peak size of ( - ) daily cases occurs for a -week lockdown duration starting at week , which is reduced further to ( - ) for an week lockdown in duration ( fig. (e) ). whilst substantially lower than the baseline peak, the initial pre-lockdown peak is relatively high. this peak is suppressed however for a lockdown starting at week ( fig. (c) ). although the secondary peak is greater at ( - ) and ( - ) daily cases respectively, it represents peak suppression throughout the epidemic in comparison to the baseline. lockdown start time has a larger impact than duration as relatively small ranges in the cases averted exist; for an asymptomatic rate of %, the total number of infections by days rose to ( - ), representing a . % increase in the infected population. for lockdown and gres, early lockdown at -weeks had a final infection attack size of ( - ) total cases for a -week lockdown, ( - ) for -week lockdown, and ( - ) for a -week lockdown ( table ) lockdown start time has a large impact on gres ( fig. and table ). with early lockdown implementation at weeks, when compared to no-exit strategy, gres averts an average of cases ( . %) in total for a -week early cessation lockdown, ( . %) for the planned -week and ( . %) for the prolonged -week. at this -week start time, gres also reduces the secondary peak size by ( . %), ( . %) and ( . %) at a ∼ -day delay respectively ( fig. (a) ). if implemented later and close to the epidemic peak at week , the efficacy of gres diminishes with ( . %), ( . %) and ( . %) cases averted in total, with no determinable sec- ondary peak ( fig. ) . gres' lessening utility with later lockdown start times is due to a large proportion of cases having already occurred in the first half of the epidemic. post lockdown peak sizes for a week start time lockdown strategy are substantially reduced with ( - ), ( - ) and ( - ) daily cases for a , and week duration lockdown with gres and ( - ), ( - ) and ( - ), respectively, without ( table ) . this represents a . , . % and . % reduction. for an earlier implementation lockdown time at weeks, a . %, . % and . % corresponding post lockdown peak reduction is observed. lockdown duration had a limited impact on gres, acting as a suppressive, not a preventative, measure. when utilising the week early cessation, planned -week lockdown and prolonged week lockdown, a difference of , and cases can be averted across the different start dates of , , and weeks using gres in comparison to lockdown alone; differing only by cases between these duration times. at a greater asymptomatic proportion of % we observed similar outcomes in terms of cumulative infection numbers for lockdown implementation on week and (supplementary figs. and ) although it represented an overall accelerated epidemic. the largest difference was observed for a -week lockdown with gres at week where ( - ) infections were observed in comparison to ( - ) at an . % asymptomatic rate. long term social distancing at durations of , , and -weeks cause resulting final infection attack sizes of ( - ), ( - ), ( - ) and ( - ) total cases across implementation start times of , , and weeks ( table ) . post social distancing peak sizes show suppression, particularly for implementation times of week , although if implemented at week , the initial peak is also reduced ( fig. ) . the secondary peaks caused by early lockdown and gres are comparable to long-term social distancing with % activity in the community and the workplace, wherein -week interventions starting at week cause a maximum of ( - ) cases for the former and ( - ) cases in the latter ( fig. (e) ). long term social distancing is less effective at durations of weeks or lower, averting up to . % of cases relative to the baseline for an implementation time at weeks ( table ) . for a duration of two weeks in social distancing, a maximum of . % of cases relative to the baseline can be averted if implemented close to the epidemic peak at weeks. for longer durations of to weeks, . - . %, . - . %, . - . % and . - . % of cases can be averted relative to the baseline for start dates of , , and weeks respectively. for a week implementation time, . % of cases can be averted critical uncertainties lie ahead on moving forward during lockdown periods in when and how to release the population back to a new normal state. our findings suggest that earlier lockdown requires a gres to prevent a large secondary peak, which becomes jid: lanwpc [m g; august , ; : ] less important the later the lockdown is implemented. as singapore entered lockdown relatively early where ∼ cases were being reported daily, a lockdown with no exit strategy could result in up to ( - ) total cases across days, which averts . % of cases in comparison to the baseline. gres can avert up to % of cases for the same scenario. for lockdowns implemented at later weeks, substantial proportions of cases are averted, as observed for other epidemics [ ] , with a final infection attack size of ( - ) at week as an example, although this will not be viable for most countries where their healthcare capacity cannot cope with large, early epidemic peaks. when gres is compared with no exit strategy for a and week implementation start time, it results in a reduction of . - . % in final infection attack size, and . - . % reduction for a and week start time as a large proportion of cases have already occurred in the initial epidemic ramp up. gres therefore shows good utility in populations where substantial proportions are susceptible to infection, reducing the overall outbreak size and slowing down infection spread with a greater number of transmission events prevented. this may provide opportunity to introduce prophylaxis or vaccination measures in the future, or allow the implementation of mandatory testing of all incoming travellers, which can prevent these infection events from occurring altogether as the epidemic dies out. this is especially paramount as the number of cases beyond days, although considerably lower than the initial peaks, still ranges from . - . cases per day for gres strategies (supplementary table a ) and . - . for long term social distancing strategies (supplementary table b ) with the ongoing risk of secondary case spread from imported cases. at the start of the epidemic however, the duration of lockdown has a limited impact on the efficacy of gres in terms of final infection attack size, which suggests that the period should be used for epidemic preparation rather than an ongoing control method, although an extended lockdown of or weeks will avert more cases. should medical capacity permit, long term social distancing remains a viable strategy provided it is carried out for a duration of at least weeks with % of the population working and schools closed. the total infection attack size is less for social distancing relative to lockdown with no exit strategy, but remains greater than gres which is the most effective strategy. for overall peak size minimization, both a social distancing and gres implementation time of weeks is optimal, although if earlier lockdowns or social distancing measures have been implemented, gres is essential for peak reduction. with a greater asymptomatic rate of %, the epidemic is considerably accelerated requiring earlier intervention at or weeks to slow infection spread. gres remains effective at a . % reduction in the final infection attack size in comparison to the baseline although these implementation dates are notably much later into the epidemic in comparison to the . % asymptomatic proportion findings. multiple complexities exist in the framing of exit strategies to the public, including the attribution of accountability among policymakers and individuals, the acceptance of uncertain economic burdens, and need for flexibility as technologies emerge and other countries respond differently as the epidemic progresses. lockdown and gres can maintain public preparation, awareness and adherence which may abate if complete cessation and re-initiation of measures are introduced for extensively long periods, as observed generally for long-term therapies and lifestyle changes [ ] . the strategy also partially mitigates isolation fatigue and social disruption, and should be conducted along with case finding, contacttracing and quarantining, mass-testing in key groups such as those working with vulnerable populations, and serological surveys. with gres in place, which will still require healthcare system ramp-up, real-time forecasting efforts can also continue to estimate appro-priate intervention trigger times should another lockdown be required. investment into the healthcare system to accommodate for the caseloads estimated in the study could avoid recurrent lockdowns, if the healthcare system can cope with the number of severe cases. the prolonged flattening, not elimination, of the epidemic across scenarios is due to the constant influx of a conservative estimated imported cases per day at the global travel hub, an estimated . % (or %) prevalence of asymptomatic infections and inevitable future relaxation of travel restrictions to allow for influxes of short and long-term worker immigration. additionally, containment measures and lockdowns vary widely in duration and severity between countries, [ ] causing differing and delayed epidemic peaks among source countries, making lockdown a temporary protection measure against highly uncertain external epidemiological forces where delays in reactive control measures abroad or within singapore will result in inevitable national case spread. although seroprevalence data has yet to be released, due to the ongoing lockdown measures, a substantial proportion of the population is suspected of being susceptible to infection, which exacerbates the effects of case importation. ongoing concerns regarding the effects of school closure remain at the forefront of covid- control policy. gres prioritises school re-opening as clinical manifestations of children's covid- appear generally less severe [ ] . the societal impacts of school closure among young children, working adult parents and older children in terms of productivity and education loss are likely to be extensive and unsustainable. with continued school closure, socioeconomic inequalities will be further exacerbated, despite governmental intervention to provide intensive distance learning for all school children [ ] . overall, outside of education, schools operate as a safety net for at-risk children, providing nutritional, emotional and social support as well as vaccinations and development opportunities. limitations of this study include uncertainties on the current number of infections, which could not be used directly to validate the initial phase of the epidemic in the agent-based model. parameter estimations from larger global studies were therefore used to simulate epidemics although wide ranges in observations continue to be reported for parameters such as asymptomatic rates. the model can be calibrated in the future with real time forecasting effort s and result s of serology surveys to better reflect covid- prevalence and incidence within singapore. intra workplace and school contact patterns were additionally not accounted for, which may cause greater or fewer localized contact events depending on internal grouping structures. further uncertainties include the current and future adherence to social distancing measures, future importation rates and spatial heterogeneities in infection rates. ongoing epidemics in high density accommodation (supplementary figure ) and their effects in the wider community were also not accounted for, which requires further investigation. bld and jrk performed the modelling and wrote the manuscript. bld, jrk, vjl and arc designed the intervention strategies. mp and sq performed data collection. jtl, hs, ys, rp, aws, lyac, vjl and arc critically revised the manuscript. the study sponsors had no role in the study design, analysis, interpretation of the data or writing of the report. lanwpc [m g first-wave covid- transmissibility and severity in china outside hubei after control measures, and second-wave scenario planning: a modelling impact assessment projecting the transmission dynamics of sars-cov- through the postpandemic period how will country-based mitigation measures influence the course of the covid- epidemic past updates on covid- local situation covid- (temporary measures) act . singapore: republic of singapore, thursday the effect of school closure on hand, foot, and mouth disease transmission in singapore: a modeling approach effectiveness of workplace social distancing measures in reducing influenza transmission: a systematic review strong national push to stem spread of covid- interventions to mitigate early spread of sars-cov- in singapore: a modelling study institutional, not home-based, isolation could contain the covid- outbreak school closure and management practices during coronavirus outbreaks including covid- : a rapid systematic review early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia estimating the asymptomatic proportion of coronavirus disease (covid- ) cases on board the diamond princess cruise ship investigation of three clusters of covid- in singapore: implications for surveillance and response measures flute, a publicly available stochastic influenza epidemic simulation model comparative estimation of the reproduction number for pandemic influenza from daily case notification data strategies for mitigating an influenza pandemic long-term adherence to health behavior change epidemiology of covid- among children in china mitigate the effects of home confinement on children during the covid- outbreak the authors declare no competing interests. supplementary material associated with this article can be found, in the online version, at doi: . /j.lanwpc. . . all data used within the study is publicly available. geodemos-r data is available on request. key: cord- -u hxyfml authors: seneviratne, chaminda jayampath; lau, matthew wen jian; goh, bee tin title: the role of dentists in covid- is beyond dentistry: voluntary medical engagements and future preparedness date: - - journal: front med (lausanne) doi: . /fmed. . sha: doc_id: cord_uid: u hxyfml the emergence of the highly infectious novel coronavirus sars-cov- has led to a global covid- pandemic. since the outbreak of covid- , worldwide healthcare systems have been severely challenged. the rapid and explosive surge of positive cases has significantly increased the demand for medical care. herein we provide a perspective on the role dentists can play in voluntary medical assistance and future preparedness for a similar pandemic. though dentists and physicians have different scopes of practice, their trainings share many similarities. hence, dental professionals, with their knowledge of basic human science and sterile surgical techniques, are an invaluable resource in the covid- pandemic response. overall, it is commendable that many dentists have risen to the challenge in the fight against covid- . for example, in singapore, national dental centre singapore (ndcs) deployed dental clinicians as well as volunteers from research laboratories to screen for suspected cases, provide consultations as well as conduct swabbing operations. dental practice will be considerably changed in the post-covid- era. there is a greater need to have refresher courses for practicing dentists on new infection control strategies. moreover, the curriculum in dental schools should be expanded to include competencies in pandemic and disaster relief. in addition, voluntary medical work should be made a part of the community dentistry curriculum. this volunteerism will leave a positive impact on developing the careers of young dentists. hence, the contribution of dentists beyond dental practice in this pandemic situation will be appreciated by future generations. the emergence of the highly infectious novel coronavirus sars-cov- has led to a global covid- pandemic. since the outbreak of covid- , worldwide healthcare systems have been severely challenged. the rapid and explosive surge of positive cases has significantly increased the demand for medical care. herein we provide a perspective on the role dentists can play in voluntary medical assistance and future preparedness for a similar pandemic. though dentists and physicians have different scopes of practice, their trainings share many similarities. hence, dental professionals, with their knowledge of basic human science and sterile surgical techniques, are an invaluable resource in the covid- pandemic response. overall, it is commendable that many dentists have risen to the challenge in the fight against covid- . for example, in singapore, national dental centre singapore (ndcs) deployed dental clinicians as well as volunteers from research laboratories to screen for suspected cases, provide consultations as well as conduct swabbing operations. dental practice will be considerably changed in the post-covid- era. there is a greater need to have refresher courses for practicing dentists on new infection control strategies. moreover, the curriculum in dental schools should be expanded to include competencies in pandemic and disaster relief. in addition, voluntary medical work should be made a part of the community dentistry curriculum. this volunteerism will leave a positive impact on developing the careers of young dentists. hence, the contribution of dentists beyond dental practice in this pandemic situation will be appreciated by future generations. keywords: covid- , dentistry, voluntary work, preparedness, infection control background the emergence of the highly infectious novel coronavirus has led to a global pandemic in a span of just months. it was only on december that first reports of pneumonia of an unknown cause detected in wuhan, china, began to surface to the world health organization (who). provisionally named as novel coronavirus ( -ncov), there was evidence of exponential human-to-human transmission in the early outbreak stage ( ) ( ) ( ) . consequently, on january , the who declared the outbreak a public health emergency of international concern (pheic). subsequently, assessment by the coronavirus study group (csg) of the international committee on taxonomy of viruses found that sars-cov- clusters phytogenetically with the species severe acute respiratory syndrome-related coronavirus (sars-covs) and genus betacoronavirus, and formally designated it as severe acute respiratory syndrome coronavirus (sars-cov- ) ( ). csg also emphasized that the name sars-cov- has no relationship to the name of the sars disease caused by sars cov- . in fact, the sars cov- genome shares only . % similarity to that of sars-cov- ( ) . the initial sequencing of the new coronavirus revealed that it is closely related to betacoronaviruses of bat origin i.e., bat-sl-covzc ( . % similarity) and bat-sl-covzxc ( . % similarity) ( ) . more recent genome sequencing showed that a bat coronavirus batcov ratg originally found in the bat rhinolophus affinis from yunnan province, china has . % genome similarly to that of sars cov- ( ) . these foregoing studies indicate that the bats are the likely zoonotic reservoir host for sars cov- . although bats may be the original source of the new coronavirus, it is assumed to be transmitted to humans via an intermediate host, possibly pangolins or wild animals currently yet unknown ( ). on february , the who announced coronavirus disease to be the disease caused by sars-cov- . subsequently, many countries continued to experience clusters of cases and community transmissions. this led the who to declare the covid- outbreak a pandemic on march . as of july , more than . million confirmed cases of covid- and , associated deaths have been reported worldwide ( ) . with the number of infected cases surging each day, researchers are racing to understand what makes it spread so easily. from the evidence so far, the transmission of sars-cov- can occur via respiratory droplets, contact and aerosols ( ) . a major factor facilitating the transmission of covid- is the high level of sars-cov- shedding in the upper respiratory tract, even among pre-symptomatic patients ( ) . it has been reported that pharyngeal virus shedding of sars-cov- reaches its peak on day of symptoms onset, and it can be over , times higher than sars-cov- ( ) . numerous cases have been reported wherein patients who had positive test results were asymptomatic at testing ( ) . moreover, the asymptomatic incubation period for infected individuals could be ∼ - days in general, although longer incubation periods as long as days have been reported. thus, symptom-based screening alone may have failed to detect a high number of covid- positive cases and most likely contributed to the rampant transmission. since the outbreak of covid- , worldwide healthcare systems have been severely challenged. the rapid and explosive surge of positive cases have led to a significant increase in the demand for medical care. on the infrastructure front, hospitals have actively scaled up their capacity of basic and critical care beds. however, global medical manpower resources are finite. consequently, many hospital-based healthcare workers have had to work overhours and take on extra shifts. such stressors have been associated with reduced job performance and fatigue-related errors which could harm patients ( ) . in responding to this crisis with a multi-sectorial, equitable and human-rights focused approach, the united nations entities have called for voluntary support from professionals with medical backgrounds for various job capacities to manage the pandemic ( ) . though dentists and physicians have different scopes of practice, their trainings share many similarities. the dental student, like his medical counterpart, has to attain proficiency in his understanding of the basic sciences such as anatomy, physiology, pharmacology, and microbiology. this is essential given that dentists are expected to competently manage dental issues of medically compromised patients. moreover, dentists must be able to expeditiously and effectively manage medical emergencies that may arise in routine dental practice. to this end, many dental practitioners would have undergone basic cardiac life support training. thus, the robust training of clinical medicine in dentistry strengthens the candidature of dentists to volunteer services for covid- control and spread. the outbreak of covid- has significantly affected the practice of dentistry. dental treatment can generate large amounts of aerosols and droplets mixed with the patient's saliva or blood ( ) . this poses a risk to dental professionals as sars-cov- has been detected in saliva of infected individuals ( ) . many dentists have therefore discontinued the provision of elective dental treatment, in accordance with guidelines released by national-level government healthcare authorities such as the centers for disease control and prevention (cdc) in the us and national health service (nhs) in the uk. only limited cases that require urgent or emergency dental care continue to be seen. the significantly reduced workload during this time, coupled with robust training in a medical setting, makes the dentist a prime candidate to volunteer in the fight against covid- . dental professionals, with their knowledge of basic human science and sterile surgical techniques, are an invaluable resource in the covid- pandemic response. licensed dentists are eligible to administer covid- diagnostic tests such as nasopharyngeal and oropharyngeal swabs. with their detailed understanding of head and neck anatomy, dentists are well placed to perform such procedures accurately and atraumatically. this is imperative as irritation to the oral or nasal mucosa while swabbing risks the patient sneezing or coughing, potentially releasing contaminated droplets and aerosols to the environment. unlike negative-pressure rooms, many makeshift medical screening facilities are unable to limit the aerosol spread of sars-cov- . this may lead to contamination of open-air healthcare facilities. in this context, dental clinics that are well equipped with facilities to control aerosol spread of infections, such as negative pressure rooms and high-volume excavators, can offer help to augment the capacity for covid- screening. in this regard, global health authorities as well as health ministries from the respective countries have provided clear standard infection control procedures for dentists ( ) ( ) ( ) . dentists can also assist their medical counterparts in the inpatient setting. such duties include patient triage, monitoring vital signs, administering oxygen and injectables, and writing prescriptions. should emergency procedures need to be performed, dentists are capable of administering local anesthesia and suturing. in addition, oral surgeons and dentist anesthesiologists are competent in performing intubation, deep sedation and general anesthesia services ( ) . the covid- outbreak as well as harsh lock down practices worldwide have created a stressful environment for many people globally. such stressful situations have been shown to lead to poor oral health ( , ) . therefore, oral healthcare professionals should consider developing online platforms to provide information on oral hygiene and oral health maintenance. digitalized healthcare services can be implemented with a qualified team of dentists being available online to provide reliable oral healthcare solutions in an accessible, affordable and appropriate manner and allay patients' dental concerns during the lockdown period. oral healthcare professionals can also engage in voluntary service for residents in community housing to promote good oral health. the recommendations on how the dental fraternity can play their part in the current crisis are summarized in table . in singapore, while limited community transmission of covid- remains, there has been a rapid surge in the number of infected cased among foreign workers living in dormitories. such facilities become conducive for rapid spread of sars-cov- as residents are housed in close proximity and share many common amenities. in a whole-of-government approach to isolate and eradicate the virus, the singapore government implemented aggressive mass-scale testing for covid- for foreign workers residing in dormitories. this major operation was undertaken by multiple agencies including singapore health services (singhealth), singapore police force and singapore armed forces. supporting this move, national dental centre singapore (ndcs) deployed dental clinicians as well as volunteers from research laboratories to the foreign worker dormitories to conduct swab operations. all patients were treated as suspect cases, and all volunteers observed universal precautions and donned appropriate personal protective equipment (ppe). the use of specially manufactured swab booths further minimized the risk of cross-infection between patients and volunteers (figure ) . in this massive operation, ndcs staff worked collaboratively with colleagues across various professional backgrounds including clinicians, nurses, pharmacists, radiographers, and medical social workers (figure ) . without the cohesive and coordinated effort, it would have been a considerable task to successfully establish and staff the field swab clinics within a short period of time. in the uk, dentists, dental support teams as well as clinical academics have played a vital role in supporting the nhs ( ). for instance, there are news reports that dental staff from bath health nhs trust and qmul institute of dentistry are helping in maternity, critical care, and emergency units. dental hospitals have undergone reconfiguration to support medical care. in the us, dentist volunteers in states such as virginia and california have responded to appeals to assist with critical emergency care needs, and have been redeployed to the frontlines. importantly, states such as california have made changes to their law to allow greater flexibility in scope and licensure in the time of a catastrophic emergency. the law provides immunity from liability for care provided "in good faith" during an emergency for a person who "voluntarily and without compensation or expectations of compensation, and consistent with the dental education and emergency training that he or she has received, figure | dental clinicians from national dental centre singapore were trained to conduct swab procedure using swab booths manufactured in singapore (photo credit: national dental centre singapore). a team of singapore health services (singhealth) volunteers assigned to manage a medical clinic at a foreign workers' dormitory in singapore. this team included a neurologist, a dental scientist, a pharmacologist, a cancer patient service associate, a radiographer and nurses (photo credit: national dental centre singapore). frontiers in medicine | www.frontiersin.org provides emergency medical care to a person during a state of emergency." this would be an important consideration for other countries to follow. covid- has been an unprecedented experience for mankind. the scale and extent of the pandemic has forced many governments to take drastic and decisive action, resulting in considerable disruption in daily life and damage to global economies. this episode has revealed the need to be better prepared for future pandemics. to this end, educational institutions can take the lead. dental schools should revise and strengthen education on infection control measures in dental practice. some areas where universal precaution protocols can be re-evaluated and strengthened include hand hygiene, donning and doffing of ppe, respiratory hygiene/cough etiquette, sterilization of instruments and devices, and disinfection of workplaces. additionally, with the growing evidence of asymptomatic transmission of covid- , infection control practices should be re-examined and improved to prevent crossinfection in a dental setting. notwithstanding, recent attempts have been made to review the current literature on precautions when providing dental care during the current pandemic, and make recommendations for dental practitioners ( , ) . the curriculum in dental schools should also be expanded to include competencies in pandemic and disaster relief. such exposure enable dentists and their dental auxiliaries to augment the existing medical professionals in response to declared medical emergencies. dentists have already been trained to undertake oral swab procedures and biopsies as part of oral cancer screening. however, in the wake of a pandemic outbreak, dental students should be additionally trained to perform nasopharyngeal and oropharyngeal swabs, as well as saliva sampling procedures. dentists can also be a part of an effective surveillance network by notifying public health authorities about unusual oral symptoms or clinical presentations detected in questionable frequency in a population. thus, dentists can facilitate the early detection of a disease outbreak or bioterrorism attack, and prevent mass casualties by prompt interventions. in addition, voluntary medical work should be made a part of the community dentistry curriculum. in dentistry, clinical outreach programs during undergraduate training are still in their infancy. such programs should be quickly scaled up. several studies have reported that overseas voluntary outreach programs are a fulfilling and life-changing experience for dentists ( ) , and that community-based learning experience brings significant positive outcomes in terms of productivity and higher professional standards of dental students ( ) . with the expanded level of contact with patients from various strata of society, students will have additional opportunities to see the complexities of social and cultural aspects of their future patients. in addition, students are likely to gain appreciation for alternative career paths in public health as well as volunteer work. these experiences also have a positive impact on their understanding of ethical and social issues related to oral health care ( ). some dental schools have already included community engagement programs as a part of the dental curriculum. such engagements instill a sense of voluntarism in the minds of the dental graduates and prepare them to contribute in future disease outbreaks. a study looking at stony brook university's humanitarian dental mission to rural madagascar found that all dental students who participated gained experience and confidence in their clinical ability and increased their speed in performing procedures under demanding conditions ( ) . beyond medical training, such programs also nurture team work, communication skills and leadership qualities in young dentists. moving forward, it is likely that dental practice will be considerably changed in the post-pandemic era. therefore, there is a greater need for refresher courses for practicing dentists on infection control in order to adjust with patients' apprehension in the post-covid- world. dental authorities and dental schools should urgently look into this need and appoint taskforces to develop protocols and appropriate courses for dental practitioners. concurrently, research on infection control in the dental setting needs to be advanced. in order to formulate best practices, new research should be conducted across all disciplines of dentistry covering all procedures and their respective infection control strategies. the field of public oral health should find new research avenues on community oral health that can provide an insight on the perception and apprehension of patients during hospital visits. such information would help to revive the financial viability of public hospitals and private clinics. the recommendations for dental implementation in the post-covid- era are summarized in table . volunteers are being selfless in providing services amid crisis. however, it should be borne in mind that similar with medical staff, volunteers are also a vulnerable group. preparation and medical support for volunteers during their placement is a significant aspect of any overseas voluntary work. lack of understanding and preparation may expose volunteers to certain diseases during community engagement as well as subject them to psychological problems ( ). hence, it is highly advisable that proper training is provided to the volunteers. volunteers should be trained on proper donning and doffing of ppe. it is important not just to minimize cross-infection but to keep it to zero. therefore, strict infection control measures such as correct use of gloves and hand hygiene steps should be practiced. volunteers working in close contact with covid- positive patients should check for proper fit and size of n masks. it is very likely for cross-contamination to occur during public mass-scale swabbing operations. a single breach of the chain of infection control will put the whole team in jeopardy leading to quarantine of its members and closure of the medical facility. not all volunteers have the same physical and mental strength and the amount of volunteering work that one can engage must be monitored by group leaders and higher level authority. frequent breaks in between and off days are necessary, in particular for a longer engagement, to support mental and psychosocial well-being of the volunteers. it is also important to provide an understanding of the precautionary safe-distancing measures to be taken with family during and after engagement in risk activities. it is essential that volunteers are mindful of their own and their family's health while serving others. overall, it is commendable that many dentists have risen to the challenge in the fight against covid- . the role of the dentist in a pandemic can be beyond dentistry. by virtue of their training and practical experience, dentists can provide services in various ways to reduce the strain on the healthcare sector. volunteerism in such a time also leaves a positive impact on the individual. pandemics rarely occur, and practical experience gained will be a lifelong lesson for the volunteer. in fact, the fighting spirit of a volunteer working in risky operations instills a high moral esteem and self-confidence. the rejuvenated personality of the volunteer can prove to be valuable in developing his career in future. the selfless voluntary service will be appreciated by the larger community and future generations. together we will be able to pull through this crisis and emerge stronger than before. written informed consent was obtained by the ministry of health singapore for the publication of any potentially identifiable images or data included in this article. clinical features of patients infected with novel coronavirus in wuhan early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study severe acute respiratory syndrome-related coronavirus: the species and its viruses -a statement of the coronavirus study group genomic characterisation and epidemiology of novel coronavirus: implications for virus origins and receptor binding a pneumonia outbreak associated with a new coronavirus of probable bat origin identifying sars-cov- related coronaviruses in malayan pangolins coronavirus disease (covid- ) situation report - transmission routes of -ncov and controls in dental practice asymptomatic transmission, the achilles' heel of current strategies to control covid- virological assessment of hospitalized patients with covid- presymptomatic sars-cov- infections and transmission in a skilled nursing facility negative impacts of shiftwork and long work hours volunteers for novel coronavirus (covid- ) pandemic response aerosols and splatter in dentistry: a brief review of the literature and infection control implications saliva is a reliable tool to detect sars-cov- covid- guidance and standard operating procedure gradual resumption of dental services after covid- circuit breaker period dentists can register to help with state's covid- pandemic response the importance of family functioning, mental health and social and emotional well-being on child oral health. child care health dev dentistry and coronavirus (covid- ) -moral decisionmaking possible aerosol transmission of covid- and special precautions in dentistry precautions when providing dental care during coronavirus disease (covid- ) pandemic dental mission for children-vietnam comparing fourth-year dental student productivity and experiences in a dental school with community-based clinical education a questionnaire study of voluntary service overseas (vso) volunteers: health risk and problems encountered cjs and ml contributed to the conception. cjs, ml, and btg drafted and critically revised the manuscript. all authors contributed to the article and approved the submitted version. the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.copyright © seneviratne, lau and goh. this is an open-access article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord- - o ey l authors: tay, kiang hiong; ooi, chin chin; mahmood, muhammad illyyas bin; aw, lian ping; chan, lai peng; ng, david chee eng; tan, bien soo title: reconfiguring the radiology leadership team for crisis management during the covid- pandemic in a large tertiary hospital in singapore date: - - journal: eur radiol doi: . /s - - -w sha: doc_id: cord_uid: o ey l abstract: the coronavirus (covid- ) outbreak poses a serious public health risk. to date, the disease has affected almost all countries in the world. the enormous scale of the outbreak and the relative lack of knowledge and information regarding a new virus, as well as the unpredictability of events, make it challenging for leadership teams to respond. this paper shares how we have reconfigured our radiology leadership team into a smaller disease outbreak task force (dotf) to respond and coordinate all related efforts during this ongoing covid- pandemic. the dotf format is modelled after the military with domain groups looking at manpower, intelligence, operations, and logistics matters on a daily basis so that timely decisions can be made and action plans executed promptly. in managing the dotf, discipline, flexibility, and teamwork are key principles, and these are built upon a strong foundation of focus on infection prevention and control, and patient and staff safety as well as staff well-being. the dotf has positioned us well to confront the many challenges to date. we believe it will also help us navigate the complex issues that will arise with future surges in cases and in formulating strategies to manage exit from the present and future lockdowns. key points: • in a pandemic, regular and directed meetings by a smaller leadership core group are required, for prompt decision making and execution of action plans. • the military format, with domain groups to look at manpower, intelligence, operations, and logistics matters, is useful in managing a pandemic. • discipline, flexibility, and teamwork with strong focus on infection prevention and control, and patient and staff safety as well as staff well-being are key principles for leadership teams managing a pandemic. during an infectious disease epidemic, timely decisions need to be made and plans executed promptly to prevent widespread transmission. in the early phase of a disease outbreak, information tends to be incomplete and decisions have to be made based on fundamental infection prevention and control (ipc) principles as well as experiences from past disease outbreaks. as an epidemic unfolds, there will be need for leadership with foresight to anticipate potential issues, to manage them, or at least to prevent them from escalating [ ] . radiology services are a critical cog in an institution's response to a disease outbreak as imaging is a key component in the detection of infected patients and radiology facilities are potentially a nidus for intrahospital disease transmission [ , ] . the existing organizational structures of radiology departments are designed to cater to day to day operations as well as to facilitate mid-to long-term strategic planning. in large departments, depending on how the leadership structure is configured, the day to day operations are largely delegated to modality imaging teams and subspecialty radiology teams, often with significant autonomy. mid-and longer-term decisions are made by a larger management team, usually through consensus and typically after comprehensive discussions and assessments. such an organizational structure may be able to manage a minor crisis but is less likely suited for handling disruptive and dynamic major events like pandemics. in these situations, there is little room and time for lengthy discussions and prompt decision making, often based on limited information, is critical. we share how we have reconfigured our radiology leadership team into a disease outbreak task force (dotf) to respond and coordinate all related efforts during this ongoing coronavirus disease (covid- ) pandemic. singapore was badly affected by the severe acute respiratory syndrome (sars) epidemic in . there were cases worldwide and singapore had the third highest number of cases (n = ) in the world. the case fatality rate was . % in singapore, compared with the worldwide case fatality rate of . %. there were extensive intrahospital transmissions, with cross infection among healthcare workers, inpatients, outpatients, and visitors. in fact, . % of the sars patients in singapore were healthcare workers, of whom five of them (two doctors, two nurses, and one healthcare attendant) died [ ] . following sars, our country has been systematically taking steps to improve our capability to deal with another major disease outbreak. the singapore government introduced the dorscon (disease outbreak response system condition) framework in to guide response in an infectious disease outbreak situation [ ] . this framework is not only designed for healthcare, but it also enables a "whole-of-government" response with formal platforms for inter-ministerial and cross-agency coordination, providing strategic and political guidance on a range of related issues such as border control, economic sustainability, security, transport, and education. within the ministry of health (moh), a disease outbreak team is responsible for medical response, surveillance, isolation, contact tracing, quarantine, and provision of medical care. similar disease outbreak teams are established in all major public healthcare institutions to interface with moh and coordinate responses and efforts in their respective institutions. there is also a communications component, which conveys the health impact of the disease to the general population and to advise them how to respond [ ] . our institution has a preparedness and response department (prd) to oversee civil emergencies, disease outbreaks, and business continuity planning. this department has representation from all relevant medical, nursing, allied health, and operations departments within the institution. meetings and table-top exercises are conducted regularly and pertinent policies and standard operating procedures are formulated and updated. as major infectious disease outbreaks are uncommon, most of the exercises have focused on mass casualty response and business continuity. existing radiology leadership organization structure at our institution, a -bed tertiary hospital, the departments of diagnostic radiology, vascular and interventional radiology, and nuclear medicine & molecular imaging are organized under a division of radiological sciences. the faculty of the three departments together with radiographers, imaging technologists, nurses, and related support staff bring the total manpower strength of the division to over . the division management committee, responsible for the day to day operations, is made up of key appointment holders of the departments and imaging modalities (general radiography, ct, mri, ultrasound, mammography, interventional radiology, and nuclear medicine) as well as leaders for nursing, radiography, support staff, administration, logistics, quality management, imaging informatics, and service development. this management committee has a total of members and meets fortnightly to coordinate and deliberate on major decisions, while allowing the various units to operate autonomously. the division also nominates representatives to participate in our institution's prd meetings. the first confirmed covid- case in singapore was diagnosed in our institution on january . our radiology management committee had convened daily to start preparations for the anticipated disease outbreak. we soon realized our existing management committee was too unwieldy for quick decision making and many of the committee members were not able to attend the increased frequency of meetings. a smaller leadership group was quickly reconfigured into a dotf to handle all matters related to the epidemic. the dotf comprised the division senior management namely the division chair, assistant division chair, heads of the three clinical departments, leaders of radiography, nursing, clinical operations, imaging informatics, and administration. the general radiography manager was incorporated into our dotf as general radiography became the key imaging modality for covid- in our practice, as was our logistics manager as we felt it was critical to track of our personal protective equipment (ppe) stocks and usage. we also incorporated personnel with experience in fast-paced operations (during their stint in military service) even though they did not hold current positions in our management committee. with this, we reduced our number to a more manageable members for the dotf. one additional feature of our dotf was that several key leaders had held significant leadership roles during sars. this proved to be valuable during the initial outbreak period as much of the initial response could then be implemented based on our experience with sars [ , ] . however, as the outbreak evolved into a pandemic, it became clear that covid- had some different features and new approaches had to be formulated [ ] [ ] [ ] . our division chair is an integral member of our institutional dotf. during the onset of the outbreak, our institutional dotf met daily in the morning and disseminated information and instructions to the rest of the hospital through a set of routine instructions in the afternoon. we decided that our dotf would meet daily in the late afternoon so that information from the institution can be incorporated into our decisionmaking process and action plans. the intent was that the meeting should not last longer than an hour. additionally, we felt that it was important that a smaller core leadership group meets first thing in the morning daily to review overnight events and changes, update the manpower situation, and anticipate issues for the day. this group comprised members, and the morning meeting lasts about min [ ] . to cater for the rapidly changing scenarios and operational demands, we decided that our dotf format and framework would be mirrored after the military format. in singapore, we have a conscript armed forces, and all males would have experienced military training, and are familiar with this format. the female members of our staff, having fathers, husbands, partners, brothers, and sons conscripted, were also attuned to this military concept. our dotf was divided into domain groups looking at manpower, intelligence, operations, and logistics matters, corresponding to the key staff functions of a military organization [ ] [ ] [ ] . this use of a military format has been advocated as a systematic and effective method for handling a crisis [ ] . briefly, the military staff structure and functions are divided into eight domains from g to g and g to g (g stands for general staff and there is no g ) where g is responsible for personnel or manpower issues, g is in charge of intelligence gathering, g is responsible for operations, g looks after logistics, g is responsible for mid-to long-term planning, g is in charge of signal/ communications, g is responsible for financial management, and g deals with civilian affairs [ ] . we adopted the first four domains for our dotf as we felt they were the most relevant. the manpower domain tracks the number of staff at work and the deployable staff numbers. staff on sick leave or on quarantine are monitored ( table ). all our staff are required to submit body temperature readings twice daily and this domain monitors the readings and scans where staff are deployed to detect any potential fever clusters forming with our division. when physical distancing was implemented, this domain coordinated the roster of staff working from home. the manpower domain also formulated a division communications strategy, to ensure all decisions made reach the ground for consistent implementation. the wellbeing of all staff is coordinated with our division staff experience team, resulting in initiatives like regular distribution of individual care packs to boost staff morale. the intelligence domain gathers all information relevant to covid- , including instructions and directives from our institution and moh. they also scan the medical literature and various media platforms for new scientific evidence or data that could impact our decisions or actions. one such example was the need for physical distancing to be implemented within our work environment, a measure that was not as robustly imposed during sars [ ] . more recently, with the deluge of publications on covid- , a more organized and systematic review of the emerging literature became necessary. the operations domain deals with formulating and implementing workflow changes and staff deployment related to handling of covid- patients and patients suspected of or at risk of covid- . these include drawing up detailed ipc guidance for the various imaging settings and scenarios, in alignment with our hospital ipc team's recommendations [ , , ] . refresher training in proper use of ppe and powered air-purifying respirator was organized. the domain also monitors workload data of the various imaging modalities closely to anticipate surges or decline in demand so that manpower and resources can be redeployed accordingly. in particular, the demand for portable radiography at various locations, namely the isolation wards, our higher risk acute respiratory infections wards, the emergency department, and fever screening areas are tracked daily. when a partial national lockdown was introduced, the need for readjusting imaging appointments was also initiated and worked on with all stakeholders. in collating this data, it is useful to have software (tableau software) that facilitates real-time analysis, so that short-term trends in terms of weeks and days can be identified and compared with historical data. another strategy that was adopted was to insert a radiology faculty into our infectious disease team, allowing us real-time information and the ability to shape our imaging service response [ ] . the logistics domain keeps track of all consumables, imaging equipment, reporting workstations, and real estate management. equipment under repair or servicing is monitored closely to ensure minimal downtime. logistics also monitors ppe usage closely and ensures adequate stocks are at hand. this domain is responsible for mask distribution to minimize wastage. when it was clear that physical distancing was necessary, the reconfiguration of all our work areas and staff rest areas was under its purview. the operations domain is tasked to conduct these meetings and serve as the secretariat. our dotf meeting agenda is composed of a fixed format to ensure that no key issue is missed (table ) . at the dotf meetings, each domain will provide updates of their respective areas. the agenda also includes reviews of problem areas that have been highlighted. one example is that a daily walkabout has been instituted to ensure ipc standards, address patient and staff safety issues, and identify ground issues. key findings during these walkabouts are presented as part of the agenda. feedback received from staff were collated and addressed, and where there were good suggestions from the ground, these were rapidly implemented. small teams are also assigned as necessary to look after specific projects that require fast turnaround, for example, planning the radiology support when our institution decided to convert a multi-storey car park on campus into a fever screening area at short notice. this multi-storey car park had been designed and pre-built to be easily reconfigured during a other issues that are identified but do not fall under the direct purview of the subgroups are delegated to additional teams to address, for example, education and research matters. at the end of each dotf meeting, information and instructions are collated and packaged for dissemination to the rest of the staff in the division. the dotf format and framework are strictly adhered to and all discussions are minuted so that outstanding issues are addressed or followed up. the dotf meetings were conducted in person initially but as the outbreak progressed and physical distancing measures were introduced, the meetings are now conducted using video conferencing platforms (zoom video communications and cisco webex). over time, the frequency of the dotf meetings has decreased to three times a week although the core leadership group continues to meet daily in the morning. after the initial response period to the outbreak, we have also resumed our fortnightly management committee meetings to address ongoing business including the implementation of annual workplans and budgets, planned equipment procurement, and addressing how these may have to be adjusted in terms of timing in the light of the pandemic. the best laid plans will not lead to robust implementation without a comprehensive communications strategy. to this end, we realized that to reach out to more than staff effectively, multiple platforms had to be adopted. official communications were sent out daily via email. for other relevant information including staff well-being initiatives, an approved social media platform was utilized (workplace by facebook). in addition, every team was informed to set up secure text messaging communications chat groups using the institutional approved platform (tigerconnect) for work-related matters including patient information so that we adhere to our privacy laws. staff chat groups using popular social media platforms (whatsapp messenger) were also encouraged for non-workrelated communications, to allow staff to stay socially connected. at the time of writing ( june ), there has been , cases of covid- reported in singapore and our institutional has managed inpatients cases in total; cases are currently admitted [ ] . we have performed x-rays, five ultrasounds, ct scans, and one mri scan on covid- positive patients. with this leadership strategy, only one member of our division has been infected, from contact within the community, and we have had no incidence of in-hospital transmission among our staff. since the onset of the outbreak, major radiology service initiatives that we have had to undertake include the implementation of portable x-ray and ultrasound services in highrisk areas, setting up of a new institution fever screening area with x-ray facilities in a multi-storey carpark to complement our emergency department, and installation of a ct scanner (loaned to us without cost by an industry partner) to increase capacity for the duration of the pandemic. we have also managed a huge surge of cases nationally for the past months. one component of effective leadership is ensuring that we do not become complacent when we appear to be having the crisis under control, but to continue to think and to plan ahead strategically [ ] . in addition to reacting to the fast-paced changes, our dotf has also been tasked to look toward the future to anticipate the "new normal" of providing imaging and image-guided treatments [ ] . as we serve more than one imaging location, we are investigating how we can better plan and interface with our patients so that the appropriate imaging study can be delivered at the right time and at the appropriate site while reducing patient dwell time in our facilities. we are also piloting teleconsultations to reduce the need for patients to travel to our facilities. many of the communications platforms we have now embraced will be key to our future initiatives in management, the delivery of clinical service, and in education. an interesting outcome that has also arisen from this crisis has been the opportunity to identify colleagues with interest in leadership and management. we have brought in younger colleagues into our dotf and they have seized the moment and demonstrated their abilities and expertise. some of our colleagues have similarly been seconded to institutional teams to lead and we in turn have had to identify additional talent to groom. a crisis of this dimension is a unique opportunity for nurturing future leadership talent [ ] . the covid- pandemic is a dynamic and fast-paced situation which mandates rapid response from all radiology leadership teams. we believe that by reconfiguring our management team into a tighter dotf based on a military format has positioned us well to confront the many challenges to date within the context of our singaporean experience. in managing the dotf, discipline, flexibility, and teamwork are key principles, and these are built upon a strong foundation of focus on ipc, patient and staff safety, and staff well-being. in formulating our response, the dotf is also tightly aligned vertically and horizontally within our institution. while the military format may not be universally familiar, many of the principles we have embraced are widely applicable in effective crisis management. we are quietly confident that our experience to date in crisis leadership management will help us to navigate the complex issues that will arise with future surges in cases and in formulating strategies to manage exit from the present and future lockdowns. leading in a crisis, part severe acute respiratory syndrome: years later-a radiology perspective covid- patients and the radiology department-advice from the european society of radiology (esr) and the european society of thoracic imaging (esti) occupational health aspects of emerging infections -sars outbreak affecting healthcare workers moh pandemic readiness and response plan for influenza and other acute respiratory diseases covid- in singaporecurrent experience: critical global issues that require attention and action deja vu or jamais vu? how the severe acute respiratory syndrome experience influenced a singapore radiology department's response to the coronavirus disease (covid- ) epidemic planning and coordination of the radiological response to the coronavirus disease (covid- ) pandemic: the singapore experience radiology preparedness in the ongoing battle against covid- : experience from large to small singapore public hospitals adapting to a new normal? key operational principles for a radiology service facing the covid- pandemic radiology department preparedness for covid- : radiology scientific expert panel the singapore army united states army field manual . . commander and staff: organisation and operations general staff. encyclopaedia britannica, inc comparing military and civilian critical thinking and information processes in operational risk management: what are the lessons? touch me not: physical distancing in radiology during covid- old threat, new enemy: is your interventional radiology service ready for the coronavirus disease interventional radiology procedures for covid- patients: how we do it what can european radiologists learn from the outbreak of covid- in china? a discussion with a radiologist from wuhan singapore ministry of health (moh) leading in a crisis, part : succeeding in battle outbreak of novel coronavirus (covid- ): what is the role of radiologists? publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations guarantor the scientific guarantor of this publication is dr. kiang hiong tay. the authors of this manuscript declare no relationships with any companies whose products or services may be related to the subject matter of the article. no complex statistical methods were necessary for this paper.informed consent written informed consent was not required for this study because it is a special report on radiology leadership.ethical approval institutional review board approval was not required because it is a special report on radiology leadership.methodology not relevant. key: cord- -tph d fl authors: de deyn, michelle lee zhi qing; ng, qin xiang; loke, wayren; yeo, wee song title: a tale of two cities: a comparison of hong kong and singapore's early strategies for the coronavirus disease (covid- ) date: - - journal: j infect doi: . /j.jinf. . . sha: doc_id: cord_uid: tph d fl nan in hksar, it is known that community-wide masking was practiced by the general population at an early stage of the pandemic . based on news reports and official press releases, it is evident that many asian countries, which have successfully contained the first wave of infections, are now experiencing a second wave of imported cases from abroad and worsening local transmission . as the authors rightly mentioned, singapore and hksar share several similarities in that they are both sprawling city states with developed economies, a high trade-to-gross domestic product (gdp) ratio, advanced infrastructure and healthcare systems, and they both had varying successes thus far in the management of the ongoing pandemic, albeit adopting different approaches , . singapore saw her first imported case of the novel coronavirus infection on january . prior to this, the authorities had a working multi-ministry taskforce, issued travel advisories for china to the public, precautionary advisory to preschools (good hygiene, travel declarations and temperature screening for staff) and implemented temperature screening at land and sea checkpoints. given the evolving situation in china at that time and the high volume of international travel to singapore, the singapore government had accurately pre-empted the possibility of more suspect cases and imported cases . after the severe acute respiratory syndrome-related coronavirus (sars-cov) outbreak, singapore authorities had put in place a multi-ministry taskforce and a disease outbreak response system condition (dorscon) framework that enables the whole-of-government to respond immediately to any disease outbreak and guide interventions . while hong kong saw her first imported case on january and had taken similar pre-emptive measures prior to this . in terms of the alert level, singapore raised its risk assessment (in accordance with the dorscon framework) from dorscon yellow to dorscon orange on february after the country saw an increased number of cases of local transmission. in hong kong, the serious response level was activated in public hospitals on january and the hospital authority activated the emergency response level on january . both countries contained the first wave of imported cases well and boasted robust testing and contact-tracing capabilities. however, a key difference was that the hong kong government implemented social-distancing measures and partial closures earlier, extending the lunar new year holidays and keeping all schools and government offices closed after the holidays, while the singapore government had all schools (including preschools) running up till the implementation of a sweeping 'circuit breaker' measure on april , only allowing residents to leave their homes to exercise alone or purchase essential items. all private or public gatherings, non-essential services and sports and recreation facilities have ceased. although both countries did not advise compulsory mask-wearing hitherto, most members of public in hong kong chose to wear a mask when going outside anyway. the initial advice from the hong kong government was for people who have respiratory symptoms, visiting hospitals and those travelling to wear a mask (and continue to do so until days after returning). the generally high mask usage amongst the public could be partly due to their previous experience with sars-cov or their distrust in the hksar central government . although there are no official statistics, it was evident from media and news reports that most singaporeans still went about their daily activities without the use of a mask, unless they were unwell . the singapore government has now dramatically reversed their recommendations on the use of masks because it is thought that they may confer additional protection against the covid- , due to the variable incubation period for clinical disease and possibility of asymptomatic spreaders . it is now mandatory to wear a mask when going out. tough laws have been put in place to enforce this; first-time offenders would be fined while egregious cases may be prosecuted in court . the covid (temporary measures) act was passed by singapore parliament on april , and under the act, the government has the powers to make regulations to further prevent or control the incidence or transmission of covid- . either way, it appears that hong kong has managed to flatten the coronavirus curve, while singapore is seeing a rapid upward trend (figure ) , mostly due to an outbreak of cases amongst foreign workers living in the dormitories . there are more than , foreign workers on 'construction work permits' in singapore, and the growing outbreak amongst workers living in the dormitories could be due to the limited space, their culture of communal cooking and sharing food, and communal toilets. given the above context and factors, it is difficult to precisely apportion the contribution of masking versus social distancing, rigorous contact tracing and other control measures to covid- containment. properly-worn face masks probably help stem the spread of the coronavirus, albeit other environmental and ambient factors such as temperature, wind velocity and humidity would also affect how the respiratory droplets travel. although the efficacy of wearing masks in public cannot be stated definitively, we believe the takeaway lessons are clear. caution and pre-emptive measures yield significant preventive benefits in this crisis. the public needs to act responsibly and pay heed to these advice and physical distancing measures. given the escalating medical and socioeconomic costs associated with this pandemic, the adage that 'prevention is better than cure' is especially relevant today. the role of community-wide wearing of face mask for control of coronavirus disease (covid- ) epidemic due to sars-cov- asia pacific steps up covid- efforts as second wave of infections strikes multinationals and the growth of the singapore economy. routledge city states in the global economy: industrial restructuring in hong kong and singapore. routledge confirmed imported case of novel coronavirus infection in singapore; multi-ministry taskforce ramps up precautionary measures macau confirms first case as new disease looms over hong kong. south china morning post flattened the curve for now but hong kong braces for a second coronavirus wave singapore u-turns on wearing masks as local virus cases climb asymptomatic transmission, the achilles' heel of current strategies to control covid- continued stringent implementation and enforcement of circuit breaker measures thousands of people in dorms pose new challenge to singapore virus fight. bloomberg the authors report no conflicts of interest. this research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. the authors alone are responsible for the content and writing of the article. key: cord- -ugeupo u authors: sim, shuzhen; ng, lee ching; lindsay, steve w.; wilson, anne l. title: a greener vision for vector control: the example of the singapore dengue control programme date: - - journal: plos negl trop dis doi: . /journal.pntd. sha: doc_id: cord_uid: ugeupo u vector-borne diseases are a major cause of morbidity and mortality worldwide. aedes-borne diseases, in particular, including dengue, chikungunya, yellow fever, and zika, are increasing at an alarming rate due to urbanisation, population movement, weak vector control programmes, and climate change. the world health organization calls for strengthening of vector control programmes in line with the global vector control response (gvcr) strategy, and many vector control programmes are transitioning to this new approach. the singapore dengue control programme, situated within the country’s larger vision of a clean, green, and sustainable environment for the health and well-being of its citizens, provides an excellent example of the gvcr approach in action. since establishing vector control operations in the s, the singapore dengue control programme succeeded in reducing the dengue force of infection -fold by the s and has maintained it at low levels ever since. key to this success is consideration of dengue as an environmental disease, with a strong focus on source reduction and other environmental management methods as the dominant vector control strategy. the programme collaborates closely with other government ministries, as well as town councils, communities, the private sector, and academic and research institutions. community engagement programmes encourage source reduction, and house-to-house inspections accompanied by a strong legislative framework with monetary penalties help to support compliance. strong vector and epidemiological surveillance means that routine control activities can be heightened to specifically target dengue clusters. despite its success, the programme continues to innovate to tackle challenges such as climate change, low herd immunity, and manpower constraints. initiatives include development of novel vector controls such as wolbachia-infected males and spatiotemporal models for dengue risk assessment. lessons learnt from the singapore programme can be applied to other settings, even those less well-resourced than singapore, for more effective vector control. vector-borne diseases (vbds) are a major cause of morbidity and mortality in the tropics and subtropics, accounting for more than % of the global burden of infectious diseases [ ] , with over % of the world's population at risk from at least one vbd [ ] . aedes-borne diseases, including dengue, chikungunya, yellow fever, and zika, are increasing at an alarming rate driven by urbanisation, local and global population movement, and climate change [ ] [ ] [ ] . aedes aegypti mosquitoes lay eggs in a wide variety of artificial containers and structures, including those that occur in discarded plastic containers, water storage containers, flowerpots, tyres, poorly constructed concrete structures in the ground, and gutters, which abound in urban environments. the main tool we have for controlling vbds is vector control [ ] . although vector control has been hugely successful against some vbds such as malaria [ ] , weak implementation of sustainable programmatic vector control has struggled to control aedes-borne diseases in many parts of the world in the past years. margaret chan, former director-general of the world health organization (who), famously said in her world health assembly address that the zika epidemic was "the price being paid for a massive policy failure that dropped the ball on mosquito control in the s" [ ] . in order to strengthen vector control, who member states called on who to develop the global vector control response - (gvcr) [ ] . this strategic document includes a framework of key priorities for vector control strengthening. the gvcr calls for collaboration within and outside the health sector, increased engagement of communities, scaling up and integration of vector control tools and approaches, and improved surveillance and monitoring and evaluation (fig ) . this is supported by a foundation of capacity and capability strengthening and by increased basic and applied research and innovation. also important are factors including country leadership, advocacy, resource mobilisation, and regulatory, policy, and normative support. who member states are reorienting their programmes in line with the gvcr [ ] , but good examples of the gvcr principles in action are currently limited. one exception is the dengue control programme in singapore, which in fact predates the gvcr but adopts many gvcr principles. this manuscript aims to document the key features of the programme, highlight how they sit within the gvcr framework, and draw out important lessons that can be applied by other vector control programmes, including those less well-resourced than singapore's. the republic of singapore is an island city-state in southeast asia with a land area of . km and a population of . million [ , ] . singapore is located at the southern tip of the malay peninsula, connected to peninsular malaysia via two causeways and by ferry services with indonesia's riau islands to the south. singapore is a travel and business hub with . million visitors in [ ] . the city-state is highly urbanised and has a high population density with almost , people per km , and typically tens of thousands of people per km in the main residential areas [ ] . since , singapore has been working towards the vision of creating a 'city in a garden', where greenery and biodiversity are seen as solutions to improving health and well-being of its citizens [ ] [ ] [ ] . seventy-nine percent of singapore's residents live in high-rise apartments built by the government's housing and development board (hdb), with the remainder living in privately owned condominiums ( %) or landed property ( %) [ ] . the climate in singapore is tropical and it is hot and humid all year round. singapore is endemic for dengue, with all four dengue virus (denv) serotypes circulating, frequent emergence of various genotypes, and a cyclical pattern of outbreaks every - years [ ] [ ] [ ] [ ] . in in , in , , and , singapore experienced explosive dengue fever outbreaks that resulted in , , , , , , and , indigenous cases, respectively, with incidence rates of . , . , . , and . per , population [ ] [ ] [ ] [ ] . in , singapore also experienced a large dengue outbreak with more than , cases [ ]. there is low herd immunity, particularly among younger generations, due to decades of low dengue transmission [ ] [ ] [ ] . the primary dengue vector is a. aegypti, and although aedes albopictus is also present, it is considered a weak secondary vector [ ] . exposure to chikungunya is low in singapore, with seroprevalence of . % among adults [ ] . the country has experienced small local outbreaks of chikungunya, with the largest ( , cases and an incidence rate of . per , ) occurring in , a year when aedes densities were high [ ] . singapore's first zika outbreak occurred in , and although it occurred at the same time as the epidemic in brazil and other latin american countries, the zika strain was found to have originated in southeast asia [ ] . malaria was eliminated in singapore in [ ] , but there are still sporadic imported cases and competent vectors including anopheles epiroticus (formally anopheles sundaicus), anopheles maculatus, and the emerging vector anopheles sinensis [ , ] . since independence, singapore has recognised that a clean and green environment is necessary not only to ensure good health and a good quality of life for its people but also for economic competitiveness. the government embarked on projects to clean up the land and waterways and invested heavily in critical sanitation and environmental infrastructure, including drainage development projects, sewerage and used water treatment infrastructure, and solid waste management. the environmental management put in place to implement this high standard of public cleanliness has greatly benefited singapore's efforts to tackle vbds. underscoring the view that aedes-borne diseases are environmental diseases, dengue control in singapore is led by the national environment agency (nea), a statutory board of the ministry of the environment and water resources (mewr). in view of the importance of infrastructure maintenance and design, environmental sanitation, people's behaviours, and use of technologies on dengue prevention, the nea collaborates closely with other government ministries (e.g., health, national development, education, finance), town councils (responsible for management and maintenance of the common property of public housing estates, including vector control), community associations, research and academic institutions, and the private sector (fig ) . intersectoral activities are coordinated by an inter-agency dengue taskforce which meets regularly, and monthly during outbreaks. in the event of a severe dengue outbreak, the taskforce membership is escalated to minister level. in addition to regular meetings, taskforce members are also in close contact via email and telephone to exchange feedback and information-for example, on unusual aquatic habitatsin a timely manner. resources for government agencies to carry out dengue control activities are allocated by the ministry of finance, to which each agency justifies its own funding needs. if necessary, nea supports these justifications, especially in an outbreak year when nea has called on agencies to step up dengue control measures. nea may also offer subsidies to town councils to support enhanced dengue control measures in public housing estates. for example, an important partner of the nea is the hdb, the statutory board responsible for public housing. in high-rise apartments in singapore, laundry is typically hung out to dry on bamboo poles fixed into tube-shaped bamboo pole holders on the side of the building. discovery of substantial numbers of aedes larvae in these holders led to provision of caps to cover them when not in use. later, the clothes-drying system was redesigned such that the bamboo poles now rest on brackets instead, eliminating the need for holders (fig ) . as mounting the bamboo poles in the holders required residents to lean out of the window, replacing the holders with brackets not only removed a mosquito breeding habitat but was also safer for residents. antimosquito valves that allow water to drain away but prevent escape of mosquitoes are installed in gully drains in hdb apartments, and hdb blocks are constructed without roof gutters, since these are difficult to access and maintain at height and therefore can become aedes habitats. nea works closely with town councils who are responsible for vector control around the hdb blocks. construction sites play an important role as a driver of sustained dengue transmission [ ] , since rainwater-filled land excavation holes, construction materials, and equipment (e.g., water tanks, skips, canvas sheeting) can become aedes habitats. the singapore contractors association limited (scal) is therefore an important partner for nea. construction sites are mandated to engage an environmental control officer (large sites may even have their own dedicated officer) who ensures appropriate action is taken to reduce vector proliferation, including larviciding with bacillus thuringiensis israelensis (bti) (fig ) . the land transport authority is responsible for good housekeeping and vector control on their infrastructure construction sites and the urban redevelopment authority conducts vector control along roads and their car parks. within the nea, the department of public cleanliness maintains a system of daily litter collection and its mandate is cleaning to 'public health standards'. approximately % of singapore's waste is recycled and the remainder incinerated, with the waste ash deposited on an offshore landfill site, semakau island, helping expand the island. this serves to reduce artificial containers in the environment which could otherwise become habitats for aedes mosquitoes. within the mewr, the nea works alongside the public utilities board (pub), which is responsible for ensuring a sustainable and efficient water supply and responsible for drainage system in singapore. vector control activities of the pub include designing drains for maintainability (accessible and with sufficient gradient to prevent water pooling) and regular flushing of drains monthly or bimonthly. the department of public cleanliness conducts regular cleaning of drains to remove any debris or refuse. the national parks board (nparks) also works closely with nea to maintain a pleasant environment with trees, plants, and water features such as ponds and streams, while keeping vector densities to a minimum. vector control measures implemented include weekly bti treatment of ponds and regular removal of floating vegetation. if vectors do become a problem, surveillance and vector control measures are quickly put in place. for example, in the first quarter of , ornamental papyrus beds in bishan-ang mo kio park encouraged the proliferation of biting midges and a. sinensis. nea's identification of the vectors responsible led to control measures including bti application, intermittent drying of the papyrus beds, and the nea corporate communications department is responsible for mass and social media communications, whereas the p (people, private, public) network division leads nea's education and publicity initiatives and programmes for the p sectors, across all environmental initiatives, not just dengue prevention. community engagement makes use of existing structures including the people's association (the statutory board responsible for promoting social cohesion) and grassroots organisations under the people's association, such as citizens' consultative committees, residents' committees in hdb estates, and neighbourhood committees in private housing estates. these groups encourage bottom-up participation by seeking residents' cooperation in checking for mosquito breeding in homes. nea also trains members of the public and the people's association's community emergency response teams as dengue prevention volunteers, who educate fellow residents on dengue prevention. each year the p network division organises the national dengue prevention campaign, with the timing of the launch dependent on the dengue forecast provided by the environmental health institute (ehi), the research arm of nea. p work through the mayors of each district, grassroots members, and dengue prevention volunteers who mobilise their communities to conduct source reduction according to the ' -step mozzie wipeout' by doing house-to-house visits, distributing educational materials, and organising block parties and other events. the ' -step mozzie wipeout' targets the top five most common habitats in residential premises in singapore. information materials are available in all four written national languages (fig ) . the ' -step mozzie wipeout' recommends to ( ) turn the pail, ( ) tip the vase, ( ) flip the flowerpot plate, ( ) loosen the hardened soil, and ( ) clear the roof gutter and place bti larvicide inside. for those interested in aedes control outside singapore, it is important to note that these aquatic habitats may not be the top five habitats in other countries, so it is important to survey local sites to identify the major sources of a. aegypti. in singapore, messaging is directed towards people taking personal responsibility for mosquito prevention and explaining that by conducting source reduction, they can protect their families from dengue. p uses different methods to evaluate knowledge, attitudes, and practices of communities over time and looks for fresh angles to prevent fatigue from regular public health messaging. besides nationwide general messaging, community engagement strategies also target specific population groups to encourage them to play a greater role in mosquito prevention, including domestic helpers, construction workers, the elderly, and school children. for example, domestic helpers and construction workers are targeted with behaviour change messaging through outreach and roadshows at dormitories, shopping malls, and other places of congregation. since these groups are often migrants and therefore transient populations, behaviour change materials are produced in the relevant languages (e.g., bahasa, hindi, indonesian, tagalog) and outreach is conducted regularly. dengue prevention roadshows are also conducted at elderly care corners and videos are available in local chinese dialects used by many elderly residents who originate from mainland china. the p network division partners with the ministry of education to include dengue prevention in school curricula at primary, secondary, and tertiary levels. timely information on the number and location of dengue cases is made publicly available on the nea website and myenv mobile app. nea also implements a community dengue alert system, in the form of colour-coded banners placed in high-visibility locations in dengue clusters to inform residents about the dengue situation in their neighbourhood and the corresponding actions they can take (fig ) . the banners use the widely recognisable 'traffic light' colour code of red (high alert), yellow (medium alert), and green (low alert) to allow for easy interpretation of the situation. communities are engaged and regularly give feedback about, for example, increased mosquito numbers, littering, and other environmental issues either online or via a -hour nea hotline. globally, aedes indices such as the house index (hi, percentage of houses positive for larvae and or pupae) are traditionally used for aedes vector monitoring, with a value of % often being used as an arbitrary dengue transmission threshold [ , ] . the singapore dengue control programme has brought the hi to very low levels (from % in the s to . % in the s). despite this low hi, singapore still experiences regular outbreaks, suggesting that the hi is no longer sensitive for dengue risk assessment [ , ] . with low vector populations, the singapore programme now uses in-house-developed gravitraps, which are designed to lure and trap gravid female aedes on the sticky lining [ ] . since , a system of , gravitraps have been deployed in public housing estates nationwide, and the scheme will be expanded to landed housing by end of [ ] . monitoring of the traps every weeks is currently outsourced, although an automated trap is currently under development by nea. gravitrap indices are plotted on a geographical information system (gis) and used to target intensified source-reduction campaigns. areas with a high gravitrap index are also published on the nea website to motivate the local community to take action to reduce dengue transmission. in keeping with the country's green aspirations, insecticides are used judiciously, with bti and temephos used as larvicides and pirimiphos-methyl as adulticide. choice of insecticide is guided by resistance monitoring, which is performed every few years. as well as aedes, surveillance is also conducted for culicines (potential japanese encephalitis vectors) and anophelines using the in-house-developed night catcher, a modified cdc light trap that keeps caught adult mosquitoes fresh and alive for analysis and segregates hourly-caught mosquitoes in separate containers. the ministry of health is responsible for case surveillance and clinical management of dengue patients. dengue is a notifiable disease, meaning that medical practitioners and clinical laboratories must report clinically suspected and laboratory-confirmed cases. if a patient presents at a health facility with suspected dengue, then blood samples are taken for diagnostic testing at a hospital or private laboratories using either rapid diagnostic tests against nonstructural protein (ns ) and immunoglobulin m (igm) antibodies or reverse transcriptase polymerase chain reaction (rt-pcr) for acute cases. alternatively, samples can be sent to the ehi for diagnosis, and through this system, ehi is able to monitor circulating dengue serotypes [ ] . an epidemiological investigation of each case, conducted by telephone or in person, is triggered by the environmental public health operations department at nea, and case locations are plotted on a gis interface. a dengue cluster is formed when two or more cases have onset within days and are located within m of each other (based on residential and workplace addresses, as well as movement history collecting during the epidemiological investigation). dengue clusters are graded and the situation communicated to the public via the colour-coded community dengue alert system: high-risk area or more cases (red); high-risk area with fewer than cases (yellow); and no new cases, under surveillance for the next days (green) (fig ) . once a cluster is formed, this triggers the nea environmental public health operations team to ramp up vector control activities in the cluster. entomological indices and dengue case numbers are not reliable measures for assessing the long-term impact of vector control programmes because of changes in surveillance and diagnostic capabilities over time [ ] . instead, nea uses blood bank igg seroprevalence to estimate the force of infection (foi) over time [ ] . the singapore dengue programme relies predominantly on source reduction and larviciding using bti, which are implemented throughout the year through community and programme efforts. in the first months of , approximately % of vector habitats were found in residential premises, rising to % in cluster areas. house inspections are conducted routinely and at increased frequency in cluster areas by the environmental public health operations team (fig ) . field staff follow a strict protocol including identifying themselves clearly and ensuring that the resident witnesses the taking of any samples for species identification at the ehi. use of insecticides is seen as a short-term solution, so fogging with organophosphates is restricted to clusters during outbreaks only. source-reduction activities are facilitated by legislation and law enforcement, which singapore uses in addition to community engagement to enhance public compliance. according to the control of vectors and pesticides act (cvpa, the main legislation dealing with mosquito breeding), the operations team can enter homes to conduct inspections and vector control, and residents are fined at least s$ (us$ ) if aquatic stages of vectors are found on their premises [ ] . inspections of construction sites and other premises are also conducted by a dedicated nea team. if aquatic stages of the vector are found, then an order can be served for vector control to be implemented within a specific time period by a registered vector control personnel. in the event that environmental management is found wanting, the cvpa allows nea to issue an order to stop any work being undertaken on the premises indefinitely or until vector control to remove favourable habitats has been carried out. a list of construction sites that currently have stop work orders are available on the nea website (www.nea.gov.sg). failure to comply with the order can lead to a fine of up to s$ , (us$ , ) and, in the case of a second or subsequent conviction, to a fine of up to s$ , (us$ , ) and/or imprisonment for up to months. the cvpa also covers pesticides registration, as well as licensing and certification of private-sector vector control operators [ ] . to address challenges such as climate change, increasing urbanisation, and the manpowerintensive nature of source-reduction activities, the singapore programme invests in research and development of new vector control technologies. for example, ehi is evaluating the use of wolbachia, a maternally inherited endosymbiotic intracellular bacterium, which when artificially introduced into a. aegypti can suppress dengue infections. singapore opted for a population-suppression strategy whereby only male wolbachia mosquitoes are released. when male wolbachia mosquitoes mate with wild-type females, the eggs produced will not hatch, because of a phenomenon called cytoplasmic incompatibility. use of suppression was favoured over a population-replacement strategy, in which both males and females are released, since it is in line with the long-term programme strategy of source reduction. wolbachia testing has followed a phased approach in two main release sites, including gaining an understanding of the basic biology of the released male wolbachia mosquitoes in the field, such as how far and how high they fly. the programme has also collaborated with the international atomic energy agency (iaea) to irradiate wolbachia mosquitoes at the pupal stage to render infertile any remaining females, so as to avoid replacement of the wild-type population with wolbachia a. aegypti mosquitoes. pilot testing has been accompanied by a careful community engagement campaign developed by ehi to emphasise that wolbachia is safe and that male mosquitoes do not bite, and to encourage continued source reduction. the programme also works with private-sector collaborators to develop and evaluate technologies for wolbachia testing and implementation. ehi works with orinno technology, a local start-up company, to develop new automated equipment to facilitate their work, including a larvae counting system, pupae sorting and counting system, and mosquito launcher to simplify and speed up the releases of the wolbachia mosquitoes by field staff. the programme also works with verily life sciences, an alphabet, inc., affiliate, to field-test the company's automated sorting and release technologies. the dengue control programme has developed a novel indicator for entomological risk assessment known as the a. aegypti breeding percentage [ ] . routine larval surveillance is not uniform spatially and temporally and so would be biased if used for risk assessment. instead, the breeding percentage expresses the number of a. aegypti-positive habitats over the total number of aedes-positive habitats (a. aegypti and a. albopictus) to cancel out the sampling error from nonsystematic inspection and cryptic breeding sites. predicting dengue outbreaks is difficult and the ehi has, in partnership with academic and research institutions including the national university of singapore, developed several different risk models to enable better resource planning and preparedness for outbreaks. for example, a risk map is prepared each year to guide resource allocation to different areas [ ] , a temporal model is used to predict dengue cases up to months in advance [ ] , and a spatiotemporal model integrating climate, vector density, population demographics (connectivity using public transport and mobile phone data), cases, infrastructure (age of building and number of units), and satellite data (vegetation) is used for high-resolution prediction and realtime allocation of resources [ ] . staff personal and professional development is a focus of the nea. for example, staff undertake continuing professional development courses organised by the internal training arm of nea, the singapore environment institute. rotations between departments are encouraged and staff can receive financial support and leave of absence to attend further education. there are possibilities for both vertical and horizontal movement within the organisation, recognising the need for both specialists and generalists. the ehi partners with academic and research institutions, and staff members have obtained phd and other degrees through their research work conducted at the ehi. the ehi of nea has been a who collaborating centre for reference and research of arbovirus and their associated vectors since . this involves consulting and advising (e.g., the director of ehi sits on the who strategic technical advisory group on neglected tropical diseases and strategic advisory group of experts working group for dengvaxia, the sanofi dengue vaccine), enhancing global outbreak preparedness (e.g., cross-border virus surveillance through unitedengue consortium, evaluation of diagnostics, etc.) and capacity building (e.g., training and sharing of best practice). the singapore dengue control programme is one of the best in the world, but what makes it so successful, and how can the lessons learnt be applied to other vector control programmes? although in many countries dengue control sits under the ministry of health, unusually in singapore it sits within the mewr. this is in line with the programme view that dengue is an environmental disease. dengue vector control uses mainly environmental management approaches, such as proactive source reduction, and environmental management including drainage and house improvements contributed to the elimination of malaria from singapore in [ ] . key individuals including the director-general of public health, could be trained as engineers or other professionals, not medical doctors. a strong sense of environmentalism stems from singapore's founding father, lee kuan yew, who oversaw the transformation of singapore after independence and in championed the idea of the 'garden city' [ ] . lee kuan yew promoted a green environment that was free of litter in order to create good living conditions for singapore's residents, but also to simultaneously encourage tourism, investment, and trade. strong political will and long-term political stability (the people's action party have been the only party to form a government since independence in ) means that this vision and trajectory has been maintained over time, for example, in the current sustainable singapore blueprint [ ] . despite sitting within mewr, the programme collaborates closely with the ministry of health with efficient systems for sharing information on confirmed cases to allow rapid intervention by the nea environmental public health operations team. adopting a similar environmental approach to vector control could enable more effective control of vbds worldwide (and incidentally was largely responsible for the success of vector control in the early and mid- s before the advent of ddt [ ] ). for example, progress in controlling malaria is stalling in many high-burden countries due to weak vector control programmes, and potentially also insecticide resistance [ , ] . since malaria is primarily a disease caused by standing water, proactively tackling immature vectors by using environmental management could be a synergistic addition to predominantly insecticide-based adult anopheline control. increasingly complicated and multidimensional public issues including climate change, globalisation, public health, and infectious disease outbreaks call for a transformation in public administration. since the s, singapore has adopted a whole-of-government approach, which 'denotes public service agencies working across portfolio boundaries to achieve a shared goal and an integrated response to particular issues' [ ] [ ] [ ] . the whole-of-government culture, propagated for decades in singapore, facilitates the view of dengue control as a shared responsibility across agencies. for example, cross-sectoral collaboration for dengue control is facilitated by the inter-agency dengue taskforce. further, rotation of leadership between different government departments and agencies means that so-called 't-shaped' managers have not only specialist expertise but a broader perspective on issues and can help to break down departmental or agency silos [ ] . this coordinated whole-of-government approach is exemplified by the singapore response to a dengue outbreak that coincided with the start of the covid- pandemic in early (box ). singapore also employs collaborative governance, whereby governing is based on collaboration between government and nongovernment stakeholders. this is exemplified by the important role of the people's association in bridging between government and communities. community outreach initiatives enjoy broad political support, as they provide an opportunity for the government to directly connect with the community. local politicians are also invested in preventing outbreaks in their constituencies and often communicate the importance of dengue prevention to residents during walkabouts. another success factor may be the use of a 'carrot and stick' approach to source reduction with community engagement and behaviour change campaigns led by the p network division, backed up by strong legislation and enforcement. a recent study conducted by ehi shows that houses that have more frequent inspections have a lower number of reported mosquito larval habitats [ ] , lending support to the system of house inspections. a lack of corruption (singapore is rated as one of the least corrupt nations in the world by transparency international [ ] ) also supports the penalty system for vector habitats. the clear accountability of mosquito breeding offences under the law makes it easier for stakeholders to understand their respective roles, thus facilitating collaborative action against mosquito breeding. strict enforcement of the law is another push factor that encourages joint efforts to take preventive measures. imposition of fines for vector habitats may not be possible in all vector control programmes globally but should be considered. singapore's dengue control response in , which is taking place amid the covid- pandemic, offers a case study of intra-and intersectoral collaboration to combat twin environmental public health threats. detection of dengue threat and raising the alert more than , dengue cases were reported in the first quarter of , double that for the same time period in [ ] . in early , ehi's risk models, incorporating case data from the ministry of health, forecasted a dengue surge in the coming months. ehi's analysis of serotype trends further detected an increase in the proportion of denv- cases, with denv- overtaking denv- as the predominant serotype in early . as denv- has not been predominant in singapore for nearly three decades, population immunity to this serotype is likely low, further increasing the risk of an outbreak. given this outlook for , nea alerted relevant government agencies and set in motion an enhanced and coordinated dengue control response. with support from political and grassroots leaders, nea brought forward the national dengue prevention campaign (typically held just before the traditional midyear peak dengue season) to late march [ ] , with the intention of raising awareness and rallying the public to conduct preemptive measures early on. this kicked off island-wide community-led outreach efforts, helmed by grassroots leaders and supported by dengue prevention volunteers, to encourage residents to carry out dengue prevention practices. at the organisational level, the nea-led inter-agency dengue taskforce met in january and march to coordinate the response across sectors and continues to meet regularly. emphasis has been placed on enhancing vector control in assets managed by various agencies (such as buildings, reservoirs, drains, and parks), especially if these are located in areas with high mosquito populations or within dengue clusters. singapore reported its first case of covid- on january [ ] . to curb local covid- spread, nea in february launched "sg clean" [ ] , a whole-of-government campaign to rally individuals and businesses to keep public areas clean (such areas include toilets, hawker centres, community spaces, and other premises). dengue control messaging was woven into 'sg clean'. a key campaign message was that enhanced public cleanliness, such as maintaining clean premises and not littering, eliminates mosquito breeding habitats and hence helps to reduce the spread of dengue in addition to covid- . in april , singapore implemented a 'circuit breaker' to curb covid- transmission, which involved stringent social distancing measures and cessation of nonessential work activities [ ] . given the high-risk dengue outlook for , nea worked at the whole-of-government level to include vector control activities as an essential service to what continues to drive transmission in singapore, where there is a well-resourced and effective dengue control programme? the dengue incidence rate in singapore has increased dramatically in the last years, but this is likely because of improved diagnostics, increased referral for testing by medical practitioners, and increased awareness among the public [ ] . a better indicator of the true infection rate is dengue foi: between the s (when singapore first implemented environmental management and vector control programmes) and the s, the dengue foi in singapore dropped -fold to approximately . ( per , individuals per year) and has since held steady at this low level [ ] . the decline in foi can probably be attributed to the effectiveness of the dengue control programme (along with an increasingly ageing population). this success in reducing disease transmission has resulted in a lowered herd immunity against dengue, leaving singapore's population vulnerable to outbreaks despite a low vector population. another challenge is the high level of population movement in and out of the country, which is known to facilitate the co-circulation of denv serotypes [ ] . singapore has , km of expressways and . km of mass rapid transit (mrt) lines across the island; over , people commute into the island state from malaysia each day [ ] ; and in , there were . million passenger movements in and out of changi airport from cities in countries and territories worldwide [ , ] . in order to reduce the foi further, the programme is evaluating innovative strategies such as wolbachia, novel community engagement mechanisms, and risk mapping for more effective intervention targeting. as well as better implementation of current tools and approaches, new vector control tools are urgently needed to combat vbds worldwide. in conclusion, the dengue control programme in singapore provides an excellent example of the gvcr in action. important elements include strong collaboration across government departments and between government and nongovernment actors, integration of tools and approaches, effective surveillance, and community engagement. as a high-income country, singapore is in an enviable position of having reliable government funding for dengue control. nevertheless, aspects such as working across sectors or implementation of environmental management do not need to be expensive, and the former can even save costs for the vector control programme. adoption of these elements could lead to more effective vector control programmes worldwide to reduce the intolerable burden of vbds. be continued during the 'circuit breaker' period. businesses and owners of premises are expected to ensure that adequate vector control activities continue at their premises (including offices, commercial buildings, schools, and construction sites), even if regular operations are on hold. nea continues to carry out island-wide routine inspections and enforcement, with precautions taken to minimise covid- transmission. these precautions include ensuring that officers carrying out inspections are healthy, wear masks, and practise good personal and hand hygiene. despite the efforts of the nea, dengue control has been particularly challenging in because of the switch to denv- , warm weather, and high numbers of people staying at home during the 'circuit breaker' period, which can increase aedes aquatic habitats and provides easy access to blood meals for female aedes mosquitoes. we thank the following individuals for their insights: dulcie chan, rama chandramogan, khoo seow poh, christina liew, sueanne mocktar, ong chin soon, tai ji choong, tony teo, and grace yap of singapore's national environment agency and nanthini elamgovan of singapore's national parks board. thanks also to manuela bernardi for her assistance in producing the figures. • vbds are environmental diseases-situation of programmes within the ministry of environment and/or strengthening environmental management is encouraged. • whole-of-government approaches (working across government ministries) and collaborative governance (collaboration between government and nongovernment) support vbd control. • strong vector and epidemiological surveillance enables targeting of vector control interventions. • consider the role of legislation and enforcement in reducing vector habitats. • stable financing supports effective vector control. • innovation and science-based approaches should be harnessed to support surveillance and control. top five papers world health organization. vector-borne diseases fact sheet integrating vector control across diseases the global burden of dengue: an analysis from the global burden of disease study urbanization and globalization: the unholy trinity of the st century the current and future global distribution and population at risk of dengue the importance of vector control for the control and elimination of vector-borne diseases the effect of malaria control on plasmodium falciparum in africa between address to the sixty-ninth world health assembly by director-general of the world health organization world health organization. global vector control response world health organization. framework for a national vector control needs assessment geneva: who online database-total land area of singapore world bank. population density (people per sq. km of land area) ministry of national development-centre for liveable cities singapore. sustainable singapore blueprint forging a greener tomorrow: singapore's environmental journey from slum to eco-city singapore's journey towards environmental and water sustainability singapore: department of statistics singapore forecast of dengue incidence using temperature and rainfall epidemiological aspects of an outbreak of dengue fever/dengue haemorrhagic fever in singapore the dengue haemorrhagic fever outbreak in singapore and its control dengue in singapore from to : cyclical epidemic patterns dominated by serotypes and communicable diseases surveillance in singapore communicable diseases surveillance in singapore communicable diseases surveillance in singapore communicable diseases surveillance in singapore environment agency. quarterly dengue surveillance data-q , q , q and q dengue seroprevalence of healthy adults in singapore: serosurvey among blood donors seroepidemiology of dengue in the adult population of singapore force-of-infection and true infection rate of dengue in singapore-its implication on dengue control and management gravitraps for management of dengue clusters in singapore seroprevalence of antibodies against chikungunya virus in singapore resident adult population hard lessons in surveillance and response from the singapore zika experience eradication of malaria from singapore risk of anopheles sinensis as an emerging malaria vector in singapore a study on anopheles maculatus and anopheles sundaicus in singapore construction sites as an important driver of dengue transmission: implications for disease control critical examination of aedes aegypti indices: correlations with abundance assessing the relationship between vector indices and dengue transmission: a systematic review of the evidence dengue prevention and years of vector control in singapore who regional office for the western pacific. guidelines for dengue surveillance and mosquito control. manila: who regional office for the western pacific dengue in singapore from to : cyclical epidemic patterns dominated by serotypes and control of vectors and pesticides act a novel entomological index, aedes aegypti breeding percentage, reveals the geographical spread of the dengue vector in singapore and serves as a spatial risk indicator for dengue. parasit vectors mapping dengue risk in singapore using random forest three-month realtime dengue forecast models: an early warning system for outbreak alerts and policy decision support in singapore memoirs of lee kuan yew. singapore: times media private limited connecting government: whole of government responses to australia's priority challenges. canberra: management advisory committee (australian government) a primer on implementing whole of government approaches. dublin: centre for effective services reviewing whole-of-government collaboration in the singapore public service introducing t-shaped managers. knowledge management's next generation nea brings forward national dengue prevention campaign and rolls out additional new tools to combat dengue, with increasing evidence of a sustained switch in dengue virus serotype confirmed imported case of novel coronavirus infection in singapore: multi-ministry taskforce ramps up precautionary measures campaign launched to rally public and businesses to work together to keep singapore clean circuit breaker to minimise further spread of covid- the effectiveness of inspections on reported mosquito larval habitats in households: a case-control study transparency international secretariat increasing airline travel may facilitate cocirculation of multiple dengue virus serotypes in asia dengue outbreaks in singapore and malaysia caused by different viral strains key: cord- -l u s w authors: liew, yixin; lee, winnie hui ling; tan, lunyi; kwa, andrea lay hoon; thien, siew yee; cherng, benjamin pei zhi; chung, shimin jasmine title: antimicrobial stewardship program, a vital resource for hospitals during the global outbreak of coronavirus disease (covid- ) date: - - journal: int j antimicrob agents doi: . /j.ijantimicag. . sha: doc_id: cord_uid: l u s w healthcare resources are being diverted for the containment and control of covid- . during this outbreak, we caution that antibiotic misuse may be increased, especially for respiratory tract infections. with stewardship interventions, duration of antibiotic therapy and length of stay of hospitalized patients can be significantly reduced. antibiotic stewardship programs should continually engage and educate prescribers to mitigate antibiotic misuse during the covid- pandemic. in early dec , reports of coronavirus disease (covid- ) patients first emerged in wuhan, china . on th jan , singapore's first reported case of covid- in singapore was identified at the singapore general hospital . since then, the ministry of health, singapore, quickly raised "disease outbreak response system condition" (dorscon) alert to orange (the second highest level of alert) on th feb , and implemented various measures nationwide, including border control, quarantine of contacts of covid- cases or those who have travelled to affected areas, temperature screening as well as restricting the number of visitors to the hospital. as of th july , singapore has had , confirmed cases. in light of increasing covid- cases locally and internationally, our hospital faced competing manpower needs arising from health crisis management, leading to uncertainty over manpower allocation of non-direct patient care personnel e.g. antibiotic stewardship practitioners. here, we aim to describe the impact of covid- on antibiotic use and the role of antibiotic stewardship program (asp) in singapore general hospital (sgh), an -bed, tertiary-care hospital. our multidisciplinary asp comprises of trained infectious diseases pharmacists, as well as infectious disease (id) physicians. the pharmacy team performs daily audits electronically, of selected broad-spectrum antibiotic prescriptions (carbapenems, piperacillin-tazobactam, ciprofloxacin and levofloxacin) for appropriateness, in terms of indication, route, duration and choice and intervenes where appropriate; the audited prescriptions of more complex cases are reviewed daily with the attending id physician who is rostered for the day. when singapore raised the dorscon alert to orange, our institution mandated cancellation of elective and non-urgent procedures / surgeries, to ring-fence more beds for dedicated respiratory and pneumonia wards in preparation for larger scale outbreak. negative pressure rooms in our hospital are solely used for covid- suspects and cases. operationally, face-to-face meetings were discouraged within the institution and the workforce was generally divided into small teams (e.g. - members per team), as part of the hospital's business contingency plan. accordingly, our asp team was divided into two pharmacy teams so that asp would still be operationally functional with one team if the other team had to be quarantined. in place of face-to-face meetings, daily asp meetings with the id physician were conducted via teleconferencing. the first covid- case was reported in singapore on the rd jan , and as the number of cases increased, a stay-at-home order and cordon sanitaire termed "circuit breaker" was implemented as a preventative measure on the th apr . this epidemic has placed enormous strain on healthcare providers and healthcare systems worldwide. locally, our country has placed a high emphasis on identifying and isolating covid- patients in our bid to contain the spread of the virus. in the early weeks of our containment strategy, patients with signs and symptoms suggestive of viral illness were actively screened and isolated until results return negative for covid- . consequently, we perceived that there were more admissions of patients with acute respiratory illness, which would otherwise have been treated in the community in prior to the covid- pandemic. these patients were usually started empirically on antibiotics used for the treatment of community-onset pneumonia coinciding with the increased utilization of these agents. furthermore, our initial hypothesis that the use of broad-spectrum antibiotics should drop together with the admission numbers was debunked. instead, prescription numbers for these agents were observed to increase as they target serious, nosocomial infections which are often associated with urgent conditions (e.g. cancer for which treatment cannot be delayed). hence, in a tertiary healthcare institution like ours, the impact of covid- as well as the continued care for hospitalized patient with complex medical issues, culminated in the higher proportion of patients on antibiotics compared to pre-covid period. it would be prudent to maintain the asp even in viral epidemics / pandemics with existing manpower support. at the start of the pandemic, we received support from hospital management to maintain the asp as an essential service, a commitment towards our continued fight against antimicrobial resistance. we also learnt the importance for asps to be operationally adaptable to different scenarios. organizational restructuring and migration to telecommuting platforms for our asp activities was crucial for maintaining our clinical service while observing distancing measures, thus ensuring patient and staff safety in this pandemic. we also realized that in addition to focusing our efforts on nosocomial treatments, this is an opportunity for our team to execute a syndromic approach towards guiding antibiotic prescribing for respiratory tract infections. to do so, we must employ digital platforms and continue to develop robust surveillance systems that are able to detect subtle changes in prescribing and resistance trends. what is also important in outbreak situations like these is on-going engagement and education of prescribers to mitigate antibiotic misuse that tends to occur with viral epidemics / pandemics, undoing years of progress in antibiotic stewardship. given that we are engaged in this covid- battle for a long haul, the role of asp is vital to ensuring the quality of our antibiotic use is upheld because the problem of antibiotic resistance remains in the long term. the singhealth centralised institutional review board approved this retrospective review of our service. informed consent was not obtained from individual patients as the operations of the asp constituted routine clinical practice and only anonymized data were analyzed. covid- ) situation report - . world health organization updates on covid- (coronavirus disease ) local situation. ministry of health singapore discontinuation of antibiotic therapy within hours of treatment initiation for patients with no clinical evidence of bacterial infection: a -year safety and outcome study from singapore general hospital antimicrobial stewardship program covid- : don't neglect antimicrobial stewardship principles! covid- and the potential long-term impact on antimicrobial resistance we would like to acknowledge all asp pharmacists for their contribution to the study. key: cord- - ulqu authors: tindale, lauren; coombe, michelle; stockdale, jessica e; garlock, emma; lau, wing yin venus; saraswat, manu; lee, yen-hsiang brian; zhang, louxin; chen, dongxuan; wallinga, jacco; colijn, caroline title: transmission interval estimates suggest pre-symptomatic spread of covid- date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: ulqu background: as the covid- epidemic is spreading, incoming data allows us to quantify values of key variables that determine the transmission and the effort required to control the epidemic. we determine the incubation period and serial interval distribution for transmission clusters in singapore and in tianjin. we infer the basic reproduction number and identify the extent of pre-symptomatic transmission. methods: we collected outbreak information from singapore and tianjin, china, reported from jan. -feb. and jan. -feb. , respectively. we estimated incubation periods and serial intervals in both populations. results: the mean incubation period was . ( . , . ) days for singapore and ( . , . )days for tianjin. both datasets had shorter incubation periods for earlier-occurring cases. the mean serial interval was . ( . , . ) days for singapore and . ( . , . ) for tianjin. we inferred that early in the outbreaks, infection was transmitted on average . and . days before symptom onset (singapore, tianjin). the estimated basic reproduction number for singapore was . ( . , . ) secondary cases per infective; for tianjin it was . ( . , . ) secondary cases per infective. conclusions: estimated serial intervals are shorter than incubation periods in both singapore and tianjin, suggesting that pre-symptomatic transmission is occurring. shorter serial intervals lead to lower estimates of r , which suggest that half of all secondary infections should be prevented to control spread. quarantined and sections of the baodi district where the store is located were sealed and put under security patrol. we screened publicly available data to identify datasets for two covid- clusters that can be used to estimate transmission dynamics within a relatively closed system, where immediate public health responses were implemented, contacts were identified and quarantined, and key infection dates were tracked and published. we use these clusters to estimate both incubation period and serial interval for covid- , in both datasets, and discuss the implications of our findings for r estimates and pre-symptomatic transmission. all datasets and r code are available on github (github.com/carolinecolijn/clusterscovid ). singapore data was obtained from the ministry of health singapore [ ] online press releases. the singapore dataset comprised confirmed cases from the date of the initial case on january , until february , . tianjin data was obtained from the tianjin health commission [ ] online press releases. the tianjin dataset comprises cases confirmed from january to february , . the symptom onsets were available on the official website for all but a few patients who had not had symptoms before being diagnosed at a quarantine center. both datasets contained information on exposure times, contacts among cases, time of symptom onset and more (see supplementary information for column descriptions and data processing). . cc-by-nc . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . https://doi.org/ . / . . . doi: medrxiv preprint for both singapore and tianjin, the daily incidence of hospitalization and mortality was plotted with the cumulative number of cases confirmed and discharged. the daily incidence rate was also visualized by date of symptom onset per probable source of infection. for the symptom onset plots, any cases that did not have information on date of onset of symptoms were removed. cases were then grouped based on information provided in the "presumed reason" column for singapore dataset and by the "infection source" column in the tianjin dataset. in the tianjin dataset, there were a small number of cases (n = ) that could be classified into two possible infection source groups (e.g. from wuhan and has a close relationship with another known case). these cases were assigned their infection source groups based on the following hierarchy of possible sources: (highest priority) known relationship > wuhan origin > other china travel > location unclear travel > mall (for shoppers, workers, or individuals living near to the baodi mall outbreak) > unknown (lowest priority). all cases in the singapore dataset were categorized into an infection source group without conflict. the group designations were not used in the statistical estimates. incubation period estimates were based on data for the earliest and latest possible exposure times, and on the reported times of symptom onset. it is impossible to confirm the exact times of exposure, so we use interval censoring (r package icenreg [ ] ) to make parametric estimates of the incubation period distribution. where the earliest exposure is not specified in the "start source" column, we noted that the case must have been exposed some time since the beginning of the outbreak (dec , ). where the last possible exposure is not given in "end source", we noted that exposure must have occurred before symptom onset. in the singapore dataset, some cases had a travel history or contact with a known location or presumed source of the virus and this defined a most recent time of exposure. for these we proceed as in tianjin. other individuals had estimated exposure times based on the symptom times for their presumed infector. for these, we define an exposure window using the symptoms of their presumed infector ± days. having defined exposure windows, we proceed with interval censoring as in the tianjin data. in both datasets . cc-by-nc . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . https://doi.org/ . / . . . doi: medrxiv preprint we stratified the data according to whether symptom onset occurred early or late and estimated incubation periods separately. serial intervals were estimated with the expectation-maximization approach described in vink et al [ ] . briefly, this approach assigns the case with earliest symptom onset in the cluster as a "putative index" (pi) status, and uses the time difference between symptom onset of subsequent cases in the cluster and the putative index as "index case to case" (icc) intervals for putative index cases in small clusters. the icc intervals are the time differences between the symptom onset in the putative index (pi) and the others, so the collection of times t j − t pi for each j in the cluster. these intervals are not samples of the serial interval distribution, because it need not be the case that the pi infected the others. vink et al [ ] used a mixture model in which icc intervals t j − t pi can arise in four ways: ( ) an outside case infects pi and j; ( ) pi infects j; ( ) pi infects an unknown who infects j and ( ) pi infects unknown who infects unknown who infects j. accordingly, if the serial interval x ∼ n (µ, σ ), the density for the icc intervals is where w i are weights of the i th component density and f i are the component densities for the i th transmission route. see [ ] for more details. expectation-maximization is used to determine µ and σ. for each dataset we create a graph whose nodes are individuals and whose edges are reported direct contacts between individuals. we use the connected components of the graph to define the small clusters. we also explored using earliest end exposure time, in case the first symptomatic case was not the index case for the cluster. a few clusters are large enough that the four models in the mixture are likely insufficient to cover the transmission possibilities, so we restrict the analysis to only the first , , or cases per cluster. the mean time difference between transmitting infection by an infector and symptom onset is . cc-by-nc . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . https://doi.org/ . / . . . doi: medrxiv preprint (assuming independence) then the difference between the mean serial interval and the mean incubation time. we calculate the reproduction number as in [ ] : r = exp rµ − / r σ with r the exponential growth rate, µ the mean serial interval and σ the standard deviation of the serial interval. to obtain confidence intervals for r we resample µ and σ from our bootstrap samples; this preserved covariation of µ and σ. statistical analyses were performed using r [ ] . figure c indicates that symptom onset occurred . ± . (mean ± sd) days after the initial presumed viral exposure and hospitalization occurred . ± . days after symptom onset. the mean length of hospital stay was . ± . days before individuals recovered and were discharged. in the tianjin dataset, new confirmed cases were documented daily from january to . (mean ± sd) days after the latest presumed viral exposure. cases were confirmed . ± . days after symptom onset. the duration of hospital stay of the tianjin cases is unknown as the discharge date of each case was not available. in both datasets, daily counts decline over time, which is likely a combination of delays to symptom onset and between symptom onset and reporting, combined with the effects of strong social distancing and contact tracing. . cc-by-nc . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. incidence curve with probable source of infection (c) disease progression timeline, including dates at which each case is unexposed, exposed, symptomatic, hospitalized, and discharged. not all cases go through each status as a result of missing dates for some cases. . cc-by-nc . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. . cc-by-nc . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . https://doi.org/ . / . . . doi: medrxiv preprint in the singapore dataset, we find that the median incubation period is . days with the weibull . , . ). the mean is ( . , . ) days. we also fitted gamma and log normal distributions; see tables and s . these are consistent with previous estimates. however, in singapore they based on a combination of cases for whom last possible exposure is given by travel, and later cases (for whom the presumed infector was used). in tianjin, social distancing measures took place. we find that the estimated incubation period is different, particularly in tianjin, for cases with symptom onset prior to january . the estimated median incubation period for pre-jan cases in tianjin is . days; the q = ( . , . ) quantiles are ( , . ) days. in contrast, post-jan the median is . days with q = ( . , . ) quantiles ( . , ) days. the means are ( . , . ) days for early cases and . ( . , . ) days for later cases. social distancing seems unlikely to change the natural course of infection, but these results might be explained if exposure occurred during group quarantine or otherwise later than the last time individuals thought they could have been exposed. pre-symptomatic transmission would enable this. in singapore we find the same effect, though less pronounced. the estimated median incubation time is . , with ( . , . ) quantiles of ( . , . ) days for early cases and . days (quantiles ( . , . )) days for late-arising cases. the means are . ( . , . ) days for early cases and . ( . , . ) days for later cases. fits of gamma and log-normal distributions are similar; see table s . in singapore, this difference could be explained by the fact that presumed top panels show unstratified data (all cases with symptom onset given). bottom panels show 'early' and 'late' cases, defined in tianjin by those with symptom onset prior to january vs later, and in singapore, those with a specified last possible exposure (all prior to or on january ). . cc-by-nc . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . https://doi.org/ . / . . . doi: medrxiv preprint our serial intervals are notably shorter than our incubation period estimates, suggesting that there is pre-symptomatic transmission, with infection occurring on average . and . days before symptom onset of the infector (tianjin, singapore). because the incubation period is different for early-and late-occurring cases in our data, on average transmission for early-occurring cases is . and . days before symptom onset (tianjin, singapore) and . , . days before (tianjin, singapore) for late-occurring cases. the fact that serial intervals are shorter than incubation periods is robust in our sensitivity analysis (table s ). these estimates are strengthened by the fact that we have estimated both incubation period and serial interval in the same population and by the fact that we obtain the same result in two distinct datasets. in both sets of estimates, samples of the incubation period minus serial interval are negative with probability . or higher (tianjin) and . or higher (singapore), suggesting that a substantial portion of transmission may occur before symptom onset (see supplementary information and figure s ), consistent with the clinical observations reported by rothe et al. [ ] and bai et al. [ ] . shorter serial intervals yield lower reproduction number estimates. for example, when the epidemic grows at a rate of . (doubling time of . days; [ ] scenario ), the reproduction number for tianjin is r = . ( . , . ) and for singapore it is . ( . , . ). in contrast, if the previous serial interval ( . days [ , ] ) is used, the estimate is r = . . . cc-by-nc . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. here we use transmission clusters in two locations where cases have reported links, exposure and symptom onset times to estimate both the incubation period and serial interval of covid- . these are integral parameters for disease forecasting and for informing public health interventions. serial intervals, together with r , control the shape and distribution of the epidemic curve [ ] . they influence the disease's incidence and prevalence, how quickly an epidemic grows, and how quickly intervention methods need to be implemented by public health officials to control the disease [ , ] . in particular, the portion of transmission events that occur before symptom onset is a central quantity for infection control [ ] . in singapore and tianjin we estimated relatively short serial intervals. of particular note, early estimates of r for covid- used the sars serial interval of . days [ , , ] . our serial interval findings from two populations mirror those of and zhao et al [ ] and nishiura et al [ ] , who estimated a serial interval of . and . days. furthermore, we estimate the serial interval to be shorter than the incubation period in both clusters, which suggests pre-symptomatic transmission. this indicates that spread of sars-cov- is likely to be difficult to stop by isolation of detected cases alone. however, shorter serial intervals also lead to lower estimates of r , and . cc-by-nc . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . https://doi.org/ . / . . . doi: medrxiv preprint our serial intervals support r values close to ; if correct this means that half of the transmissions need to be prevented to contain outbreaks. we stratified the incubation period analysis for tianjin by time of symptom onset (pre-or post-jan , ; motivated by quarantine/social distancing measures) and found that the apparent incubation period was longer for those with post-quarantine symptom onset. the reason for this is unclear, but one possible explanation is that there were (unknown, therefore unreported) exposures during the quarantine period. if people are quarantined in groups of (presumed) uninfected cases, pre-symptomatic transmission in quarantine would result in true exposure times that are more recent than reported last possible exposure times. there are several limitations to this work. first, the times of exposure and the presumed infectors are uncertain, and the incubation period is variable. we have not incorporated uncertainty in the dates of symptom onset. we have used the mixture model approach for serial intervals to avoid assuming that the presumed infector is always the true infector, but the mixture does not capture all possible transmission configurations. our r estimates are very simple and could be refined with more sophisticated modelling in combination with case count data. we have not adjusted for truncation (eg shorter serial intervals are likely to be observed first). however, the serial interval estimates are consistent between the two datasets, are robust to the parameter choices, and are consistently shorter than the estimated incubation times. in conclusion, in both the singapore and tianjin covid- clusters we identified both the incubation period and the serial interval. our results suggest that there is substantial pre-symptomatic transmission, with the serial interval shorter than incubation period by - days. we find differences in estimated incubation period between early and later cases; this may be due to presymptomatic transmission or differences in reporting and/or in perceived exposure as the outbreak progressed, in the context of social distancing measures. finally, our shorter serial intervals lead to an estimate of the basic reproduction number of approximately in both datasets, suggesting that stopping half the transmission events may be sufficient to control outbreaks. . cc-by-nc . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . https://doi.org/ . / . . . doi: medrxiv preprint . cc-by-nc . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. . cc-by-nc . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . https://doi.org/ . / . . . doi: medrxiv preprint table s table s table s table s details of the singapore and tianjin datasets in the singapore dataset: "related cases" are direct known contacts between cases; "cluster links" are cases that are linked together through an identified cluster event; "presumed infected date" and "presumed reason" are the earliest known date and the reason that each case was known to likely be infected; "last poss exposure" and "symptom presumed infector" are sub-classifications of "presumed infected date," representing either the last date that each case could have been infected -the date of arrival in singapore for travellers from wuhan -or the date that each case was likely infected during a local transmission event in singapore, respectively; "cluster" is the ministry of health singapore's classification of cases into transmission cluster events. in the tianjin cases summary spreadsheet, the main columns are: gender, age, symptom onset, symptom type, confirmation date, severity and death date [ ] ; detailed information from daily reports for the first patients provided travel or exposure history and contact information, from which we obtained exposure windows (start source, end source). for backup and to complete missing information for later cases we also referred to jinyun news, tianjin official local media: [ ] who used baodi local government reports [ ] . they reported detailed activity for those confirmed cases when their corresponding epidemiological history investigation was finished. . cc-by-nc . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . https://doi.org/ . / . . . doi: medrxiv preprint statistical methods we explored several distributions for the incubation period: weibull, gamma and log normal. as shown in figure , once fit the resulting distributions all provide very similar results. table s summarizes the parameter estimates for the gamma and log normal distributions. table s gives the parameters for the incubation period for early-and late-occurring cases in both datasets. we used bootstrapping to explore the range for the point estimates of µ and σ from the mixture model. figure s shows the results. the mean of the bootstrapped mean estimates is . ± . for tianjin and . ± . days in singapore. bootstrap values are consistent with a serial interval that is considerably shorter than the incubation periods in both datasets. table s shows the sensitivity analysis; we varied the the number of cases per cluster to include in the icc interval data and we explored sorting the cases in the clusters according to the time of last exposure (ie the putative index status assigned to the individual with the earliest end to their exposure window, instead of the first symptomatic individual). we sampled the estimated serial interval and incubation period distributions to estimate the probability that the incubation period minus the serial interval is negative. this could indicate the portion of transmission that occurs before symptom onset, but it makes the strong assumption that incubation period and onset of symptoms occur independently and it does not take the growth curve of . cc-by-nc . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . https://doi.org/ . / . . . doi: medrxiv preprint the outbreak, or censoring or truncation, into account. we find that the portion of negative samples is . for early cases and . for unstratified (overall incubation period) cases in singapore, and . (early) and . (all) cases in tianjin. early cases have shorter estimated incubation periods so the fractions are lower. late cases have higher portions ( . , . ) but this is due to the long incubation estimate and fixed serial interval distribution; it may be influenced by censoring and truncation. figure s illustrates the distributions. estimates of incubation period and serial interval from other studies are shown in table s . of note, the majority of studies do not estimate both incubation period and serial interval in the same population. . cc-by-nc . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . https://doi.org/ . / . . . doi: medrxiv preprint figure s figure s : samples of the incubation period distribution minus the serial interval distribution, assuming independence and without considering the (unknown) growth curve of the outbreaks or the extent of censoring. . cc-by-nc . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . https://doi.org/ . / . . . doi: medrxiv preprint table s : incubation period estimates using a gamma distribution. % confidence intervals for the shape and scale (log mean and sd for log normal) parameters are shown in brackets. . cc-by-nc . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . https://doi.org/ . / . . . doi: medrxiv preprint table s . cc-by-nc . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . https://doi.org/ . / . . . doi: medrxiv preprint infector-infectee pairs* pairs - . ( ci . - . ) nishiura et al [ ] *note: included infector-infectee pairs from this singapore cluster. remainder from vietnam ( ), south korea ( ), germany ( ), taiwan ( ) and china ( ) . cc-by-nc . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . https://doi.org/ . / . . . doi: medrxiv preprint early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia clinical features of patients infected with novel coronavirus in wuhan the continuing -ncov epidemic threat of novel coronaviruses to global health -the latest novel coronavirus outbreak in wuhan coronavirus and the race to distribute reliable diagnostics initial public health response and interim clinical guidance for the novel coronavirus outbreak -united states detection of novel coronavirus ( -ncov) by real-time rt-pcr. euro surveillance : bulletin europeen sur les maladies transmissibles nowcasting and forecasting the potential domestic and international spread of the -ncov outbreak originating in wuhan, china: a modelling study the transmissibility of novel coronavirus in the early stages of the - outbreak in wuhan: exploring initial point-source exposure sizes and durations using scenario analysis does sars-cov- has a longer incubation period than sars and mers? epidemiologic characteristics of early cases with novel coronavirus ( -ncov) disease in republic of korea incubation period of novel coronavirus ( -ncov) infections among travellers from wuhan, china incubation period and other epidemiological characteristics of novel coronavirus infections with right truncation: a statistical analysis of publicly available case data serial interval of novel coronavirus ( -ncov) infections. medrxiv updates on covid- (coronavirus disease ) local situation icenreg: regression models for interval censored data in r serial intervals of respiratory infectious diseases: a systematic review and analysis how generation intervals shape the relationship between growth rates and reproductive numbers r: a language and environment for statistical computing. r foundation for statistical computing the serial interval of covid- from publicly reported confirmed cases. medrxiv transmission of -ncov infection from an asymptomatic contact in germany presumed asymptomatic carrier transmission of covid- real-time estimation of the risk of death from novel coronavirus (covid- ) infection: inference using exported cases transmission dynamics and control of sars: the - epidemic. philosophical transactions of the royal society of london. series b: biological sciences factors that make an infectious disease outbreak controllable early transmissibility assessment of a novel coronavirus in wuhan estimating the serial interval of the novel coronavirus disease (covid- ): a statistical analysis using the public data in hong kong from jinyun news reference early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia epidemiologic characteristics of early cases with novel coronavirus ( -ncov) disease in republic of korea incubation period of novel coronavirus ( -ncov) infections among travellers from wuhan, china incubation period and other epidemiological characteristics of novel coronavirus infections with right truncation: a statistical analysis of publicly available case data estimating the serial interval of the novel coronavirus disease (covid- ): a statistical analysis using the public data in hong kong from serial interval of novel coronavirus ( -ncov) infections. medrxiv we thank the ministry of health singapore [ ] and the tianjin health commission [ ] for publishing information about cases through online press releases. we thank the participants of 'epi-coronahack' at simon fraser university for their roles in curating these two datasets. we thank the public health teams and the patients whose data have been included in these analyses. key: cord- -vhymj rw authors: lim, peter a; ng, yee sien; tay, boon keng title: impact of a viral respiratory epidemic on the practice of medicine and rehabilitation: severe acute respiratory syndrome date: - - journal: arch phys med rehabil doi: . /j.apmr. . . sha: doc_id: cord_uid: vhymj rw lim pa, ng ys, tay bk. impact of a viral respiratory epidemic on the practice of medicine and rehabilitation: severe acute respiratory syndrome. arch phys med rehabil ; : – . severe acute respiratory syndrome (sars) is a new respiratory viral epidemic that originated in china but has affected many parts of the world, with devastating impact on economies and the practice of medicine and rehabilitation. a novel coronavirus has been implicated, with transmission through respiratory droplets. rehabilitation was significantly affected by sars, because strict infection control measures run counter to principles such as multidisciplinary interactions, patients encouraging and learning from each other, and close physical contact during therapy. immunocompromised patients who may silently carry sars are common in rehabilitation and include those with renal failure, diabetes, and cancer. routine procedures such as management of feces and respiratory secretions (eg, airway suctioning, tracheotomy care) have been classified as high risk. personal protection equipment presented not only a physical but also a psychologic barrier to therapeutic human contact. visitor restriction to decrease chances of disease transmission are particularly difficult for long-staying rehabilitation patients. at the height of the epidemic, curtailment of patient movement stopped all transfers for rehabilitation, and physiatrists had to function as general internists. our experiences strongly suggest that rehabilitation institutions should have emergency preparedness plans because such epidemics may recur, whether as a result of nature or of bioterrorism. o n march , , a previously healthy patient in her early twenties was admitted to tan tock seng hospital (ttsh), a public teaching hospital in singapore, with progressively severe pneumonia nonresponsive to routine antibiotic therapy. this was the start of a new viral respiratory epidemic for the island-nation of million; the infection rapidly spread from this index case, who was in a multibed ward without barrier infection control measures. those infected at ttsh included of approximately family members and friends who visited this patient, of the patients in adjacent beds, of the physicians, and of the nurses who attended to her. based on nasopharyngeal and serum samples of patients, the infective agent implicated was a novel coronavirus. [ ] [ ] [ ] the name severe acute respiratory syndrome (sars), adopted for this infection, was an appropriate recognition of its nature and virulence. sars started as an atypical pneumonia in the guangdong province of china in november , affecting people and causing deaths. , it was carried into hong kong and transmitted to vacationing singaporeans (including the index case), apparently while they were waiting for a hotel elevator along with a sars-infected person. the epidemic spread to many countries across the globe, with the hardest hit areas being the cities of beijing, hong kong, taipei, singapore, and toronto. the last probable case of sars in singapore was hospital-isolated on may . as of june , , the tally in singapore was a total of probable cases, with recovered and discharged home, dead, and still hospitalized. on july , , the world health organization issued a declaration that sars had been contained worldwide. although the sars outbreak had a relatively high mortality rate and sars can lead to residual lung damage in serious cases, the epidemic arguably had a devastating impact well beyond the absolute numbers affected by the disease. fear of the unknown with a new disease entity and the potential for uncontrollable spread resulted in much apprehension and the implementation of far-reaching measures. in singapore, the economic toll has been significant and estimates suggest that sars may have taken % from the gross domestic product growth in . this resulted not only from direct costs to control the epidemic, but also from losses in productivity, decreased demand for sales and services, and a massive blow to the important airline and tourist industries. tourism to singapore decreased drastically and international conferences were postponed. many multinational business corporations instituted policies against travel to affected countries like singapore. travel from singapore to other sars-affected countries was similarly curtailed. in simple terms, nobody wanted to put themselves at risk of contracting the sars virus. in health care, the costs to combat sars have been in the hundreds of millions-us$ million was spent on direct operating expenditures, such as medical supplies, protective gear for health care workers and patients, free sars screening and ambulance services, administering and enforcing home quarantine orders, setting up fever clinics, contact tracing, and a sars hotline center. us$ million was spent on infrastructure expenditures, including construction of isolation rooms and renovation of wards and medical facilities. the fears and concerns generated by the disease also had a considerable impact on hospitals. a striking feature of sars was the significantly increased risk to health care workers, with a large proportion of those infected in singapore ( / [ %]) from among these ranks. the fear of the "super-spreader" (a person who directly infected Ն other persons with minimal contact), lying undiscovered in the wards, asymptomatic or minimally symptomatic, was of considerable concern and caused much stress. the singapore general hospital (sgh), from which this account of events arose, is a -bed public tertiary teaching hospital. with the national dental, eye, heart and cancer centres on the same campus, it offers services in most areas of medical expertise. the department of rehabilitation medicine in sgh provides comprehensive inpatient and outpatient services, and had between and inpatients at the time of the epidemic. this article recounts chronologically the effect of sars on medical and rehabilitation services. it reviews the preventive and control measures taken, and it describes the solutions and adaptations taken to overcome some of the problems faced by rehabilitation medicine. once the highly infectious and virulent nature of sars became apparent, a process was rapidly implemented for identifying suspected patients. this process centered on the clinical findings of fever, cough, respiratory difficulties, and radiographic changes, including consolidation or findings of adult respiratory distress syndrome. it was also important to determine any history of close contact with someone infected by sars or travel to sars-affected regions (appendix ). at the time, the nature of the virus was still unconfirmed, and no diagnostic tests were yet available. the ministry of health (moh) singapore, which had authority over of the , hospital beds in the country, placed ttsh and its communicable disease centre under quarantine. ttsh was designated for assessment and isolation of suspected sars cases, either by direct admission or by transfer from any other health care facility. non-sarssuspected cases were diverted to the other public sector hospitals, resulting in a shift of acute health care workloads to the other hospitals. for rehabilitation medicine, this meant having to cope with a noticeable increase of patients needing rehabilitation from events such as strokes and traumatic injuries. hospital staff who became sick or had a fever, defined as a tympanic temperature higher than . °c confirmed by oral retesting, had to report to the employee clinic or to the emergency department for screening. this in turn necessitated redeployment of staff from other departments to these areas, to help cope with the dramatically increased workload, because they had become busy frontline areas for staff and patients, respectively. ironically, a significant number of healthy staff with higher body temperatures were ordered to take sick leave until it was determined that these people had higher baseline temperatures and waivers were issued. all nonemergency leave and vacation time were suspended. an appeal was put out by the moh for private practitioners to help out by filling locum clinic roles and nonspecialized areas, such as employee clinics and clinical audits. all staff received retraining in infection control practices, as appropriate. this included proper hand-washing techniques and donning and doffing of personal protection equipment (ppe), which included head cover, goggles, n- masks, gowns or plastic aprons, gloves, and shoe covers. n- masks, certified by the national institute for occupational safety and health, with a % or greater filter efficiency against oil-free particulate aerosols of . in size, became mandatory for health care workers with direct patient contact. although potentially preventing sars transmission, these masks required increased breathing effort, and the staff found itself fatigued more quickly or even dizzy after using these masks. this was particularly difficult for our therapy and nursing staff because of their physical work duties, although doctors and others were also affected. work efficiency dropped considerably with the need for donning and doffing fresh ppe with each patient. the discomfort and stress of ppe was particularly difficult for pregnant or claustrophobic staff, and it was made worse by having to wear gowns in a tropical climate. knowing that one could still get infected while using protective measures was not helpful. equipment such as stethoscopes, sphygmomanometers, therapy plinths or platforms, examination tables, and trolleys had to be wiped down after each use with an antiseptic solution (eg, alcohol, sodium hypochlorite, phenolic acid). fastidious and frequent hand washing affected staff with eczema and allergies to the antiseptic soaps or hand rubs that were compulsory after each and every patient contact no matter how trivial. in rehabilitation medicine, a heightened vigilance and a tighter screening process was adopted before transfer of patients to the rehabilitation ward, especially those with fever or a history of pneumonia. specifically explored during rehabilitation consultations were the issues of patient fever, travel or contact history, and respiratory symptoms or issues. rehabilitation medicine was increasingly affected by everstricter infection control measures regarding close contacts and interactions between health care workers. multidisciplinary team meetings were canceled; instead, telephone updates or intranet e-mails were strongly encouraged. nevertheless, oneon-one meetings between masked team rehabilitation members still occurred, to pass on progress reports and to discuss important issues. the use of telephone or e-mail was encouraged for specialist consultations unless a personal examination or bedside consultation was felt to be necessary, in which case ppe was expected before entering the patient's room. the hospital was already partially converted to electronic medical records; hence, it was possible to pull out laboratory tests, radiologic reports, and medical summaries from any hospital computer terminal using individualized physician passwords. rehabilitation consultations often ended with a recommendation for transfer to a smaller community hospital with therapy services, because sars had left these institutions relatively unaffected. alternatively, those well enough to go home were sent for outpatient therapies at one of the various facilities for day rehabilitation across the city, and home-based therapy was also available although limited because of personnel constraints. the first death from sars in singapore was reported on march , . moh's official strategy focused on areas of control: ( ) eliminate nosocomial transmission through sub-stantially enhanced infection-control practices; ( ) prevent additional importation of infection through health screening and travel advisories at the airport and seaports; and ( ) stop community transmission through education, contact tracing, and quarantine measures. sgh implemented a modular system, with physical barriers (eg, gypsum boards, closed fire doors) quickly installed between sectors, in an attempt to contain and limit any subsequent outbreaks. rehabilitation medicine was organized into such a module. doctors were not permitted to move out of modules or between outpatients and inpatients. no patient transfers were permitted between modules, except to the isolation or intensive care units. departments were encouraged to separate into teams to enable a backup in case team became exposed and prophylactic quarantine necessary. where possible, only doctor was to examine the patient to avoid excessive contact. visitors to the hospital were restricted and eventually banned altogether, except for immediate family of dangerously ill patients. temperatures and contact history were taken at checkpoints set up at entry points to the patient wards and the visitor restrictions enforced here. group therapy and patients using therapy gyms in relatively close quarters were prohibited to avoid spread of the virus. therapies thus became exclusively one-on-one and were provided at the bedside. rehabilitation equipment, such as parallel bars, step platforms, therapy balls, and assistive walking devices, were distributed to modules depending on estimated therapy load because the therapy gyms were closed. rehabilitation medicine was directly affected when the entire neurology ward, including patients and health care staff, were transferred out to ttsh for isolation and observation because of suspicious clusters of fevers that involved both patients and staff. several patients from this neurology ward, who had previously been transferred to us for rehabilitation, were also transferred out. as secondary contacts, the rehabilitation team, including doctors, nurses, and therapists, were placed on a prophylactic -day home quarantine. fortunately, our policy of grouping transferred patients into physical area according to previous wards meant the chance of their contaminating other rehabilitation patients was minimal. management of the remaining rehabilitation patients was taken over by physicians from the adjacent ward for the quarantine period, with continued input from the physiatrist unaffected by the quarantine order-he was running the outpatient clinic at the time of the outbreak and hence had not been exposed to the virus. ultimately, it was determined that none of the staff nor patients had the sars virus. nevertheless, it demonstrated how entire units, including rehabilitation medicine, could abruptly be closed down by any possibility of sars. the need to avoid unnecessary contact and interactions, as well as to generally isolate our patients from one another, struck the rehabilitation unit with full force. rehabilitation patients were not allowed to move around or interact with each other. surgical masks, which some patients found uncomfortable or intolerable, had to be worn by those with a fever or cough. the rehabilitation staff had to don full ppe, including n- mask, head cover, face shield, gown, and gloves, before contact with each patient, introducing not only a physical but also a psychologic barrier. conceivably, close patient contact (eg, during transfers) could transmit infection by way of fomites. the amount of physical, occupational, or speech therapy that each patient received was significantly reduced, because of staff fatigue from the masks and heat from the gowns. staff had to refrain from the usual acts of comforting patients, such as holding hands and appropriate touching, unless it was through the ppe. scrubs and t-shirts were provided to all staff working in patient areas or having patient contact. shower facilities were opened for baths and staff changed into street clothes before heading home at the end of the shift. because the virus is typically found in the respiratory secretions (and, to a lesser extent, in feces), certain tasks were now deemed to need a higher level of precaution and protection. to prevent spread of the sars virus among staff, a positive air purifying respirator (papr) was worn on top of the ppe during procedures such as suctioning of respiratory secretions. the papr is a battery-operated device that continuously blew filtered air out through the hood worn, thus preventing the virus from being inhaled. however, the additional protection had a price in terms of heat retention and weight, both of which resulted in profuse sweating, especially in non-air conditioned patient care areas. it also restricted movements and required adequate operator hydration and rest periods. sufficient numbers were necessary because of the many procedures for which it would be needed, and effort and time was required for cleaning after each use. staff lounges and cafeterias were closed, to avoid interactions between health care workers, and free packed meals were provided for all on duty. foreign guest workers, especially nursing staff and aides who shared apartments but worked in different hospitals in singapore, were provided with optional housing, such as hostels and rented apartments. teaching programs and meetings were suspended, again to avoid unnecessary interactions. bedside teaching with patients was stopped. face-to-face and group meetings were avoided where possible, and a system (lotus sametime) for virtual meetings and conferencing via the hospital intranet was instituted for heads of clinical departments, to ease communication. after the incident involving the transfer of neurology patients (see risks of rehabilitation transfers), no other patients were transferred into the rehabilitation unit. instead, rehabilitation medicine, along with other specialty departments such as neurology, renal medicine, and gastroenterology, provided general internal medicine care for any patient admitted to their respective wards. our department took care of patients with diagnoses ranging from congestive heart failure to renal failure, and from fresh strokes to psychiatric disorders including drug overdose. it became a matter of chance whether a patient would be transferred from the emergency department to the rehabilitation ward. it was understood, however, that during triage in the emergency department, staff would try to direct patients to an appropriate departmental ward-for example, strokes to the neurology or rehabilitation medicine module. patients admitted with fevers were sent to the isolation wards and were managed by respiratory medicine and infectious-diseases physicians, with the help of medical personnel seconded from other departments, including ours. all elective procedures and surgeries were canceled, and only urgent or emergency surgeries were performed. training for rehabilitation medicine physicians in singapore is a -year program after a residency-equivalent training and certification examination in internal medicine. in addition, rehabilitation medicine trainees are part of the internal medicine call schedule for the hospital. this turned out to be an important reason for the relatively easy time our doctors had coping with their new roles as internists. similarly, therapists with special interests or those who worked predominantly with certain patients (eg, stroke, amputees, sports medicine) now found themselves practicing outside their usual area of expertise. despite experience or training with populations such as those with spinal cord injury, therapists might find themselves working with amputee patients or performing chest physiotherapy (pt). the number of patients presenting for outpatient evaluations and follow-ups dropped dramatically, because the public avoided hospitals whenever possible. recognizing this, medical record reviews of scheduled outpatients who did not show up for appointments were performed to determine the urgency of follow-up. telephone contact was made as necessary, especially where follow-up was important to assess for any problem. where indicated, medication refills were dispensed and sent by courier to patients' homes. new appointments were rescheduled before the end of the medication prescription period, by which time the sars epidemic we hoped would have abated. the pt department set up a service known as e-physio via the hospital's internet web site (http://www.sgh.com.sg), whereby patients with access to the internet could book appointments for assessment and therapy sessions through webcams from their own homes. lock-downs of modules occurred sporadically, whenever a fever cluster or sars-suspicious patient was discovered. patients and staff affected were monitored for at least a -day period, longer than the sars incubation period of days previously described, to allow for an increased margin of safety. this meant, however, that patients in the same physical vicinity, who might have otherwise been discharged home, ended up with an enforced prolongation of hospital stay while being monitored for development of fever and other signs and symptoms. active contact-tracing efforts by the moh and at each hospital was in full force, with every suspected or infected patient mapped for movements and recent human contacts, and home quarantined for the disease incubation period imposed. patients with immune system disorders and pathologies were deemed to be immunocompromised, and this included people with diabetes mellitus, malignancies, and chronic renal failure. the possibility of these patients contracting sars and not presenting with the typical fever and respiratory symptoms was a very real concern. this was borne out by a cluster of sars infections at sgh that originated from a single patient with renal failure. patients eligible for discharge who were immunocompromised in some manner were instructed to stay at home for days and to monitor their temperatures. needless to say, this included many of our patients with diabetes, which is such a common risk factor for stroke and amputation. discharging these patients to a step-down facility, such as a community hospital or an extended-care facility, became a problem, because these facilities stopped accepting such cases as a precaution against inadvertently importing sars. as discussed earlier, certain ward procedures relatively common for rehabilitation patients were among those classified as high risk. these included nasopharyngeal aspiration, bronchoscopy, endotracheal intubation, airway suctioning, and even noninvasive ventilation procedures. caution was also needed with chest pt and postural drainage, because there was potential for coughing and producing respiratory secretions, as well as with the occasional cardiopulmonary resuscitation. during such procedures, full ppe and papr were mandatory, which meant that several sets of this equipment had to be ready and available at all times. because of the risk of aerosolized virus particles or droplet spread of the virus, nebulizers for respiratory medications, such as albuterol (salbutamol), were used only when absolutely necessary, and only under controlled situations, generally in a closed single room and with the health care worker in papr. wherever possible, spacer devices, to which the medications' pocket inhalers could be connected, were substituted. care was also taken when using nasal intermittent positive pressure ventilation devices for respiratory rehabilitation patients. fecal transmission was theoretically possible; hence, even patient hygiene and laundering bedding after fecal incontinence were classified as a high-risk procedure. handling of diapers, disposal of excreta, and manual digital evacuation were done with full ppe worn and due care and diligence. patients. with regulations that initially limited visitors and subsequently prohibited visitors except to patients on the dangerously ill list, boredom and lack of emotional support became a major factor for our longer-staying patients. only private-rate paying patients had individual bedside telephones; hence, hospital-wide loaner cellular phones (with airtime donated by local telecommunication companies) were made available on request to any other patient who wished to talk with family. connections were made for video conferencing whereby the family, either at the sgh visitors' center or at of several designated community centers, booked slots to use real-time video cameras to talk to their loved ones on the ward. personal laptop computers were permitted and encouraged for those with their own e-mail accounts. rather than aiming for optimal functioning, the rehabilitation goal became one of quickly getting patients as adequately functional as possible, to where their families could manage caregiving at home despite an earlier discharge than pre-sars days. staff. beyond the underlying fear of infection and the physical stress of working with protective equipment and regulations, security staff in particular came under risk of verbal abuse and physical threats from aggravated members of the public. this mainly originated from frustration with the regulations restricting visitors, but it was occasionally triggered by someone who refused to be screened for contact or travel history or to undergo a temperature check. incidents occurred where armed police were needed to enforce security. incidents also arose in which health care workers were shunned and even discriminated against, probably because of the fear of catching sars. nursing staff in particular, who still routinely wore uniforms in singapore, were easily identified. nurses reported that taxicabs did not stop when hailed. they also noticed having ample seating on public transportation, because no one wanted to sit next to them. on a more subtle level, children of health care workers noted that their friends' parents canceled play dates and social events for vague reasons. this issue was quickly picked up by the media, and a successful campaign ensued that helped health care workers be treated as brave professionals, rather than as potentially infectious persons. as the number of new sars cases dropped and affected patients were discharged home, cautious attempts at service recovery and a return to normality began. this was dampened in part by news of a resurgence of sars in toronto, canada, when an infected elderly patient with hip fracture transferred to a rehabilitation facility, thus creating another cluster of infections. the principle of the day for singapore hospitals thus became one of vigilance and caution, to avoid a similar occurrence. fever monitoring in both patients and staff several times daily continued as a routine, and infection control audit teams roamed the hospitals to detect and discourage breaches of control measures. a computerized system was set up for cluster monitoring in the wards, whereby any cluster of or more patients in the vicinity with fever greater than °c triggered an alert. the coronavirus genome was sequenced and a polymerase chain reaction (pcr) test became available. it was a valuable tool for testing stools and respiratory secretions, although the test's accuracy was still believed to be relatively low. other tests available included blood tests for sars antibody seroconversion (appendix ). a vaccine for sars was still not available and not expected for several years. regulations for readmission and transfer of patients between hospitals, generally still to be avoided, were instituted and included absence of clinical findings, negative chest radiographs, stool pcr test, or serum sars antibody. step-down facilities, such as community hospitals and nursing homes, cautiously began accepting patients again, after placing similar preconditions (eg, absence of fever, negative sars pcr or antibody tests). this shifted some of the burden of unnecessary prolonged stays, because disabled patients who were still unable to return home but were otherwise suitable for a step-down facility could now be moved appropriately. the impact that sars had on health care, and rehabilitation medicine in particular, would have been the same as that for any uncontrolled infectious disease, whether arising from nature (eg, a zoonotic infection), or from bioterrorism, a growing concern in these times. infection control measures effectively compromised the fundamental principles of rehabilitation, including interdisciplinary interactions, patients mingling and learning from each other, use of touch to encourage and comfort patients, and close physical contact during therapy. there were significant financial considerations that stemmed from limited group therapies and reversion to a strictly oneon-one therapy approach. similarly, routine use of infection control measures, including the costs of ppe, time taken to don and doff, and greatly reduced work efficiency among health care workers need to be factored in. the question of expertise arose when physiatrists had to manage medical complications themselves instead of being able to call in consultants or transfer patients to an appropriate specialist. the accuracy of a telephone consultation that relies on the reported history and examination findings of the doctor calling the consult may be questioned. there is a high probability of fatigue and stress after a prolonged period under semimilitary rules and regulations, and attentiveness and vigilance to precautions may slip. health care workers may need to prepare for extended periods in full ppe. rehabilitation departments may need to split into self-contained teams, each with physiatrist, nurses, and therapists, to avoid cross-infection. preparations need to be made to ensure continuity of care for outpatients unable to come for clinic reviews by systematic chart review. potential offsite facilities should be identified as satellites for caregiver teaching and possibly as outpatient clinics for follow-up and therapies in the event of an outbreak. an adequate supply of ppe, including masks, gown, and gloves, needs to be stockpiled and available while awaiting sources to ramp up emergency supplies. rethinking may be necessary about having large common and open therapy areas for patients from several wards. alternatively, smaller areas located near patient wards could be identified for rapid conversion, if necessary, into "mini"-therapy areas by moving in basic therapy equipment. technologic and telecommunication aids, such as the computer, video, and television, can be used to teach rehabilitation. the emotional well-being of patients, especially the ability to communicate easily with loved ones, can also be aided by technology. a system of segregating rehabilitation patients transferred to the hospital should be developed to avoid cross-infection in the early stages or in the event of a controlled outbreak. admission criteria, such as patient temperature, contact and travel history, chest radiographs, and laboratory or serologic evidence of being noninfected, can be predetermined. many of these recommendations will not be so critical if a vaccine is developed soon. physiatrists may also need to keep current with internal medicine skills. this will allow them to continue to care for patients in a crisis where at least for the interim the practice of rehabilitation medicine is limited. therapists may want to engage in crosstraining or intermittently work with patients outside their usual realm, in order to remain comfortable with nonfamiliar therapy activities. sars is a new respiratory epidemic with a devastating impact on the practice of medicine, and, in particular, rehabilitation medicine. besides changes to patient care, the measures taken to control sars have implications for personal freedom and privacy; they may also involve medicolegal issues. the psychobehavioral and medicolegal questions raised will need to be explored and dissected, and it is suggested that committees be set up to examine potential issues and to formalize protocols. new legislation possibly akin to good samaritan laws may have to be proposed, to allow all physicians to function as best as possible under emergency circumstances. we have been able to proceed with service recovery and to return to normal levels of service as the sars epidemic has abated. nevertheless, our experience leads us to conclude that leaders in rehabilitation medicine should anticipate such an infectious epidemic occurring in their institutions. an emergency preparedness plan should be put in place at the facility level, and possibly at the state and national levels, ready for implementation if the need arises so that it does not have to be created as events unfold. severe acute respiratory syndrome (sars) in singapore: clinical features of index patient and initial contacts coronavirus as a possible cause of severe acute respiratory syndrome a novel coronavirus associated with severe acute respiratory syndrome identification of a novel coronavirus in patients with severe acute respiratory syndrome a major outbreak of severe acute respiratory syndrome in hong kong sars battle cost govt $ m-and more. straits times the immediate psychological and occupational impact of the sars outbreak in a teaching hospital severe acute respiratory syndrome-singapore singapore ministry of health. statistics health facts singapore cluster of severe acute respiratory syndrome cases among protected health-care workers-toronto, canada development of a standard treatment protocol for severe acute respiratory syndrome sars: experience at prince of wales hospital, hong kong world health organization. case definitions for surveillance of severe acute respiratory syndrome (sars) (revised use of laboratory methods for sars diagnosis positive sars diagnostic test a) confirmed positive pcr for sars virus at least different clinical specimens (eg, nasopharyngeal and stool), or same clinical specimen collected on or more days during illness (eg, or more nasopharyngeal aspirates), or two different assays or repeat pcr using original clinical sample on each occasion b) seroconversion by elisa or ifa negative antibody test on acute serum followed by positive antibody test on convalescent serum, or four-fold or greater rise in antibody titer between acute and convalescent phase sera tested in parallel c) virus isolation isolation in cell culture of sars cov from any specimen, plus pcr confirmation using validated method note. adapted by permission of the world health organization. , abbreviations: cov, coronavirus; elisa, enzyme-linked immunosorbent assay; ifa, immunofluorescent assay. key: cord- -fio cjj authors: nan title: peripheral nerve society meeting july – , sitges, barcelona, spain date: - - journal: j peripher nerv syst doi: . /jns. sha: doc_id: cord_uid: fio cjj nan the peripheral nerve society was founded in from two groups of academic investigators, peripheral nerve study group and peripheral neuropathy association of america, interested in the basic biology and function of the peripheral nervous system and its application to the clinic. their invite only biennial meetings involved - attendees in cloistered settings organized by shoestring and local initiative. from this, we have grown remarkably. we now have an annual meeting of over people including meetings within the meeting for the special interest groups in inflammatory, diabetic and hereditary neuropathy. with this substantial growth and the success of jpns, the journal of the peripheral nervous system the society continues to flourish. has proven to be a year full of exciting changes for the society. pns has transitioned from a biannual, to an annual meeting. next year, the meeting will be taking place at the renaissance baltimore harborplace hotel from - july in baltimore, maryland. the development of a new website has been completed, please visit www.pnsociety.com to see the new face of the society. finally, pns has adopted new executive staff. with their guidance and the leadership of an active and diverse board of prominent professionals in the field the peripheral nerve society continues to grow and anticipates more exciting changes in the year to come. the peripheral nerve society provides annual meetings, teaching courses, guidelines, and other resources to aid in the education of members. becoming a member of pns means collaborating with prominent global professionals in the field to develop and provide the best treatments for people with peripheral nerve diseases and setting standards of care within the field. please participate in our future by joining the pns, volunteering for a project aligned with your interests and sending your ideas for the future to the executive office, or board member. peles e . department of molecular cell biology, rehovot, israel. two schwann cell-dependent mechanisms control the presence of na + channels at the nodes of ranvier: i. clustering of the nodal complex by glia-derived proteins and ii. restriction of nodal proteins within the nodal gap by the paranodal junctions. these mechanisms depend on specific cell adhesion molecules that mediate the contact between myelinating glia and their underlying axons at the forming nodes and the paranodal junction. during myelination, na + channels initially clustered at heminodes that border each myelin segment. this process requires gliomedin, nrcam and neurofascin (nf ), three cell adhesion molecules (cams) that mediate the interaction between schwann cell microvilli and the axon. na + channels clustering activity of gliomedin is tightly regulated by two distinct and functionally opposing proteolytic events. while the clustering activity of gliomedin is enhanced by its shedding from the surface of schwann cells by a furin protease, its activity is negatively regulated by bone morphogenetic protein /tolloid-like (bmp /tld), and tolloid-like (tll ) metalloproteinase. cleavage by these enzymes restricts the activity of gliomedin to the nodal area and prevents the formation of ectopic clusters along axons that are devoid of myelin segments, as well as below the myelin internodes. hence, proteolytic processing of gliomedin facilitates, yet limits, the clustering of na + channels to specific sites along the axon in a timely manner. furthermore, axon-glial contact mediated by gliomedin and nf at the nodes, not only plays a role in na + channel clustering during development, but also contributes to the long-term maintenance of na + channels at nodes of ranvier. in addition to clustering by gliomedin, the distribution of na + channels is restricted between two growing myelin segments by the flanking paranodal junction. at this site, axon-glia contact is mediated by a distinct set of cell adhesion molecules (i.e., caspr, nf and contactin) that also delineate the underlying axonal and glial cytoskeleton. this paranodal junction-dependent restriction of na + channels to the nodes is mediated by the spectrin-based paranodal axonal cytoskeleton. illa i . neuromuscular unit, neurology department, hospital santa creu i sant pau, universitat autònoma de barcelona, barcelona, spain. chronic inflammatory demyelinating polyradiculoneuropathy (cidp) is an autoimmune disorder of the peripheral nerves with clinical and immunological heterogeneity. currently, the diagnosis of cidp is based on clinical and electrophysiological criteria and does not take into consideration the presence of immune biomarkers. several autoantibodies against proteins of the node of ranvier in patients with cidp have now been described. these antibodies define specific cidp subtypes sometimes referred to as nodopathies and can have diagnostic and prognostic implications. anti-contactin (cntn ) antibodies. we have described the presence of antibodies to cntn in a small subset of patients with cidp. these patients shared a phenotype and have poor response to ivig. the anti-cntn antibodies are predominantly igg . pathological studies from skin and sural nerve biopsies of patients show morphological changes in the paranodes. experimental data supporting the pathogenicity of anti-cntn igg antibodies include: a) demonstration in vitro that the antibodies disrupt the binding of the cntn -caspr complex to neurofascin- (nf ); b) intraneural injections of antibodies progressively and specifically disrupt the paranodal axo-glial junction; and c) chronic infusion of antibodies induced clinical and electrophysiological worsening in animals with experimental autoimmune neuritis (ean). anti-nf antibodies. antibodies to neurofascins were first reported in patients with guillain-barré (gbs) and cidp and subsequently, antibodies specific to the nf isoform were found in a small group (< %) of patients with cidp. studies by us and confirmed by others have demonstrated that patients with cidp and anti-nf antibodies have a distinct phenotype that often includes a low-frequency tremor and poor responses to ivig. the autoantibodies are predominantly of the igg subtype. the passive transfer of monoclonal anti-neurofascin antibodies (which recognize all neurofascin isoforms) to mice with ean strongly exacerbated the severity of the pathology, but no studies have yet demonstrated that patient-derived anti-nf igg antibodies are pathogenic. a pathogenic role of the antibodies is however supported by sural nerve biopsies from patients with cidp and anti-nf antibodies that showed paranodal demyelination in the absence of inflammation, the loss of septate-like junctions and, the interposition of cellular processes between the paranodal loops and the axolemma. these alterations are reminiscent of those found in nfasc-null mice suggesting that anti-nf antibodies may specifically disrupt the nf -cntn -caspr complex at the paranodes. antibodies to other nodal proteins. recently neurofascin- and neurofascin- were reported as the main targets of autoantibodies in five patients with igg reactivity against the nodes of ranvier; the antibodies were predominantly igg . these patients presented with clinical features distinct from those in patients with anti-nf igg antibodies. four of these patients had subacute onset of sensory ataxia without tremor. the presence of anti-caspr antibodies has been reported in two patients with inflammatory neuropathies, one classified as cidp, the other as gbs. both patients had intense neuropathic pain. the skin biopsy from both patients showed paranodal disruption. some patients whose sera show nodal or paranodal reactivity in teased nerve fiber preparations have antibodies against other nodal proteins, such as gliomedin or neuronal cell adhesion molecule (nrcam) . the skin is equipped with specialized mechanoreceptors that allow the perception of the slightest brush. indeed some mechanoreceptors can detect even nanometer-scale movements. movement is transformed into electrical signals via the gating of mechanically-activated ion channels at sensory endings in the skin. the sensitivity of piezo mechanically-gated ion channels are controlled by stomatin-like protein- (stoml ), which is required for normal mechanoreceptor function. under pathophysiological conditions following nerve injury or diabetic neuropathy the slightest touch can produce pain. it is at present unclear whether peripheral changes in sensory mechanotransduction may underlie hypersensitivity associated with neuropathic pain. here we have examined the role of the stoml modulation of piezo channels in mechanoreceptors and nociceptors to under pathophysiological conditions. we recently developed small molecules that act as inhibitors of stoml function. peripheral application of stoml inhibitors can alleviate hypersensitivity in models of neuropathic pain. our data strongly suggest that tactile evoked pain in models of peripheral neuropathy may be at least partly driven by sensitization of sensory mechanotransduction driven by stoml . coleman m . john van geest centre for brain repair, cambridge, uk. axons are lost early in many neurodegenerative disorders of peripheral and central nervous system. the degeneration of transected axons (wallerian degeneration) can be slowed tenfold by overexpression of a variety of nad-synthesizing enzymes, such as isoforms of nmnat or the related mutant fusion protein, wld s . wallerian degeneration is also delayed by deletion of tlr adapter protein sarm , a protein recently reported to promote nad degradation. it is important to understand fully the mechanism of wallerian degeneration because related mechanisms contribute to axon loss in a number of disease models, including models of peripheral neuropathies, parkinson's disease, multiple sclerosis and glaucoma. new data also suggest a role in hereditary spastic paraplegia. while depletion of nad is an attractive hypothesis for the mechanism of wallerian degeneration, especially as nad can be increased by dietary methods, it cannot explain a number of key observations. fk , an inhibitor of nampt, blocks the nad salvage pathway and strongly depletes nad, including within axons. however, instead of killing axons as the nad hypothesis would predict, it does precisely the opposite: it phenocopies the protective effect of wld s . moreover, ectopic expression of the bacterial enzyme nmn deamidase, a protein absent in mammals, protects injured axons both in transgenic mice and in primary neuronal cultures, but it has no effect on nad levels either under basal conditions or in degenerating nerves. these observations fit better with a proposed toxic role for the nad synthesis intermediate nmn, a model that can also explain the protective effect of wld s . a full understanding of the pathway should identify a number of points where intervention could be a treatment for multiple axonopathies. as with any medical discipline, expansoin of knowledge about the fundamental science behing a disorder of the human nervous system comes part and parcel with a change in our understanding of the epidemiology of any given disorder or groups of disorders. recent advances in our fundamental understanding of inflammatory neuropathies of the peripheral nervous system have been accompanied by drastic changes in our understanding of the neuroepidemiology of these disorders -the specific populationss affected by peripheral neuropathies, as well as the varying importance / contributions of select peripheral neuropathies to the overall burden of peripheral nervous system (pns) disease, and how this shift in epidemiological understanding influences the clinical approach to diagnosis and management of patients with pns disease. the past few decades have witnessed a paradigm shift in many aspects of pns disease diagnosis and treatment; from the association of human immunodeficiency virus (hiv)-associated neuropathies; to the increassing recognition of hereditary / familial peripheral neuropathies; to the increased recognition of specific neuropathies such as multifocal motor neuropathy with conduction block. in addition, timely events such as the recent, and increasingly irrefutalbe evidence for a link between zika virus and a guillain-barré syndrome, and the rather unexpected resurgence of peripheral neuropathies due to previously 'exotic' etiologies such as lepromatous neuropathy require prompt clinical attention. this plenary session aims to describe the evolving neuroepidemiology of peripheral nervous system disorders, and how these changes may influnece the clinical approach to the diagnosis, prognostication, and treatment of otherwise 'unusual' periphal nerve diseases. oxaliplatin chemotherapy for colorectal cancer is seriously limited by neurotoxic side effects which are not fully understood. oxaliplatin-induced peripheral neurotoxicity (oipn) comprises an acute syndrome and a chronic sensory neuropathy. the acute symptoms, notably cold hyperalgesia, have been attributed to transient ion channel dysfunction, and the worse they are the more severe the chronic neuropathy that ensues. we designed a combined in vitro and in vivo project, using neurophysiology to better understand the pathogenesis of oipn. in the in vitro study, differentiated f cells (rat drg neurons x mouse neuroblastoma n tg- cell line) were incubated for and hours in . m oxaliplatin, and their electrophysiological properties studied by patch-clamp. the treated f cells showed relatively depolarized resting membrane potentials, significantly decreased firing frequencies, and increased sodium current densities. moreover, a decrease in erg (ether-à-go-go-related gene) potassium current was also evident. in the in vivo study, we applied nerve excitability testing (net) to a wistar rat model of oipn. to investigate the acute syndrome, we compared behavioural and neurophysiological data of animal cohorts (controls and oipn rats, n= each) before and after oxaliplatin administration ( mg/kg, iv). twenty-four hours after the injection we observed differences between the groups in behaviour (cold plate test, p= . ) and in superxcitability of motor axons (p= . ). to investigate the chronic neuropathy, we compare a control group (n= ) with a treated group (n= , oxaliplatin mg/kg twice weekly x weeks, iv). both groups are studied with behavioural, neurophysiological (sensory and motor nerve conduction studies, net), and pathological (caudal and sciatic nerve, skin biopsy, drgs) methods. data are collected at baseline, end of treatment and weeks after treatment; to obtain a full net profile of all significant changes. in this highly translational approach to oipn, the in vivo net changes in the acute and chronic rat models can be matched on the one hand to findings from in vitro experiments, and on the other to clinical data, since net is also easily applied in humans. of these results. in denmark there is a unique situation to conduct epidemiological studies facilitated by the danish civil registration and the danish national hospital registry (dnhr). this enables us to identify all gbs patients in denmark in a given period. from the same period as the igos cohort was included we have identified all gbs patients admitted to or seen in outpatient's clinics of hospitals in denmark (september st to december st ). records from the population based danish cohort will be reviewed for demographic and clinical data and compared to the patients included in igos from denmark, as well as with the igos europe/america cohort. during this period patients from denmark have been included in igos. the danish group is comparable to the europe/america group not counting the danish patients (n= ) of the igos cohort in regard to sex and age at entry, gbs disability score at nadir, and percentage of patients needing mechanical ventilation. in the danish igos group % are males, the median age is ( - ) years, the mean(sd) gbs disability score at nadir . ( . ), and % of the danish group needed mechanical ventilation. in the europe/america group % are males, the median age is ( - ), mean(sd) gbs disability score at nadir . ( . ) and % of the group needed mechanical ventilation. at the meeting we will compare and present data from the danish population based cohort as well as epidemiological data. chronic inflammatory demyelinating polyneuropathy (cidp) is a common autoimmune disease of the peripheral nervous system (pns) that causes sensorimotor impairment. mice with a dominant autoimmune regulator gene (aire) g w mutation on the non-obese diabetic (nod) background (nod.aire gw/+ mice) develop spontaneous autoimmune peripheral polyneuropathy (sapp) resembling cidp. in sapp, demyelination is caused primarily by th t cells; however, the contributions of nerve-resident cells such as schwann cells are poorly understood. we identified a population of non-hematopoietic, integrin alpha + (itga +) cells in the pns that increases in frequency and number during sapp. these itga + cells coexpress numerous schwann cell markers including sox , p , s b, myelin protein zero, and peripheral myelin protein , suggesting that itga + cells are schwann cell-like. additionally, during sapp, these itga + cells upregulate the extracellular matrix protein periostin (postn), which has recently been shown to promote macrophage recruitment and activation in inflammatory disease and cancer. our data indicate that macrophages are pathogenic during sapp. therefore, we hypothesized that itg a+ cells promote macrophage recruitment during sapp via postn production. to test this hypothesis, we performed in vitro chemotaxis assays. conditioned media from nod.aire gw/+ nerve promoted significantly more macrophage chemotaxis than conditioned media from postn −/− nerve. furthermore, postn recombinant protein was sufficient to induce macrophage chemotaxis in vitro. our findings show that itg a+ schwann cell-like cells mediate macrophage chemotaxis by upregulating postn during sapp and suggests postn as a novel target for the treatment of cidp. "wear-off" frequency will be analyzed by assessing the proportion of subjects with any given degree of gs and rods intracycle fluctuation and the proportion of cycles in which gs and r-ods fluctuation occurs. to determine the extent of "wear-off" the degree of difference between maximum and minimum gs, r-ods, tugs, onls, and vas scores will be analyzed. currently subjects from different sites have been enrolled ( sites eligible for enrollment). this interim study report will provide preliminary representative data, demonstrating ivig "wear-off" effects on gs and other outcome measures. by better understanding the frequency and extent of ivig treatment-related fluctuations we expect that these results will help facilitate development of cidp treatment optimization strategies. we also expect that this information will be important in forming hypotheses to be tested in future studies (for example, comparing different dosage intervals, optimal ivig taper guidelines, or assessing the long-term outcome of short-term cycle to cycle clinical fluctuations). neuropathic pain is a frequent feature of peripheral neuropathy causing a significant impact on patients' quality of life and health care costs. resolving the genetic architecture of painful neuropathy will lead to better disease management strategies, risk stratification, and counselling. therefore, we aim to develop a reliable technique to rapidly and accurately re-sequence multiple genes in a large cohort of painful neuropathy patients at low cost. whole exome sequencing of thousands of samples remains expensive for clinical use. several targeted enrichment approaches are currently available to selectively enrich for genomic regions of interest. in this study, we compared the sensitivity, specificity, targeting efficiency, reproducibility of performance and cost effectiveness of truseq ® custom amplicon-next generation sequencing (tsca-ngs) and molecular inversion probes-next generation sequencing (mips-ngs) methods. for both methods, we constructed a targeted enrichment kit to capture the coding and exon-flanking intron sequences of nine sodium channel genes (scn a, scn a-scn a, and scn b- b) expressed in nociceptive neurons. probes were designed for the two methods using their respective informatics pipelines. in total, patients with diabetic and idiopathic neuropathy were tested by both methods. among the patients, patients were tested previously by sanger sequencing for scn a-scn a. approximately kb was captured and sequenced. % of the targeted regions showed an average coverage of ≥ x in tsca-ngs, and % in mips-ngs. we managed to identify potential pathogenic mutations and polymorphism variants by mips-ngs and tsca-ngs. moreover, we observed a perfect agreement ( %) between sanger sequencing data and those obtained using mips-ngs and tsca-ngs. both ngs approaches showed user-friendly software to design probes and exhibited a similar on-target efficiency. although the overall coverage per region varied across different dna samples, it was sufficient to detect any variant in these regions. mips-ngs has more versatile assay design, demonstrated a high degree of flexibility with probes re-placement and > x cheaper than tsca-ngs. mips-ngs is a reliable, flexible, and inexpensive method to detect genetic variations in thousands of patients. in our centers, this technology is currently implemented as a routine diagnostic tool for screening of sodium channel genes in painful neuropathy patients. alonso-jiménez a , , belvis-nieto r , diaz-manera j , , illa i , , querol l , . neuromuscular diseases unit, neurology department, hospital de la santa creu i sant pau, universitat autònoma de barcelona, spain; centro para la investigación biomédica en red para enfermedades raras, ciberer, madrid, spain; neurology department, hospital universitario dexeus, barcelona, spain. most acute demyelinating polyneuropathies have an immune-mediated pathogenesis and are included within the guillain-barré syndrome spectrum. occasionally, other mechanisms such as metabolic, infectious or toxic may lead to gbs-like presentations. thermatrim ® and pura alegria ® are different brands of the same illegal slimming product that is sold through online vendors and in which the exact composition is unknown. here we present a patient with an acute demyelinating polyneuropathy secondary to the intake of the slimming product "pura alegría". a year-old woman with no remarkable medical history reported days history of distal numbness in her feet that progressed in one week to her knees and her left hand. she had had an upper respiratory tract infection ten days prior to these symptoms. the neurological examination showed absent distal vibratory and arthrokinetic sensations and arreflexia in lower limbs, decreased vibratory sensation in her hands and a ataxic gate. the lumbar puncture showed . g/l of proteins with no cells. the emg fulfilled diagnostic criteria for acquired demyelination. intravenous immunoglobulin therapy was started but the symptoms kept worsening and corticosteroids were started. the patient mentioned then the slimming product. a brain mri showed diffuse leukoencephalopathy that was asymptomatic. steroids and the pura alegria slimming products were withdrawn and the patient recovered completely after one year of follow-up. "pura alegría", "thermatrim" and "thermatrim plus" are slimming products that were forbidden in spain after several cases of acute leukoencephalopathy and acute polyneuropathy. exact composition is unknown although the spanish drug agency detected the pesticide malonoben, a tyrosin kinase inhibitor, among the components. since nine cases of pura alegria/thermatrim neurological toxicity, including leukoencephalopathy and polyneuropathy have been described. all cases had good outcomes after treatment withdrawal, although recovery is slow and may be incomplete. our case highlights the need to carefully consider drug toxicity, including dietary supplements, in the differential diagnosis of gbs specially when evolution does not follow typical patterns. alvarez s , klein d , martini r , moldovan m , , krarup c , . center for neuroscience, university of copenhagen, denmark; department of neurology, developmental neurobiology, university hospital würzburg, germany; department of clinical neurophysiology, rigshospitalet, copenhagen, denmark. charcot-marie-tooth neuropathy type a (cmt a) resulting from peripheral myelin protein kda (pmp ) overexpression is the most common hereditary motor and sensory neuropathy in humans. the transgenic pmp (pmp tg) mouse line c carrying copies of the human pmp gene, has a slowly progressing neuropathy phenotypically like cmt a with thin and abnormally thick myelin profiles and supernumerary schwann cells. in addition, pmp tg nerves showed activated macrophages leading to axon-myelin compartment disruption and maldistribution of k+ channels (kohl b et al, am j pathol. ; : ) . the aim of the present study was to investigate the motor axon excitability in pmp tg versus wt littermates. multiple measures of motor axon excitability under anesthesia were carried out by stimulation of the tibial nerve at ankle and "threshold-tracking" the plantar compound muscle action potential (cmap). at age months, when the post-developmental maturation was nearly complete in the wt, the pmp tg cmap showed an increase in latency by %. the cmap amplitude was decreased by %, although the mean motor unit size (mscan method) appeared unchanged indicating a lack of collateral sprouting. furthermore, pmp tg showed abnormalities in both passive cable properties and voltage dependent parameters. at age month, the cmap latency of pmp tg was increased by % as compared to wt. in contrast to this marked conduction slowing along the tibial nerve from to months of age, the progression of excitability changes localized at ankle appeared modest. nevertheless, when pooling data from to months, the increase in pmp tg latency was correlated (spearman p< . ) with an increase in accommodation half-time during depolarizing electrotonus (+ % of threshold) from to ms and a reduction of the late subexcitable period of the recovery cycle from to % of threshold, both changes consistent with a redistribution of k+ currents consistent with the maldistribution of k+ channels. our data suggest that in the pmp tg cmt a model, a functional, thus potentially reversible abnormality in k+ channel distribution, accumulates along the nerve and aggravates the conduction impairment due to impaired myelin formation and maintenance. alvarez s , krarup c , , moldovan m , . center for neuroscience, university of copenhagen, denmark; department of clinical neurophysiology, rigshospitalet, copenhagen, denmark. mice heterozygously deficient of myelin protein p gene (p +/−) show a mild progressive dysmyelinating neuropathy, with conduction slowing and impaired excitability, phenotypically similar with charcot-marie-tooth disease type b (cmt b). we found that in p +/− the accumulating myelin abnormalities were paralleled by progressive changes in voltage-dependent motor axon function resulting in neurotoxic membrane depolarization (rosberg mr, et. al. neurobiol dis. : ) . the aim of this study was to investigate the relationship between demyelination and motor axon function in p +/−. demyelination of the right sciatic nerve by topic lysophosphatidylcholine (lpc) application was carried out in p +/− and wild-type (wt) mice, in year (mature) and years (aged) groups. multiple measures of motor axon excitability under anesthesia were carried out by stimulation of the tibial nerve at ankle (distal to lpc demyelination) and "threshold-tracking" the plantar cmap responses. live imaging studies by cellvizio (mauna kea technologies, paris, france) confocal laser endomicroscopy were carried out in transgenic mice expressing the fluorescent reporter yfp in peripheral nerve axons under the thy promoter. in mature wt the sciatic morphological and electrophysiological demyelinating features following lpc could be readily observed at hours but disappeared by weeks. no morphological changes could be observed at the tibial level. consistently, no conduction or excitability changes could be observed at the right tibial neve level as compared to the left tibial nerve in wt. in contrast, in p +/− the motor axon function was impaired at the tibial nerve level at weeks after sciatic lpc demyelination. in mature p +/−, although the cmap amplitude appeared preserved, the distal motor latency was prolonged whereas the excitability measures showed reduced deviations during threshold electrotonus and increased refractoriness at the expense of superexcitability of the recovery cycle, both consistent with membrane depolarization. furthermore, in aged p +/− the delayed tibial conduction was associated with a drop in cmap amplitude and a prolongation of the strength-duration time constant. taken together these data suggest that focal demyelination aggravates membrane dysfunction along the entire motor axon in p +/− providing a novel experimental model to explore the link between demyelination and axonal membrane dysfunction in cmt b. amass l , li h , gundapaneni b , schwartz j , keohane d . pfizer inc., new york, ny, usa; inventiv health inc., burlington, ma, usa. a number of factors can influence disease progression in transthyretin familial amyloid polyneuropathy (ttr-fap), a rare, fatal, hereditary amyloidosis. this analysis evaluated the specific role of baseline neurologic severity on neurologic disease progression in ttr-fap. a predictive model was created based on longitudinal data from val met patients who participated in the tafamidis (a selective ttr stabilizer) clinical development program. data from the intent-to-treat population of the double-blind, placebo-controlled registration study (tafamidis group, n= ; placebo group n= ) and its two consecutive open-label extension studies in which all patients received tafamidis were used. the second extension study is ongoing, but a formal, prospectively-planned interim analysis was conducted with the cut-off date of december , . this analysis focused on the first months of treatment for the overall study cohort analyzed. the neuropathy impairment score-lower limbs (nis-ll) was used to assess neurologic functioning at baseline and at subsequent study visits. a linear mixed-effects model for repeated-measures (mmrm) analysis, with baseline nis-ll, treatment, and their interactions with time as fixed effects, was used, and the slope and intercept for each patient were included as random effects. patients were primarily caucasian with early-stage neurologic disease (baseline nis-ll mean [standard deviation]: tafamidis, . [ . ]; placebo, . [ . ] ). across both groups, disease progression increased with increasing levels of baseline severity (nis-ll) (p< . ). however, the predicted magnitude of change from baseline to month for tafamidis was consistently less than that for placebo across a range of observed baseline nis-ll values, suggesting a disease-modifying effect of tafamidis. similar findings were observed for the nis-ll muscle weakness subscale. this mmrm analysis in patients with val met ttr-fap demonstrates that disease progression strongly depends on baseline neurologic impairment and highlights the disease-modifying effect of tafamidis across a range of baseline levels of neurologic severity. clinicaltrials.gov identifiers: nct , nct , nct . amino h , misawa s , sekiguchi y , shibuya k , watanabe k , suichi t , kuwabara s . department of neurology, chiba university, chiba, japan. guillain-barré syndrome (gbs) is a potential life threatening neurological disorder and respiratory insufficiency is one of the critical complications. eramus gbs respiratory insufficiency score (egris) is a method for predicting the chance of respiratory insufficiency in gbs. however, clinical characteristics and courses can vary for subtypes of gbs, whose occurrences differ for each region: acute inflammatory demyelinating polyneuropathy (aidp) is very common in european countries, whereas acute motor axonal neuropathy (aman) is frequently seen in asian countries. the aim of this study is to investigate the usefulness of egris in japan, where aman is more common than in the netherlands. clinical and electrophysiological profiles of consecutive gbs cases, who visited our hospital within days after symptoms onset between and , were reviewed. of the gbs patients, % were classified as aidp and % as aman according to the electrodiagnosis criteria by ho and colleagues. higher egris scores correspond to higher risk of respiratory insufficiency in total of the gbs patients, as well as in aidp patients. however, in patients with aman, egris scores did not always match the chances of respiratory insufficiency: up to % of the patients with low risk of egris showed respiratory failure, whereas only % of the patients with high risk of egris needs intubation/mechanical ventilation. in aman, associations with mechanical ventilation were seen for rapid progression (shorter duration between onset and hospital admission), more decreased vital capacity, and more frequent autonomic involvement. egris is useful also for japanese gbs patients. however, for aman patients, it should be used with discretion. another score to predict respiratory insufficiency might be required in asian countries. anandan c , litchy wj , laughlin rs , leep hunderfund an , naddaf e . mayo clinic, rochester, usa. in patients with suspected ulnar neuropathy, nerve conduction studies (ncs) are commonly requested to help with diagnosis and localization. however, routine ncs are often normal or not localizing. ulnar ncs recording from the first dorsal interosseous muscle (ncs-fdi) is thought to increase the diagnostic yield of electrodiagnostic testing, although not commonly considered. we developed a quality improvement strategy to routinely perform ulnar ncs recording from the abductor digiti minimi muscle (ncs-adm) as well as ulnar ncs-fdi in all patients referred for suspected ulnar neuropathy. we utilized the dmaic (define, measure, analyze, improve, control) model of process improvement to define our problem and create a map of the current process for ulnar neuropathy diagnosis in our electromyography laboratory. we determined baseline performance via review of distal sensorimotor polyneuropathy (dpn) is the most common complication of diabetes and risk factors beyond hyperglycemia have proven important particularly in type diabetes (t dm). only few prospective studies from early-stage t dm exist. we aimed to study the development of dpn during the first years after a screening-based diagnosis of t dm. from the addition-denmark study participants were eligible for this study. dpn was assessed by the michigan neuropathy screening instrument questionnaire (mnsi) at four time-points during follow-up. dpn was defined by a mnsi score ≥ . participants ( %) were positive in mnsi at baseline and thus excluded from this study. by kaplan-meier plot we evaluated the cumulative incidence of dpn and in cox proportional hazard models we calculated hazard ratios (hr) for the intervention groups in the addition trial and for various covariates proposed to influence the development of dpn. models were adjusted in steps for intervention group, age, sex, baseline mnsi, lipid-lowering and anti-hypertensive treatment. this study cohort consists of participants ( % men) with a median age of . years (p ;p : . ; . ) and median baseline hba c of . (p ;p : . ; . ). a cumulative incidence of % was seen during years of diabetes. there was no statistically significant difference in hr between the intervention groups or by sex but a significantly higher hr of . ( %ci: . ; . ) was seen for age (per year). the highest hr was found for a history of cardiovascular disease (myocardial infarction or stroke) up to ten years prior to the diabetes diagnosis with a hr of . ( . ; . ). weight, waist circumference, body-mass index and methylglyoxal (log transformed) showed modest but statistically significant associations with incident dpn with standardized hrs of . ( %ci: . ; . ), . ( %ci: . ; . ), . ( %ci: . ; . ) and . ( %ci: . ; . ) respectively. this study demonstrates a fairly low cumulative incidence of dpn in people with screen-detected t dm and provides evidence that macrovascular disease, obesity and oxidative stress are important risk factors for dpn even at the earliest stages of t dm. andermann syndrome, also known as agenesis of the corpus callosum and peripheral neuropathy (accpn), is an autosomal recessive disorder with a broad spectrum of mild to severe neuromuscular and psychiatric consequences. the gene variants causing disease were first identified in french-canadian families. in the present study, we intended to phenotype and genotype a series of non-french-canadian familial cases presenting with charcot marie tooth disorder associated with agenesis/dysgenesis of the corpus callosum. for this purpose, seven families, of consanguineous marriage, were studied. patients were clinically and para-clinically investigated using mri and electrophysiology (mncvs). for some, a sural nerve biopsy was taken. microsatellite markers around the accpn locus were used in two large families; followed by sanger sequencing of all the exons and intron-exons boundaries of the gene, in one patient from each of the families. the age at onset of the disease was at birth in the patients from the largest consanguineous family ( affected individuals). the biopsy from one patient showed a severe demyelinating neuropathy with many hypomyelinated fibres and mostly secondary axonal changes. these finding were compatible with electrophsiological data where the mncvs are of demyelinating range. dysgenesis of the corpus callosum in one patient and agenesis in another sib were revealed by mri. we identified one homozygous truncating mutation in this family. interestingly, no causative variant was found in a patient from another family and showing homozygous haplotype. two different heterozygous variants were identified at one hit in two patients from two non-consanguineous families. genetic investigations will be continued to identify the possible second hit. in the remaining families, no variant was found. the negative family cases will be subjected to ngs. at this stage, it is tempting to speculate on the genetic heterogeneity of accpn in our series. baba m , suzuki c , ogawa c , tomiyama m . department of neurology; diabetes center, aomori prefectural central hospital, aomori, japan. in we introduced a staging system of severity of diabetic polyneuropathy (dpn) by nerve conduction study (ncs) of the lower limb: sensory ncs of the sural nerve and motor ncs of the tibial nerve. the system consists of five stages; ncs- (normal): no abnormalities, ncs- (mildly abnormal): presence of delay of mcv, scv, minimal f-wave latency, or positive a-wave, ncs- (moderately abnormal): decrease in sural snap less than uv, ncs- (severely abnormal): decrease in plantar muscle-cmap to - mv, ncs- (ultimately abnormal): plantar muscle-cmap lost or less than mv with trace of sural-snap. to examine validity of the system, we conducted -year prospective observation on development of diabetic foot (df) by the ncs staging system. in addition, occurrence of ischemic heart disease (ihd) and stroke (is), and death of neuro-vascular events were also counted. n - , we carried out ncs in diabetics, and categorized them by the ncs staging system: % was ncs- , % was ncs- , another % was ncs- , % was ncs , and % was ncs- . we then followed them and prospectively counted the occurrence of df, ihd and is in patients (mean age ys). the occurrence of df during the following years was; ncs- : %, ncs- : %, ncs- : %, ncs- : %, ncs- : %. occurrence of any of df, ihd and/or is was as follows; ncs- : %, ncs- : %, ncs- : %, ncs- : %, ncs- %. there was no death from nsc- , − , and − groups (n= ), while two from ncs- group (n= ) were found dead in a bed or on a driver's seat, and other two from ncs- group (n= ) died of sudden cardiac arrest or infection after foot amputation. in summary, the present ncs grading system seems to work satisfactory not only for diagnosis of severity of the current dpn, but also for prognostic prediction of the dpn-related foot and vascular events. bacon c , feely sme , shy me . university of iowa hospital, iowa city, ia, usa. for patients with charcot-marie-tooth disease, also known as hereditary motor and sensory neuropathy, the rasch modified cmtnsv is a validated measurement of symptoms and impairment. the score is comprised of nine parameters of a clinical examination, including nerve conduction studies (ncs) . each parameter has an individual score ranging from zero to four, with the composite score having a maximum of prior to rasch modification. for patients who do not complete a ncs, the cmt exam score (cmtesv ) is used, with a maximum score of before rasch modification. one parameter of the cmtesv is the vibration sense. using a rydel tuning fork, a care-giver measures vibration sense in a patient's feet, ankles, and knees and a score is determined by the severity of reduced vibration sense. in cmt a patients, % received a score of out of , noted by a reduced vibration sense at the knee. in order to capture a more sensitive vibration measurement, we tested ways of taking the total raw score of the rydel tuning fork at each point of vibration sense, the toe, ankle, and knee bilaterally. scores range from zero to , with reflecting full vibration sense. in this modified measurement, vibration sense scores varied in wider distribution. for cmt a patients captured in this studied, a modified vibration sense score results in a potentially more sensitive total cmtesv score. bae dw , an jy . st. vincent's hospital, the catholic university of korea, suwon, korea. diabetic lumbosacral radiculoplexus neuropathies (dlrpn) are usually subacute painful, monophasic, asymmetrical lower limb neuropathies with incomplete recovery due to ischaemic injury and microvasculitis. the diagnosis relies mostly on clinical suspicion and characteristic electromyographic findings. however, in acute phase, neuroimaging has more important diagnostic significance than electrophysiological studies. here we describe mri and ultrasound findings in a -year-old woman with dlrpn who was diagnosed with diabetes three years ago, but has not received any other treatment. she had a -day history of acute-onset severe pain with weakness of muscles innervated by left femoral and obturator nerve and decreased sensation in left l -l dermatome. nerve conduction studies showed reduced amplitude in left femoral nerve and electromyography showed only increased insertional activity in left iliopsoas muscle and no volitional activity in muscles innervated by left femoral and obturator nerve. ultrasound revealed increased cross-sectional area (csa) of left femoral and lateral femoral cutaneous nerve. mri showed enhancement in left l , nerve roots and proximal femoral nerve and increased signal intensity in left iliacus and iliopsoas. we diagnosed her with dlrpn and started corticosteroid. nerve ultrasound has not been previously reported in a patient with cabin air in commercial airliners originates from aircraft engines or auxiliary power units. this bleed air may occasionally be contaminated with hydraulic fluids and engine oil that contains a number of potentially hazardous chemicals including tricresyl phosphate (tcp). over the last years reports are emerging about aircrew members that experience symptoms such as tingling or burning of extremities in addition to headache, and vertigo. this "aerotoxic syndrome" is controversially discussed in the literature and has been attributed to exposure to organophosphate contaminated cabin air. since tcp has been associated with peripheral neuropathy we aimed to determine the frequency of peripheral neuropathy among frequent flyers. civilian air crew members and frequent flying passengers (m:f = : , median age years, median exposition time in aircrafts of . hours) were examined at the university hospital of cologne or at the frankfurt airport (iata code fra) by a detailed questionnaire of past medical conditions, a standardized neurological examination and nerve conduction studies of sural, tibial, and ulnar nerves. we identified subjects with clinical and electrophysiological evidence for large fiber peripheral neuropathy. incidence of peripheral neuropathy was not correlated to exposition time in aircrafts. in addition subjects showed signs of ulnar neuropathy, subjects reported abnormal vibration sensation, subjects suffered from gait imbalance and individuals reported tingling of extremities. our study shows a . % prevalence of large fiber peripheral neuropathy among frequent flyers. comparison of these data with prevalence rate in an age-matched control group will reveal a possible association of chronic exposure to cabin air and risk for peripheral neuropathy. the high incidence of the symptom tingling in our cohort warrants further studies to determine the risk for small fiber neuropathy in this condition. intravenous immunoglobulin (ivig) are human igg derived from plasma pools of healthy donors. although there are studies in literature evaluating their effectiveness in different pathological animal models, there are no data about their possible role on bortezomib (btz)-induced peripheral neuropathies. female wistar rats were treated following a preventive schedule (btz and ivig co-treatment for and weeks) and a therapeutic schedule ( weeks of btz treatment followed by a -week ivig-btz co-treatment). caudal nerve conduction velocity (ncv), plantar and dynamic tests were performed at different time points. animals were sacrificed after ws (acute phase) or ws (chronic phase) and tissue samples (dorsal root ganglias -drg-, sciatic nerve, caudal nerve, skin) were collected for morphological, morphometrical and immunohistological analysis.in the preventive schedule, ivig was not able to rescue caudal ncv reduction caused by btz neither after nor after weeks of co-treatment. same results were observed in the therapeutic schedule. on the other hand, the evaluation of mechanical allodynia and cold hyperalgesia showed that ivig injection protected from btz effect in both treatment schedules. morphometric analysis evidenced that, even if not statistically significant only the preventive schedule has a tendency to protect the caudal nerve from btz damage. this result is consistent with the morphological evaluation of the nerve. also, intra-epidermal nerve fibers density was preserved in the preventive schedule but not in the therapeutic one. finally, sciatic nerve and drg macrophage infiltration levels tended to be reduced in the therapeutic schedule and were brought back to ctrl (rats not treated or injected with ivig alone) levels in the preventive one. in conclusion, we were able to demonstrate for the first time that ivig treatment especially used as preventive treatment option may reduce btz-induced neuropathic painful pointing out the possible role of inflammation in the pathogenesis of this invalidating pathology. this work was supported by kedrion spa. we studied the prevalence, the molecular cause and clinical presentation of hereditary motor neuropathies in a large cohort of patients from the north of england. detailed neurological and electrophysiological assessments and next generation panel testing or whole exome sequencing were performed in patients with clinical symptoms of distal hereditary motor neuropathy (dhmn, patients), axonal motor neuropathy (motor cmt , patients) or complex neurological disease predominantly affecting the motor nerves (hmn plus, patients) . the prevalence of dhmn is . affected individuals per . inhabitants ( % confidence interval: . - . ) in the north of england. causative mutations were identified in out of index patients ( . %). the diagnostic rate in the dhmn subgroup was . %, which is higher than previously reported ( %). we detected a defect of neuromuscular transmission in cases and identified potentially causative mutations in patients with demyelinating multifocal motor neuropathy. many of the genes were shared between dhmn and motor cmt , indicating identical disease mechanisms therefore we suggest changing the classification and include dhmn also as a subcategory of cmt. abnormal neuromuscular transmission in some genetic forms provides a treatable target to develop therapies. barohn rj , gajewski b , pasnoor m , brown l , herbelin l , kimminau k , jawdat o , parks c , shlemon p , dimachkie mm and the pain-controls study team . the university of kansas medical center, kansas city, ks, usa. cryptogenic sensory polyneuropathy (cspn) is a common slowly progressive neuropathy that affects adults and presents with significant neuropathic pain for which multiple medications have been tried including antiepileptics, antidepressants, topicals and narcotics. a web based survey among neuromuscular experts suggested pregabalin as being more effective than other medications, however there are presently no comparative studies to assess the most effective medication. the objective of this study was to determine which of the pharmaceutical therapies (pregabalin, duloxetine, nortriptyline or mexiletine) is most effective for neuropathic pain and best tolerated in cspn. to achieve this objective we performed a prospective randomized open labelled comparative effectiveness adaptive design study of cspn patients through the patient centered outcomes research institute (pcori). cspn patients who fulfilled the inclusion and exclusion criteria were enrolled into this study. patients underwent a baseline neurological evaluation and randomly assigned to one of the neuropathic medications for months. the primary outcome is the change in likert-like pain scale. the secondary outcomes included nih pain interference scale, nih fatigue interference scale, nih sleep disturbance scale, sf- and adverse events. the outcome measures are performed at baseline, month , and . statistical analysis using bayesian adaptive design developed by berry consultant software will be performed to determine winner and losers (winner = greater than point improvement in pain). total number of patients to be enrolled is . recruitment has been challenging and a number of recruitment techniques have been used. to date, there have been patients screened, patients randomized from us sites. anticipated completion of enrollment by june and end of final patient assessment by september . interim analysis performed after first patients completed their months as part of bayesian adaptive design analysis and occurs every weeks. the distribution of randomization of patients to the medications at last adaptive design randomization was . % to medication , % to medication , . % to medication and . % to the th medication. this study may give physicians and patients evidence for future management of cspn patients. transthyretin amyloidosis (attr), which encompasses a group of disorders with significant clinical variability, is caused by transthyretin (ttr) derived amyloid deposition. the clinical aspects of autonomic nervous system involvement in attr are only partially known. the ongoing, multinational, longitudinal, observational transthyretin amyloidosis outcomes survey (thaos) provides the opportunity to expand our understanding of dysautonomia in attr. data from all symptomatic subjects enrolled in the thaos registry with a diagnosis of attr (cut-off date: january , ) were assessed for the presence and temporal course of autonomic symptoms, genotype and phenotype associations, and clinical burden according to the frequency and severity of symptoms. of symptomatic subjects enrolled in thaos, ( . %) had autonomic symptoms at enrollment including: gastrointestinal ( subjects, . %), urinary ( , . %), erectile dysfunction ( , . %), orthostatic hypotension ( , . %), xerophthalmia ( , . %) and dyshydrosis ( , . %). subjects with autonomic manifestations, compared with those without, were younger (mean age [standard deviation, sd] of . [ . ] vs . [ . ] years), with a longer duration of attr symptoms ( . [ . ] vs . [ . ] years). autonomic dysfunction was less common with wild-type attr ( of subjects, . %) than in mutation groups: val met ( / , . %); non-val met/non-cardiac ( / , . %); and "cardiac mutations" (val ile, leu met, thr ala, or ile leu mutations; / , . %). similarly, time (mean [sd] , years) from first attr symptoms to onset of autonomic symptoms, was longest for wild-type attr ( . [ . ] ) followed by "cardiac mutations" ( . [ . ]), non-val met/non-cardiac ( . [ . ]), and val met ( . [ . ] ). autonomic symptoms were present at disease onset in over a third of subjects ( , . %) . autonomic dysfunction was less frequent in subjects with cardiac phenotype ( of subjects, . %), than with mixed ( / , . %) or neurologic ( / , . %) phenotypes. the burden of autonomic symptoms (mean [sd] ) varied by genotype, val met ( . [ . ] , non-val met/non-cardiac ( . [ . ], "cardiac mutations" ( . [ . ]), wild-type attr ( . [ . ]), and by phenotype, mixed ( . [ . ]), neurologic ( . [ . ]), cardiac ( . [ . ]). dysautonomia is common, and a significant burden, in subjects with hereditary forms of attr. its prevalence is higher in val met than in other genotypes, and in the neurologic or mixed phenotypes. the objective of this study is to assess the usefulness of motor unit number index (munix) technique in charcot-marie-tooth type a (cmt a) disease and to test correlation between munix and clinical impairment. munix technique was performed in abductor pollicis brevis (apb), abductor digiti minimi (adm) and tibialis anterior (ta) muscles in the non-dominant side. a munix sum score was calculated by adding munix of these muscles. muscle strength was measured using the mrc (medical research council) scale. disability was evaluated with several functional scales including cmt neuropathy score version (cmtnsv ) and overall neuropathy limitation scale (onls). cmt a patients with known pmp gene duplication were enrolled. the munix of the adm, apb and ta muscles were correlated with the mrc of the corresponding muscle (p< . ). munix sum score was correlated with clinical scales: cmtnsv (r=− . , p< . ), onls (r=− . , p< . ). in conclusion, munix correlates with muscle strength and clinical measurements of disability in cmt a patients. the munix technique evaluates motor axonal loss and correlates with disability. the munix sum score may be a useful outcome measure of disease progression in cmt a. the objective of this study was to assess the usefulness of mri in charcot-marie-tooth type a (cmt a) disease and to test correlation between muscle fat fraction and clinical impairment. mri was performed in the non-dominant lower limb of cmt a patients and healthy controls. fat fraction of tibialis anterior muscle, cross section area and volume of sciatic nerve were determined. muscle strength of dorsiflexion was measured using a dynamometer. disability was evaluated with cmt neuropathy score version (cmtnsv ). cmt a patients with known pmp gene duplication were enrolled. fat fraction of tibialis anterior muscle was significantly increased in patients compared to healthy controls. it was correlated with muscle strength (r=− . , p< . ) and cmtnsv score (r=− . , p< . ). cross section area and volume of sciatic nerve were significantly increased in patients compared to healthy controls. in conclusion mri fat fraction correlates with muscle strength and clinical measurement of disability in cmt a patients. it may thus be a useful outcome measure of disease progression in cmt a. basta i , peric s , cobeljic m , bjelica b , bozovic i , kacar a , nikolic a , rakocevic stojanovic v , stevic z , lavrnic d . neurology clinic, clinical center of serbia, school of medicine, university of belgrade, belgrade, serbia. there is a complete lack of data about epidemiological and clinical features of chronic inflammatory demyelinating polyneuropathy (cidp) in serbia and surrounding countries. furthermore, there is a striking scarcity of information about quality of life (qol) in cidp patients and all qol studies have been conducted in countries with high standards of health care. in august we have designed the iness (inflammatory neuropathy study of serbia) in order to comprise as many patients with cidp from serbia, republic of srpska (bosnia and herzegovina) and montenegro covering population of more than nine million people. our first aim is to analyze overall impact of cidp on physical, mental and social areas of life measured with generic, symptom specific and disease specific questionnaires -sf- , inqol and cap-pri, respectively. furthermore, we aim to analyze influence of the disease on patients' working status and presence of depressive mood measured by beck's inventory. following features of patients are included: sociodemographic data, clinical aspects of the disease, level of disability, severity of sensory symptoms, presence of comorbidities, electrophysiological characteristics, as well as fatigue, autonomic symptoms and neuropathic pain. we intend to define the most significant predictors of decreased qol in order to focus on patients with the highest risk and to improve care of cidp. we also want to see if cidp patients in complete remission as per clinical findings still have reduced quality of life. we have recruited patient so far and we expect to include around subjects overall. we will present the first data of the study at the pns meeting . beaudonnet g , prud'hon s , cauquil c , labeyrie c , not a , bouilleret v , adams d . neurophysiology chu bicêtre, le kremlin bicêtre, france; neurology chu bicêtre, le kremlin bicêtre, france. familial amyloid neuropathy (fap) is a life-threatening disease of autosomal dominant inheritance due to transthyretin (ttr) gene mutation, a liver-produced protein. current treatments slow down its natural course and are indicated from the very first objective symptoms. we aimed to evaluate two neurophysiological markers: sympathetic skin response (ssr) and heart rate variability (hrv) in the early detection of sympathetic damages due to fap. ssr and hrv were assessed in ttr gene mutated patients with neither clinic nor electroneuromyographic abnormalities and controls matched on gender and age. cases were recruited consecutively from current care in the french reference center for rare diseases of bicetre university hospital. ssr was recorded on the two palms and on the sole of the left foot with to stimulations between and ma. hrv was registered during three conditions of seconds each: normal breathing, deep breathing ( cycles of seconds of inspiration and seconds of expiration) and valsalva manoeuver during seconds. valsalva ratio, defined by the ratio between the longest and shortest rr intervals, was significantly higher in the control groups after bonferroni correction (means of . and . , respectively, p< . ). there was no significant difference between the two groups for any ssr parameter, although means of amplitudes were systematically higher in controls than among cases. our results confirm that autonomic nervous fibers are damaged early in both clinical and electroneuromyographic asymptomatic patients mutated on the ttr gene. valsalva ratio seemed to be the most discriminative marker. long-term follow-up with test repetition and confrontation with cardiologic assessment will help to precise how these tests could be used in current care. they might help to identify high risk patients to propose them an appropriate early treatment and could be used to follow treatment efficacy. familial amyloidotic polyneuropathy (fap) was originally characterized by andrade as an axonal neuropathy which subsequently was found to be associated with a number of mutations in the plasma protein transthyretin (previously named prealbumin). it is now recognized that cardiomyopathy may be a significant factor in a majority of patients with the hereditary form of transthyretin amyloidosis (fap) and many of the transthyretin (ttr) mutations are associated with cardiomyopathy with no or minimal signs of peripheral neuropathy. attr-wt also called senile cardiac amyloidosis and senile systemic amyloidosis is recognized as late-onset, usually in the th or th decade of life, and the fact that the majority of patients are males. transthyretin neuropathy proven by nerve biopsy has been rarely reported in this population. here we report our experience with patients having attr-wt characterized by cardiomyopathy but also with varying degrees of peripheral neuropathy. clinically, the neuropathy appears as typical axonal or mixed axonal/demyelinating neuropathy as is seen in fap. pathologically, two types of ttr deposition have been found, ( ) intraneural ttr amyloid deposits as seen in fap are present in some patients and ( ) other patients have extensive vascular deposition of amyloid in both perineural arteries and veins without deposits within nerve trunks. in conclusion, peripheral neuropathy may definitely be a part of the attr-wt clinical presentation and with the increase in numbers of attr-wt cardiomyopathy patients being identified, it is important to ascertain whether any evidence of peripheral neuropathy is due to the amyloidosis and not to compounding syndromes such as diabetes mellitus type ii. besora s , santos c , izquierdo c , martinez-villacampa m , simó m , bruna j , , velasco r , . neuro-oncology unit, hospital universitari de bellvitge-institut català d́oncologia, ĺhospitalet, barcelona, spain; medical oncology department, institut català d́oncologia, ĺhospitalet, barcelona, spain; department of cell biology, physiology and immunology, institute of neurosciences, universitat autònoma de barcelona and centro de investigación biomédica en red sobre enfermedades neurodegenerativas (ciberned), bellaterra, spain. oxaliplatin (oxa) is the first-line chemotherapy agent in the treatment of colorectal cancer (crc). oxa-induced peripheral neuropathy is the most frequent long-term side-effect. retreatment with oxa is frequently considered in patients as salvage treatment. patients receiving oxa-based chemotherapy regimen at least twice at our institution between and were reviewed. the aim of this study was to investigate whether retreatment with oxa increases the risk of developing or worsening previous oxa-induced peripheral neuropathy. the severity of neuropathy was measured by national cancer institute-common toxicity criteria (nci), total neuropathy score (tns) © and nerve conduction studies. one hundred twenty-five crc patients were included. median age was years. after first-line oxa-based chemotherapy, . % of patients developed neuropathy according nci, after a median of [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] cycles. severity of neuropathy was grade ( . %), grade ( %), and grade ( . %). median time to retreatment with oxa was months. frequencies of neuropathy before retreatment were as follows: . % grade , . % grade , and . % grade . after retreatment, severities of neuropathy were . % grade and . % grade . no patient developed grade . . % of patients did not develop neuropathy. peripheral neuropathy was the reason for stopping prematurely treatment after first-line and retreatment in . % and . % of patients, respectively. worsening of previous nci score was observed in . % of patients. the great majority of patients ( . %) remained within the same nci score than before retreatment after median [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] cycles. among those patients that did not develop neuropathy after first treatment (n= ), only and patients developed grade and , respectively, after a median of [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] cycles. among those patients who initially developed grade and neuropathy, no differences in tnsc © scores just before and after finishing retreatment with oxa were identified ( [ - ] vs [ - ], p= . ). retreatment with oxa in crc patients is a feasible option even in patients who developed moderate or severe neuropathy previously. lack of worsening of previous neuropathy is observed in the great majority of patients. neurological monitoring of patients candidates to retreatment with oxa should be considered. bessaguet f , sturtz f , magy l , , desmouliere a , bourthoumieu s , demiot c . ea -myelin maintenance & peripheral neuropathy, faculties of medicine and pharmacy, university of limoges, limoges, france; department of neurology, reference center for rare peripheral neuropathies, university hospital of limoges, limoges, france. prolonged pressure and the resulting local ischemia are widely accepted as the primary etiology of skin pressure ulcers (pus) but precise mechanisms of their formation remain unclear. in this study, we wanted to study the potential role of sensory small nerve fibers in regulation of inflammation during pus formation. to achieve this goal, we developed a mouse model of a purely sensory neuropathy and this was induced by resiniferatoxin (rtx). in this model, seven days after a single injection of rtx ( g/kg; ip), mice present a thermal and mechanical hypoalgesia associated with large substance p (sp) and calcitonin gene-related peptide (cgrp) depletion without neurodegeneration. this model mimic quite well what is observed in early stages of sensory nerve fiber defect. studies have shown that sp and cgrp are involved in cutaneous inflammation regulation. in fact, these neuropeptides are released by sensory fibers and are pro-inflammatory mainly through recruitment of immune cells and vasodilation. thus, we studied gene expression of pro and anti-inflammatory cytokines by a rna array approach during pus formation in control and rtx mice. seven days after a single injection of rtx, epidermis, dermis and subcutaneous tissue layer were pinched with magnetic plates during hours. pressure induced a stage pus. gene expression was evaluated in each compressed area h after pressure. results showed mainly a down-regulation of gene expression in pus of rtx mice compared to control mice. a decrease of cgrp/sp in skin sensory small fiber increased pus formation associated with an increase of interleukins (il)- , il- , il- and il- expression and a decrease of il- expression in rtx mice. supplementary experiments with rt-qpcr for each cytokine will be necessary to confirm these preliminary results. these observations suggest a cgrp/sp role in regulation of cytokines expression during pus formation. the new inflammatory profile exhibited in this study might help in the design of new treatments improving the quality of life of neuropathic patients prone to developing bedsores. bhattacharyya bj , jayaraj nd , belmadani a , ren d , rathwell ca , hackelberg s , miller rj , menichella dm . department of neurology, northwestern university, chicago, il, usa; department of pharmacology, northwestern university, chicago, il, usa. painful diabetic neuropathy (pdn) is one of the most common and intractable symptoms of diabetes, affecting % of diabetic patients. the hallmarks of pdn are neuropathic pain and small fiber degeneration, manifested by the loss of dorsal root ganglion (drg) nociceptor axons. neuropathic pain is associated with nociceptor hyper-excitability in the absence of physiologically appropriate stimuli. in states of neuropathic pain, drg nociceptors become increasingly responsive to a variety of excitatory influences, including inflammatory cytokines. in particular, we have shown that stromal cell derived factor- (sdf- ) and its receptor cxcr are necessary for the generation of neuropathic pain in mouse models of pdn. however, the molecular mechanisms leading to the hyper-excitability of drg nociceptors in pdn are unknown, as are the mechanisms leading to small fiber degeneration. this fundamental gap in our knowledge represents a critical barrier to progress in developing novel therapeutic approaches for pdn. the objective of this study is to identify the molecular cascade linking cxcr /sdf- chemokine signaling to drg nociceptor hyper-excitability, neuropathic pain, and small fiber degeneration in pdn. drg nociceptors can be identified by a series of molecular markers, including expression of the sodium channel na v . . indeed, > % of na v . -expressing drg neurons are nociceptors. feeding mice a high fat diet (hfd) for several weeks induces glucose intolerance, obesity, and mechanical allodynia, a particular pain hypersensitivity associated with pdn. using the hfd model combined with dreadd receptor technology, we have shown that reducing excitability of na v . -expressing neurons prevents and reverse neuropathic pain, neuronal calcium overload, mitochondrial dysfunction, and small fiber degeneration. furthermore, we have shown that cxcr receptors are necessary for neuropathic pain and small fiber degeneration in pdn. taken together these data demonstrate that na v . nociceptor hyperexcitability in pdn is driven through the activation of cxcr receptors. inhibition of hyperexcitability can prevent and reverse the development of pdn. furthermore, these observations will advance our understanding as to how changes in excitability, calcium influx, and mitochondrial dysfunction in nociceptors contribute to neuropathic pain and small fiber degeneration in pdn, which is a critical barrier to progression for effective and disease modifying treatment for pdn. bianco m , terenghi f , gallia f , nozza a , scarale a , fayoumi mz , giannotta c , morenghi e , nobile-orazio e . poems (polyneuropathy, organomegaly, endocrinopathy, m protein and skin changes) syndrome is an unusual multisystem disease with neurological disability due to a severe disabling polyneuropathy, with high mortality by multiorgan failure. peripheral blood stem cell transplantation (pbsct) is considered the treatment of choice for poems while lenalidomide is the most promising therapy for patients not eligible for pbsct. the aim of the present study was to compare the long-term effects on clinical, biological and neurophysiologic parameters in patients with poems treated with lenalidomide or pbsct. the clinical, biological and neurophysiologic data were reviewed in poems patients treated with pbsct (n: ) or lenalidomide (n: ). the mrc sumscore on muscles, onls scale, vegf serum levels and nerve conduction studies were assessed before (t ) and after (t ) and years (t ) of treatment and the differences were compared using anova. combining the two groups of patients, there was a significant improvement after treatment in the mean mrc sumscore (t = ± ; t = ± ; t = ± ; p = . ), in the mean onls score (t = . + . ; t = . + . ; t = . + ; p = . ), in the ulnar mean distal motor latency (t = . ± . msec; t = . ± . msec; t = . ± . msec; p = . ), distal compound muscle action potentials amplitude (t = . ± . mv; t = . ± . mv; t = . ± . mv; p = . ), motor conduction velocity (t = . ± . m/sec; t = ± m/sec; t = . ± . m/sec; p= . ) and serum vegf levels (t vs t : p = . ; t vs t : p = . ). the difference was also significant when we separately analyzed patients treated with lenalidomide and pbsct and there was no difference between the two groups in any of the analyzed parameters. treatment with pbsct and lenalidomide significantly and similarly improved clinical, biological and neurophysiologic parameters in patients with poems syndrome up to two years. since pbsct may not be suitable for all patients, lenalidomide may represent an effective and a valuable alternative in these patients or in those relapsing after pbsct inducing a prolonged clinical, biological and neurophysiologic improvement. bis d , tao f , abreu l , sleiman p , hakonarson h , zuchner s and inherited neuropathy consortium. dr. j.t. macdonald department for human genetics, hussman institute for human genomics, university of miami, miami, fl, usa; center for applied genomics, the children's hospital of philadelphia, philadelphia, pa, usa. inherited peripheral neuropathies are clinically and genetically heterogeneous diseases that can cause distal muscular atrophy and sensory loss. alleles in over one hundred different genes have been shown to cause peripheral neuropathies; yet, greater than % of axonal neuropathy patients do not receive a genetic diagnosis. large scale exome studies are now beginning to be sufficiently powered to perform mutational burden analysis. this approach compares damaging allele frequencies of cmt cases with a control group to identify additional causes for neuropathies. this approach will also identify genes that require an oligogenic inheritance to cause a phenotype. in a deviation from the classic linkage-based and heuristic variant filtering approaches to gene identification, we are performing burden analyses in a large cohort of cmt families. in known neuropathy genes, we saw that neuropathy cases carried on average . rare, non-synonymous variants, while unrelated non-neuropathy controls harbored . variants (p= . e- , mann-whiney u-test). enrichment of rare, non-synonymous variants in cmt disease genes within inherited peripheral neuropathy cases suggests the presence of multiple weaker alleles in individual patients. we also performed an unbiased exome-wide gene-based burden analysis and ranked genes after multiple testing correction. several new candidate genes were identified that need further follow up conformational studies. a number of known cmt and related genes were observed in the list of top candidates. we are currently analyzing additional aspects of this sample and are actively seeking more cmt exomes to enlarge our study. in summary, statistical methods traditionally reserved for more 'common' phenotypes' increasingly are becoming available for rare disease genetics. c bl/ mice were treated with bortezomib alone or in combination with monastrol. neuropathic changes were assessed by nerve conduction studies and histological analysis. analysis of axonal morphology was performed with light and electron microscopy. anti-neoplastic properties of monastrol alone and in combination with bortezomib were assessed in different blood cancer cell lines. prolonged treatment with bortezomib induced a sensory neuropathy in mice. significant changes in axonal morphology correlated with reduced function of peripheral nerves. the administration of monastrol substantially ameliorated morphological features of axonal alterations and sensory neuropathy. cytotoxicity studies in blood cancer cell lines showed no interference of monastrol with the cytostatic effects of bortezomib. our data indicate that monastrol may alleviate bortezomib induced neuropathy. the favorable cytotoxic profile of monastrol makes it an interesting candidate as neuroprotective agent to prevent bortezomib-induced neuropathy. boczonadi v , meyer k , gonczarowska-jorge h , , bartsakoulia m , roos a , , bansagi b , zahedi rp , talim b , bruni f , kaspar b , , lochmüller h , boycott km , müller js , horvath r . jwmdrc, wtcmr, igm, newcastle university, newcastle upon tyne, uk; rinch, columbus, oh, usa; leibniz-institute für analytische wissenschaften-isas-e.v., dortmund, germany; capes foundation, brazil; department of pediatrics, hacettepe university children's hospital, ankara, turkey; dbbb,university of bari aldo moro, bari, italy; department of neuroscience, the ohio state university, columbus, oh, usa; department of genetics, cheo, university of ottawa, ottawa, canada. while autosomal dominant mutations in gars, encoding the glycyl-trna synthetase, have been identified in patients with charcot-marie-tooth peripheral neuropathy (cmt d) and distal spinal muscular atrophy type v (dsma-v), autosomal recessive mutations cause mitochondrial disease affecting skeletal muscle and heart. gars is a bi-functional enzyme and it is responsible for normal protein translation both in mitochondria and the cytoplasm. in this study we have focused on the mitochondrial function of the gars by investigating a mouse model (gars c r) , human fibroblasts and induced neuronal progenitor cell lines (inpcs). mild mitochondrial abnormalities were detected in skeletal muscle of the gars c r mice while no other tissues were affected. control and patient fibroblasts harboring gars mutation were directly converted into inpcs. we identified tissue specific impairment of mitochondrial function in neuronal cells carrying not only recessive but also dominant gars mutations, suggesting neuron-specific effects of mitochondrial alterations.comparative proteomic analysis of inpcs showed significant changes in mitochondrial proteins. furthermore, the reduction of the vesicle-associated membrane protein-associated protein b (vapb) and its downstream pathways in gars-deficient inpcs suggests that altered mitochondria-associated endoplasmic reticulum (er) membranes (mam) may also contribute to the motor neuropathy. boczonadi v , king ms , bansagi b , roos a , , eyassu f , borchers c , lane m , ramesh v , lochmüller h , pyle a , griffin h , smith ac , chinnery pf , , alan j robinson aj , edmund rs kunji ers , horvath r . jwmdrc, wtcmr, igm, newcastle university, newcastle upon tyne, uk; mitochondrial biology unit, medical research council, cambridge; leibniz institute of analytic sciences (isas), dortmund, germany; uvic-genome bc proteomics centre, vancouver, canada; paediatric neurology, royal victoria infirmary, newcastle upon tyne foundation hospitals nhs trust, newcastle upon tyne, uk. members of the mitochondrial carrier family (slc ) transport nucleotides, keto acids, amino acids, fatty acids, co-factors and inorganic ions across the mitochondrial inner membrane. several inherited diseases with very variable clinical presentations are associated with dysfunctional mitochondrial carriers. we report a patient with childhood-onset spinal muscular atrophy and mitochondrial myopathy caused by a homozygous mutation in slc a , encoding the mitochondrial oxodicarboxylate carrier (odc). the mutation renders the carrier dysfunctional and, consequently, -oxoadipate cannot be imported into the mitochondrial matrix. computer modelling of the metabolic defect caused by the mutation predicted that the impaired transport leads to accumulation of -oxoadipate, pipecolic acid and the known neurotoxin quinolinic acid, which were precisely confirmed by targeted metabolomics in serum and urine. exposure of -oxoadipate and quinolinic acid reduced the level of mitochondrial complexes in sh-sy y cells in-vitro suggesting a possible pathomechanism. here we demonstrate that -oxoadipate and quinolinic acid are toxic for spinal motor neurons and their increased levels may contribute to neuropathy. and families have been reported. interestingly, most mutations target the same amino acid residue (k e, k m, k n, k t) in the highly conserved -crystallin domain of the hspb protein. the spectrum of diseases caused by mutations in the hspb gene was recently expanded to distal myopathy. hspb is ubiquitously expressed, but is highly expressed in motor neurons and muscles. the hspb is a chaperone that participates in clearing misfolded poly-q containing proteins such as mutant huntingtin and ataxin- involved in respectively huntington's disease and spino-cerebellar ataxia. hspb directly interacts with the co-chaperone bag and their role in chaperone-assisted selective autophagy is well described. to delineate the molecular deficits and functional consequences of hspb mutations we generated a knock-in (ki) mouse model for the k n missense mutation mimicking the neuropathy phenotype. we observed that homozygous mutant mice (hspb k n/k n ) develop a progressive axonopathy, with decreased compound motor action potential amplitudes, and loss of large and medium myelinated axons. this results in locomotor deficits with an impaired performance at the rotarod and grip strength tests. at the ultrastructural level, the hspb -ki model displays severe signs of axon degeneration and a clear myofibrillar myopathy, as observed in some patients with hspb mutations. interestingly, hspb positive aggregates were found in the sciatic nerve and gastrocnemius muscle of our mutant mice. additionally, our model allowed us to generate hspb knock-out (ko) mice using the same targeting vector. strikingly, the homozygous hspb -ko animals do not show any sign of axonopathy and display a much milder myopathy than the hspb -ki animals. these data suggest that part of the pathomechanisms is due to toxic gain-of-function of the mutant protein. boutahar n , reynaud e , nasser y , camdessanché jp , antoine jc . university hospital, saint-etienne, france. dysimmune sensory neuronopathies (snn) depend on neuron cell death induced by an inflammatory reaction in dorsal root ganglia. we have recently identified the intracellular tyrosine kinase (trk) domain of the fibroblast growth factor receptor- (fgfr ) as the target of antibodies in a subset of patients with non paraneoplastic snn. fgfr is one of the four fgfrs and has been involved in sensory neurons maintenance during development and cell death induction after axotomy. fgfrs ligand fixation results in the activation of several intracellular pathways through adaptator protein interactions with the trk domain. in particular ras activation may lead to cell proliferation or apoptosis through erk / or p map kinase signaling. the p mapk pathway is also involved in neuronal cell death induced by nmda and ampa receptor activation. as fgfr is a cell surface protein, human antibodies may interfere with the receptor functioning as a growing number of evidence has showed with other cell surface antibodies in neurological diseases. to test this hypothesis we developed an in vitro model using fvbn mice cortical neurons culture exposed to a rabbit polyclonal antibody reacting with the trk domain of fgfr . comparatively to normal rabbit iggs, the fgfr antibody induced neuron cell death in a dose dependent manner. neuron cells were exposed to fgfr antibody concentration leading to - % cell death in absence or presence of the p mapk inhibitor sb and the expression of fgfr , glur subunit of ampa receptors and nr subunit of nmda receptor was measured by quantitative rt-qpcr. the fgfr antibody induced an upregulation of fgfr while the glur and nr subunits were modulated. these changes were prevented in presence of sb . these preliminary results indicate that anti-fgfr iggs may interfere with the functioning of the intracellular domain of the protein and the expression of nmda and ampa receptors through the p map kinase pathway. this model may be used to test the effect of human anti-fgfr iggs in vitro. braathen gj , tveten k , holla Øl , busk Øl , hilmarsen ht , svendsen m , høyer h . section of medical genetics, department of laboratory medicine, telemark hospital, skien, norway. next-generation sequencing (ngs) has during the last years entered the clinical diagnostics. ngs has proven to be very efficient in the diagnostics of disorders where multiple genes can be involved. our ngs-based targeted gene panel consists of hereditary neuropathy genes, i.e. mostly charcot-marie-tooth genes. this study is a retrospective study of clinic samples received between may and february . we describe the identified novel likely pathogenic sequence variants, according to international guidelines. in this period we identified novel, not previously described, likely pathogenic sequence variants in the following genes: aars, fgd , gan, hint , litaf, lrsam , mme, mpz, nefl, pmp , sbf , sh tc and yars. there is now a large range of genes causing hereditary peripheral neuropathies and many likely pathogenic sequence variants. likely pathogenic sequence variants are not only identified in old well established neuropathy genes but also in the newer genes like mme. modelling brown-vialetto-van laere syndrome in c. elegans mutations in slc a and slc a , which encode the riboflavin transporters rfvt and rfvt . patients with rfvt deficiency exhibit proximal and distal limb weakness, sensory ataxia, diaphragmatic paralysis, optic atrophy, sensorineural deafness and bulbar palsy. riboflavin is critical for the biosynthesis of flavin mononucleotide and flavin adenine dinucleotide, essential cofactors for carbohydrate, amino-acid and lipid metabolism. mutations in slc a reduce or abolish rfvt expression resulting in impaired riboflavin uptake into sensory and motor neurons. high-dose riboflavin treatment can improve or stabilise a patient's condition, however the optimum dose and long term effects of riboflavin treatment, and disease pathomechanisms remains poorly understood. to further understand the pathophysiological consequences of slc a mutations, we propose developing an animal model for bvvl. caenorhabditis elegans (c. elegans) are small round transparent nematodes extensively used for studying the genetics and molecular biology of neurodegenerative diseases. there are two c. elegans riboflavin transporter genes, rft- and rft- . based on protein sequence homologies and expression profiles for both genes, rft- is the ortholog of rfvt . the expression of rft- is regulated by riboflavin availability and knock-down of the rft- gene by sirna perturbs c. elegans development. our aim is to develop a knock-in c. elegans model of bvvl. human rfvt and c. elegans rft- protein sequences were aligned with clustal omega to identify conserved amino acid residues associated with bvvl mutations. the amino acid involving the l p rfvt mutation is conserved in rft- (residue l ). to create our model, we will introduce the l p rft- mutation into the rft- locus in c. elegans genomic dna using crispr/cas- technology. this bvvl c. elegans model will allow us to explore the pathogenic consequences of rfvt deficiency underlying motor nerve degeneration and to evaluate drug therapy regimes by determining the optimal riboflavin dose and treatment initiation, and trialing other compounds that may improve benefits seen with riboflavin supplementation. chronic inflammatory demyelinating polyradiculoneuropathy (cidp) is an autoimmune-mediated inflammatory disease of the peripheral nervous system. cidp can present chronic progressive or relapsing-remitting courses and can predominantly affect motor but also sensory nerve fibers causing weakness of proximal and distal muscles. it represents the most common chronic autoimmune neuropathy and is pathologically characterized by focal inflammatory-mediated demyelination followed by axonal degeneration. recently, we have developed a new animal model for cidp, the chronic-ean, induced in lewis rats by active immunization with s-palmitoylated p ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) peptide. this model fulfills electrophysiological criteria of demyelination with axonal degeneration, a result confirmed by immunohistopathology. the late phase of the chronic disease is characterized by an accumulation of il- + cells and macrophages in sciatic nerves and as well as high serum il- levels. it is a reliable and reproducible animal model for cidp that can now be used for translational drug studies for chronic human autoimmune-mediated inflammatory diseases of the peripheral nervous system, particularly cidp, for which, there is a real need for new immunotherapies. the aim of this study was to test the therapeutic efficacy of ivig and a recombinant fc fragment (fcrec) in this new cidp animal model. treatments with ivig and fcrec proved effective in preventing further progression of cidp in rats. the therapeutic treatments not only decreased the maximal clinical scores of the cidp rats compared to albumin treatment but also abolished the disease chronicity. interestingly, a better efficacy of fcrec treatment compared to ivig was demonstrated at histological level, with the myelinated fibers well preserved and the greatly reduced accumulation of macrophages and il- + cells in sciatic nerves. ivig and fcrec therapeutic activities in this model can also be followed by measurement of antibodies in the serum and could therefore be used as biological markers. the current study provides for the first time direct evidence that ivig is effective in the treatment of cidp rats and suggests that a novel fcrec compound is more effective than ivig. it will contribute to the development of more effective and safer drugs for the treatment of autoimmune peripheral neuropathies like cidp. each time, one measurement with supramaximal stimulation according to the conventional ncs and another measurement with % enhanced stimulation intensity were conducted. we analyzed the results with special consideration of minimal and maximal fiber velocities and of the velocity with maximal fiber proportion. as a result, we detected statistically significant differences between cidp patients and controls in all these parameters. compared with controls, cidp patients had slower minimal and maximal fiber velocities and also the spectrum of motor conduction velocities was definitively shifted to slower velocities. slower minimal conduction velocities could be detected in some cidp patients by using the enhanced stimulation intensity. interestingly, in some cidp patients the conventional ulnar ncs were normal, but the collision technique showed fibers with a conduction velocity of less than m/s, indicating demyelination. to our knowledge, this is the first study using hopf's collision technique systematically in cidp patients. significant differences between the variation of ulnar motor nerve conduction velocity of cidp patients and controls could be detected. this method also showed signs of demyelination in some cidp patients with normal ulnar ncv. by enhancing stimulation intensity above the threshold of supramaximal stimulation in conventional ncs, the collision technique may be even more valuable. the clinical course of guillain-barré syndrome (gbs) is highly variable and some patients may develop treatment-related fluctuations (trfs) as an indication of ongoing disease activity and temporary treatment effect. other patients present as gbs, but subsequently develop repetitive relapses as an indication of acute-onset chronic inflammatory demyelinating polyneuropathy (a-cidp). this distinction is important because treatment may differ. we determined the frequency and clinical presentation of patients with gbs-trf and a-cidp in the first patients included in the international gbs outcome study (igos) with a follow-up of at least months. thirty-eight patients ( %) were excluded because of alternative diagnoses. of the remaining patients, ( %) had at least one trf, ( %) had a-cidp. preliminary analysis showed no significant differences between the groups (total-gbs, gbs-trf and a-cidp) for sex, age, sensory symptoms, cerebrospinal fluid results and mechanical ventilation. a-cidp patients had a median age of years (iqr - ), % was male, and all patients were treated in the acute phase of the disease (intravenous immunoglobulins (ivig) ( ), plasma-exchange (pe) ( ) or methylprednisolone (mp) ( )). gbs-trf patients has a median age of years (iqr - ), % was male and all patients received treatment (ivig ( ) and pe ( ). gbs-trf patients showed more antecedent events ( % versus %, p= . ), a higher gbs disability score (≥ ) at nadir ( % versus %, p= . ) and less frequently developed ataxia ( % versus %, p= . ) than patients with a-cidp. onset to nadir was longer in a-cidp than in gbs-trf ( days (iqr - ) versus days (iqr - ), p= . ) and the total gbs group ( days (iqr - ), p= . ). the time until the first clinical deterioration tends to be longer in the a-cidp patients (median days (iqr - ) versus median days in the gbs-trf group, not significant). the diagnosis a-cidp was made after a median of days . in conclusion, this first analysis identified distinctive characteristics of gbs-trf and a-cidp in support of a different pathogenesis that may help with early identification of these disorders in clinical practice. additional results will be presented at the conference. chronic inflammatory demyelinating polyneuropathy (cidp) is a disorder with a highly diverse clinical presentation, electrophysiological phenotype, response to treatment and outcome. this heterogeneity may indicate the presence of distinct subtypes of cidp, which may have a different pathogenesis and require more personalized treatment. the international cidp outcome study (icos) is a prospective, observational, international multi-center study that aims to describe this variation in clinical and electrophysiological subtypes and to define the clinical and biological determinants of these subtypes, disease activity, treatment response and outcome. in addition icos aims to provide an infrastructure for conducting new (therapeutic) studies in cidp, similar to the international gbs outcome study (igos). all patients fulfilling the efns/pns ( ) diagnostic criteria for cidp can be included in icos, independent of age, duration and severity of disease or treatment. we collect information on neurological deficits, diagnostic characteristics, various validated clinical outcome measures, previous and current treatment and we collect biomaterials (dna, cerebrospinal fluid, nerve biopsies and repeated serum samples). icos was started as a pilot study in dutch university centers. by february , patients were included in icos, patients recently diagnosed with cidp and previously diagnosed patients. included were ( %) males and ( %) females with a median age of years (iqr - ). the current cohort consists of classic (sensory-motor) cidp, madsam and pure motor variants. of the patients diagnosed in the past, patients ( %) were treated (intravenous immunoglobulins (ivig) ( ), prednisolone ( ), subcutaneous immunoglobulins (scig) ( ), dexamethasone ( ), plasma-exchange ( ) and ivig with methylprednisolone (mp) ( )). the recently diagnosed patients all received treatment (ivig ( ), dexamethasone ( ), plasma-exchange ( ) and patients were treated in a pilot study with ivig with methylprednisolone (mp)). the protocol has been evaluated and adjusted and will be shared with other researchers via the inflammatory neuropathy consortium and igos consortium. our aim is to include at least cidp patients worldwide with a minimum follow-up period of years. dominant mutations in glycyl trna synthetase (gars) cause inherited axonal neuropathy (charcot-marie-tooth type d). mutations in the mouse gars gene cause a similar phenotype, and represent valid disease models. we routinely use two mouse strains, one with a severe neuropathy, and one with a milder, later onset neuropathy. using these mouse models, we are exploring the mechanisms through which gars mutations cause peripheral axon degeneration. efforts include ribosome tagging to isolate ribosome-associated mrnas specifically from motor neurons, and non-canonical amino acid tagging to visualize and isolate newly synthesized proteins. taking advantage of the anatomy of motor neurons, we are able to analyze cell bodies separately from peripheral axons in both of these approaches. in addition, we are using these mouse models for preclinical studies testing gene therapy approaches to treat cmt d. consistent with our previous genetic studies in mice, knockdown of the mutant transcript, while preserving sufficient levels of the wild type, is a very successful approach when administered before the onset of neuropathy. we are now testing this approach in mice after the onset of symptoms, and in mice carrying a mutant gars allele associated with human disease. these studies are potentially translational, and also address mechanistic questions such as the timing and cell autonomy of the pathophysiology. burnor e , yang l , hao z , patterson k , quinn c , scherer ss , lancaster e . the university of pennsylvania, philadelphia, pa, usa; the second xiangya hospital, central south university, hunan, china. autoantibodies to two isoforms of neurofascin (nf and nf ) have been reported in patients with guillain-barre syndrome (gbs) or chronic inflammatory demyelinating neuropathy (cidp). it is not clear which of these responses reliably distinguish autoimmune neuropathies from other severe neuropathies, which responses are transient versus persistent, or which responses may target multiple isoforms of neurofascin. in addition, approximately % of neuropathy patients have no known cause, and it is unknown whether a subset of these patients may have autoantibodies to neurofascins. we have studied cohorts of patients with autoimmune neuropathy (n= ), genetic neuropathy (n= ), and idiopathic neuropathy (n= ) for igg and igm responses to neurofascins. neurofascin antibodies were found in ( %) of patients with autoimmune neuropathy, and ( . %) idiopathic neuropathy patients, but only % ( of ) in patients with genetic neuropathy. follow-up serum samples were available for positive cases. persistent responses were associated with chronic neuropathy while transient responses were seen in gbs or with remission of cidp. most patients had responses specific to either nf of nf . however, a particularly severe, treatment-resistant form of cidp, approaching a locked-in state, was seen in a patient with a unique response to all three isoforms of neurofascin (nf , nf , nf ). treatment of this patient with rituximab resulted in clinical improvement and resolution of the neurofascin antibody response. in conclusion, autoantibodies to neurofascins distinguish autoimmune neuropathies from severe genetic neuropathies, but the clinical phenotype may depend on the persistence and isoform specificity of the immune response. antibodies to the common domains shared by nf and nf may portend a severe but treatable neuropathy. a subset of idiopathic neuropathy patients may have an autoimmune mechanism. burns j , , sman ad , cornett kmd , wojciechowski e , , walker t , menezes mp , , mandarakas mr , rose kj , , bray p , , sampaio h , farrar m , , refshauge km , raymond j and the fast study group. university of sydney, new south wales, australia; sydney children's hospitals network (randwick and westmead), new south wales, australia; university of new south wales, sydney, australia. exercise has undisputed benefits for human health and potentially as a treatment for neuromuscular disease. but there is also a risk of harm due to overwork weakness. we report the results of a -month randomised, double-blind, sham-controlled trial evaluating progressive resistance exercise of foot dorsiflexor muscles in pediatric cmt. sixty patients ( cmt a, cmt e, cmt f, cmt a, cmt c, cmtx , cmtx ) aged - years were randomly assigned to undergo -weeks ( sessions) of moderate-intensity progressive resistance exercise or sham exercise. the primary endpoint was change in isometric dorsiflexion strength between groups assessed by hand-held dynamometry (expressed as a z-score based on age-and sex-matched normative reference values, positive values indicate an improvement in strength). the primary safety endpoint was change in muscle and fat volume of the muscles responsible for dorsiflexion by mri between groups. secondary outcomes were function (balance, long jump, -min walk test), walking ability ( d gait analysis), self-reported ankle instability, parent-reported quality of life (physical summary, psychosocial summary and global impression of change scores), and adverse events. fifty-five ( %) children completed the trial. adherence was comparable between exercise ( %) and sham ( %) groups. while patients experienced muscle soreness during training in the exercise group, adverse events did not differ between groups. the mean z-score for dorsiflexion strength increased in the exercise group by % at -months (from − . ± . to − . ± . ) and decreased in the sham group by %, mirroring the natural history of cmt (from − . ± . to − . ± . ). between-group ancova-adjusted difference at -months was . ( %ci, . to . ; p= . ). the mean scaled scores for mri muscle volume and fat volume were comparable between groups at months (p> . ). the global impression of change scores favoured the exercise group at -months (p= . ) and -months (p= . ). there was no other measurable effect of exercise. pre-specified subgroup analyses according to age ( - years vs. - years) showed a larger treatment effect with exercise in adolescents. targeted progressive resistance exercise was effective at halting progression of dorsiflexion weakness without detrimental effect on muscle morphology or other signs of overwork weakness in children with cmt. byung-nam y , yoon-ho h , suk-won a , seok-jin c , jung-joon s . inha university hospital, incheon, south korea; seoul metropolitan government boramae medical center, seoul national university, seoul, south korea; joong ang university hospital, seoul, south korea; seoul national university hospital, seoul, south korea. a years old female patient visited the hospital with weakness in both upper limbs from months under the suspicion of motor neuron disease with the finding of extensive denervation changes on electromyography. whole spine mri showed ventral nerve rootlet enhancement in the c and t bundles. the emg had confirmed active denervation changes in the muscles innervated by bilateral c ∼c roots. the cerebrospinal fluid culture test showed a protein (csf) elevation to mg / dl. she got a steroid pulse therapy. she had the symptoms of dry mouth and dry eyes during the recent years. a salivary gland scan test was performed for the possibility of sjögren's syndrome, and as a result, absorption of the contrast agent in both parotid and submandibular glands was decreased. the shammer test showed mm on the right side and mm on the left side. she was diagnosed of sjögren's syndrome. after weeks, overall strength improvement was observed, and bilateral shoulder abduction was improved to mrc grade or higher. the follow-up spine mri also showed that the initially seen ventral nerve root enhancement was disappeared. the case had visited the hospital with major symptoms of weakness and atrophy of the muscles, showing similar pattern to motor neuron disease, and was diagnosed as inflammatory polyradiculopathy and confirmed as primary ss during differential diagnosis. this case suggests that primary ss may induce inflammatory polyradiculopathy, which shows motor symptoms as major symptoms rather than sensory symptoms, and that a fast and accurate diagnosis is needed in terms that it can be treated with steroids and appropriate immune suppressive agents. traumatic injuries to peripheral nerves are frequent. however, effective pharmacological treatments are lacking. curcumin, a polyphenol found in rhizomes of curcuma longa, has been shown to develop antioxidant, anti-inflammatory, and neuroprotective properties. however, due to its poor hydrosolubility and its extensive metabolism, the use of large curcumin doses is required for therapeutic purpose. the aim of the present study was to investigate the effects of a local infusion of a low curcumin dose on nerve regeneration and functional recovery after sciatic nerve injury in rats. the experiments were conducted in g sd male rats submitted to unilateral sciatic nerve crush at d . curcumin was solubilized in polyethylene glycol and continuously administered using osmotic pumps ( . mg/day until d ) with a catheter delivering the drug near the lesion site. functional analyses using von frey, beam walking, static sciatic index (ssi) and grip strength tests were carried out at d (reference test) and every week after injury (d , d , d , d and d ). in addition, an evoked electromyogram was performed at d and d . after euthanasia (d ), nerve and muscle samples were collected and analyzed by light and electron microscopy. functionally, a significant improvement of the mechanical sensitivity (+ %) was observed at d in the curcumin-treated group (n= ) vs. vehicle group (n= ). in curcumin-treated group, skillful walking and finger spacing of the ipsilateral paw (ssi) were fully restored respectively at d and d contrary to vehicle group. furthermore, curcumin treatment improved the grip strength recovery (+ % at d ). the electrophysiological results indicated a full recovery of motor nerve conduction velocities (mncv) after days of curcumin treatment, while mncv remained altered in vehicle group ( % of the mncv at d ). morphometric analysis of nerve sections using g-ratio showed an improvement in the thickness of the myelin sheath in curcumin treated animals (+ % vs. vehicle group). histological investigation of gastrocnemius muscle indicated decreased neurogenic lesions in curcumin group. proteomic analysis is currently under investigation to understand the mechanisms involved in curcumin effects. our data could lead to the development of new therapeutic strategies in peripheral nerve regeneration using low doses of curcumin. previous studies suggest that the metabolic syndrome (mets) is associated with distal symmetrical polyneuropathy (dsp), and that diabetes, pre-diabetes, and obesity are the main metabolic drivers. the aim of this study is to investigate the association of mets components with retinal and cognitive function in a bariatric surgery cohort prior to surgery. patients were recruited from the adult bariatric surgery clinic at the university of michigan and lean controls from a research website (no mets components based on ncep/atpiii definition). participants underwent extensive metabolic phenotyping including a glucose tolerance test and fasting lipid profile. dsp was defined using the toronto consensus definition of probable clinical neuropathy. retinal function was measured with frequency doubling technology perimetry (average mean deviation), and cognitive function with the nih toolbox (composite score). univariate linear regression models were used to evaluate the association between mets components and retinal and cognitive function. to date, we have recruited bariatric surgery participants and lean controls. in the bariatric population, the mean (sd) age was ( . ) with % female compared with a mean age of . ( . ) with % female in the lean group. in the bariatric group, . % had diabetes, . % pre-diabetes, and . % normoglycemia. the dsp prevalence was % in lean controls, . % in normoglycemic, . % in pre-diabetic, and . % in diabetic bariatric participants (p< . for trend). retinal function was . ( . ), − . ( . ), − . ( . ), and − . ( . ) (p= . for trend), and cognitive function was . ( . ), . ( . ), . ( . ), . ( . ) (p= . for trend) in these same groups for lean controls, normoglycemics, pre-diabetics and diabetics, respectfully. pre-diabetes (− . , %ci: − . ,- . ) was the only mets component associated with retinal function, and waist circumference was the only one associated with cognitive function (− . , %ci − . ,- . ). dsp and retinal function, but not cognitive function decline with worsening glycemic status. similar to previous data for dsp, pre-diabetes and obesity are associated with retinal and cognitive function respectively. interestingly, while clinical dsp is common in this population, clinical retinopathy and dementia are not, indicating that dsp may be the first metabolic complication in the morbidly obese. and anti-cntn antibody-positive cases were confirmed by cba and were of igg subclass in half of them. by cba we identified additional / ( %) anti-caspr seropositive patients, whose isotype is currently being tested. sera of anti-nfasc and anti-cntn igg seropositive patients and patients with anti-caspr antibodies stained paranodes by indirect immunofluorescence on mouse teased nerve fibers. of note, seronegative patients for known antibodies showed reactivity against node and/or paranodes. compared to other seronegative cipd patients, seropositive patients had more frequently subacute onset of the neuropathy and a younger age at onset, particularly for nfasc or caspr antibodies. weakness was more severe and was often associated with proprioceptive loss, sensory ataxia and tremor. neuropathic pain was not a feature of caspr -seropositive patients. frequent findings were increased distal motor latencies and temporal dispersions on nerve conduction study and a higher protein level in csf. finally seropositive patients tended to have a higher disability and showed worst response to ivig. rituximab was effective in one patient with anti-nfasc antibodies and two patients with anti-cntn antibodies showed good and persistent recovery after cyclophosphamide. prevalence of antibodies was % in italian cidp patients and their presence was associated with distinctive clinical features. their determination, followed by characterization of igg subclass in positive cases, has clear clinical impact, by helping to guide therapeutic choices. the reactivity against nodal and paranodal components in sera from patients without known antibodies suggests that other targets could play a role in the autoimmune response in cidp and they still need to be identified. mutations in amynoacyl trna synthetases (arss), enzymes that catalyse the covalent attachment of amino acids to their cognate trna, are responsible for autosomal dominant cmt , intermediate cmt (cmt-i) and dhmn. we report the case of a male of italian ancestry who first presented with bilateral ankle clonus at three months, followed by toe walking and ankle instability. the ankle clonus subsided during adolescence. in the third decade he developed progressive walking difficulties followed by distal sensory loss. neurological examination at the age of revealed a steppage gait, distal lower limb weakness, decreased pinprick to the ankles, and reduced vibration sensation at the knees. reflexes were brisk in the upper limbs, reduced at the knees and absent at the ankles. muscle tone was increased in the lower limbs and plantar responses were extensor. nerve conduction studies revealed an axonal neuropathy. brain and spinal cord mri were normal. sanger sequencing of pmp , gjb , mpz , gdap and mfn were negative. sureselect focused exome sequencing (agilent technologies, santa clara ca, usa) demonstrated a c. g>a, p.arg his mutation in aars. the p.arg his mutation in aars has previously been reported in families with intermediate or axonal motor-sensory neuropathy, and in one case was associated with sensory-neuronal deafness. cns involvement has not previously been described with this mutation. mutations in aars have been associated with a range of phenotypes including cmti, cmt and dhmn with variable age on onset ranging from to years (mean years). of note, the aars p.gly arg mutation has been reported in a family with cmt and pyramidal signs. this study provides further evidence that pyramidal tract involvement can be an early feature of cmt n due to mutations in aars, further expanding the spectrum of arss-associated phenotypes. small fibres in the skin are vulnerable to damage in metabolic or toxic conditions such as diabetes mellitus or chemotherapy resulting in small fibre neuropathy and associated neuropathic pain (np). whether injury to the most distal portion of sensory small fibres due to a primary dermatological disorder can cause np is still unclear. recessive dystrophic epidermolysis bullosa, (rdeb) is a rare condition in which mutations of proteins of the dermo-epidermal junction lead to cycles of blistering followed by regeneration of the skin. damage is exclusive to the skin and mucous membranes, with no known direct compromise of the nervous system. it is increasingly recognised that most rdeb patients experience daily pain, the aetiology of which is unclear but may include inflammation (in the wounds), musculoskeletal (due to atrophy and retraction scars limiting movement) or np. in this study we investigated the incidence of np and examined the presence of nerve dysfunction in rdeb patients. around three quarters of patients presented with pain of neuropathic characteristics which had a length dependent distribution. quantitative sensory testing of the foot revealed striking impairments in thermal detection thresholds combined with an increased mechanical pain sensitivity and wind up ratio (temporal summation of noxious mechanical stimuli). nerve conduction studies showed normal large fibre sensory and motor nerve conduction however skin biopsy showed a significant decrease in intraepidermal nerve fibre density. autonomic nervous system testing revealed no abnormalities in heart rate and blood pressure variability however the sympathetic skin response of the foot was impaired and sweat gland innervation was reduced. we conclude that chronic cutaneous injury can lead to injury and dysfunction of the most distal part of small sensory fibres in a length dependant distribution resulting in disabling np. these neuropathic pain (np) following peripheral nerve injury is associated with hyperexcitability in damaged myelinated sensory axons which begins to normalise over time. we investigated the composition and distribution of shaker type potassium channels (kv channels) within the nodal complex of myelinated axons following injury. at the neuroma that forms after damage, expression of kv . and . (normally localised to the juxtaparanode) was markedly decreased. in contrast kv . and . , which were hardly detectable in the naïve state, showed increased expression within juxtaparanodes and paranodes following injury, both in the rat and in humans. within the dorsal root (a site remote from injury) we also noted a redistribution of kv channels towards the paranode. blockade of kv channels with dtx after injury reinstated hyperexcitability of a-fibre axons and enhanced mechanosensitivity. changes in the molecular composition and distribution of axonal kv channels, therefore represents a protective mechanism to suppress the hyperexcitability of myelinated sensory axons that follows nerve injury. members of the francophone anti-mag cohort group are listed in "appendix". appendix polyneuropathy with anti-mag igm antibodies is classically progressive, predominantly sensory, and distal with ataxia and sometimes postural-intention tremor. we assessed clinical, biological, electrophysiological, and histopathological features in patients with igm gammopathy and anti-mag antibody titres higher than btu. we focused on characteristics of patients according to the anti-mag antibody titres at diagnosis. we retrospectively and prospectively analysed standardized report forms of patients from fourteen french-speaking neuromuscular centres. mean age at onset was . years (range - . ). mean time between symptoms onset and last follow-up was . years ( . - . ). about . % of patients presented with a "variant" clinical phenotype independently of anti-mag titres (< or ≥ btu). this included acute or chronic sensorimotor polyradiculoneuropathies, paucisymptomatic sensory polyneuropathy and multifocal neuropathy. at the most severe disease stage, . % of patients were significantly disabled. anti-mag antibody titres at diagnosis were low (< btu), medium ( - ) or high (≥ ) in respectively , and % of patients. patients presented with mgus or waldenström's macroglobulinemia in respectively % and % of cases. sixteen percent of patients did not meet the electrodiagnostic criteria of definite demyelinating neuropathy, independently of anti-mag titres (< or ≥ btu). nerve biopsy, performed in nineteen patients, provided support to the diagnosis of anti-mag neuropathy in some particular issues (low titres of anti-mag, unusual clinical or electrophysiological phenotype). we assessed the degree of probability (probable, possible or uncertain) that patient neuropathies are directly related to anti-mag antibodies, according to anti-mag titre, electrophysiological data and nerve biopsy characteristics if available. it appears uncertain in patients with low anti-mag titres ( . % of the whole population). the clinical phenotype didn't appear to be different according to anti-mag antibody titre. many of the patients with low anti-mag titres presented "genuine" anti-mag neuropathy as demonstrated by edx studies, clinical presentation and sometimes nerve biopsies. for a small proportion of these patients, a direct relation between neuropathy and anti-mag antibodies is uncertain due to atypical clinical presentation, axonal neuropathy pattern or nerve biopsies, and positivity of antigangliosides antibodies. we assessed therapeutic management, response to immunotherapies and adverse events in a cohort of patients presenting with igm gammopathy and anti-mag antibody titres higher than btu. we retrospectively and prospectively analysed standardized report forms of patients from french speaking neuromuscular centres. mean age at onset was . years (range - . ). mean time between symptoms onset to diagnosis and last follow-up were respectively . ( - ) and . years ( . - . ). anti-mag antibody titres at diagnosis were low (< btu), medium ( - ) or high (≥ ) in , and % of patients. patients presented with mgus or waldenström's macroglobulinemia in respectively % and % of cases. seventy eight percent (n = ) of patients received immunotherapies. transient response to ivig or plasma exchanges at six month was observed in less than and % of patients respectively. chemoimmunotherapies and rituximab were more frequently administered in the group of patients with malignant hemopathies (n = ) compared to mgus (n = ) (mean lines of therapy = . , range - , sd . versus . , range - , sd . , p = . ). more than % of patients (n = ) received rituximab monotherapy. clinical worsening, mostly transient and reversible, was observed in / patients after rituximab. clinical response to rituximab at months and/or during - months follow-up period was observed in . % of patients, and correlated with anti-mag titre ≥ btu ( / responder versus / non-responder patients, p = . ). at - months follow-up, responder patients presented shorter symptom duration compared to non-responders, though not significant after logistic regression ( . years, range . - . , sd . in responder patients versus . years, range . - . , sd . , in non responder patients, p = . ). in some cases, electrodiagnostic studies were recorded during rituximab treatment follow-up and showed in responder patients a clear improvement of motor conduction velocities. these data may support another clinical trial to study benefice of rituximab in anti-mag neuropathies early in the disease. it raises issues about the value of incorporating electrodiagnostic parameters as end-points. schwann cells (scs) are essential for axon integrity and myelination in the uninjured pns. after pns injury, scs function as "first responders" , undergoing phenotypic re-programming and orchestrating many processes that lead to functional nerve repair. receptors in scs that contribute to sc repair programs remain incompletely understood. we identified a member of the ionotropic glutamate receptor (igr) family, n-methyl-d-aspartate receptor (nmda-r), in scs that is upregulated after nerve injury and acts as a co-receptor with ldl-receptor related protein (lrp ). lrp is a well-known regulator of the sc response to pns injury. herein, we used pcr to profile igr expression in cultured rat scs. obligate receptor subunits required for assembly of nmda-rs, ampa-rs, and kainate receptors were identified. treatment of rat scs with - microm glutamate or . - . microm nmda robustly activated akt and erk / . the response was transient and bimodal; glutamate concentrations greater than microm failed to activate cell-signaling. phosphoprotein profiling demonstrated other cell-signaling and transcription factors regulated by glutamate in rat and human scs, including p s -kinase, glycogen synthase kinase- , ribosomal s kinase, c-jun, and creb. activation of cell-signaling by glutamate in scs was blocked by eliminating calcium from the medium, by the selective nmda-r antagonist, mk , and by genetic silencing expression of the obligate nmda-r nr subunit. phosphoinositide -kinase/pi k functioned as an essential upstream activator of both akt and erk / in glutamate-treated scs. by activating pi k and erk / , glutamate promoted sc migration. glutamate ( microm) or nmda ( microm) injected into crush-injured sciatic nerves robustly activated p-erk / in both myelinating and non-myelinating scs in vivo. these results identify igrs as potentially important cell-signaling receptors in scs that may promote axon-glial interactions. understanding the function of sc nmda-r is important given current efforts to develop nmda-r-targeting drugs for patients with pain, depression, and alzheimer's disease. while frequently overlooked in a therapeutic context, scs are extremely important in the pathogenesis of chronic neuropathic pain. if these drugs modulate the activity of sc nmda-r and sc physiology, the response to pns injury may be altered and the possibility that neuropathic pain develops increased. candayan a , atkinson d , durmus tekce h , parman y , jordanova a , battaloglu e . department of molecular biology and genetics, bogazici university, istanbul, turkey; center for molecular neurology, antwerp university, antwerp, belgium; istanbul medical school, istanbul university, istanbul, turkey. charcot-marie-tooth (cmt) disease is a group of inherited peripheral neuropathies affecting one in individuals worldwide. the disease presents both clinical and genetic heterogeneity. so far, mutations in genes and loci are associated with cmt with autosomal dominant, autosomal recessive, x-linked and mitochondrial inheritance. despite the advances in genetic testing, approximately % of all cmt patients worldwide remain without a molecular diagnosis. we have investigated unrelated cmt patients of turkish descent, in all of which pmp duplication has been excluded previously. we used multiplex amplification of specific targets for resequencing (mastr) assay to sequence exonic regions of common cmt genes. recurrent mutations were identified in cases in mfn , gjb , mpz and hint genes. we have also identified novel variants in cases in mfn , pmp , gars, aars, ighmbp and gdap genes, all of which are very rare or not present in the variation databases and are predicted to be pathogenic by in silico tools. familial segregation analyses are ongoing for novel variations. mfn and gjb genes were the most commonly mutated causative genes in this cohort. cases without molecular diagnosis after the mastr testing are candidates for further analyses such as whole exome sequencing or whole genome sequencing. outcomes of the current study and our previous experience with turkish cmt patients suggest a high genetic heterogeneity. our insight is that different genetic strategies or larger panels are essential to determine the causes underlying cmt especially in regions where rare recessive types of the disease can be observed due to high frequency of consanguineous marriages. capoccitti g , giannini f , ginanneschi f , casali s , insana l , rossi a . university of siena, siena, italy. several efforts have been made to elaborate new electrophysiological criteria for early diagnosis of guillain-barré syndrome (gbs) and to differentiate demyelinating (aidp) from axonal (aman/amsan) forms. the aims were to verify the diagnostic power of total cmap (tcmap) duration, firstly applied in gbs field. this parameter was compared with commonly used neurophysiological measures, including negative phase cmap duration (ncmap), and was added to modified rajabally criteria. we reviewed the clinical and electrophysiological data of patients with gbs (level or of brighton clinical criteria). each patient underwent at least two neurophysiological studies, the first within weeks, the second between and weeks from symptom onset. at least four motor and three sensory nerve conduction studies were recorded for each test. regarding early diagnosis, the binary logistic regression model with multiple variables, including ncmap duration, showed that the features of predictive model presenting greater significance (p < . ) were tcmap duration, sural sparing and a-waves. among these, tcmap duration showed greater significance (p = . ). the tcmap was diffusely prolonged in aidp compared to aman/amsan, already in first examination and confirmed in the second one. roc analysis for tcmap duration in aidp vs. aman/amsan showed: cut-off . ms, auc . , ppv . %. we propose the tcmap duration as a new useful electrophysiological measure for early diagnosis of "generic" gbs and for early differentiation between aidp and aman/amsan. moreover, the prolongation of tcmap, the presence of a-waves and sural sparing represent a strongly diagnostic predictive triad of aidp. aifm (apoptosis-inducing factor, mitochondrionassociated- ) has captured great attention from biomedical researchers due its critical role in the regulation of cell apoptosis. this flavoprotein is typically located in the mitochondrial intermembrane space where it is associated with respiratory chain complex-i. upon a cell-death insult, aifm is cleaved into a kd protein that is released into the cytosol. the kd peptide may enter the nucleus to trigger chromosome condensation and fragmentation, initiating a caspase-independent pathway of apoptosis. however, this nuclear translocation may be blocked by cytosolic heat-shock protein- (hsp ) that binds with the fad domain (aa - ) of aifm . mutations in aifm gene have resulted in several clinical phenotypes, including a family with cmtx (glu val). clinical deficits in these patients usually involve multiple organs. in this study however, we identified a family with a novel missense mutation (phe leu) in aifm that developed a late-onset sensory motor axonal polyneuropathy by nerve conduction criteria. the proband and affected siblings exhibited distal muscle weakness and atrophy with normal cognitive and cranial nerve functions. there was no obvious phenotype from other organs. interestingly, this phe leu mutation affects a highly conserved amino acid at the center of the fad domain. we hypothesize that this mutation impairs the binding between aifm and hsp , leading to an enhancement of cell-death signaling. this family therefore provides a unique opportunity to explore how altered apoptotic signaling affects peripheral nerve system. supported by grants from ninds (r ns ) and the national center for advancing translational sciences (ul tr chronic inflammatory demyelinating polyneuropathy (cidp) can be the key symptom leading to diagnosis of associated lymphoma. patients with diagnosis of cidp according to efns/pns criteria associated with b cell lymphoproliferative disorders (bld), in one center, between november and november were included. demographical, clinical, nerve conduction, immunological, histological data and response to treatment were recorded retrospectively. eight patients ( men), median age yo were included. onset of polyradiculoneuropathy was either chronic (n= ) or acute (n= ). neurological condition led to diagnosis of bld in all but one case, because of onset (n= ) or worsening of neuropathy (n= ). clinical presentation was that of cidp in patients or pseudo-canomad in and plexopathy in one. lymphoma type was: lymphoplasmacytic (n= ), diffuse large b cell (n= ), small lymphocytic (n= ), marginal zone (n= ), unclassified small b cell (n= ). only patients presented with lymphadenopathies. bld was diagnosed in all patients on myelogram or bone marrow biopsy, performed because of cytopenia (n= ), atypical (n= ) or severe (n= ) neuropathy. monoclonal gammapathy was identified in / patients (igm n= , igg n= ). neuromuscular biopsy was performed in patients and disclosed endoneural infiltration in . anti-neuronal or antigangliosides antibodies were positive in patients. none of the patients presented a systemic autoimmune disease, hemolytic anemia associated with bld (n= ). immunomodulating treatment was administered in all patients (ivig n= , plasma exchange n= , steroids n= ) and immunosuppressants (n= ). immunochemotherapy for lymphoma was initiated because of lymphoma type or severity in cases, in cases because of the associated neuropathy. median follow-up was of months after treatment initiation. four out of patients treated within months of neurological onset improved as well as one out of patients whose preexisting neurological condition had worsened. two patients presented neurological relapse during progression of lymphoma. two patients died. unusual presentation of cidp -i.e., rapid progression or treatment failure -should lead to further testing for associated lymphoma. because general symptoms and lymphadenopathy often lack, diagnosis requires analysis of bone marrow with lymphocyte phenotyping. early treatment with immunochemotherapy was associated with better prognosis in our series. cardiac scintigraphy is a useful tool for the diagnosis, prognosis and pre-symptomatic early detection of familial amyloidosis-associated neuropathies three main types of familiar amyloidosis: transthyretin (ttr), apolipoprotein a and gelsolin. cardiac involvement is a leading cause of morbidity and mortality; one new described mutation strongly related with isolated cardiac amyloidosis is the ttr val ile. the discovery of tests that allow early diagnosis of cardiac involvement in amyloidosis and to infer about the etiology of the disease is of major importance. in a cohort of patients with different types of familiar ttr amyloidosis, we aimed to assess the role of mtc- , -diphosphono- , -propanodicarboxylic acid ( mtc-dpd) in detecting myocardial amyloid infiltration. we enrolled four patients diagnosed with late familiar amyloidosis, which mutations were documented at deoxyribonucleic acid analysis: three patients with ttr val met mutation and one patient with ttr val ile mutation. three patients were asymptomatic for cardiac involvement and one patient (val ile mutation) had a previous diagnosis of heart failure. myocardial uptake of mtc-dpd scintigraphy was semiquantitatively and visually assessed at five minutes and three hours.the uptake of mtc-dpd highly demonstrated amyloid in cardiac area in two out the three cases of ttr val met and in ttr val ile. ttr val ile case presented the highest uptake due to the exclusive deposition of amyloid in cardiac area resulting in severe heart failure. in hereditary transthyretin-related amyloidosis, including the mutations ttr val met and val ile, mtc-dpd cardiac scintigraphy can identify infiltration even in asymptomatic individuals, allowing an early diagnosis of cardiac compromise in this group of diseases. we can consider that this non-invasive test would be a tool with potential importance in the diagnosis, prognosis and pre-symptomatic early detection of cardiac amyloidosis, giving emphasis on its applicability in familial forms of amyloidosis. cervellini i , galino j , zhu n , birchmeier c , bennett dl . ndcn university of oxford, oxford, uk; max-delbrück-center for molecular medicine, berlin, germany. erk/mapk pathway has a critical role in pns development since its involvement in many physiological processes. sustained erk / mapk activation in schwann cells enhances myelin growth during development and overcomes signals ending myelination leading to a continuous myelin production. however, strong activation of erk has also been shown to cause schwann cells dedifferentiation and demyelination in vivo. our aim was to investigate whether a mild activation of this signalling pathway in adult schwann cells (scs), by expression of gain of function mek dd allele, could have a beneficial role in remyelination and regeneration after injury. erk/mapk activation in adult scs in plpcreer t ;mek dd mutant mice, did not affect myelination during development. following sciatic nerve injury, wallerian degeneration was enhanced in mutants pushing towards a dedifferentiation stage of scs as previously described. however, mapk activation was detrimental during regeneration with a delay in functional recovery and a negative impact in both myelinated and non-myelinated fibres compared to controls. one month after injury the total number of axons in mutant sciatic nerves was half of the controls. although no differences in g-ratio have been found in the two groups, mutants presented a higher number of myelinated axons showing myelin disruption with start of myelin decompaction, lack of cajal bands, abundant sc processes surrounding axons and a shorter sc elongation, as seen by decreased internodal distance. in addition, we found a negative effect of mapk activation also in small diameter axons with the presence of abnormal remak bundle structures, reduced number of c-fibres/remak bundle and a significant decrease in intra epidermal nerve fibres density in the skin. we concluded that mild mapk activation has a different role in development and remyelination where negatively affects axon survival, myelin stability, remak bundle formation and small fibres regeneration. cervellini i , galino j , zhu n , bao lu , bennett dl . ndcn, university of oxford, oxford, uk; harvard medical school, boston, ma, usa. neprilysin (nep) is an endopeptidase which has been of interest due to its potential role in neurodegeneration and pain as a consequence of its ability to degrade amyloid and substance-p respectively. nep expression is not limited to cns and it has been reported to be expressed in schwann cells, nodes and schmidt-lanterman incisures. our interest in this gene was related to recent findings that have associated homozygous and heterozygous nep mutations with charcot-marie-tooth type- . in old mice lacking nep subtle morphological changes have been reported. our aim was to determine whether nep expression was modulated by nerve injury and to investigate its role in axon regeneration and re-myelination. we find that nep gene expression was decreased after nerve crush and furthermore was dependent on the growth factor (and pro-myelin signal) neuregulin- . in control mice nep expression was transiently reduced and returned to baseline at day after injury, in neuregulin- knock-out (ko) mice, in which re-myelination was impaired, the expression was still decreased at day . in assessing behavioural measures of locomotor and sensory function one month after sciatic nerve crush, nep ko mice showed a functional regeneration comparable to wt, as seen by sciatic functional index measurement, beam and toe spreading tests. the only significant difference we observed between wt and ko was in the sensorial test, showing ko mice recovering faster in the pinch test by days after crush. the results for all the tests at baseline did not differ between the two groups. detailed histological analysis of nerve repair was undertaken using electron microscopy. there was no difference between wt and ko in total axon number, g-ratio, axon diameters and other myelin features one month post crush. in summary, although nep expression is regulated by nerve injury in a neuregulin- dependent fashion this endopeptidase is dispensable for axon regeneration and re-myelination after nerve injury in the rodent. diabetes neuropathy is a common complication of diabetes, and neuropathic pain has a detrimental impact on quality of life. this study investigated sensory nerve excitability properties to elucidate the axonal changes of diabetic neuropathy. a total of diabetes patients ( type ii, and type i) were enrolled in this study. clinical assessment, nerve conduction studies, and nerve excitability testing data were analyzed to determine axonal dysfunction in diabetic neuropathy. among those patients, seventeen subjects had complained of spontaneous painful sensation over feet or hands (painful cohort), and seventy-eight patients had no sensory symptoms or decreased the sensation over foot (non-painful cohort). sensory nerve excitability of the painful cohort showed reduced late subexcitability (p= . ), increased superexcitability (p= . ) in compared to the non-painful cohort. there is no difference in disease duration, blood glucose levels (hba c) between these two cohorts. these findings suggested the possible pathogenesis of painful sensory axons might be hyperpolarized or slow potassium channels dysfunction. these insights our further understanding of painful diabetic neuropathy, and may provide a basis for neuroprotective or therapeutic approaches for painful polyneuropathy. the main purpose of this study was to assess the clinical feasibility of diffusion tensor imaging (dti) for the diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (cidp). between march and december , we prospectively enrolled patients with definite cidp according to the efns criteria and two control groups: healthy volunteers matched on age and sex and patients with cmt- a. using a -t magnetic resonance imaging scanner, we obtained dti scans of brachial plexus of these groups and prepared fractional anisotropy (fa) maps, and compared these values between groups. adc values and cervical nerve roots diameters on stir sequences were evaluated too. two neuroradiologists, blinded to clinical informations, reviewed mri studies independently. in all patients with cidp, we also performed clinical evaluation and electroneuromyography. significantly decreased fa values (p< . ) and increased adc values were observed in cidp patients compared with healthy subjects. there is no significant difference between cidp and cmt group. inter-observer concordance was excellent for fa values ( c= . ; p< . ) and moderate for adc values ( c= . ; p< . ) and cervical nerve root diameters ( c= . ; p< . ). there is a significant correlation between fa and disease duration (r = − . , p < . ), inclusion mrc score (r = . , p < . ) and between fa mesured on c c and incat score at inclusion (r = − . , p < . ). no significant correlation is observed between fa and electrophysiological indices. compared with healthy subjects, cervical nerve root diameters were significantly increased (p< . ) in patients with cmt and cidp. contrary to fa values, moderate level of concordance was found between inter-observers measurements of diameters (cclin = . ). our preliminary data prove the clinical feasibility and reproductibility of dti for the evaluation of plexus and cervical nerve roots in patients with cidp. cheng yj , teng a , goh ejh , umapathi t . yong loo lin school of medicine, national university of singapore, singapore; department of neurology, national neuroscience institute, singapore. the sural-sparing pattern of the sensory nerve action potentials (snap) of guillain-barré syndrome (gbs) has been attributed to greater immunological injury of the blood-nerve barrier at its most vulnerable regions. we asked if entrapment sites, such as median nerve at the wrist, are more predisposed than the distal nerve endings to such injury. we compared the median snap with radial snap measured antidromically at digit in gbs patients whose nerve conduction study showed the sural-sparing pattern. the terminal nerves at digit are of similar length, but those of median nerve are prone to compression, often subclinically, at the carpal tunnel while those of radial nerve are not. we defined the sural-sparing pattern as a greater decrease in median and or ulnar snap than that of the sural, compared to age and height-matched normal controls. a total of gbs and miller fisher patients from our institution's database were studied. patients had the sural-sparing pattern, of whom had pre-existing carpal tunnel syndrome. of the remaining patients with sural-sparing, had abnormal median snap at digit , while had both abnormal median and radial snaps at digit . none had isolated abnormality of the radial digit snap. among the cases that had abnormal median and radial snaps at digit , the mean percentage decrease when compared to age and height matched norms was greater in median nerve compared to radial nerve ( % and % respectively). of the patients without sural-sparing pattern, had normal snaps; patient had inexcitable sensory nerves while the other had a length-dependent decrease in snap. in the latter patient, unlike those with sural-sparing, there was no differential decrease of median snap over radial snap at digit . our findings suggest that the disruption of blood nerve barrier at entrapment sites rather than the distal nerve endings may underlie the pathophysiology of the sural-sparing pattern seen in gbs. chiba a , uchibori a , gyohda a . kyorin university, tokyo, japan. serum igg anti-gq b antibody is the most specific biomarker for fisher syndrome and its related disorders (fs-rd), but approximately - % of the patients are seronegative for it in conventional assays (gq b-seronegative). some molecules need ca + cation to interact with their ligands, and antibodies with such a property (ca + -dependent antibodies) are reported. we have found that such a ca + -dependency is also present in igg anti-gq b antibody, and majority of gq b-seronegative patients with fs-rd have this type of antibodies. in patients with final clinical diagnoses as fs-rd (fisher syndrome, guillain-barré syndrome with ophthalmoplegia, bickerstaff brainstem encephalitis, and acute ophthalmoplegia), were seropositive for igg antibodies against gq b-related antigens (isolated gq b in , and gq b-conatinig complexes in two) in conventional elisa using phosphate-buffered saline. in the remaining patients, eight ( %) turned positive for igg antibody against gq b-related antigens (isolated gq b in seven and gq b-conatinig complexes in one) in elisa using ca + -added tris-buffered saline. the reaction strengths increased depending on ca + concentration, and reached to nearly maximum level in the physiological concentration. all the patients with the ca + -dependent antibodies were also positive for igg antibody against gt a-related antigens, suggesting that the terminal disialo residue common to both the gangliosides would be important as an epitope also for the ca + -dependent antibodies. in the patients with ca + -non-dependent antibodies, only two showed increased titers of igg anti-gq b antibody by adding ca + , and showed significantly decreased titers. this difference in the effect of ca + -addition between ca + -dependent and ca + -non-dependent antibodies suggests that ca + would not be just an enhancer of the antigen-antibody reaction. there are four single bonds between the two pyranose rings in the terminal disialo, and those rotatable bonds make it possible for the disialo structure to take various conformations. a molecular model shows that the distance between two minus-charged carboxy groups in the disialo could vary from nearly zero to approximately , pm and that the disialo would take specific conformations, if divalent ca + cation, which size is approximately pm in diameter, interacts with these two minus-charged groups. the ca + -dependent antibodies might recognize such particular conformations of gq b. charcot-marie-tooth disease (cmt) is a genetically and clinically heterogeneous disorder with variable inheritance modes. it is characterized by loss of muscle tissue and touch sensation, predominantly in the feet and legs but also in the hands and arms in the advanced stages of disease. as several molecules have been reported to have therapeutic effects on cmt, depending on the underlying genetic causes, exact genetic diagnostics have become important for executing personalized therapy. aminoacyl-trna synthetase (arss) genes encode enzymes responsible for charging trna with corresponding amino acids. arss are ubiquitously expressed, essential enzymes responsible for performing the first step of protein synthesis. specifically, arss attach amino acids to their cognate trna molecules in the cytoplasm and mitochondria. recent studies have demonstrated that mutations in genes encoding arss can result in neurodegeneration, raising many questions about the role of these enzymes in neuronal function. mutations in six cytoplasmic ars genes have been reported as the cause of cmt. this study was performed the whole exome sequencing to identify genetic defects in korean cmt patients from unrelated families. variants were sorted with cmt gene list that includes almost genes were related cmt neuropathy, and additionally sorted wes data as ars genes. capillary sequencing for family members and more than controls revealed five novel mutations, c. g>a (p.d n), c. c>t (p.s f), and c. c>a (p.p h) in gars; c. c>a (p.p t) in mars; _ ga>at (p.d i) in yars gene in each family. the mutation sites were well conserved between different species and each mutation were located in the well-conserved catalytic domain or between two catalytic domains or anticodon-binding domain. in silico analysis predicted all mutations may affect protein function. clinical features were similar to those reported in other countries, but differed in terms of age at onset and degree of disability. we believe that those novel ars mutations are the underlying causes of the each family. a -year-old man presented with a -year-history of weakness in biltearal upper limbs. he was complaining of intermittent fasciculation of upper and lower limbs with gradually worsening of paresthesia for years. dysphagia and dysarthria were also presented years ago. there was no patient affected muscle weakness and bulbar symptoms in his family members. in neurological examination, the patient had weakness in biltereal upper and lower limbs (mrc grade ) and prominent distal sensory loss were combined in length dependant pattern. deep tendon reflexes were absent on bilataral biceps and knee joints. in nerve conduction study, there was consistent with demyelinating sensorimotor polyneuropathy. molecular diagnostic analyses those spinobulbar muscular atrophy (sbma) and mutation related to peripheral myelin protein (pmp ) gene were performed and confirmed expansion of expansion of a polymorphic cag in androgen-receptor (ar) gene and deletion of pmp gene. smba, also known as kennedy disease, is an adult-onset, x-linked recessive trinucleotide, polyglutamine (poly-g) disorder caused by expansion of a polymorphic cag tandem-repeat in exon of ar gene on chromosome xq - . charcot-marie-tooth disease (cmt) is the most common hereditary neuropathies and cmt cases with motor conduction velocities(mcvs) of upper limb below m/s are defined as demyelinating (cmt ) and those with mcvs above m/s are defined as axonal (cmt ). most families with cmt linked to duplication of pmp gene on the short arm of chromosome ( p . ), called cmt a. the reciprocal deletion of pmp gene is a responsible genetic defect in % of hereditary neuropathy with liability to pressure palsy (hnpp). these "classical" phenotypes of cmt a and hnpp have been considered which are determined by different mutation mechanism of the same gene. however, an overlap of cmt a and hnpp due to pmp gene deletion was reported that suggestion the phenotype of hereditary neuropathies may differ variably. herein, we report a patient who simultaneously presented clinical and electrophysiologic features of smba and cmt a with genetical confirmation of cag expasion and deletion of pmp gene. charcot-marie-tooth type a disease (cmt a) is an inherited peripheral neuropathy stemming from overexpression of pmp protein in schwann cells due to the duplication of the pmp gene. this leads to abnormal schwann cell differentiation and dysmyelination, eventually leading to axonal loss and muscle wasting. no approved treatment is currently available for cmt a. we conducted a systems biology level analysis of the signaling network putatively underlying the processes driving cmt a pathology. based upon this, we identified and tested three repurposed drugs -baclofen, naltrexone and sorbitol -alone and in combination to determine their ability to rescue aberrant myelination in cultures derived from cmt a transgenic rats overexpressing pmp gene. to this end, we studied a validated in vitro co-culture model of sensory neurons and schwann cells adapted to -well culture plates. this model allows measurement of the appearance of myelin proteins as an index of the physiological process of in vivo myelination. total myelin length was quantified with an automatic image analyzer following pmp immunostaining. we first determined the full dose-response curves of single drugs, emphasizing their promyelinating activities. we then tested binary combinations of very low and inactive doses of each drug and compared these to the activity of the combination of the three, namely pxt . whereas combination of any two drugs was not significantly active at the doses tested, combination of all three produced a synergistic improvement in myelination. these findings clearly demonstrate the necessity of using pxt over its single components and highlight the value of pleiotropic combinational repurposing of drugs at low doses as a novel approach for rapid drug development in cmt a and other disorders. autonomic dysfunction is frequently observed in guillain-barré syndrome (gbs) and affects approximately % of the patients. it has been shown that the sweating function can be impaired in gbs. the aim of the present investigation is to summarize the current knowledge on sweating disturbances in gbs patients. we have used appropriate terms to systematically search for references published until and indexed in the following databases: medline, embase, lilacs and cochrane. the inclusion criteria were a diagnosis of gbs and a description of the methods used to test the sudomotor function. the search was limited to the english language. relevant information about study design, methods of assessing the deficit of sweating, patient's characteristics and main results were collected. we selected original references for the final analyses. the majority of the studies were cross-sectional in nature and there were two longitudinal studies. the severity of sweating impairment varied according to the applied method, ranging from normal to almost sympathetic nervous system failure. in seven research papers, the sympathetic skin response was used to evaluate the sudomotor function in patients, and approximately % demonstrated abnormal results. however, researchers used different stimulation protocols and parameters to interpret their results. regarding whole-body sweating test, four research papers applied the thermoregulatory sweating test in patients and they showed areas of anhidrosis on the lower limbs in all of them. eight patients presented sweating impairment on the upper limbs and abdominal wall. results on the sudomotor axon reflex test suggested a length-dependent pattern of sweating loss according to one case report. in another study, eight gbs patients were tested only on the distal leg and foot dorsum and the authors proposed an association between post-ganglionic sudomotor function and antiganglioside antibodies. the present literature review showed that the studies of sweating disturbances in gbs patients included only small cohorts. future studies with larger patients sample sizes are necessary to investigate the patterns of sweating loss in gbs and their changes along the follow up. funding: grants # / - and # / - , são paulo research foundation (fapesp). sensory neuronopathy (sn) represents a rare subgroup of peripheral neuropathies characterized by degeneration of primary sensory neurons at the dorsal root ganglia on the spinal cord. depending on the neuronal population affected, its clinical presentation may manifest as gait ataxia, proprioceptive sensory loss and positive and negative sensory symptoms. although a few reports have mentioned areas of anhidrosis in sn, we were not been able to find previous case series studies on the sweating function in sensory neuronopathies. the aim of the present investigation was to study the whole-body distribution of sweating on both anterior and posterior surfaces in patients diagnosed with sn. quantitative sensory testing for cold and warm sensation threshold (method of levels) was performed on the dorsum of the hands and feet in a randomized order. we tested the thermoregulatory sweating using a sweat chamber ( to ∘ c air temperature and % relative humidity). the oral and skin temperature was monitored and the test time did not exceed min. in order to study the sudomotor axon reflex we employed the q-sweat device on standardized body sites. the test was performed on both sides, simultaneously. we included seven patients (three male; mean age . years) with a mean disease duration of . months (range - ) and a confirmed diagnose of sn. patients presented an asymmetrical loss of cold and warm threshold on hands or feet compared with healthy control (p< , ). regarding the tst results, we found a striking variation of sweating disturbances, ranging from small areas of anhidrosis on the trunk to complete failure of the sympathetic nervous system. two patients underwent the axon reflex test and there was an asymmetrical and mostly distal pattern of sweating loss in one of them and a distal-symmetrical on the second one. our findings indicate a great variability of sweating losses in sn, not overlapped to the sensory loss areas. currently, we are testing more patients in order to confirm our results. funding: grants # / - , # / - and # / - , são paulo research foundation (fapesp). diet, exercise, and inflammation are established modulators of peripheral nervous system function, including pain. prior work examining exercise consistently demonstrates a benefit on heightened pain from a number of acute and chronic pain models. in the present work, we investigated several parameters of peripheral nerve function relevant to pain in rats bred for high (high capacity runners, hcr) or low running capacity (low capacity runners, lcr). the longtime selective breeding of these rat substrains has created divergent intrinsic aerobic capacities and predisposition of metabolic conditions between lcr and hcr rats. examination of the role of sex in the development of chronic pain has established key differences in males and females. to understand gender specific differences, this study focused on female rats to understand the role of metabolic status and peripheral nerve function in females. our analysis identified numerous parameters of peripheral nerve function relevant to pain and neuropathy that are different among lcr and hcr female rats. lcr female rats display reduced hind paw mechanical sensitivity, increased hind paw intraepidermal nerve fiber density and trka-positive epidermal axons, increased numbers of langerhans and mast cells in the hind paw dermis, and increased overall fat mass relative to body weight compared to female hcr rats. examination of sensory and motor nerve conduction velocities, thermal sensitivity, and mrna expression of selected genes relevant to peripheral sensation found no differences between hcr and lcr females. together these results suggest that a genetic component of aerobic capacity and metabolic status can influence sensory sensitivity and specific aspects of inflammation and immune responses in peripheral tissues, which may lead modify the animal's responses to tissue damage and painful stimuli. the lcr and hcr rat model will provide a useful model in the future to assess the involvement of metabolic status in the development of pain. ivig is often considered treatment of first choice in chronic inflammatory demyelinating polyradiculoneuropathy (cidp) because of its rapid onset of action and its relatively safe long-term adverse event profile. clinical trials published so far focused on a loading dose of . g/kg ivig and/or a standard maintenance dosage of . g/kg ivig once every weeks, but have not investigated different dosing options. this study is a prospective, double-blind, randomized, parallel group, multi-center phase iii efficacy study and will be conducted in centres in canada, eu, russia, ukraine and australia. adult patients with definite or probable cidp according to the efns/pns criteria will be enrolled and randomized : : to receive either . g/kg or . g/kg or . g/kg ivig (panzyga ® ) for seven maintenance infusions at -week intervals during the dose-evaluation phase. the starting loading dose will be . g/kg ivig (panzyga ® ) for all patients. primary objective: efficacy measured as percentage of responders (decrease in adjusted incat score by at least point) in the . g/kg ivig (panzyga ® ) arm (given every weeks) at week as this should corroborate the existing and published evidence on efficacy of ivig in cidp. secondary outcome: percentage of responders at week in the . g/kg and . g/kg ivig (panzyga ® ) arms relative to baseline and compared to the . g/kg arm. the procid study aims to confirm published clinical results obtained with the . g/kg standard dose and will in addition evaluate one higher and one lower maintenance dose, with the aim to offer cidp patients a more adequately dosed and effective treatment policy. * este medicamento no se encuentra comercializado en españa. understanding the rate of disease progression in patients with charcot-marie-tooth disease (cmt), both within and between subtypes is important for clinical prognosis and is crucial for clinical trial design. due to the progressive nature of cmt, intervening at the earliest stages of the disease is a priority. measuring progression of a disease with both motor and sensory deficits requires a multi-item composite scale. the cmt pediatric scale (cmtpeds) is a well-tolerated psychometrically robust -item scale measuring fine and gross motor function, strength, sensation and balance for children and adolescents aged - years with cmt. the aim of this study was to determine the rate of disease progression of children and adolescents within and between genetic subtypes of cmt. ( female) participants aged - years enrolled in the inherited neuropathies consortium were included in this study. demographic, anthropometric and diagnostic information were collected at baseline and -year follow-up. disease progression was measured with the cmtpeds. on average cmtpeds scores progressed at a rate of . points over -years ( % change from baseline, p< . ). there was no difference in rate of disease progression between males and females. of the most common genetic subtypes, participants with cmt a/pmp duplication progressed by . points ( % change from baseline, p< . ), nine participants with cmt b/mpz mutation progressed by . points ( % change), six participants with cmt a/mfn mutation progressed by . points ( % change) and seven participants with cmt c/sh tc mutation progressed by . points ( % change). participants with cmt a progressed faster than those with cmt a (p= . ). children with cmt a progressed consistently during childhood and adolescence while children with cmt b and cmt a progressed faster during childhood than adolescence. overall, children with cmt progress at a significant rate over -years according to the cmtpeds. understanding the rate at which affected children deteriorate is essential for adequately powering clinical trials of disease-modifying interventions. queen square, london, uk; department of neurology, university of iowa carver college of medicine, iowa city, ia, usa; department of neurogenetics, the national hospital for neurology and neurosurgery, ucl institute of neurology, london, uk; department of molecular neuroscience, ucl institute of neurology, london, uk and national hospital for neurology and neurosurgery, queen square, london, uk. in recent years, targeted ngs panels have changed the diagnostic work-up in patients with inherited neuropathies. however, there is limited data on the impact of targeted ngs panels on the diagnosis of cmt patients in everyday practice. the aim of this study was to investigate the impact of targeted ngs panels on the diagnosis of cmt across two tertiary referral centres in the united kingdom (london) and united states (iowa). in london, patients with a diagnosis of cmt (previous pmp duplication and common cmt genes excluded in appropriate cases) underwent targeted ngs panel sequencing covering genes associated with cmt and additional genes associated with hsp or als. a variable number of genes, ranging from to , were analysed depending on the clinical phenotype of the patients. a definite molecular diagnosis was achieved in cases ( %) including pathogenic and likely pathogenic mutations in sh tc ( cases), gjb ( cases, including cases with mutations in the promoter and 'utr regions), gdap ( cases), fgd ( cases), aars ( cases), ighmbp ( cases), mpz ( cases), nefl ( cases). vus were further identified in patients. the diagnostic rate was higher in demyelinating cmt cases ( / , %), compared to cases with axonal cmt ( / %), dhmn ( / , %) and hsn ( / , %). in iowa, patients were investigated by ngs panels covering to genes associated with cmt. a molecular diagnosis was reached in / ( %), and in particular / ( %) demyelinating and / ( %) axonal cmt cases. the most frequent genes identified were gjb ( cases), mfn ( cases), sh tc ( cases) and ighmbp ( cases). vus were identified in patients, including cases with novel variants in aars, warranting additional testing such as segregation of the variant in the family or functional validation studies. in clinical practise, targeted ngs panels represent an effective approach for the diagnosis of cmt. the lower diagnostic rate in london is likely to be due to prior sanger sequencing and exclusion of mutations in common cmt genes in this patient population. more than genes are known to cause cmt and an even larger number are known to cause peripheral neuropathy as part of a more complex neurological disorder. despite the use of custom panels, a significant proportion of patients with inherited neuropathy have no molecular diagnosis. the aim of this study was to investigate the diagnostic yield of a disease-associated gene exome (sureselect focused exome, agilent technologies, santa clara ca, usa) in the diagnosis of cmt and in cases with complex neurological syndromes associated with neuropathy. thirty-one patients with molecularly undiagnosed inherited neuropathy were analysed with sureselect focused exome sequencing. six patients had a more complex phenotype including learning difficulties, cerebral white matter changes, ataxia and pyramidal tract involvement. a genetic diagnosis was achieved in / ( %) of cases by detecting a mutation in cmt-associated genes mpz ( cases), aars, nefl, bscl , bicd and trpv . of note, six cases had mutations in genes which are not covered by currently available diagnostic targeted ngs panels, including kif a, polg, mme ( cases), dnajb , and a novel candidate gene. the average coverage was higher compared to the usual coverage of whole-exome sequencing; % of the targets were covered at x or more, and % of the targets were covered at x or more. this study provides evidence that the sureselect focused exome is a useful tool for the diagnosis of cmt and complex neurological disorders and provides further insight into the phenotypic spectrum of genes associated with inherited neuropathy. changes in the cis-regulatory sequences of a gene's untranslated regions (utr) are increasingly recognised as a significant cause of inherited disease in humans. for example, variants in the non-coding region of gjb account for % of all mutations in our cohort of cmtx patients. one of the biggest challenges in analysing the large number of non-coding variants in a gene is identifying those that are disease-causing and those which are polymorphisms. the aim of this study was to implement a reliable method for the in-vitro functional validation of non-coding variants in the promoter and 'utr regions of gjb . in our cohort of cmtx patients we have previously identified seven mutations (c.- _ inst, c.- g>a, c.- t>g, c.- t>c, c. t>c, c.- g>c, c.- c>t) in the promoter region and one novel mutation in the 'utr (c. c>t), which were considered likely to be pathogenic based on the clinical phenotype, segregation in affected family members and absence in control databases. we have now generated a luciferase-based reporter system and optimised it in a hela cell line. mutations in the promoter region were generated by site-directed mutagenesis using a commercially available gjb promoter clone (genecopoeia). our preliminary results show a reduction of luciferase activity for the c.- t>c and c.- _ inst mutations compared to the wild-type promoter. this difference was increased when transcription factors sox or egr were co-transfected with the t>c and c.- _ inst mutations respectively. validation of other variants is currently ongoing. if successful, our study will provide a useful tool for the validation of mutations in non-coding regions of gjb . moreover, it will constitute a proof-of-principle approach to the functional validation of non-coding variants in other cmt genes known to cause disease by a loss of function. recessive and dominant mutations in leucin-rich repeat and sterile alpha-motif-containing (lrsam ) have been associated with cmt p. lrsam is a ubiquitin e ligase containing a ring domain in its c-terminal, which is crucial for correct protein folding and ubiquitination activity. to date, the majority of dominant mutations reported have resulted in a frame shift disrupting a major portion of the ring-domain, although point mutations in this domain have also been described. the aim of this study was to report the prevalence, clinical features and genetic findings of patients with cmt p in our centre. we performed targeted next-generation sequencing in genetically undiagnosed cmt patients and identified cases with heterozygous mutations in lrsam ( . %) from unrelated families. the mutations identified included frameshift insertions and deletions, a non-frameshift deletion and non-sense and missense point mutations. all of the mutations were novel and were located in or flanking the ring domain. the average age of disease onset was in the rd decade but an earlier onset was reported in two cases. four had a positive family history in keeping with autosomal dominant inheritance. symptoms at presentation were heterogeneous and encompassed distal numbness, unsteadiness, distal weakness of upper or lower limbs and foot deformities. positive sensory symptoms, including tingling and shooting pains, and cramps were also frequently reported. neurological examination showed mild to moderate distal atrophy and weakness, with early ankle plantar flexion involvement in three patients. loss of vibration and reduced joint position sense were often prominent in the lower limbs and appeared to be disproportionate to the degree of weakness and impairment of pinprick sensation. ankle jerks were absent but knee and upper limb reflexes could be normal or brisk. after an average disease duration of years, all but one patient was able to walk independently. nerve conduction studies showed a sensory and motor axonal neuropathy with normal conduction velocities. our study highlights that mutations in lrsam are a relevant cause of cmt and are associated with prominent large fibre sensory loss. in recent years, the implementation of ngs panels for the molecular diagnosis of cmt has increased the number of patients with a genetic diagnosis. nevertheless the interpretation of a particular variant as disease causing can be challenging especially when multiple variants are identified in a single patient. we report two illustrative cases of such challenges. the first index case was born of non-consanguineous healthy parents. he presented with falls in early childhood. over the years he developed foot deformities and progressive length dependent weakness. he had multiple orthopaedic operations to his feet. the past history was also notable for kyphoscoliosis, sensorineural deafness from the age of and bilateral cataracts. nerve conduction studies at the age of revealed a demyelinating neuropathy consistent with the clinical phenotype of cmt . his younger brother had a similar, although more severe phenotype. a litaf (c. c>t,p.pro ser) mutation was identified by sanger sequencing and was present in both affected brothers but also in the unaffected sister. ngs for cmt -associated genes was therefore performed and identified two compound heterozygous pathogenic mutations detected in sh tc (c. c>t, p.arg *; delg, p.arg serfs* ), which segregated with the disease in the family. the second case describes a brother and sister with early onset demyelinating cmt associated with scoliosis and cranial nerve involvement. the male proband underwent ngs and a single previously reported pathogenic intronic splice-site mutation in sh tc (c. - a>c) was found. relative read-depth analysis of ngs was performed to look for possible copy number variants in sh tc , thus identifying a deletion of exon , which was confirmed by long pcr. cruz-velásquez gj , miramar-gallart md , alarcia-alejos r , roche-bueno jc , rodríguez-valle a , capablo-liesa jl . neurology service, university hospital miguel servet, zaragoza, spain; genetics unit, clinical biochemistry service, university hospital miguel servet, zaragoza, spain. charcot-marie-tooth disease (cmtd) defines a clinical and genetically heterogeneous group of inherited peripheral neuropathies characterized by chronic motor and sensory impairment. the type cmtd- also known as cowchock syndrome, is the product of the mutation in the apoptosis inducing factor mitochondria associated gene (aifm ). it is a slowly progressive, recessive, x-linked disease characterized by axonal neuropathy, deafness, and cognitive impairment. our purpose is to describe new cases, brothers, children of non-consanguineous parents, with a characteristic phenotype and a new mutation in the aifm gene. both siblings present from childhood, progressive weakness in lower limbs with diffuse amyotrophies. needing tenotomy before the year due to equinovarus foot. likewise they develops sensory deafness and one of them requires unilateral support at and the other wheelchair at , this one need a pacemaker for an atrioventricular block at . with brain functions and normal language, sensorial deafness, proximal and distal weakness in the four limbs with intense amyotrophies, predominantly distal. tactile and painful sensitivity decreased in glove and sock pattern. an extensive metabolic and biochemical study was normal. the electroneurography demonstrates an axonal neuropathy without response in most of the nerves explored. the electromyography shown a myogenic pattern with distal predominance. brain mri was normal in both cases. through a genetic study by exoma targeting genes associated with cmt and inherited related neuropathies was identified the homicigosis mutation in the aifm gene (p.glu lys), located in the chromosomal region xq . (cmtx ). cowchock syndrome is a rare entity, with few cases described in the literature. the in silico analysis indicates in of the predictors used (provean, sift, polyphen , lrt, mutationtaster, mutationassessor and condel) , that it is a deleterious variant. we audited all patients with peripheral neuropathy caused by a paraprotein, who received treatment and attended king's college hospital peripheral nerve service between - . patients were identified retrospectively from our database of patients attending the peripheral nerve outpatient clinic. clinical information was obtained retrospectively from hospital electronic patient records. we excluded patients with poems syndrome or in whom the neuropathy was not felt to be caused by the paraprotein. we identified patients with a diagnosis of paraproteinaemic neuropathy. we excluded four who did not fulfill the diagnostic criteria and eleven who had received no treatment or were under diagnostic study. we included patients in the final audit. ( %) had igm paraprotein. the haematological diagnosis was monoclonal gammopathy of undetermined significance (mgus) in %, waldenstroḿs macroglobulinaemia %, and lymphoma or plasmacytoma %. after treatment, overall ( %) patients improved neurologically, ( %) stabilised, and ( %) worsened. in the patients who received more than one type of treatment, we analysed outcomes according to the most powerful treatment received. patients received rituximab alone of which ( %) improved, ( %) stabilised and ( %) worsened. nine patients received rituximab combined with cyclophosphamide or bendamustine, of which ( %) improved, ( %) stabilized and ( %) worsened. eight patients received intravenous immunoglobulin, of which ( %) improved, ( %) stabilized and ( %) worsened. four patients received other chemotherapy, of which improved, stabilised, worsened. two patients received corticosteroids and both worsened. there was improvement in / ( %) with mag antibodies and / ( %) without. there was improvement in / ( %) with mgus and / ( %) with haematological malignancy. there was improvement in / ( %) with kappa light chains and / ( %) with lambda. factors associated with better outcome (by univariate analysis) were negative mag antibodies, kappa light chain, and haematological malignancy. there was no significant difference between treatments in the proportions who improved. cumberbatch m , cox a . addenbrooke's hospital, cambridge, uk. treatment of patients with autoimmune neuropathies such as chronic inflammatory demyelinating polyradiculoneuropathy (cidp) and multifocal motor neuropathy (mmn) has centred on the use of intravenous immunoglobulin (ivig). however, ivig therapy is associated with systemic side-effects, treatment wear-off effects and regular hospital attendance. subcutaneous immunoglobulin (scig) is an efficacious alternative that can be flexibly dosed, self-administered at home and avoids the 'peaks' and 'troughs' observed with ivig. these factors may combine to improve patient satisfaction and alleviate hospital capacity issues. here, we report on clinical and patient experience of switching from hospital-based ivig to home-based manual push scig for the treatment of cidp and mmn. this was a clinical case series of patients ( cidp, mmn; mean age . years) who were clinically stable on ivig and wished to switch to manual push scig. starting scig dose was equivalent to the final ivig dose for each patient (mean . g/kg week). clinical efficacy (medical research council sum score, -m walk, modified inflammatory neuropathy cause and treatment score, overall neuropathy limitations scale, romberg test) and patient-reported outcomes ( -item short form health survey , life quality index [lqi] ) were assessed at baseline and at regular intervals until the final visit ( - months after switching). at baseline, patients cited 'convenience' as their primary reason for switching to scig. eight patients completed the full assessment period and successfully undertook administrations at home (via hospital-at-home service in cases). dose adjustments, based on clinical need, were required in patients. treatment efficacy and patient quality of life, measured by sf- , were maintained after switching to scig; overall patient satisfaction, measured by lqi, increased from % to %. in the lqi, 'convenience', 'travel time/cost' and 'interference-work' were significantly improved (p< . ) after switching to scig therapy. adverse events included mild erythema and localised swelling, as expected for a ml subcutaneous injection. these findings suggest that manual push scig therapy is a viable alternative to ivig for patients with cidp and mmn, as it maintains disease stability, is more convenient for patients and may help ease hospital capacity concerns. cumberbatch m , soares regua d , cox a . addenbrooke's hospital, cambridge, uk. intravenous immunoglobulin (ivig) is used to treat a number of chronic autoimmune neurological diseases. in most centres, infusions are given at slow rates as there is a perception that this reduces the risk of adverse events (aes). this results in longer in-patient admissions, or frequent day case attendances, impacting on both the patients' quality of life and hospital capacity. however, there is little evidence to suggest that slow infusion rates are required. we used the manufacturer recommendations to optimise infusion rates and reduce the time patients spend in hospital. we report a retrospective audit which describes the impact of different ivig infusion rates on patients' clinical condition. the audit comprised three -month assessment periods: january-june (cohort ; infusion rates of . ± . ml/kg/hr, n = ); january-june (cohort ; . ± . ml/kg/hr, n = ) and july-december (cohort ; . ± . ml/kg/hr, n = ). clinical data were reviewed to determine: patient demographics, duration of infusion; time spent in hospital; and incidence of aes. the three cohorts were well matched in terms of patient demographics ( patients were treated in all treatment periods). cohorts and had significantly shorter treatment episodes than cohort ( . and . vs. . hours, p< . ), spent less time on the unit over the month period ( . and . vs. . hours, p< . ) and had fewer admissions/patient ( . and . vs. . , p< . ). the overall incidence of confirmed aes (mainly headaches) was similar across the cohorts (cohort : %; cohort : %; cohort : %). these findings indicate that increases in ivig infusion rate are well tolerated and significantly reduce treatment time, which benefits patients and offers potential cost savings and reduced pressures on hospital capacity for healthcare providers. cunningham me , yao d , meehan gr , barrie ja , willison hj . university of glasgow, glasgow, uk. one mechanism of injury in the acute motor axonal neuropathy (aman) form of guillain-barré syndrome (gbs) is the attack of peripheral nerve axons by anti-ganglioside antibodies (agabs). rodent models have demonstrated that that binding of these antibodies activates the complement cascade, resulting in the insertion of the terminal component, membrane attack complex (mac) into the axonal membrane. complement activation also results in the release of anaphylatoxins, which are known to recruit phagocytic immune cells to the site of injury. our current in vivo mouse model of agab and complement-mediated injury are acute and severe, resulting in respiratory distress over several hours of such magnitude to warrant termination of experimental procedures. to observe and potentially target immune cell infiltration following agab and complement-mediated injury, a subacute model extending over days is required. here, we demonstrate the development of such a model. to compare differences in immune cell infiltration subacutely under control and injury conditions, mice with endogenous expression of egfp in monocytes and macrophages underwent a modified agab and complement-mediated injury, resulting in a less severe phenotype than previously published models. six days following injury, immune cells in the diaphragm were compared by immunofluorescence and flow cytometry. flow cytometry found overall presence of neutrophils was significantly increased in the diaphragm. macrophages were also increased in injured mice, although did not achieve statistical significance at this timepoint. these results were reflected in immunofluorescent staining of the diaphragm where egfp+ macrophages were quantified surrounding the neuromuscular junction (the primary injury target in this model). the development of an extended mouse model of agab and complement-mediated injury is important, since acute models do not take into consideration either the late-term effects of complement-mediated activation at the nerve membrane, or the recovery phase. future studies will look at the effect of inhibiting complement activation on the presence of immune cells in distal motor nerves. family- is a large australian family with an autosomal dominant form of dhmn (dhmn : omim % ) -a group of length-dependent neurodegenerative disorders affecting the lower motor neurons leading to chronic disability. we recently reported a novel . mb chromosomal insertion within the dhmn locus which we hypothesise is likely to cause disease by dysregulating the expression of one or more nearby genes. studying gene dysregulation in peripheral nerve disease is challenging as the relevant tissues (spinal cord and peripheral nerve) are not easily accessible in patients. therefore, alternative strategies are needed to elucidate the disease mechanisms and pathways involved in peripheral nerve degeneration. to address this problem, we have devised a two-tiered strategy to assess dysregulation of candidate genes using patient lymphoblast and fibroblast cell lines. these cell lines can be easily established, are minimally invasive to obtain, and will harbour the natural mutation and genetic background of patients. our strategy firstly uses lymphoblast gene expression profiles as an initial screening tool to prioritise candidate genes for assessing altered expression. differentially expressed genes will then be modelled in c.elegans where behavioural and nerve morphology can be assessed. using rt-pcr, we have screened dhmn candidate genes in patient and control lymphoblast cell lines. eighteen candidate genes were expressed in lymphoblasts. twelve of the eighteen genes were prioritized for further analysis based on expression in both lymphoblast and neural tissues. quantitative analysis using qrt-pcr taqman assays revealed that ube c, was differentially expressed between patients and controls. it is important that patterns of differential expression can be recapitulated in neural cell-specific models. as part of our second strategy, we have generated patient and control induced pluripotent stem cell derived motor neurons (ipsc-mns) from reprogrammed fibroblasts. using this model, we will perform rna-seq and qpcr experiments to examine disease-relevant alterations in gene expression in neural tissue. we predict that utilization of these two strategies will shed light on the pathogenic mechanisms underlying the dhmn insertion and provide useful insights of pathways leading to peripheral nerve degeneration. the outcome of guillain-barré syndrome remains unchanged since plasma exchange and intravenous immunoglobulin were introduced over years ago. pathogenesis studies on gbs have identified the terminal component of complement cascade, the membrane attack complex, as a key disease mediator and thus a therapeutic target. the inhibition of complement in guillain-barré syndrome (ica-gbs) trial looked at the first use of c pathway inhibition with eculizumab in humans with gbs in a randomised, double-blind, placebo-controlled trial. its primary outcome was to look at safety and tolerability of administration concomitantly with ivig and in the context of severe (gbs disability score or greater) disease. participants were recruited for a month period, with regular follow up. subjects were screened, with ( %) being randomised. the two main causes for failure to proceed were participant concerns around eculizumab side effect profile, specifically the meningitis risk, and also intercurrent infection precluding treatment. five received eculizumab for four weeks, alongside standard intravenous immunoglobulin treatment, with receiving placebo. the safety outcomes, monitored via adverse events capture at each trial visit, showed eculizumab to be well tolerated and safe when administered in conjunction with ivig. the most common adverse events were mild derangement in transaminases or infection. there were no infusion reactions. primary and secondary efficacy outcomes were captured via gbs disability scores, mrc sum scores, rasch overall disability scores and overall neuropathy limitation scores. for the primary efficacy outcome at weeks after recruitment, of placebo and of eculizumab-treated subjects had improved by or more grades on the gbs disability score. all patients had improvements in other measured parameters. this trial highlights the challenges in recruiting acutely unwell patients, due to time constraints and intercurrent infection. although the small sample size precludes a statistically meaningful analysis, these pilot data indicate further studies on complement inhibition in gbs are warranted. charcot-marie-tooth disease (cmt) affects about one in . people. currently more than genes have been identified, with the most different phenotypes. the majority of cases in western countries are autosomal dominant and classified as demyelinating and axonal according to electroneuromyography (enmg). the clinical condition is characterized by weakness and predominant sensory changes in the feet and hands. sometimes there are different phenotypes. recently, variants in heterozygotes in the hars gene (histidil-trna synthetase) have been described associated with cmt called type w.to report a case of cmt-sensitive phenotype with a probable new mutation in hars gene (p.leu arg).a male patient, adopted son, caucasian, drug addict, for three years suffered pain in lower limbs, of great intensity, refractory to drug treatment. the examination showed retrognathism, abolition of patellar and achilleas reflexes, painful and thermal anaesthesia and apalesthesia in the feet.the enmg showed reduced sensory action potentials in sural and superficial fibular nerves. laboratory investigations for painful polyneuropathy of thick and fine fibres was normal. sural nerve biopsy revealed axonal predominance neuropathy. exome sequencing revealed a mutation in the hars gene with a pathogenic variant in heterozygosity, with replacement of the amino acid leucine at position by arginine. our patient, although we did not know the antecedents, presented painful polyneuropathy, whose genetic research, although not unequivocal, indicated a variant called cmt w. few cases of this variant were described, with several mutations. our case revealed mutation hitherto unknown (p.leu arg). we conclude by the importance of a thorough genetic evaluation, in cases of sensory polyneuropathy of unknown cause. small fiber neuropathy (sfn) is a condition that affects the small a -and c-fibers, leading to severe neuropathic pain and autonomic dysfunction. several sodium channel gene mutations have been found in patients with sfn, with scn a-gene mutations being the most frequent. because current available sodium channel blockers are not selective for na v . , these treatments often result in numerous side effects. lacosamide is an anticonvulsant that targets specific sodium channels with a slow-inactivation state, while sparing those with normal activity. several mutations of the scn a-gene with an impaired slow-inactivation of na v . have been found in patients with sfn. therefore, a positive effect of lacosamide on pain reduction in these patients is expected. the primary objective of this study was to determine the effect of lacosamide versus placebo on pain in subjects with scn a-associated sfn. secondary objectives were to determine the effect of lacosamide on autonomic symptoms, sleep interference, and quality of life, and to examine the safety and tolerability. the lacosamide-efficacy-'n'-safety in sfn (lenss) study was a randomized, placebo-controlled, double-blind, crossover-design study. subjects were randomized to start with lacosamide and end with placebo or vice versa. during both of the two phases of the study, the subjects were treated for a period of eight weeks of mg bid, preceded by a titration period, and ended by a tapering period. patients filled in a pain diary twice daily and scored a set of validated questionnaires on autonomic symptoms, sleep interference, and quality of life at multiple study visits. in total patients with scn a-associated sfn were included between november and february . the subjects had a median age of years, ranging from to years. sixty percent of the patients were female. the final results of the study, including the primary and secondary outcomes, will be presented. de la oliva n , del valle j , navarro x . department of cell biology, physiology and immunology, institute of neurosciences, universitat autònoma de barcelona and centro de investigación biomédica en red sobre enfermedades neurodegenerativas (ciberned), bellaterra, spain. intraneural interfaces must be in intimate contact with nerve fibres to have a proper function, but it has been shown that this is compromised due to the foreign body reaction (fbr). this fbr is the first response of the nonspecific immune system against an implanted device and is characterized by a first inflammatory phase followed by a second antiinflammatory and fibrotic phase. this process results in the formation of a tissue capsule around the interface causing function loss due to the physical separation between the active sites of the electrode and nerve axons. taking this into account, here we have tested several anti-inflammatory drugs such as dexamethasone, ibuprophen and maraviroc to reduce macrophage activation as well as clodronate liposomes to reduce monocyte/macrophage infiltration. moreover, sildenafil have been administered as an antifibrotic drug to reduce collagen deposition in a fbr model with longitudinal parylene c-based intraneural devices implanted in rat sciatic nerve. briefly, animals were systemically treated with dexamethasone, ibuprophen, sildenafil, maraviroc or clodronate liposomes for two weeks, and nerve damage, inflammatory reaction and matrix thickness around the implant were assessed. treatment with dexamethasone, ibuprophen or clodronate liposomes significantly reduced the inflammatory response in the nerve in comparison to saline group while sildenafil or maraviroc had no effect on iba positive cells infiltration in the nerve. however, only dexamethasone was able to significantly reduce the matrix deposition around the implant after two weeks of treatment. these results support the idea that inflammation triggers the foreign body response in peripheral nerves and a potent anti-inflammatory treatment with dexamethasone could have a beneficial effect on lengthening intraneural interfaces lifespan. de la oliva n , del valle j , navarro x . department of cell biology, physiology and immunology, institute of neurosciences, universitat autònoma de barcelona and centro de investigación biomédica en red sobre enfermedades neurodegenerativas (ciberned), bellaterra, spain. intraneural interfaces functionality decreases over time, among other factors, due to the foreign body response (fbr), which encapsulates the implanted devices and physically separates the active sites from the nervous tissue. here we have studied the fbr to parylene c or polyimide thin devices implanted in rat sciatic nerves, assessing thickness of the tissue capsule, signs of inflammation and nerve damage. we have characterized the responsible cells of this response and several molecular mediators over months of implant to find differences between the fbr to both materials. after weeks of implant, the inflammatory response due to the surgery was already decreased, whereas in the implanted nerves it reached its highest levels to then decrease at chronic time points. besides, the amount of foreign body giant cells (fbgc), as a result of macrophage fusion, found in the tissue capsule around the implant also increases progressively to reach a maximum after weeks. on the other hand, molecular analysis of the environment revealed a peak of inflammatory cytokines during the first day of implant to return to standard levels thereafter. however, an increase on ccls molecules was found at later time-points for both materials. with regard to the capsule thickness, all the devices were surrounded by a tissue deposition which appeared soon after the implantation. however, in the case of polyimide devices, the tissue capsule showed a peak weeks after the implant and signs of remodeling thereafter, while the parylene c devices showed a second increase from to weeks in comparison to polyimide devices. immunohistochemical and electron microscopy analysis revealed two different cell types implicated in the fbr in nerve to both materials: macrophages, in close contact with the interface, and fibroblasts which appear after weeks surrounding the tissue capsule. although further analyses are needed to elucidate the differences in the fbr to parylene c and polyimide polymers, these results can help to determine therapeutic targets in order to reduce this response and to improve the intraneural interfaces lifespan. delmont e , antoine jc , paul s , boucraut j , attarian s . referral centre for als and neuromuscular diseases, marseille, france; referral centre for neuromuscular diseases, saint etienne, france; immunology laboratory, saint etienne, france; immunology laboratory, marseille, france. peripheral neuropathies with antibodies against myelin associated glycoprotein (mag) are chronic sensory neuropathies characterized by the presence of an igm monoclonal gammopathy and high levels of anti-mag antibodies. these antibodies recognize a specific epitope called human natural killer (hnk ) shared by nk lymphocytes and several components of the peripheral nerve (mag, p , pmp , sgpg, phosphocan). recently an elisa test has been developed to detect antibodies against hnk epitope. our objectives were to determine the sensitivity and the specificity of anti-hnk antibodies in the diagnosis of anti-mag neuropathy and to know if these antibodies were correlated with the severity of the disease. anti-hnk antibodies were assessed in anti-mag neuropathies and in negative controls: chronic inflammatory demyelinating polyradiculoneuropathies (cidp), miller fisher syndromes, sensory neuronopathies, length-dependant axonal sensory polyneuropathies, healthy controls. in anti-mag neuropathies, were recorded age, disease duration, incat sensory sum score (iss), overall neuropathy limitation scale (onls), rasch-built overall disability scale (rods), mrc sum score, anti-mag antibodies titer, peak dosage of the igm monoclonal gammopathy. anti-hnk antibodies were measured with gangliocombi™ mag elisa test and anti-mag antibodies with anti-mag autoantibodies elisa test both from buhlmann company. anti-hnk antibodies were positive in / anti-mag neuropathies, and in / controls (sensitivity %, specificity %). in anti-mag neuropathies, anti-hnk titer was correlated with sensory deficiency evaluated with the iss score (r= . , p= . ) and with disability evaluated with the rods (r= − . , p= . ) and onls scales (r= . , p= . ). anti-hnk titers were not related to age, disease duration, mrc sum score, anti-mag antibodies titer, peak dosage of the paraproteinemia. anti-mag antibodies titers were associated with none of the characteristics of the patients with anti-mag neuropathy. anti-hnk antibodies have good sensitivity and specificity in the diagnosis of anti-mag neuropathy. compared to anti-mag antibodies, their value is that their titers are related to the disease severity. these results need to be confirmed in a larger prospective cohort. chronic inflammatory demyelinating polyradiculoneuropathy (cidp)is a heterogeneous and treatable immune-mediated disorder that critically lacks biomarkers to support diagnosis. recent evidences indicate that paranodal proteins (contactin- , contactin-associated protein- , and neurofascin- ) are the targets of autoantibodies in a subset of patients with cidp showing distinct clinical presentations. particularly, these biomarkers appear to have clinical relevance and help to orientate therapeutic choice. here, we examined five patients presenting an igg reactivity against the nodes of ranvier and the axon initial segment. using a proteomic approach, cell-based assays and elisa, we identified neurofascin- (nfasc ) and neurofascin- (nfasc ) as the main targets of autoantibodies at the nodes of ranvier. four patients displayed predominantly antibodies of the igg subclass, whereas one patient presented igg antibodies that activated the complement pathway in vitro. these antibodies recognized different epitopes than the previously described anti-neurofascin- igg suggesting different pathogenic functions. accordingly, patients with anti-nfasc / igg showed a distinctive clinical presentation. most patients had a severe phenotype associated with conduction block or decreased distal motor amplitude. tremors or neuropathic pain were not observed. four patients presented with a subacute-onset and sensory ataxia. of interest, the neuropathy occurred concomitantly with nephrotic syndromes in two patients and with an igg -related retroperitoneal fibrosis in one patient. this suggested that autoantibodies could be responsible for the occurrence of both disorders. intravenous immunoglobulin and corticosteroids were effective in three patients, and one patient improved following cyclophosphamide and rituximab treatment. clinical remission was found to correlate with the depletion of anti-nfasc / antibodies and the loss of igg reactivity toward the nodes of ranvier. in addition, recovery of conduction block and of distal motor amplitude were observed following remission and suggested a nodo-paranodopathy. our data demonstrate that nodal antigens are the target of autoantibodies in a subgroup of patients with cidp. this emphasizes that the pathogenic mechanisms involved in chronic immune-mediated demyelinating neuropathies are broad and may include dysfunctions of the nodes of ranvier. mutations in the neurofilament heavy (nefh) gene have been recently identified as a rare cause of autosomal dominant, axonal charcot-marie-tooth disease (cmt ). the clinical spectrum of this condition remains to be delineated. we report two french families with an axonal, predominantly motor, dominantly inherited form of cmt caused by two previously unreported mutations in the nefh gene. twelve patients belonging to two different families were included in the study. they displayed an axonal motor and sensory neuropathy, with no mutations in known axonal cmt genes. a remarkable feature in all patients was the early involvement of proximal muscles of the lower limbs, occurring approximately to years after the onset of motor deficit. proximal weakness affected predominantly the iliopsoas muscle, whereas quadriceps and hamstring muscles were relatively preserved. muscle weakness and muscle wasting progressed rapidly, with most of the patients requiring walking assistance after years of disease evolution. three patients in family had brisk reflexes. nerve-conduction velocity studies displayed evidence of a motor and sensory axonal neuropathy predominantly affecting the lower limbs. original deletions of nucleotides near the end of the coding sequence of nefh were identified: in family , c. _ del (p.lys argfs* ), and in family c. _ del (p.lys glyfs* ) causing a frameshift. interestingly, this frameshift leads to the loss of the terminating codon and to the translation of additional amino acids encoding a cryptic amyloidogenic element, suggesting that this type of mutations could induce protein aggregation. consistently, we showed that overexpression of the mutated forms of nefh in a human neuroblastoma cells induced the formation of protein aggregates. we also observed that it triggered caspase activation and apoptosis. using electroporation of chick embryo spinal cord, we confirmed in vivo that mutated nefh formed aggregates and triggered apoptosis of spinal cord neurons. altogether, this suggests that these mutations in nefh cause protein aggregation and neurotoxicity in neurons expressing nefh. progressive loss of such neurons would explain the early motor involvement and the pyramidal signs observed in some patients. our results provide a physiological explanation to the presence of cmt and als clinical features in affected patients. del valle j , , delgado-martínez i , righi m , santos d , , cutrone a , bossi s , d'amico s , micera s , , navarro x , . neuroprosthetic devices that are aimed to restore sensorimotor limb function of amputee patients require highly selective electrodes designed to establish a tight relationship with the nerve, allowing the bidirectional transduction of signals between nerve fibres and the interface and enabling close-loop control from the user. differently from extra-or intraneural interfaces, regenerative nerve electrodes are designed to enable electrical interface with regrowing axonal bundles of injured nerves, aiming to achieve high selectivity for recording and stimulation. however, most of the developed designs pose an obstacle to the regrowth mechanisms due to low transparency and cause an impairment of the nerve regeneration. in this work, we present a novel double-aisle planar regenerative electrode, a new type of highly transparent, non-obstructive regenerative electrode, which allows the selective stimulation and recording of separated nerve fascicles. the design consists of a thin and flexible double-sided electrode longitudinally inserted across a conduit thus creating two separated aisles in which regenerating fascicles can independently regrow after nerve transection. electrodes implanted in acutely transected nerves of rats showed the capability of selectively stimulating and recording different fascicles inserted in the aisles. moreover, chronic implantation of the electrode in a nerve gap of mm after sciatic nerve section allowed for fascicle regeneration and reinnervation of distal muscles as confirmed by the high number of myelinated axons inside each aisle, good biocompatibility, and adequate nerve conduction. in addition, three and six months after implantation, independent stimulation and recording of each separately regenerated fascicle were possible. our results demonstrate the potential contribution of the doubled-aisle regenerative electrode to selectively interface different fascicles of an injured nerve with no deleterious effects on nerve regeneration. therefore, this multi-aisle regenerative electrode may be suitable for neuroprosthetic applications, such as prostheses for the restoration of hand function after amputation or severe nerve injuries. demichelis c , garnero m , franciotta d , cortese a , callegari i , mancardi gl , schenone a , leonardi a , benedetti l . department of neuroscience, rehabilitation, ophthalmology, genetics, maternal and child health, university of genoa and irccs aou san martino-ist, genoa, italy; laboratory of neuroimmunology, irccs, "c. mondino" national neurological institute, university of pavia, pavia, italy; u.o. neurology, asl imperiese, imperia, italy. querol et al. showed that neurofascin (nf ) antibodies identify a chronic inflammatory demyelinating polyradiculoneuropathy (cidp) phenotype characterized by severe polyradiculoneuropathy, poor response to intravenous immunoglobulins (ivig), and disabling tremor. neurological improvement after therapy with rituximab has been previously reported in three patients with cidp with igg anti-nf antibodies. herein we describe the acute-onset of a case of cidp positive for nf igg antibodies resistant to conventional therapies and responsive to rituximab. the patient is a year-old woman who presented acute onset ataxia and gait disturbances; her symptoms progressed over two weeks and distal weakness, numbness and paresthesias appeared too. the nerve conduction study was suggestive for a motor-sensory polyradiculoneuropathy mainly demyelinating. the cerebrospinal fluid analysis showed elevated protein level and normal cellular count. the patient was initially diagnosed with guillain-barré syndrome (gbs) and treated with plasma exchange without improvement. an ivig cycle was started with a partial relief but at the time of admission to the rehabilitation center the patient still had a marked weakness in all four limbs. after six months she presented a further clinical deterioration and she was restricted to wheelchair. there was no response to additional treatment with ivig, while pulse corticosteroid treatment determined a significant clinical improvement. during the next months, despite the maintenance of steroid therapy, the patient presented a progressive deterioration and she was again restricted to wheelchair. postural and intention tremor appeared at upper limbs and became progressively more disabling. anti-nf ab dosage resulted positive. rituximab was administered at a dosage of mg/m /weekly for weeks. after three months the tremor improved, allowing her to eat independently and the patient was able to walk with bilateral support. antibodies anti-nf were negative. after six months she walked without support and she was able to stitch crochet. as previously reported, in this case a cidp positive for igg nf developed severe polyradiculoneuropathy with predominant distal weakness, ataxia, disabling tremor and resistance to conventional therapies. interestingly the onset was gbs-like. the correct identification of these cidp subtypes has diagnostic, prognostic and therapeutic implications. rituximab con be useful in these patients. demir Ö , yazıcı t . department of neurosurgery, university of gaziosmanpaşa school of medicine, tokat, turkey; department of neurosurgery, kent hospital, giresun, turkey. it is still challenging problem to maintain motor and sensory functions of peripheral nerve after nerve transection. after the nerve injury, calcium concentration in the damaged area increases. then the calcium ions act like cytotoxic agents in the damaged area. nifedipine is calcium channel blocker. we aimed to investigate the effects of nifedipine on nerve regeneration by modulating calcium in the damaged area. twenty-four swiss albino male rats were divided into two groups. left sciatic nerve transection surgery was performed to the all rats in both groups. then the all transected nerves were sutured primarily with epineural interfascicular method. in the experimental group, the anastomosis sites were wrapped with a piece of gel foam soaked into diluted nifedipine solution. in the control group, the anastomosis sites were wrapped with a piece of gel foam soaked into saline solution. we evaluated the effect of nifedipine by using functional, electro-physiological and histopathological studies after the surgeries. in the postoperative second week, walking test was performed and sciatic function index was calculated. in the postoperative third week electroneuronography (enog) was performed. there are significant differences between two groups. nifedipine improved nerve recovery functionally (p< . ) and electro-physiologically (p< . ). in the postoperative fourth week, we performed histopathological examination. in the experimental group with nifedipine there were more organized axons that reached the aim. we conclude from these results that nifedipine is an effective nerve protective agent when used locally at the anastomosis site after the transection of the nerve. the lack of effective, disease-modifying therapies for cmt highlights the need for novel preclinical models suitable for drug discovery. studies in rodent models of cmt tend to be time-consuming, and findings so far have translated poorly into clinical trials. primary and induced pluripotent stem cell (ipsc)-derived neuronal cultures are an established model of neurological diseases. however, due to the random distribution of neuronal bodies and neurites that happen when plating these cells, this system is not ideal to investigate axonal, length-dependent processes like peripheral neuropathies and particularly cmt. to optimize this well-established model system, we developed a robust human platform to study axonal morphology and physiology based on motor neuron neurospheres. we differentiated motor neurons from human induced pluripotent stem cells, purified them by magnetic sorting and cultured them in suspension until they formed neurospheres. floating neurospheres can be maintained in agitation for months as a reliable source of motor neurons. after neurospheres are platted, axons rapidly grow out of them in a radial fashion, resembling dorsal root ganglia cultures. this configuration allows for a better visualization of axons in imaging studies and for continued axonal growth over at least a -day period. axons grew at an average rate of micrometers/day and reached up to cm in length. neurospheres can be fixed and stained allowing for morphological analysis and investigation of protein distribution in axons. this system is also ideal for time-lapse imaging to study axonal transport of organelles and neurofilament kinetics. lastly, our motor neuron neurosphere system lends itself well for high content screening platform. neurospheres can be plated in -well plates where multiple compounds can be tested and the axons easily imaged by a high content screening microscope. in summary, we developed a new platform to investigate motor axons in vitro, which are particularly useful to study length-dependent processes such as inherited peripheral neuropathies and may facilitate the identification of new therapeutic compounds using high content screening systems. mutations in the neurofilament light chain (nfl) gene cause autosomal dominant axonal charcot-marie-tooth neuropathy (cmt e). nfl is a major component of the neuronal cytoskeleton, and is believed to function in conjunction with nfm and nfh to provide structural support for the axon and regulate axon diameter. despite the significant advances in understanding its biological basis, there is still no effective, disease-modifying therapy for cmt e, in part due to the paucity of preclinical models suitable for drug discovery. the development of novel preclinical platforms that can faithfully mimic mechanisms of axonal degeneration in vitro would be an essential and valuable resource to better understand the biology of cmt e and identify potential targets for therapy development. to address this, we generated control and cmt e patient-derived motor neurons and cultured them in suspension until they formed neurospheres. immunostaining of cmt e neurospheres with nfl and tubb antibodies revealed numerous areas of nfl accumulation in n s cmt e axons, resembling the accumulations of mutant nfl protein seen in the processes of catecholaminergic neuronal cell line cad overexpressing several nfl mutants. further analysis demonstrated that areas of nfl accumulation were also immunopositive for nfh, pnfh and nfm and that at least nfl and nfm co-localized in the same areas of deposits. taken together, these results demonstrate that abnormal axonal neurofilament distribution is a feature of cmt e ipsc-derived motor neurons and involve all three neurofilament subunits. we also developed an image analysis routine to allow for automatized quantification of neurofilament distribution. preliminary quantification of nfl signal intensity revealed that axons from patients have a weaker nfl signal compared to control axons, but present several signal peaks above the range observed in controls, which related to the areas of nfl accumulation. these results suggest that nfl accumulates in certain regions of cmt e axons but is reduced in the areas with no accumulation. these findings can be readily adapted into a high content screening platform and will be used to identify compounds able to reverse this axonal phenotype. in summary, we identified a strong axonal phenotype in human cmt e motor neurons with potential as a screening platform for drug discovery. nodal and paranodal proteins have been identified as antigens in peripheral inflammatory neuropathies, however the frequency and clinical relevance of antibody responses against these targets remain poorly investigated in gbs. patients with acute onset inflammatory neuropathies were identified by exploration of the local databases of the departments of neurology and the institute of neurology of the medical universities in innsbruck and vienna. patient data, electrophysiological classification and presence of anti-gangliosid antibodies were retrospectively retrieved by review of patient records. only patients with typical clinical presentation and electrophysiological results consistent with one of the subtypes of gbs were included in the study. among forty-nine patients, thirty-five were classified as aidp, six aman, three amsan, three mfs, and two pharyngo-cervico-brachial gbs. of the included patients had anti-ganglioside-antibodies. ten patients with the initial suspicion of aidp had a disease duration of more than months and were reclassified as cidp. all patient and twenty sera of control patients with non inflammatory polyneuropathy were screened by an optimized tissue based assay using rat brains for immune responses against surface antigens, and by cell-based assays with transfected hek cells for antibodies against contactin (cntn ), contactin (cntn ), contactin-associated-protein (caspr ) and neurofascin- (nf ). in the tissue based assay some of the patients showed a light neuropil staining. none of gbs patient's sera had antibody reaction to cntn , cntn , caspr or nf in cell-based assays. among the cidp patients, two patients demonstrated reactivity against cntn with similar clinical presentation as previously described. none of the control patients had any antibody reaction to the performed tests. our results suggest that antibody responses to cntn , cntn , caspr or nf are absent in austrian gbs patients, although more patients will be screened to substantiate these preliminary results. furthermore, it remains to be established whether antibodies against cntn may predict a chronic course in acute onset inflammatory neuropathies. a few variants of chronic inflammatory demyelinating polyradiculoneuropathy (cidp) have been described with a frequency of - %. their relation and possible evolution into typical-cidp remain unclear, as is their treatment response possibly because of differences in diagnostic criteria. we used the data from a web-based database on italian patients with cidp to determine the frequency and characteristic of these variants, the possible evolution into typical-cidp, and their treatment response. all the patients were assessed at study entry and the disease course before inclusion was analyzed. by february- , we included patients ( men, women), aged - years (median years) with a mean disease duration of . years (range . - years) and complete data available from . based on the clinical data and our revised diagnostic criteria, patients ( %) were classified to have atypical cidp at onset and for the following two years including with dads ( %), with motor cidp ( %), with sensory cidp and cisp ( . %), with lewis-sumner syndrome ( . %), and with recurrent cranial neuropathy. at study entry, patients ( %) had progressed into typical cidp after - years (median years) while ( %, % of total) still had atypical cidp after . - years (median years) with a similar proportion of progression ( - %) within each group. the diagnosis of atypical cidp at entry fulfilled efns/pns criteria in ( %). csf studies were diagnostic in / ( %) patients, nerve biopsy in / ( %), and nerve imaging in / ( %) tested patients. similarly to typical cidp, % of treated patients with atypical cidp improved after treatment with a proportion of response varying from % to % in the different forms. most patients with sensory or motor cidp had however an unsatisfactory response to steroids. this study shows that he proportion of patients with atypical cidp varies during the course of the disease with almost % of the patients evolving into typical cidp within years from onset. in addition, response to treatment is frequent in atypical cidp even if not all the forms respond to the same therapies. only few studies investigated the frequency of antecedent events and comorbidities in patients with chronic inflammatory demyelinating polyradiculoneuropathy (cidp), and little is known on the role of possible predisposing factors, dietary, and lifestyle habits, on the onset and progression of the disease. we used the data from a web-based database on italian patients with cidp to determine the frequency of antecedent events and comorbidities and the possible role of predisposing factors including lifestyle and dietary habits and exposure to toxic agents, using a structured questionnaire. partners of patients served as controls. impairment was evaluated using the mrc sumscore and disability with incat and r-ods scales. logistic regression was used to calculate odds ratio (or) with % confidence interval (ci) for the risk of cidp. sex and disease-duration were included as covariates. by february- , patients were enrolled, with complete data on patients for antecedent events and comorbidities and patients and controls for lifestyle habits. ninety-two patients ( %) reported an antecedent event, mostly infection or vaccination ( %). one or more comorbidity were present in % of the patients including hypertension ( . %), thyroid disorders ( %) and diabetes ( . %) and in % influenced the choice of initial therapy. exposure to toxic environmental agents (odds ratio [or] = . ; % ci, . - . ), cigarette smoke (or = . ; % ci, . - . ), and dietary supplements (or = . ; % ci, . - . ) were associated with a higher risk of cidp while rice consumption was associated with a reduced risk (or = . ; % ci, . - . ). concerning disease severity, more severely affected patients more frequently consumed raw-meat (or = . ; % ci, . - . ) and white meat (or = . ; % ci, . - . ), while rice (or = . ; % ci, . - . ) and soft drink consumption (or = . ; % ci, . - . ) and physical activity were associated with lower disability (or = . ; % ci, . - . ). this study confirms that comorbidities are frequent in patients with cidp and often influence the choice of initial therapy. in addition preliminary data show that toxic exposure and some lifestyle and dietary habits may influence the onset and progression of cidp. doppler k , schuster y , weishaupt a , sommer c . department of neurology, university hospital würzburg, würzburg, germany. autoantibodies against the paranodal protein contactin- have recently been described in patients with cidp. in most patients, autoantibodies of the igg subclass are predominant and are supposed to be pathogenic. the role of igg anti-contactin- is so far unclear. in the present study, igg of three different patients, one with igg anti-contactin- , one with a low titer of igg anti-contactin- and one with a high titer of igg anti-contactin- , and of controls were injected into the sciatic nerves of lewis rats. nerve conduction studies of the injected nerve and motor and sensory testing were performed before and after injection. conduction blocks and motor deficits were detectable in the two patients with high titers of igg and igg , not in the patient with low titers. the percentage of conduction blocks was . % in rats injected with igg of the igg patient and % in those injected with igg . motor deficits were detectable in both patients with conduction blocks but were most apparent in the patient injected with igg of the igg patient. no differences in sensory testing were observed. conduction blocks and motor deficits improved after five days and were normal after seven to eight days. our data give the first evidence of pathogenicity of igg anti-contactin- autoantibodies, not only igg . igg of the igg patient induced a more severe clinical and electrophysiological phenotype compared to the igg patient. remarkably, this reflected the clinical phenotype of the patients, as the igg patients showed an acute-onset of sensorimotor symptoms at the time of blood withdrawal whereas the igg patient presented with a more chronic course of disease. doppler k , frank f , koschker a-c , reiners k , sommer c . department of neurology, university hospital würzburg, würzburg, germany; endocrinology and diabetes unit, department of medicine i, university hospital würzburg, würzburg, germany. axoglial dysjunction and paranodal demyelination have been discussed as potential mechanisms of nerve fiber damage in diabetic neuropathy. studies on human tissue are limited, as nerve biopsies are invasive and only rarely performed in patients with confirmed diabetic neuropathy. skin biopsy has recently been suggested as a good tool to analyze paranodal and nodal changes of myelinated fibers. in the present study, we analyzed the paranodal and nodal region in myelinated fibers of skin biopsies of patients with diabetic neuropathy, patients with diabetes mellitus without neuropathy, and normal controls. immunofluorescence of skin sections with antibodies against caspr, neurofascin, sodium channels and myelin basic protein was performed to assess paranodal/nodal architecture, segmental demyelination and myelinated nerve fibers. staining with antibodies against protein gene product . was used to quantify unmyelinated nerve fibers. we found an increase of elongated ranvier nodes and a dispersion of neurofascin at the distal leg in patients with diabetes mellitus with and without neuropathy and at the finger in patients with diabetic neuropathy. an increased dispersion of caspr was only found in biopsies of the finger in patients with diabetic neuropathy. our data show that skin biopsy is an appropriate tool to analyze nodes of ranvier in patients with diabetes mellitus. structural nodal changes are detectable in diabetic neuropathy, and even in diabetic patients without neuropathy. dourado me , fernandes u , vital al , ramos e , urbano jc , sena a , queiroz jw , jeronimo smb . federal university of rio grande do norte, natal, brazil. the erasmus gbs outcome score (egos) is a validated prognostic model that uses acute phase and easy-to-obtain clinical characteristics to determine outcome at months in patients with gbs. this study aims to assess the validity of egos in rio grande do norte, brazil, and to compare with another european study. data collected prospectively from a cohort of patients with gbs of rio grande do norte, brazil, between june and august , was assessed. ninety patients were excluded for missing data or diagnoses of miller fisher syndrome and atypical forms of gbs. to calculate the egos, the gbs disability score was assessed in the second week of disease and at months. to compare this study with the european one in independent group proportions, we used the student's t-test, being considered statistically significant p< , . the patients included were divided in four groups based on egos. thus, patients had egos between and ; had egos between . and . ; had egos and had egos between . and . in the first, second, third and fourth group, ( %), ( . %), ( . %) and ( . %) of the patients were unable to walk independently after six months of the disease, respectively. overall, of the patients analyzed, ( . %) had poor outcomes in this study. in the european paper, based on the same group division, of ( . %), of ( %), of ( %) and of ( %) were unable to walk independently. comparing both studies, the patients of this study were younger, more seriously ill in the first weeks and with more sensitive deficits. there were no difference relative to sex, cranial nerves deficits and presence of anti-gangliosides antibodies. using the student's t-test for ability to walk after months according to egos stratification, we achieve in the first group p= . ; in the second p= . ; in the third p= . ; and in the fourth p< . .the egos did not have a good capacity to predict the ability to walk after months of gbs in rio grande do norte, brazil. historically, guillain-barré syndrome (gbs) epidemics are rarely seen. between and , we treated and followed cases of gbs in the state of rio grande do norte with a yearly incidence of . / , . no seasonality was observed. the mean age of the patients was years (range, - ), with % of the cases younger than years. demyelinating variant was the most frequent subtype of gbs. in march , the first report of autochthonous transmission of zika virus (zikv) was determined in natal, brazil. later that month, we documented an increase in incidence of gbs in natal, brazil. the incidence in was of . / . . of the cases of gbs diagnosed in , were diagnosed from march through may, which coincided with the outbreak of zikv in natal, brazil. eighteen patients ( % of the cases) had a history of rash and fever prior to onset of gbs symptoms, with the median age of years (range, - ) . the electroneuromyography studies of these patients indicated that ( . %) had acute inflammatory demyelinating polyneuropathy, ( . %) had acute motor axonal neuropathy, and ( . %) was inconclusive. the mean time from onset of zikv infection symptoms to onset of the gbs were days (range, - ). the mean time of nadir was days (ranged, - ) . cranial neuropathies were present in patients ( . %). nine patients were bedridden ( %) and ( . %) required mechanical ventilation. the mean protein content of the central spinal fluid was . g/l, with the white blood cell count below /mm in all patients. they were all treated with intravenous igev. they all improved quickly. anti-gm was negative in all patients. rt-pcr was negative for dengue, chikungunya and zika. serum mac-elisa igm for zika and dengue was made in patients and it had % of positivity. prnt for zika and dengue had % positivity. in summary, we report a geographically and temporally defined cluster of gbs associated with an outbreak of acute rash in the state of rio grande do norte, brazil. as the prevalence of diabetes mellitus continues to increase worldwide, diabetic complications represent a growing burden to patients and society. distal symmetrical polyneuropathy (dsp) is a common complication that affects up to % of diabetic patients. dsp reduces patient quality of life due to chronic pain, ulcerations, and may lead to lower extremity amputations. despite its high prevalence, the mechanisms underlying diabetic dsp are poorly understood and several mechanisms are believed to play a role. we hypothesize that diabetic dsp arises from microvascular complications characteristic to diabetes. specifically, capillary dysfunction -disturbances in capillary flow patterns -is a likely candidate to explain development of dsp, as it can limit oxygen and nutrient delivery to nervous tissue, causing nerve dysfunction and damage, and thus development of dsp. we will study this hypothesis utilizing the state-of-the-art blood flow imaging techniques to visualize and quantify endoneureal blood flow and then link these findings with measures of dsp (e.g. nerve conduction velocity; intra-epidermal nerve fibre density) in animal models. we will include several animal models of diabetic dsp caused by either type or type diabetes. two photon microscopy and optical coherence tomography allow visualisation and quantification of capillary transit times and blood flow within peripheral nerves at high resolution. we hypothesise that changes in blood flow patterns and subsequent impairment of nutrient and oxygen delivery to nervous tissue precede the onset of diabetic dsp. if our experiments support this prediction, we will attempt to develop interventions that improve capillary blood flow to prevent or delay the development of dsp. duman o , saracoglu m , haspolat s , bozkurt o . department of child neurology, akdeniz university hospital, antalya, turkey. axonal polyneuropathies are very heterogeneous group of diseases which are very rarely seen during infantile age. some of them may be accompanied by developmental retardation, severe muscle weakness and progressive course. we aimed to present two cases of axonal sensorymotor neuropathy with infantile onset and atypical course. our -year-old boy patient was admitted to our clinic for progressive gait loss since one month. he was the first offspring of consanguineous parents with normal prenatal and natal history. electromyography revealed axonal sensorymotor polyneuropathy. metabolic and cerebrospinal fluid (csf) examinations for etiology were all normal. brain and spinal magnetic resonance imaging (mri) were normal. he had partial benefit from oral steroid treatment. in the course of disease along with four neuropathy attacks he had significant benefit from serial intravenous immunoglobulin treatments in two years clinical course. a month-old girl who is the first offspring of nonconsanguineous parents was admitted to the clinic for acute tetraparesis. axial sensorymotor polyneuropathy was detected in the electromyography. metabolic and cerebrospinal fluid (csf) examinations were normal. she had three more acute polyneuropathy attacks during ivig cessation period. both patients revealed with serial immunoglobulin treatments but unresponsive to riboflavine treatment. we aimed to discuss our rarely seen and the pathogenesis is not completely understood cases' course. serial ivig treatment may be helpfull for such patients' treatment. transthyretin-related familial amyloid polyneuropathy (ttr-fap) is an autosomal dominantly inherited disorder caused by mutations of the transthyretin (ttr) gene. the mutant amyloidogenic transthyretin protein causes the systemic accumulation of amyloid fibrils that result in organ dysfunction. ttr-associated fap is a progressive and fatal disease, if left untreated, and should be considered in the differential diagnosis of any person presenting with a progressive polyneuropathy, particularly with accompanying autonomic involvement. the clinical, electrophysiological, histopathological, and genetic characteristics of patients from turkey ( female, male) from eleven families with polyneuropathy and mutations in ttr were evaluated. two patients had no family history of ttr-fap and were considered as sporadic cases, and the remainders were familial cases displaying an autosomal dominant inheritance pattern. sequence analysis of the ttr gene revealed five mutations (p.val met, p.glu gln, p.gly glu, p.glu gly and p.gly glu). most common mutation was p.val met (in unrelated families). mean age at disease onset was . ± . years (range - years). the most commonly reported initial complaint was paresthesia in the feet (asymmetric in three patients). four patients ( male) with the p.glu gln mutation presented with carpal tunnel syndrome. two patients with the p.gly glu mutation showed episodes of dysarthria and hemiparesis, consistent with this genotype. seven patients died during the follow-up period as a result of systemic involvement. this study suggests that our cohort of ttr-fap patients from turkey exhibits clinical and genetic heterogeneity. ebenezer gj , liu y , judge dp , cunningham k , truelove s , carter nd , sebastian b , byrnes k , polydefkis m . department of neurology, johns hopkins university, baltimore, md, usa; division of cardiology, johns hopkins university, baltimore, md, usa; department of epidemiology, johns hopkins bloomberg school of public health, baltimore, md, usa. effect of amyloid deposition on cutaneous nerves was assessed in subjects with pathogenic ttr variants and control subjects. three groups of subjects each including ttr-fap patients, age/gender-matched healthy subjects and disease controls as well as ttr mutation carriers without neuropathy (ttr-nopn) and with al-amyloid underwent neurological examination and mm skin biopsies. micron sections were stained with anti-pgp . , anti-ttr and congo red. amyloid burden with imagej, intraepidermal (ienfd) sweat gland (sgnfd) and pilomotor densities (pmnfd) measured and correlations between amyloid burden, fiber subtype, neuropathy impairment score-ll (nis-ll) and nis sensory subscore were evaluated. ienfd, sgnfd, and pmnfd were all significantly reduced in ttr-fap patients vs. healthy controls while mutation carriers had intermediate reductions. lower nerve fiber densities were associated with nis-ll (p< . ). congo red staining revealed brilliant red amyloid deposits with apple-green birefringence within dermal collagen, sweat glands, and arrector pili muscles. amyloid infiltration was observed in the endoneurium and perineurium of small fiber sensory and autonomic nerves that innervate sweat glands and arrector pili muscles. cutaneous amyloid deposition was detected in % of ttr-fap and not in healthy or disease controls subjects. both al and / ttr-nopn subjects were congo red positive. amyloid burden was inversely correlated with ienf (p< . , r=− . ) sgnf (p< . , r=− . ), pmnf (p= . , r=− . ) distal leg densities, and correlated with nis-ll (p= . , r= . ) and nis sensory subscore (p= . , r= . ). wild-type ttr staining was less prominent in pathogenic ttr carriers. the diagnostic sensitivity and specificity to detect amyloid in skin were % and % in ttr-fap. the repeat measurement of the amyloid burden from the same section with imagej was r = . , p< . and different sections from the same biopsy was r = . and p< . . we conclude that endoneurial amyloid contributes to sensory and autonomic nerve injury. amyloid burden correlated strongly with sensory/autonomic axon densities and nis-ll. skin punches offer a convenient alternative to establishing a tissue diagnosis. amyloid burden is an attractive biomarker marker for ttr-fap and treatment effect. the study was supported through a grant from pfizer. ebenezer gj , truelove s , polydefkis m . department of neurology, johns hopkins university, baltimore, md, usa; department of epidemiology, johns hopkins bloomberg school of public health, baltimore, md, usa. we investigated differences of unmyelinated sensory nerve fibers in the distal limb among healthy-weight subjects (bmi < kg/m ) and overweight/obese subjects (bmi ≥ kg/m ), aged - years. subjects underwent neurological examination and mm skin punches from distal leg (dl), thigh (dt), and proximal thigh (pt) sites, from which micron sections were stained with anti-pgp . antibody; intraepidermal nerve fiber density (ienfd; fibers/mm) and epidermal thickness were assessed. a second dl biopsy was processed for electron microscopic examination and both thick and thin sections were examined for ultrastructural changes. multivariable linear regression models were used to assess the effect of age, gender, height and weight. after controlling for height, age, and obesity, females were found to have lower distal leg ienfd (− . ; p= . ). increasing age and height were significantly associated with decreasing dl ienfd, with decreases of − . fibers/mm per years (p<. ) and − . fibers/mm per cm (p< . ), respectively. even after controlling for height, being overweight/obese was associated with reduced dl ienfd, with . fibers/mm lower dl enfd than healthy-weight individuals (p=. ). these findings remained consistent across distal thigh and proximal thigh enfd, though not all associations remained significant. the epidermis was thicker in obese subjects across the lower limb, most pronounced at the distal leg (μm, mean± sd, healthy-dl: ± . , dt: . ± . , pt: . ± . , obese-dl: . ± . , dt: ± . , pt: . ± . ). under em very few intact dermal nerve bundles were identified at the proximal thigh sites. the atrophic and degenerating axons were seen with perineurial infiltration by dense collagen in obsess/overweight subjects but not age/gender matched controls. obesity further accelerates attenuation of epidermal nerve fibers across the lower limb even after controlling for other associated factors. echaniz-laguna a , geuens t , petiot p , péréon y , adriaenssens e , haidar m , capponi s , maisonobe t , fournier e , dubourg o , degos b , salachas f , lenglet t , eymard b , delmont e , pouget j , juntas morales r , goizet c , latour p , timmerman v , stojkovic t . strasbourg university hospital, strasbourg, france; peripheral neuropathy group, vib department of molecular genetics and institute born bunge, university of antwerp, antwerpen, belgium; lyon university hospital, lyon, france; nantes university hospital, nantes, france; hôpital de la pitié-salpétrière, paris, france; nice university hospital, nice, france; marseille university hospital, marseille, france; montpellier university hospital, montpellier, france; bordeaux university hospital, bordeaux, france. in this study, we describe the phenotypic spectrum of distal hereditary motor neuropathy caused by mutations in the small heat shock proteins hspb and hspb and investigate the functional consequences of newly discovered variants. among unrelated patients with distal motor neuropathy, we identified mutations in hspb ( index patients/ ; . %) and hspb ( index patients/ ; . %) genes. patients have slowly progressive distal ( %) and proximal ( %) weakness in lower limbs, mild lower limbs sensory involvement ( %), foot deformities ( %), progressive distal upper limb weakness ( %), mildly raised serum creatine kinase levels ( %) and central nervous system involvement ( %). we found a broad range of disease onset with some patients presenting with foot drop at the age of years, and others presenting symptoms only after years. disease progression was slow in all patients, and even with a disease duration of more than years patients were still able to walk. none of our patients were wheelchair dependent. muscle pathology, nerve pathology and electrophysiology showed in all cases a slowly progressive, mostly symmetrical and predominantly distal motor axonal neuropathy. mild sensory involvement was observed upon nerve conduction studies, mostly the lower limbs, in % of cases. we identified hspb and hspb mutations, including respectively and not previously reported. transmission was either dominant ( %), recessive ( %) or de novo ( %). three missense mutations in hspb (pro ser, gly asp, gln arg) cause hyperphosphorylation of neurofilaments, while the c-terminal mutant ser leu triggers protein aggregation. two frameshift mutations (leu fs, ala fs) create a premature stop codon leading to proteasomal degradation. two mutations in hspb (lys met/asn) exhibited increased binding to bag . we demonstrate that hspb and hspb mutations are a major cause of inherited motor axonal neuropathy. mutations lead to diverse functional outcomes further demonstrating the pleotropic character of small heat shock proteins. eftimov f , querol l , rajabally ya and on behalf of all participants of the st enmc workshop. academic medical center, amsterdam, the netherlands; hospital de la santa creu i sant pau, universitat autònoma de barcelona, spain; aston university, birmingham, uk. although chronic inflammatory demyelinating polyneuropathy (cidp) is a treatable neuropathy further research is urgently needed to define the diagnostic clinical and electrophysiological boundaries of cidp and its subtypes, and to define the role of biomarkers in supporting the diagnosis, monitoring disease activity and predicting response to treatment and outcome. in recent years, several national registries and biobanks have been developed to enable systematic data collection in cidp. an international registry with large number of patients is needed to allow answering many important questions and develop validated prognostic models to predict outcome in individual patients with cidp. at the inflammatory neuropathy consortium (inc) meeting in , the inc members agreed that a european neuromuscular center (enmc) workshop would be the ideal setting to reach a consensus on the infrastructure of database and biobanks. the st enmc workshop will take place on may - , with participants representing different countries. primary objective of the workshop is to reach a consensus on inclusion and exclusion criteria, core sets and recommended sets of clinical data, diagnostic data and follow-up points and a manual of operations for collection of biomaterials. a secondary objective is to construct an infrastructure to allow sharing data between different databases and biomaterials. conclusions of the consensus meeting and outline of further perspectives will be presented at the peripheral nerve society meeting in . eichinger kj , burns j , cornett k , bacon c , shepherd m , mountain j , sowden j , shy r , shy me , herrmann dn . clinical outcome assessments that measure functional ability are important endpoints for clinical trials. dr. burns has led the development/validation of a functional outcome assessment (cmtpeds) for individuals with charcot marie tooth disease (cmt) ages - years in the inc rdcrn. the cmtpeds is reliable and sensitive to change. however a validated functional outcome measure (fom) for adults with cmt is needed. our data in - year-olds indicated that the cmtpeds could be modified for adult use. however, some items of the cmtpeds (e.g. balance beam and jumping) have floor effects in adults with cmt. we have developed an adult cmt-fom modeled on the cmtpeds, and refined based on literature review, patient interviews, a large-scale cmt patient survey and expert opinion. the cmt-fom is a performance-based scale comprising items that are combined to form a composite score to quantify functional ability of adults with cmt. the cmt-fom shares items with the cmtpeds. four items were added to measure functional abilities relevant to adults (sit to stand, meter walk/run, stair climb, and timed up and go test). the cmt-fom scoring mirrors the cmtpeds. to generate a score ranging from - , raw item scores are converted to z scores, based on age-and sex-matched normative reference values form the norms project and categorized to a - likert along a continuum of impairment levels. we have conducted a pilot study of the cmt-fom in adults with cmt a ( male, female, age . ± . yrs) of differing severity (cmt exam score (cmtes) range - ). the cmt-fom is feasible, individuals were able to complete all items, and takes minutes to perform. the mean cmt-fom score was . ± . (range - ). concurrent validity of the cmt-fom is supported by an association with the cmtes (r = . ). the overall score did not demonstrate floor or ceiling effects. in summary the adult cmt-fom is well-tolerated and captures upper and lower limb strength, dexterity, balance, speed, ambulation and endurance. the cmt-fom requires validation in a large longitudinal cohort, prior to application in clinical trials. estilow t , glanzman am , burns j , cornett kmd , menezes mp , shy r , moroni i , foscan m , pagliano e , pareyson d , laurà m , bhandari t , muntoni f , reilly mm , finkel rs , sowden j , eichinger k , herrmann dn , shy me , yum sw , ramchandren s and on behalf of the inherited neuropathies consortium. cmt is associated with progressive impairment of the hands. reducing this impairment by treating children who are in the early stages of the disease is crucial. studies assessing measures of cmt hand function in children and their associations with patient-reported outcomes are lacking. we analyzed the upper extremity items from the cmt pediatric scale (cmtpeds) and pediatric cmt quality of life scale (pcmt-qol) in children ages - years enrolled in the inherited neuropathies consortium, to explore the relationships between measures of hand function (impairment, activity, and activities of daily living), and patient-reported outcomes. weak grasp ( %), hand pain ( %), and tremor ( %) were prevalent impairments. performance on activity level tasks, the nine hole peg test ( hpt) and functional dexterity test (fdt), were impaired in % and % of the cases, respectively. patients reported difficulty "sometimes" to "always" in opening a jar/lid ( %), zipping/buttoning ( %), writing ( %), carrying a plate without spilling food ( %) and putting on shoes ( %). patients reporting tremor showed significant differences on the hpt (p=. ). grip strength was shown to have a moderately significant correlation with performance on the fdt (r=. ; p<. ). stepwise multiple linear regression showed that grip strength (beta=−. ; p<. ), hand pain (beta=. ; p<. ) and fdt (beta . ; p<. ) were predictive of ability to open a jar (adjusted r =. ; p<. . grip strength (beta=−. ; p<. ), and fdt (beta . ; p<. ) were predictive of ability to carry plate without spillage (adjusted r =. ; p<. ). grip strength (beta=−. ; p<. ), hpt (beta=. ; p<. ) and fdt (beta . ; p<. ) were predictive of ability to put on shoes (adjusted r =. ; p<. ). hand pain (beta=. ; p<. ) and fdt (beta . ; p<. ) were predictive of ability to zip/button (adjusted r =. ; p<. ). hand pain (beta=. ; p<. ) and hpt (beta . ; p<. ) were predictive of ability to use a pen/pencil (adjusted r =. ; p<. ). children with cmt present with frequent limitations in adl performance impacting qol. the upper limb measures of the cmtpeds are associated with hand performance and interventions to improve grip strength and reduce pain should be investigated further with respect to their impact on improving function, and ultimately qol. evans me , morrow jm , wastling s , sinclair cdj , fischmann a , shah s , emira ak , hanna mg , yousry ta , thornton js , reilly mm . mrc centre for neuromuscular diseases, ucl institute of neurology, london, uk; neuroradiological academic unit, ucl institute of neurology, london, uk; university of basel hospital, basel, switzerland. responsive outcome measures are needed in charcot-marie-tooth disease (cmt) to allow adequately powered clinical trials to test novel therapeutics. we have shown high responsiveness of mri quantified intramuscular fat accumulation in calf muscles of cmt a patients over months. the aim of the present study was to assess the responsiveness and longitudinal validity of quantitative mri over a year follow-up period. we undertook two further sets of quantitative mri, myometric and clinical assessments in the original mrc centre cmt a quantitative mri cohort. mri sequences included fat quantification using the point dixon fat-water separation method, t quantification and magnetisation transfer imaging. of the patients with genetically confirmed cmt a were assessed at baseline ( male, mean age . ± . years), underwent repeat assessments a median on months (data already published), underwent repeat assessments at a median of months, and underwent a final assessment at a median of months. the primary outcome measure currently being analysed is mean calf muscle fat fraction at a single axial slice a fixed distance distal to the knee joint. results of this analysis and correlation with clinical measures will be presented at the peripheral nerve society meeting. fainmesser y , dori a , , drory ve , . department of neurology and neuromuscular service, tel-aviv medical center, tel-aviv, israel; department of neurology, sheba medical center, ramat gan, israel; sackler faculty of medicine, tel aviv university, israel. the use of anabolic drugs by those who wish to increase lean body mass is widespread and not well supervised medically. a years old man was referred for evaluation of a slowly progressive sensory and motor disturbance in the distribution of the left ulnar nerve. his symptoms began months after repeated self-injections of anabolic steroids and vitamin e into the biceps and triceps brachii muscles bilaterally. his examination showed increased muscle mass of the injected muscles with a hard-rubbery consistency, atrophy and weakness of left interossei, mild weakness of the bilateral biceps brachii and sensory loss in an ulnar nerve distribution. nerve conduction studies showed a left ulnar neuropathy with reduced motor and sensory response amplitudes and denervation in the left first dorsal interosseus, as well as mild myopathic changes with significantly reduced insertional activity in both biceps muscles. mri of the soft tissues of the arms showed massive fibrosis and infiltration of fat in the arm muscles compressing the ulnar and median nerves on the left. neurolysis of the left ulnar nerve was performed, and the ulnar nerve was found enclosed in a fibrotic mass throughout the entire length of the upper arm. the brachial artery and the median nerve were similarly enclosed in fibrotic tissue and were released. a biopsy of the affected muscles showed muscle necrosis and fibrosis. the patient was treated with physiotherapy and losartan with only mild improvement in the consistency of the muscles, but without clinical improvement in ulnar nerve function, and worsening of nerve conduction. this case illustrates severe peripheral nerve damage due to entrapment in massive muscle fibrosis following improper intramuscular injection of anabolic steroids for cosmetic purposes. fabrizi gm , testi s , høyer h , braathen gj , squintani g , bertolasi l , ferrarini m , taioli f , cabrini i , pancheri e , cavallaro t , tonin p . department of neuroscience, biomedicine and movement, university of verona and department of neuroscience, aoui verona, italy; section of medical genetics, department of laboratory medicine, telemark hospital, skien, norway. inherited diseases of nerve and muscle may overlap phenotypically or coexists as facets of the same disorder. two families whose probands were initially diagnosed with a lower motor-neuron (lmn) syndrome and a hereditary distal motor neuropathy (dhmn) turned out to represent a vcp (valosin-containing protein)-related syndrome and a gne (udp-n-acetylglucosamine -epimerase/n-acetylmannosamine kinase)-related "distal myopathy" . both conditions shared the presence of rimmed vacuoles (rv) in muscle biopsies. in family , the year-old male proband had a lmn syndrome manifesting at age years (wasting/weakness, cramps, fasciculations of thigh muscles, later involving the distal upper limbs). his year-old brother had lower limb weakness and diffuse pain in bones/joints since age . the father was diagnosed with a "muscular dystrophy" thirteen years before dying a years; by age years he had developed a behavioural frontotemporal dementia (ftd). electrodiagnosis (edx) disclosed myopathic changes with ongoing denervation together with a mild sensory-motor axonal polyneuropathy in the proband, and a chronic sensory-motor axonal polyneuropathy in the brother. mri showed fatty replacement of weakened muscles in both siblings and diffuse changes of bones consistent with paget disease (pd) in the elder sibling. in family , a year-old african woman was affected by weakness and wasting starting at the distal lower-limb muscles at age years and soon progressed proximally; parents were not consanguineous and two sisters out of six siblings, deceased in their thirties for post-partum complications, had a similar disease. edx mainly disclosed a neurogenic process with ongoing denervation. muscle biopsies from the three family- patients and from the family- proband showed a myopathy with rv. next-generation sequencing demonstrated a heterozygous c. c>t change of vcp leading to a known pathogenic p.arg cys substitution in all family- patients, and two compound heterozygous c. g>a and c. g>a changes of gne in the family- proband leading to known p.ala thr and p.ala thr substitutions. vcp is known to cause autosomal dominant amyotrophic lateral sclerosis- , charcot-marie-tooth disease type y or inclusion body myopathy (ibm) with pd and ftd (ibmpfd); gne causes the autosomal recessive nonaka myopathy (alias ibm ). both cases emphasize the clinical and neurophysiological heterogeneity of those disorders. fargeot g , vandendries c , labeyrie c , viala k , theaudin m , adams d . neurologie, crmr nnerf, aphp, filnemus, chu bicêtre, le kremlin-bicêtre, france; neuroradiologie, crmr nnerf, aphp, filnemus, chu bicêtre, le kremlin-bicêtre, france; neurologie, groupe hospitalier universitaire pitié salpêtrière, paris, france. the diagnosis of cidp is often challenging, especially when electrophysiological signs of demyelination are lacking. plexus mri has documented nerve abnormalities in small series of typical cidp but its contribution in patients with no electrophysiological signs of demyelination remains to be proved. we report the results of plexus mri in a serie of patients suspect of having cidp without efns pns definite electrophysiological criteria. we did a retrospective study of patients consulting in kremlin bicetre and pitié salpétrière hospital. lumbar or brachial plexus mri (or both) were performed and we assessed nerve trophicity, t -stir signal intensity and gadolinium enhancement as well as the topography of abnormalities. a consensus diagnosis was made by a group of experts (based on clinical data and other supportive criteria) and allowed us to classified patients in "cidp" or "other diagnosis". the practical contribution of plexus mri to the diagnostic algorithm has been studied. diagnosis of cidp was made in patients. mri was abnormal in % of cidp patients and showed nerve roots hypersignal/hypertrophy/enhancement in respectively . / . / . % of patients. the pattern of abnormalities was often asymetrical ( . %), diffuse ( . %) or multifocal ( . %). after unblinding, the mri confirmed the diagnosis of experts in . % of patients and changed the diagnosis in % of patients. plexus mri has shown to be useful in our serie to confirm the diagnosis of experts or to modify it in patients ( %) . the "classical" pattern described in definite cidp (diffuse nerve root hypertrophy and hypersignal) was documented in % of our cidp patients whereas less typical pattern (focal or multifocal abnormalities, hypersignal without hypertrophy) was found in %. plexus mri seems usefull when facing patients suspected of having cidp when electrophysiological criteria are not met: both symetrical diffuse or asymetrical multifocal patterns can be found and should be always correlated to the clinical examination and other supportive criteria. the specificity of such abnormalities remains to be studied. feely sme , rebelo a , abreu l , tao f , bacon c , zuchner s , shy me . university of iowa, iowa city, ia, usa; dr. john t. macdonald department of human genetics and hussman institute for human genetics, miller school of medicine, university of miami, miami, fl, usa. mutations in bcle-associated athanogene (bag ) have been shown to cause a distal myofibrillar myopathy and cardiomyopathy that can severely affect children or only affect adults depending upon the particular mutation. children with severe cardiomyopathy and myopathy have also developed axonal peripheral neuropathy, consistent with the known localization of bag in neurons as well as in muscle. we have identified two large autosomal dominant families with adult onset charcot-marie-tooth disease (cmt ) with the identical novel missense mutation pro ser, a codon previously shown to cause severe or mild myopathy depending on the amino acid substitution. these families expand the phenotypes caused by mutations in bag to include cmt and provide an additional example of adult onset cmt that may previously have been diagnosed as chronic idiopathic axonal neuropathy (ciap). feely sme , saade d , shy me . carver college of medicine, university of iowa, iowa city, ia, usa. myelin protein zero (mpz), expressed only by myelinating schwann cells, has sequence alterations that have previously been reported to cause demyelinating, intermediate, and axonal forms of charcot marie tooth (cmt) disease. we describe a rare duplication in mpz which is causing an early onset, demyelinating form of cmt in our patient. patient was a product of a normal pregnancy and delivery. early milestones were delayed. she began walking at months of age. she was not able to keep up with her peers and was the slowest runner. she started wearing smos at years of age and afos by years of age. she was diagnosed with scoliosis at years of age and started wearing a brace at years. her examination at years of age showed that her fdi, apb, and adm were all / bilaterally. weakness in her lower extremities included / foot eversion and / great toe dorsi flexion. she had tight heel cords bilaterally. pinprick sensation was reduced throughout in her upper and lower extremities and absent at her toes bilaterally. vibration sensation with a rydel tuning fork was absent at her toes and ankles and reduced at her knees and fingers. nerve conduction studies were performed and revealed no responses in all sensory nerves tested with the exception of the radial nerve which had normal latency and mildly slowed conduction velocity ( m/s). prolonged latencies, demyelinating range slowing (between - m/s), and low cmap amplitudes in almost all segments of the median and ulnar motor nerves were also observed. these findings were consistent with a hereditary sensorimotor demyelinating polyneuropathy. she was diffusely areflexic and her total cmt pediatric score (cmtpeds) was / which is in the severe range. her cmt neuropathy score (cmtns) was / in the moderate range. the duplication of mpz has previously been identified as a rare cause of cmt b. inherited neuropathy consortium is part of the nih rare diseases clinical research network (grant# u ns - ). feely sme , saade d , shy me . carver college of medicine, university of iowa, iowa city, ia, usa. mutations in egr cause a severe, demyelinating form of cmt, cmt d. we describe a novel mutation in egr which led to extreme variability in severity in a family. proband was a year old girl who was the product of a normal pregnancy and delivery. early milestones were on time. problems with walking started at years of age. at . she was unable to use stairs, run, or jump. at she was wearing bilateral afos. by she was using a wheelchair and started breathing assist at night. she lost arm lift but could still hold a pen. by she could not ambulate independently and breathing assist was required day/night. she lost the ability to write and developed a head drop. by years she could not sit up. on exam her head and neck muscles were / . upper limbs, deltoids, biceps, wrist ext/flex, finger ext, fdi, and adm were / bilaterally. triceps were / ; finger flexors and apb were / bilaterally. lower limbs were / and she had contractures on the right. sensory examination was normal. she was diffusely areflexic. ncvs were absent. both the cmtns and cmt pediatric score were severe at / and / . exome sequencing revealed a r l variant in egr which was likely pathogenic. the probands' mother also had this mutation. she had no reported symptoms at the age of with strength at / throughout with the exception of left foot eversion which was +/ and great toe dorsi flexion which was -/ bilaterally. sensory exam showed a decrease of vibration and pinprick sensation at left toe. she had a normal gait, tandem gait and could toe walk, but not heel walk. she was diffusely areflexic. ncvs showed absent sensory responses. motor ncvs showed her latencies were prolonged and velocities reduced ( - m/s). cmtns was mild ( / ). additional family members who had the r l mutation were evaluated including maternal grandmother who was moderately impaired ( / ) and maternal aunt who was severe ( / ). no other mutations that could cause another known neuropathy or myopathy were identified and mitochondrial sequencing was normal. inherited neuropathy consortium is part of the nih rare diseases clinical research network (grant# u ns - ). fisgun a , luan x , hoke a . johns hopkins university, baltimore, md, usa. molecular mechanisms that underlie slow distal axonal degeneration seen in chemotherapy induced peripheral neuropathy (cipn) are unclear. however, several identified molecular targets suggest shared mechanisms with wallerian degeneration. since spontaneous mutation in wlds mice and genetic deletion of sarm gene lead to slow wallerian degeneration, we asked if wlds or sarm knockout (ko) mice are resistant to distal axonal degeneration induced by several chemotherapy agents. we chose chemotherapeutic drugs from different classes of agents, paclitaxel (taxane), cisplatinum (platin-based drugs) and bertozomib (proteasome inhibitor), to model cipn in mice. primary outcome measure was evaluation of epidermal nerve fibers in the hind paw plantar footpads. secondary outcome measures included thermal sensation and nerve conduction studies. sarm ko mice were almost % protected against development of sensory neuropathy but the protection in wlds mice was partial. this study confirms the pivotal role sarm plays in mediating axonal degeneration and identifies inhibition of sarm activity as a potential therapeutic target for prevention of cipn. florio f , scapin c , ferri c , feltri ml , wrabetz l , d'antonio m . myelin biology unit, san raffaele scientific institute, milan, italy; hjkri-university of buffalo, ny, usa. myelin protein zero is the most abundant structural protein in myelin of the pns. in humans, more than mutations in p are associated with hereditary neuropathies. deletion of serine causes charcot-marie-tooth (cmt) b disease in humans and a similar demyelinating neuropathy in mice (wrabetz et al., ) . p s del protein is misfolded and is retained in the er where it gives rise to a dose-dependent unfolded protein response (upr) (pennuto et al., ) . the upr results in the activation of transcriptional and translation control programs that reduce protein synthesis and increase the folding and degradative capacity of the cell. usually, when this first response is not sufficient the cells may activate apoptosis resulting in cell death. however, in p s del schwann cells there is no cell death suggesting that these cells may respond differently to chronic stress. transcriptomic analysis performed on p s del nerves showed increased expression of transcription factors normally present only in the early phases of differentiation such as c-jun, sox and id (d' antonio et al. ) . in order to understand the role of the expression of these factors in the peripheral nerve myelination we used ex vivo and in vivo approaches and we showed that sox and id act as negative regulators of myelination. these results suggest that the expression of sox and id may contribute to the hypomyelination observed in p s del mice. as such, we reasoned that their ablation could ameliorate the phenotype. surprisingly, the ablation of these factors in the p s del mouse severely worsens the neuropathy bursting schwann cell differentiation and increasing the expression of both p wild type and mutant allele with concomitant exacerbation of the upr. this suggests that the overexpression of early differentiation factors in schwann cell under chronic er-stress is an adaptive mechanism that limits differentiation and reduces the expression of toxic proteins. intravenous immunoglobulin (ivig) is the treatment of choice for the guillain-barré syndrome (gbs). the working mechanism of ivig in gbs is undefined, but most likely all potential effects are dose dependent. the pharmacokinetics (pk) and pharmacodynamics (pd) of ivig in gbs are highly variable between patients and a rapid consumption or clearance of ivig is associated with poor recovery. in the current study we developed a model to predict the pk of a standard dosage of ivig ( . g/kg for consecutive days) in individual patients with gbs. non-linear mixed-effects modelling (nonmem) was used to construct a model based on a cohort of gbs patients, with a total of sequential serum igg levels. the final model accurately describes the day to day increment in igg levels during the -day course and the initial rapid fall and graduate decline to steady-state levels thereafter. we explored several potential covariates that improved the predictive capabilities and decreased the between-subject variation in the model. the model including these covariates were evaluated successfully (bootstrap analysis) and through numerous simulation studies each based on (simulated) gbs patients. in conclusion, a first accurate and robust nonmem model for the pk/pd of standard ivig treatment in gbs was developed. the model can be used to predict the pk in individual patients applying a few simple baseline characteristics. in addition, the effect of different treatment regimens of ivig in gbs on a population pk/pd level can be simulated. this modeling technique is a new tool to optimize the pk in individual patients and the study design for new trials with ivig in gbs. forese mg , pellegatta m , rivellini c , podini p , quattrini a , previtali sc , taveggia c . axonal neuregulin (nrg ) type iii is an essential instructive signal for peripheral nervous system (pns) myelination, as its expression determines whether axons are myelinated as well as the thickness of the myelin sheath. we recently demonstrated that gamma-secretase cleavage of nrg type iii generates an axonal intracellular fragment, which translocates in the nucleus to upregulate the expression of the prostaglandin d synthase (l-pgds) gene in neurons. l-pgds catalyzes the conversion of prostaglandin h into prostaglandin d (pgd ). we also showed that specific inhibition of l-pgds activity impairs in vitro myelination. accordingly, myelin in l-pgds null mice is noticeably thinner, thus indicating that l-pgds is a new modulator of developmental pns myelination. previous studies have shown that prostaglandins are involved in the process of wallerian degeneration (wd) and axonal regeneration after injury. thus, to determine whether l-pgds and pgd could be important in pns regeneration and remyelination, we performed sciatic nerve crush injury in months old l-pgds null and wild type control mice and we analysed nerves by morphologic, biochemical, histological and molecular approaches at different time points (t) after crush. we focused on three phases: degeneration (t -t ), axon regeneration (t -t ) and remyelination (t ). our results indicate that in l-pgds null mice the amount of myelin proteins synthesized after crush as well as the number of remyelinated fibers do not change, suggesting that l-pgds might be dispensable for remyelination. however, we observed an increased number of macrophages in null nerves during regeneration (t ), possibly as a consequence of an increase in the blood-nerve barrier (bnb) permeability, indicating potential alteration in the regeneration process in l-pgds null mice. these results suggest that l-pgds could have a different role in developmental pns myelination and after injury. whether other prostaglandins and synthases might compensate for l-pgds activity is currently under investigation. fornasari be , , raimondo s , , ronchi g , , crosio a , budau ca , el soury m , muratori l , , tos p , battiston b , geuna s , , gambarotta g . department of clinical and biological sciences, university of turin, italy; neuroscience institute cavalieri ottolenghi, turin, italy; microsurgery unit, health and science city, cto, turin, italy; hand microsurgery and surgery, gaetano pini hospital, milan, italy. to repair nerve gaps following severe peripheral nerve injuries, chitosan tubes were proved to give good results, comparable with those obtained with nerve autografts, the gold standard technique. to further improve peripheral nerve regeneration using chitosan tubes, a conduit enrichment strategy was developed using longitudinal skeletal muscle fibres, which have been previously shown to be good fillers in the "muscle in vein" experimental paradigm, where they played a trophic and a structural role. to this aim, rat median nerve gaps were repaired using two different conduits: mm chitosan tubes filled with a longitudinal piece of pectoralis major muscle ("muscle in tube") and hollow chitosan tubes. samples were harvested at early time points ( , , , days) for biomolecular and morphological analysis, and later ( months) for stereological analysis. autologous nerve grafts were used as gold standard positive control in the early time points. biomolecular analysis carried out on in vitro degenerating muscle and on "muscle in tube" at early time points show that the muscle produces high levels of soluble isoforms of neuregulin , a key factor for schwann cell survival and activity, usually released by schwann cells after nerve injury. functional assay and stereological analysis carried out on the distal part of regenerated nerve months after nerve repair, show no significant differences in the regeneration outcome between hollow chitosan tube and "muscle in tube" groups. therefore, we conclude that for short gaps (≤ mm), both hollow chitosan tube and "muscle in tube" are good techniques to repair nerve defects and we suggest that the "muscle in tube", which spontaneously releases neureg-ulin , might be a promising strategy to promote regeneration when the gap is longer or the repair is delayed in time. foucquier j , bertrand v , jouve e , truillet r , mandel j , laffaire j , blin o , magy l , lehert p , , hajj r , guedj m , cohen d , attarian s . pharnext, issy-les-moulineaux, france; aix marseille université, aphm, marseille, france; hôpital dupuytren, limoges, france; university of melbourne, melbourne, vic , australia; faculty of economics, louvain, belgium. charcot-marie-tooth disease type a (cmt a) is a rare disease belonging to a group of inherited, progressive, chronic motor and sensory peripheral neuropathies. the charcot-marie-tooth neuropathy score (cmtns) (shy et al., ) and the overall neuropathy limitations scale (onls) (graham & hughes, ) are considered as the main clinical scales for evaluating progression of disability associated with cmt. as cmt a is a slowly progressive neurodegenerative disease, the choice of endpoints and their ability to monitor small changes over time remain a major concern for clinical drug development. with this in mind, we studied a cohort of french cmt a patients with a follow-up ranging from months to . years resulting from the merge of two multicentre clinical trials (micallef et al., ; attarian et al., ) and a non-interventional study (unpublished) . the sensitivity to change of both cmtns and onls were assessed using a mixed effect model estimating annual progression with time in years, cmtns or onls baseline value as covariates, study centre as a fixed factor and patients as a random effect to account for the repeated measures. disease progression was estimated to be + . points per year on the cmtns (p = . ) and + . points per year on the onls (p = . x − ), both corresponding to a deterioration of impairment and disability. while both endpoints have similar and favourable properties, our set of observations led us to conclude that the onls could be more promising to monitor disease progression in cmt a. frasquet m , , lupo v , mas f , , vílchez r , chumillas mj , , espinós c , sevilla t , , . hospital universitari i politècnic la fe, valencia, spain; instituto de investigación sanitaria la fe, valencia, spain; centro de investigación príncipe felipe, valencia, spain; eresa, valencia, spain; centro de investigación biomédica en enfermedades raras (ciberer), valencia, spain; departamento medicina, universitat de valencia, valencia, spain. mutations in the bicd gene are a cause of dominant spinal muscular atrophy, lower extremity predominant (smaled). we report six patients belonging to three spanish families who carry three different novel mutations in the bicd gene. we describe clinical, electrophysiological and magnetic resonance imaging (mri) data. we provide results of muscle biopsy of one patient and skin biopsy for the study of epidermal nerve fiber density (enfd) of other two patients. genetic diagnosed was reached using a gene panel for genetic testing of cmt and dhmn. three novel mutations in the bicd gene that segregated with the disease were detected: p.val gly; p.tyr his and p.s l. the most frequent clinical phenotype consisted of mild weakness in proximal muscles of lower limbs combined with foot deformities. one patient had prominent sensory symptoms and abnormalities on sensory examination. other two patients had minor sensory abnormalities on examination. in one patient sensory and motor nerve action potentials were reduced, in the rest of patients electrophysiological studies showed normal motor and sensory nerve responses, with chronic denervation predominantly in muscles of lower limbs. mri studies at the level of tight and calf were performed in all patients. the most affected muscles were rectus femoris, vastus lateralis and medial gastrocnemius. mri studies at the level of feet were obtained from five patients and showed that there was not fatty infiltration in intrinsic foot muscles. mri at the level of pelvis muscles performed in four patients showed marked fatty infiltration of gluteus medius muscle in two of them. muscle biopsy performed in one patient showed myopathic features. skin biopsy was performed in two patients of the same family. in the older patient, who had minor sensory abnormalities on examination, there was a marked reduction of enfd that followed a length-dependent pattern. in conclusion, we report three new pathogenic mutations in the bicd gene. in our study we include mri findings at the level of pelvis and feet, which allow us to better define the pattern of muscle involvement related with this gene. our results also raise the subject of a possible sensory involvement in the disease. hereditary neuropathy with liability to pressure palsies (hnpp) is an autosomal dominant disorder that usually results from deletions in the pmp- gene. the neuropathy is unique in that it manifests with recurrent mono-neuropathies at common sites of compression. while spontaneous recovery from episodes of nerve injury usually occurs, it is often incomplete, and over time patients may develop a length dependent polyneuropathy. given the relapsing/remitting nature of hnpp symptoms, standard clinical scores, such as the cmt neuropathy score, are not effective at capturing the severity or progression of the disease. a specific tool is therefore needed for measuring clinical severity of hnpp in preparation for emerging clinical trials. in the current study, we evaluate a new pilot measure, the hnpp severity score (hnpps). the score is composed of patient reported questions addressing current and prior sensory and motor symptoms, and the impact of symptoms on quality of life, followed by items based on a motor examination. total scores vary from - , with higher scores indicating increased disease severity. in this study, the hnpps was administered to patients with genetically confirmed hnpp at the ucl institute of neurology. subjects included males and females with a mean age of years (+/− , range - ). the mean hnpps was . points (+/− . , range - ) and the data did not demonstrate major skew. the cronbach alpha for the hnpps was . , and items based on the physical examination showed the least variability. a modest correlation was observed between the hnpps and the cmt examination scores (pearson correlation . , ci . - . ). we conclude that the hnpps may be a useful measure of clinical severity in hnpp, and should be refined in larger patient cohorts. fridman v , sillau s and on behalf of the inherited neuropathies consortium (inc) . university of colorado hospital, aurora, co, usa; university of iowa hospitals and clinics, iowa city, ia, usa. the most common of the hereditary neuropathies (hn) is cmt a, an autosomal dominant demyelinating neuropathy that results from duplications in the pmp- gene. recent advances in defining the pathomechanisms of the disease have led to an increasing number of potential therapies; however, the absence of reliable natural history data and the paucity of sensitive clinical outcome measures have been barriers to effective clinical trials. the charcot marie tooth neuropathy score (cmtns) was developed to quantify impairment and measure progression in hn. it was observed that while the score discriminates well between mildly and severely impaired patients, it tends to cluster together patients in the middle range of severity. to improve the score's sensitivity, rasch analysis-based weighted category responses were developed. we report a longitudinal study of weighted cmtns and cmt examination scores (cmtes) over a three-year time frame in patients with cmt a. baseline, one year, two year and three year wcmtnsv /wcmtesv scores were available for / , / , / and / patients respectively. mean wcmtns (sd)/wcmtes (sd) scores were as follows: . ( . )/ . ( . ) at baseline, . ( . )/ . ( . ) at one year, . ( . )/ . ( . ) at two years and . ( . )/ . ( . ) at three years. a mixed regression model showed significant change in wcmtns and wcmtes at years (mean change from baseline at years was . points (p=. ) for wcmtns and . points (p=. ) for wcmtes. significant change as compared to baseline was also seen at years (mean change from baseline . points (p= . ) for wcmtns and . points (p= . ) for wcmtes. we conclude that weighted cmtnsv scores show change over the first three years of the inherited neuropathies consortium natural history study and are a helpful measure of progression in cmt a. fridman v , novak p , david w , macklin ea , mckenna-yasek d , walsh k, oaklander al , brown r , hornemann t , eichler f . massachusetts general hospital, boston, ma, usa; university of massachusetts medical school, worcester, usa; university hospital zurich, zurich, switzerland. hsan is an autosomal dominant, severe sensory motor polyneuropathy caused by mutations to serine palmitoyl-coa transferase. mutations shift the substrate preference from serine to alanine leading to formation of neurotoxic -deoxysphingolipids ( -deoxysl). treatment with high-dose l-serine has been shown to reduce -deoxysl accumulation and improve neuropathy in transgenic hsan mice. we report a two-year, delayed-start, placebo-controlled clinical trial evaluating the safety and efficacy of oral l-serine in hsan . eighteen hsan subjects were equally randomized to l-serine ( mg/kg/d) or placebo for year. at -weeks, the placebo group crossed-over and all participants took open-label l-serine for one additional year. sixteen subjects completed their -week visit, and no serious adverse events related to l-serine were reported. participants randomized to l-serine experienced a decline in charcot marie tooth neuropathy scores (cmtns) over year relative to placebo (− . units, % ci − . to − . , p = . ). both groups improved in the second year of the study, with a diminished difference in cmtns at weeks (− . units, % ci − . to . , p= . ). skin biopsies from the distal leg site were largely devoid of intra-epidermal nerve fibers (ienf), but at year, a greater increase in ienf density was seen in participants on l-serine versus those on placebo (median change of vs. fibers/μm , p= . ). -deoxysl levels declined among participants on l-serine versus those on placebo after one year of treatment ( % decrease in deoxysphinganine vs. % increase on placebo, p < . ), and placebo participants experienced similar declines in -deoxysl levels after crossing over to l-serine. we conclude that l-serine is a safe and potentially efficacious treatment for hsan . fu liong h , yusuf r . regional neuromuscular clinic, queen elizabeth hospital, university hospitals of birmingham, birmingham, uk; school of life and health sciences, aston brain centre, aston university, birmingham, uk. the relationship between guillain-barré syndrome (gbs) and malignancy is uncertain. under the diagnostic criteria of paraneoplastic neurological syndrome (pns) by euronetwork, , neuropathy with no definite onconeural antibodies identified due to gbs has been classified as "non-classical" paraneoplastic disorder. we retrospectively analyzed data of consecutive patients admitted with gbs from birmingham, u.k. ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) to calculate the relative cancer risk using different definitions and determined characteristics of malignancy-associated gbs. patients were classified according to definitions: ) all cases of malignancies excluding preceding diagnoses > year before gbs and with no evidence of malignant disease activity at the time of gbs diagnosis, and ) malignancies diagnosed > years post-gbs onset as per pns criteria. total number of gbs patients with malignancy was ( . %). a total of patients ( . %) fulfilled requirements for inclusion as malignancy-associated gbs as per existing criteria for pns. associated malignancy consisted of angioimmunoblastic t-cell lymphoma ( ), poorly differentiated squamous cell carcinoma of nasal septum ( ), gastric adenocarcinoma ( ), hepatocellular carcinoma due to hepatitis b ( ), rectal carcinoma with liver metastasis ( ) and myelodysplastic syndrome ( ). malignancy was globally commoner in our gbs cohort compared to the general population (odds ratio: . ; ci: . - . ; p = . ). however, this was unconfirmed if paraneoplastic criteria were applied. gbs patients with cancer were significantly more likely to be older (p = . ), hyponatremic (p = . ) and demonstrate more electrophysiological axonal loss (p < . ). cerebrospinal fluid (csf) protein levels were lower in the malignancy group (p = . ) and neurological improvement was less likely (p = . ). in-patient mortality was significantly higher in patients with malignancy (p < . ). none of the patients in the malignancy group had positive anti-ganglioside antibodies or anti-neuronal antibodies (anti-hu, yo, ri, crmp ). we conclude global cancer risk is higher in gbs than in the general population, although definition-dependent. application of the strict published criteria for paraneoplastic syndrome reduced the number of cases and suggested absence of a link. malignancy requires consideration in elderly, hyponatremic subjects with normal csf protein, severe electrophysiological axonal loss who fail to improve post-treatment. fu liong h , aude-marie g , anne-catherine an , emilien d , julien c , shahram a , yusuf r . anti-myelin associated glycoprotein antibody (anti-mag) neuropathy is a slowly progressive neuropathy resulting in disability through distal sensory more than motor deficits and tremor. there are currently no evidence-based treatments for anti-mag neuropathy and the effect of the disease on quality of life (qol) in this patient population is unknown. our objective was to assess determinants of qol in patients with anti-mag neuropathy. the sf- questionnaire was assessed in patients, from marseille, angers (france) and birmingham (united kingdom). routine clinical evaluations included mrc sum score, incat sensory score, inflammatory rasch built overall disability score (i-rods), ataxia score, jamar grip dynamometry, timed meter-walk, neuropathic pain symptom inventory (npsi) score, and fatigue severity score (fss). there were males and females. mean age was . years (sd: . years). mean disease duration was . years (s.d.: . years). there were no significant differences between the french and u.k. cohorts in terms of gender distribution, age, disease duration, anti-mag antibody titre. all physical assessments, including mrc sum score (p= . ), jamar grip dynamometry (p= . ), onls (p= . ), irods (p= . ), incat sensory score (p= . ), -meter timed walk (p= . ), ataxia score (p= . ), tremor score (p= . ), were comparable. prevalence and/or severity of pain (p= . ), fatigue (p= . ), restless legs syndrome (p= ) and cramps (p= . ) were also similar. physical component summary (pcs) and mental component summary (mcs) of the sf questionnaire were significantly lower than in reported normal subjects of both countries (p< . ). all sf- qol domains correlated with i-rods, except mcs for which significance was however approached (p= . ). pcs correlated with mrc sum score, ataxia score, timed m-walk, tremor, jamar grip dynamometry, npsi pain score, fss and level of social support. mcs correlated exclusively with fss and level of social support. in multivariate regression, pcs was associated independently with i-rods (p< . ) and npsi pain score (p= . ), whereas mcs was associated independently with fss (p= . ). qol is accurately predicted in anti-mag neuropathy by the i-rods and fss, lending support to their use in clinical and research settings. effective measures to improve qol should include tremor and neuropathic pain treatment, fatigue management and improved social support. fu liong h , yusuf r . regional neuromuscular clinic, queen elizabeth hospital, university hospitals of birmingham, birmingham, uk; school of life and health sciences, aston brain centre, aston university, birmingham, uk. the electrophysiological diagnosis of guillain-barré syndrome (gbs) is dependent on a number of abnormalities affecting different parameters in peripheral nerves on nerve conduction studies (ncs). diagnostic sensitivity varies with different electrodiagnostic criteria, practices as well as extensiveness of nerve study. however, the most efficient method of performing electrophysiology for guillain-barré syndrome (gbs) is unknown. we retrospectively analyzed electrophysiological data of consecutive gbs patients from birmingham, uk ( - ), studied ≤ weeks post-onset. we first identify abnormal nerves from various regions which produced gbs electrodiagnosis using the recently described criteria by rajabally et al. we subsequently used pre-established hypothetical nerve conduction study protocols to determine the potential optimal method of achieving electrodiagnosis. we found the sensitivity of electrophysiology for each gbs subtype was dependent on the upper and lower limb nerves tested. in acute inflammatory demyelinating polyneuropathy (aidp), abnormalities were predominant in the arms, whereas leg abnormalities predominated in axonal gbs. in aidp, the most common abnormal parameters were distal motor latency ( . %) and conduction block ( . %), and the most frequently affected nerve was the median ( . %). prolonged f-waves were present in % and f-waves were absent in %. mcv was the least frequently abnormal ( . %) with demyelinating range slowing, significantly lower than cb or dml prolongation (p< . in both cases). in axonal gbs, reduced motor amplitudes ( . %) and conduction block ( . %) were the most common parameters, and the most frequently abnormal nerve was the tibial ( . %). f-waves were absent in . %. . % of all motor nerves were unexcitable, significantly more common in lower limb nerves compared to upper limb nerves (p= . ). on comparison of different hypothetical ncs protocols ( unilateral protocols with nerves, with nerves as well as the protocols with -nerves and with exclusive bilateral upper limb and lower limb testing), unilateral -nerve (median, ulnar, common peroneal and tibial) testing produced the highest diagnostic sensitivity for both aidp ( . %) and axonal ( . %) gbs. electrodiagnostic sensitivity in gbs is thus dependent on nerves tested and parameters considered. each subtype preferentially involves specific nerves and parameters. these findings may help per-procedure interpretation, improve electrodiagnostic sensitivity, and reduce patient discomfort. funakoshi k , nagashima t , kokubun n , hirata k , yuki n . department of neurology, dokkyo medical university, tochigi, japan; department of neurology, mishima hospital, nagaoka, japan. recently, igg anti-ganglioside complex (gscs) antibodies have been reported in patients with guillain-barré and miller fisher syndrome. some researchers (nobile-orazio et al., ) reported igm anti-gscs antibodies in multifocal motor neuropathy (mmn) and other chronic immune-mediated neuropathies. in ten of eleven mmn patients with anti-gm antibody, there was a decreased reactivity to gm /gd a compared to single antigen gm . similarly, in one of two chronic inflammatory degenerative polyradiculoneuropathy (cidp) patient with anti-gm antibody, there was a decreased reactivity to gm /gm , gm /gd a, gm /gd b, gm /gt b compared to gm . these relationships were defined negative interaction. in one cidp with anti-gd b antibody, anti-gm /gt b and -gm /gt b reactivity increased although gm and gm were negative (positive interaction). in japan, on the other hand, this correlation remains unclear. sera were investigated from one mmn patient ( y/o male) with anti-gm , and anti-gd a antibody, one cidp patient ( y/o female) with anti-gm , and one subacute sensory motor polyradiculoneuropathy ( y/o male) with anti-gd b, and anti-gq b. igm antibodies to gscs gm /gd a were tested with a mixture of gm and gd a (each pmol/well) as antigen. anti-gm /gd a antibodies were judged to have positive interactions when the optical density was . greater than the sum of the antibodies against individual gm and gd a, and negative interactions when the optical density was % or less compared to the antibodies against individual gm or gd a. antibodies to at least one combination of two of the six gangliosides (gm , gm , gd a, gd b, gt b, and gq b) were similarly tested and judged for positive or negative interactions. in one mmn, anti-gm /gd a had negative interactions. in one cidp, anti-gm /gd a, and anti-gm /gq b had negative interactions. in one subacute sensory motor polyradiculoneuropathy, various anti-gscs antibodies including gd b or gq b had negative interactions. in the cidp patient mentioned above, anti-gm /gt b or anti-gm /gt b had no positive interactions. the relationship between this attenuated reactivity presumably driven by adjacent gangliosides and the mechanism of chronic immune-mediated neuropathies needs to be clarified. galino j , cervellini i , zhu n , stöberl n , fricker fr , lee g , hütte m , lalli g , bennett dl . the nuffield department of clinical neurosciences, john radcliffe hospital, university of oxford, oxford, uk; wolfson card, king's college london, guy's campus, london, uk. schwann cells (scs) are the myelinating cells in peripheral nerve system and are important for normal peripheral nerve development and repair. rala and ralb are small gtpases that have been implicated in neural tube closure, neurite branching and have been described as upstream effectors of proteins involved in cell migration and membrane dynamics. due to their potential role in sc function here we investigated, by genetic ablation in transgenic animals of one or both gtpases, their importance in sc function in adulthood and in nerve repair. we showed that ral gtpases are dispensable for sc function in the naïve state. however ral signalling (provided by rala or ralb) is required for effective remyelination of axons following nerve injury. moreover, absent ral signalling produced defects in axon reinnervation of distal organs and a delay in motor function recovery after nerve injury. we also studied the ral dependent cellular mechanisms that may be responsible for impaired sc remyelination and noted abnormal sc lamellipodia formation that prevent normal axial and radial axon remyelination. this work demonstrates for the first time a novel mechanism for ralgtpases that controls sc lamellipodia formation and their importance in normal sc function during peripheral nerve repair. garcía-lareu b , , , ariza l , cobianchi s , , chillón m , , , , navarro x , , , bosch a , , . tumor necrosis factor (tnf) alpha has been implicated in the pathogenesis of diabetic peripheral neuropathy (dpn), among other inflammatory demyelinating diseases and neuropathic pain. tnf alpha is a pro-inflammatory cytokine that can act at several stages in the demyelination process. it is produced by schwann cells (scs) in the peripheral nervous system (pns) after nerve injury and released into the local environment to attract and activate macrophages at the site of injury, contributing to wallerian degeneration. in vivo studies demonstrated a local inflammation in the sciatic nerve of rats after injection of tnf alpha, followed by demyelination and axonal degeneration. furthermore, the application of tnf alpha resulted in acute mechanical hiperalgesia, a main characteristic of neuropathic pain and therefore tnf alpha is postulated as a biomarker for painful changes after nerve injury. with the aim to characterize tnf alpha effects in chronic neuropathic pain and in diabetic neuropathy, a transgenic mouse model overexpressing tnf alpha cdna under the peripheral myelin protein p promoter was generated. here we characterized the overexpression of tnf alpha in myelinated scs at different stages of myelination (postnatal days , and ) showing that high levels of tnf alpha in sciatic nerve leads to the downregulation of the major pns myelin proteins (p , mbp, pmp , mag) compared to wild type mice, correlating with the loss of structured myelin and an increase in p ntr, a marker for immature and non-myelinated scs in the sciatic nerve. iba staining showed high levels of macrophage infiltration in both sciatic nerve and spinal cord tissues, compared with wild type animals. stress conditions were induced by sciatic nerve crush surgery after which recovery and subsequent remyelination were delayed in the transgenic mice, as evaluated by the sciatic functional index (sfi) and electrophysiological tests. on the other hand, mechanical and thermal nociception seemed to be unaltered, with or without lesion. this model could be helpful in the characterization of the role tnf alpha in pain development, injury and dpn as well as in developing efficient therapeutic strategies to modulate such pathological conditions. garcía-sobrino t , , blanco-arias patricia , , vidal-lijó mp , quintáns bea , , sobrido mj , , pardo j , . department of neurology, hospital clínico, santiago de compostela, spain; neurogenetics research group, instituto de investigaciones sanitarias (idis), santiago de compostela, spain; genomic medicine group (u ), centre for biomedical network research on rare diseases (ciberer), spain; department of neurophysiology, hospital clínico, santiago de compostela, spain. charcot-marie-tooth (cmt) disease is a genetically heterogeneous group of hereditary motor and sensory neuropathies. more than genes were involved in the disease pathogenesis. the objective of this study was to assess the genetic distribution of cmt disease in galicia (northwestern spain). patients were diagnosed as cmt if they had a consistent neurological and/or neurophysiological examination or if they had sensory motor neuropathy with a positive family history. a total of cmt adult patients ( % females) were evaluated with a median age of [ - ] years. the molecular diagnosis was achieved in patients ( %) with a higher success in cmt ( %) than cmt ( %). globally, pmp duplication was the most frequent finding ( %), followed by mutations in mpz ( %), mfn ( %), gjb ( %) and gdap ( %). in cmt , with expception of the pmp duplication, pathogenic variants in egr , nefl and mpz gene were most common. pathogenic variants in mfn and gdap accounted for % of cmt patients. several patients referred to our institution as cmt were diagnosed as hereditary motor neuropathy (hmn) and pathogenic variants in the bscl gene were the most frequent. pathogenic variants not previously related to cmt were identified in mpz, mfn , gjb , egr , nefl and sh tc genes. sporadic or autosomal recessive (ar) cmt accounted for the % of all diagnoses. the genetic epidemiology of cmt in galicia follows a similar pattern to other populations, although some remarkable features are axonal gdap and demyalinating egr pathogenic variants as well a seemingly elevated proportion of ar cases. mutations in mpz gene are associated to a wide range of phenotypes. the r c, in particular, is associated to a severe and early onset disease. some cmt patients respond to immunosuppressive or immunomodulatory treatment, some of them harbouring mpz mutations. we present the case of a -year-old brazilian female with a severe cmt b (r c) that presented an acute episode of worsening after a febrile exanthematic disease. she complained of tingling, stopped walking without support, and could not raise her arms. her emg showed an asymmetrical reduction of motor cv, reduced amplitudes, severe temporal dispersion and possibly conduction block. csf protein was mg%, with normal cell count. diagnosed as gbs, she received ivig. curiously, she markedly improved, regaining the functional status of youth, recovering functions that she had long lost. on emg, motor amplitudes improved significantly, but cv remained the same. reviewing carefully her past history, we identified some motor fluctuations along her adult life. at age , while pregnant, she developed positive sensory symptoms, became unable to get up from the chair and could not walk without assistance. after delivery, she improved, but did not return to baseline. one year later, she presented a new transitory functional worsening after an influenza illness. her parents were healthy but two out her children have a severe cmt. her first daughter never walked and died at the age of six. six months after treatment with ivig, she faced a new relapse. we pulsed with corticosteroids, with great response. she remains stable to date, four months after treatment. the episodic fluctuations and the evident response to treatment clearly suggest an associated immunomediated process. the fast improvement of the amplitude with maintenance of cv suggests that another mechanism in addition to demyelination and axonal degeneration is involved. we propose the existence of an associated channelopathy. funded by cnpq, faepa, pronas (ministry of healthy) gbs is an acute, immune-mediated neuropathy that comprises three major subtypes: aidp, aman, and amsan. on clinical grounds, this distinction is based on nerve conduction studies (ncs): aidp is a demyelinating neuropathy, aman is an axonal motor neuropathy, and amsan, an axonal sensory and motor neuropathy. recently, it has been demonstrated that axonal gbs, in addition to axonal degeneration, may present conduction block (cb) that can progress to axonal regeneration or revert, characterising a reversible conduction failure (rcf), a finding usually associated to good prognosis. patients presenting axonal cb are frequently diagnosed as having aidp, a mistake that can be avoided with two sets of ncs, one as early as possible and the second after three weeks of disease. following these recommendations, we retrospectively classified a brazilian group with gbs followed in our institution that had been submitted to two ncs sets. from september to january , patients fulfilled clinical criteria for gbs at clinical hospital of ribeirão preto and had more than one ncs accomplished. at least four motor nerves (median, ulnar, peroneal, and posterior tibial) and five sensory nerves (medial, ulnar, radial, sural, and peroneal superficial) were evaluated in each examination, according to routine procedures. first ncs revealed patients with aidp ( %), cases of axonal gbs ( aman, amsan, %), and patients with equivocal results ( %). at follow-up study, patients ( %) had their classification changed. the main shifts were from aidp to axonal group and from equivocal results to aidp. aidp increased to % (n = ), axonal gbs increased to % (n = , aman, amsan), and there were no more equivocal patients. although the majority of studies have shown that aidp is more frequent in western countries while axonal gbs predominates in eastern countries, we found a different pattern of distribution in our population, with predominance of the axonal subtypes. the considerable increase of axonal gbs at follow-up studies reinforces that serial emg are mandatory for accurate diagnosis of gbs subtypes. prospective studies are now being carried out in order to confirm these results. in amyloid light chain (al) amyloidosis, misfolded light chain (lc) accumulates and causes progressive peripheral neuropathy (pn) and progressive failure of critical organs such as the heart and kidneys. progressive ascending sensorimotor neuropathy is often a related clinical finding. the deposition of toxic lc amyloid in peripheral nerves is associated with paresthesias, pain, muscle weaknesss, orthostatic hypotension, and diarrhea or constipation in approximately % of patients with al amyloidosis. there are no approved treatments for al amyloidosis. current therapeutic approaches for al amyloidosis are intended to limit lc production but do not directly target misfolded lc deposited as amyloid in organs. we report phase / trial results of neod , an investigational monoclonal antibody that targets misfolded lc and may neutralize circulating lc aggregates and clear insoluble deposits. trial inclusion criteria were one or more plasma cell-directed treatment completed before enrollment, partial or greater hematologic response to any previous therapy, and persistent organ dysfunction. neod was administered intravenously every days during a dose-escalation phase ( patients; . , , , , , , or mg/kg in a + study design) and an expansion phase ( patients; mg/kg). we assessed safety, tolerability, pharmacokinetics, immunogenicity, organ responses based on consensus criteria, and pn responses using the neuropathy impairment score-lower limb (nis-ll). neod treatment was not associated with dose-limiting toxicities or serious adverse events, drug-related discontinuations, or antidrug antibody development in any patient (n = ). of patients with measurable pn at baseline (n = ), % achieved pn response based on the nis-ll score after months of treatment, which resulted in a median % nis-ll score reduction (mean baseline nis-ll, . ). in a best response analysis, % of cardiac-evaluable patients (n = ) and % of renal-evaluable patients (n = ) met respective criteria for organ response. improvements in neuropathy have not been previously shown in al amyloidosis. these results demonstrated that monthly neod infusions were safe, well tolerated, and associated with responses across three different organ systems. gervais cbl , ross ma , goodman bp , khoury ja , muzyka i , smith be . mayo clinic in arizona, scottsdale, az, usa. this work describes clinical, examination and electrophysiologic findings in a cohort of patients with length dependent sensorimotor peripheral neuropathy (ldsmpn) with ventral abdominal sensory loss. ldsmpn affects the longest nerve fibers, namely those innervating structures in the feet and hands. what is less well appreciated is that length dependent involvement of sensory nerve fibers in ldsmpn from the thoracic segments gives rise to ventral abdominal sensory loss. consecutive patients seen for ldsmpn (n= ) were evaluated for the presence or absence of ventral abdominal sensory loss. demographic variables, symptoms and quantitative neurologic findings (neuropathy impairment score [nis]) were examined using descriptive statistics. final diagnoses were noted. ventral abdominal sensory loss to pinprick (which was asymptomatic in all patients tested) was documented in / ldsmpn patients ( . %), mean age was . years (range - ), m:f gender ratio was . ( : ), mean nis was . (range - ), ncs/emg abnormalities were found in / patients (the remaining showing objective evidence of small fiber sensory involvement). ldsmpn patients without ventral abdominal sensory loss (n= ) had a mean age of . (range - ), m:f of . ( : ), and mean nis of . (range - ). no patient ( / ) had dorsal torso sensory loss between the shoulder and buttock levels on either side. diagnoses of the ldsmpn patients with vs. without ventral abdominal sensory loss included charcot marie tooth or other hereditary neuropathy (n= vs. ), abnormal carbohydrate metabolism (n= vs. ), idiopathic (n= vs. ), hypothyroidism (n= vs. ), inflammatory (n= vs. ) and other (n= vs. ). ventral abdominal sensory loss appears to be common in patients diagnosed with ldsmpn of a variety of causes including inherited neuropathies; in addition to those innervating distal limb territories, distal sensory fibers from the thoracic region represent another category of length dependent involvement in ldsmpn; ) the clinical examination of ldsmpn should include the ventral abdomen. gibbons c , garcia j , casasola m , freeman r . beth israel deaconess medical center, harvard medical school, boston, usa. objective: to determine the relationship between measures of autonomic function, electrochemical sweat conductance (esc) and intra-epidermal (ienfd) and sudomotor nerve fiber density (sgnfd). background: structural and functional measures of small fiber neuropathy have been studied in patients with diabetes, but little information comparing these techniques exists. design/methods: we studied patients with diabetes (ages ± yrs, gender f) and healthy control subjects (age ± yrs, gender f). subjects underwent examination scores (nis-ll), quantitative sensory testing, autonomic testing (heart rate variability, valsalva maneuver, tilt test), esc, and millimeter punch skin biopsies at the distal leg and distal thigh for ienfd & sgnfd. results: there were strong correlations between exam scores (nis-ll) and biopsy ienfd (r=− . , p< . distal leg; r=− . , p< . distal thigh), and sgnfd (r=− . , p< . distal leg; r=− . , p< . distal thigh). moderate correlations were noted between exam scores and qst (r values . - . , p< . ), ienfd and qst (r= . - . ). modest correlations were noted between esc and parasympathetic function (r= . - . , p< . ). modest correlations were noted between esc and ienfd (r= . , p< . , but only at the distal leg) and esc and nis-ll (− . , p< . ). no correlations between exam scores and autonomic function were noted. no correlations were detected between esc and sgnfd (r=− . - . ) or esc and sympathetic adrenergic function (r= . ). conclusions: differences between tests are expected based on our understanding of the pathophysiology and natural history of diabetic neuropathy. exam scores, qst results and biopsy results do correlate, and are consistent with prior studies. in contrast, there was little relationship between tests of autonomic function and exam scores, similar to prior studies and our understanding of autonomic function and differences in p. esc had little correlation with either exam scores or biopsy ienfd or sgnfd. there was a modest correlation between esc and parasympathetic function. the exact relationship between esc and diabetic peripheral neuropathy is not clear, and further research studies are needed to determine the role this technique has in clinical practice. objective: to determine the optimal tissue thickness of skin biopsy sections for studies of cutaneous nerve fibers. background: although analysis of intra-epidermal nerve fiber density (ienfd) is routinely reported using μm thick tissue sections, many recent studies of peripheral alpha-synuclein deposition use or μm frozen sections, or μm paraffin embedded tissue sections. design/methods: we compared the results of biopsies from patients with parkinson's disease (pd), using tissue sections each of , and μm thickness. tissues were stained with pgp . and stained for phosphorylated alpha-synuclein (p-syn). the total number of dermal structures (hair follicles, sweat glands, pilomotor muscles) were quantified, nerve densities analyzed, and the frequency of p-syn positive results. we also studied μm paraffin embedded tissue samples from patients with pd. results: in the biopsies of patients with pd there were no differences in the number of sweat glands, hair follicles or pilomotor muscles in , or μm sections. there were significantly fewer blood vessels noted in and μm sections compared to μm sections (p< . ). ienfd and sgnfd declined with tissue thickness (p. . , all) and there was increased variability in results in thinner tissue sections. there was a highly significant reduction in p-syn positive sections in thinner tissue sections (p< . , all tissues compared to μm sections). paraffin embedded tissue sections had significantly lower nerve densities and positive p-syn results (p< . ) compared to all frozen tissue sections of , and μm thickness. thinner tissue sections carried a greater risk of false positive result or indeterminate results due to difficulty interpreting overlap with pgp . . conclusions: tissue sample thickness plays a critical role in interpretation of skin biopsy results. thinner tissue sections, or paraffin embedded tissue sections, do not provide equivalent data and significantly underestimate nerve densities and positive alpha-synuclein results with increase false positive results despite similar numbers of dermal tissue structures. ace- is an investigational protein therapeutic that acts as a localized ligand trap for myostatin and other negative regulators of muscle growth. local injection of ace- into the gastrocnemius muscle of wild-type, mdx, and sod mice produced dose-dependent increases in muscle mass and force without systemic effects. in a phase single-center, double-blind, placebo-controlled dose escalation study in post-menopausal women, unilateral injections of ace- into the rectus femoris (rf) or tibialis anterior (ta) muscle were generally safe and well tolerated. mean percent changes from baseline in muscle volume of the injected muscle were + . % in the rf and + . % in the ta at the highest dose administered with minimal changes observed in the contralateral side and placebo-treated subjects. frequent related aes (≥ %) included injection site pain, pain in extremity, injection site discomfort, and muscle twitching, with similar incidence in ace- and placebo-treated groups. all aes were grade - and reversible. together, these preclinical and clinical results support further studies of ace- in myogenic and/or neurogenic diseases with focal loss of muscle strength and function, including cmt. a phase study is ongoing in facioscapulohumeral muscular dystrophy (fshd). study a - is an ongoing multicenter, two-part, phase study to evaluate the safety, tolerability, pharmacodynamics, efficacy, and pharmacokinetics of ace- in patients with cmt and cmtx. part is open-label and will enroll up to dose-escalating cohorts ( patients per cohort); part is randomized, double-blind, and placebo-controlled, and will enroll an additional patients. ace- will be administered bilaterally to the ta muscle once every three weeks for up to five doses. a safety review team will meet periodically throughout the study to review safety data and make dosing recommendations, including the recommended dose level for part . eligible patients must have genetically confirmed cmt or cmtx with mild-moderate weakness in ankle dorsiflexion. safety and tolerability will serve as the primary outcome for part , muscle volume evaluated by mri for part . additional outcome measures of interest include strength by quantitative muscle testing, function by motor tests, and quality of life by the cmt-health index questionnaire. our study was aimed to evaluate the functional and morphological consequences of cellular and humoral responses in chronic inflammatory demyelinating neuropathy (cidp), using extensive standardized high-resolution sonography (hrus) and nerve conduction study (ncs) protocols in incident treatment-naive patients. we enrolled consecutive, newly diagnosed, treatment naive patients with cidp. in addition to all relevant clinical examinations, all patients underwent a standardized ncs and extensive hrus protocol, of median, ulnar, tibial, fibular and sural nerves. we assessed standard nerve and fascicle size, and echogenicity. we found focal sonographic enlargements in multiple nerves and nerve segments with and without ncs abnormalities. the degree of nerve hypertrophy was not associated with presence of ncs features of demyelination, i.e. / ( %) of median nerve segments showed enlargement without strong decrease in motor conduction velocity and / ( %) hypertrophic median nerve segments revealed no conduction block. a lower distal cmap of median nerve was related with lower mrc sums-scores (p < . ). we found no correlation between age, disease duration or mrc sum-score and nerve size. cellular and humoral responses in cidp may lead to nerve enlargement along the length of nerves, that can be detected by hrus, whereas ncs allows identification of its' specific focal disruption in nerve function. the most common complication of diabetes is peripheral neuropathy, which has prevalence as high as % and is characterized by damage to neurons, schwann cells and blood vessels within the nerve. the concept of schwannopathy as an integral factor in the pathogenesis of diabetic neuropathy is re-emerging, and it is now known that schwann cells cultured in hyperglycemic environments underproduce neurotrophins and exhibit loss of axonal associations, further indicating a non-optimal glial cell activation and function. furthermore, the increased expression of p ntr in myelin sheaths around fibers that are susceptible to axonal degeneration in diabetic neuropathy suggest an important role for this molecule in disease progression. with this project, it is our main goal to evaluate how disruption of p ntr signaling in the schwann cells affects the pathophysiology of diabetic neuropathy. by using a fluorescent live/death cell viability assay, our preliminary data indicate that wild-type schwann cell cultures present increased cell death rate h after stimulation with high levels of glucose. the p ntr has a highly recognized role in the activation of death signals and when absent, we observed that schwann cells are significantly more resistant to apoptosis in hyperglycemic conditions. the role of p ntr receptor signaling in neuron-schwann cell communication and myelination under in vitro diabetic conditions was investigated with primary schwann cell-sensory neuron co-cultures. after eight days of ascorbic acid stimulation, both under euglycemic and hyperglycemic conditions, myelination was assessed by confocal microscopy using specific markers for neurons and myelin. results highlight a compromised ability of wild-type schwann cells to myelinate axons when exposed to a hyperglycemic environment, which was even intensified in co-cultures with schwann cells lacking the p ntr . to complement the in vitro studies, we are modeling type diabetes in a p ntr schwann cell conditional ko mouse model and plan to investigate nerve mrna expression profile to disclose genetic regulation depending on this receptor signaling and its modulatory role in endoneurial hypoxia and neuroinflammation. the results from this project will provide an integrated vision of how impaired schwann cell activity guides neuropathy progression. gondim faa , barreira aa , cruz mw , cunha fmb , de freitas m , frança mc jr , marques w jr , nascimento ojm , oliveira asb , pereira rc , pupe c , rotta ft , schestatsky p . panelists on behalf of the scientific department of peripheral neuropathy, brazilian academy of neurology, brazil. neuropathy is one of the most common neurological manifestations of several diseases and sfn has been progressively receiving more attention in the medical literature. the aim of this study is to generate a set of recommendations to define and diagnose sfn in brazil. a group of neurologists, members of the scientific department of peripheral neuropathy from the brazilian academy of neurology reviewed a preliminary draft prepared by the first author that was distributed by email. the panelists got together on . . at the city of fortaleza, brazil, to discuss and finish the text for the first submission of the manuscript. sfn can be defined as a subtype of neuropathy characterized by selective involvement of unmyelinated or thinly myelinated sensory (sometimes also autonomic) fibers. it is usually characterized by sensory (pain/dysesthesias/pruritus) or combined sensory and autonomic complaints, associated with an almost entirely normal neurological examination (except for sensory changes). electromyography is normal. a growing list of medical conditions has been linked to sfn, although there is no evidence-based literature to support the use of any specific set of screening tests to diagnose the etiology of sfn (the panelists will suggest a basic screening panel). sfn may also serve as a fallacious but useful terminology to uncover discrepancies in the normal values from different neurophysiology laboratories. in brazil, skin biopsy is not usually performed and initial forms of leprosy may have predominant small fiber involvement. there are several tests to demonstrate involvement of small sensory and autonomic fibers. skin wrinkling test, sympathetic skin responses & heart rate variability (conducted on emg machines) and thermoregulatory sweat test may be low-cost screening alternatives. after the final meeting on . . , we finished the first draft for submission to arquivos de neuropsiquiatria (together with a translation to portuguese as supplementary material), the official journal of the brazilian academy of neurology to serve as a source for the definition and diagnosis of sfn in brazil. the final draft will be submitted after presentation at the pns meeting in barcelona on . . the lower cranial nerves (lcn) include the paired glossopharyngeal, the vagal, the accessory and the hypoglossal nerves. these are involved in the execution of swallowing, speech, phonation, tasting, as well as sensory and autonomic functions. lcn can be affected in central and peripheral nervous system diseases. this study investigates the use of ultrasound (us) to detect lesions of the peripheral course of lcn. in addition mri can be used in unilateral lcn local lesions to demonstrate indirect signs of nerve lesions such as muscle atrophy. the patients were examined in supine position with the neck in maximum extension with either a regular or a portable us system (logiq e and logiq e ge healthcare, milwaukee, wisconsin) and high frequency transducers ( to mhz). according to the detected pathology longitudinal or transversal images were recorded. a series of exemplary observations are demonstrated. in one case a paraganglioma in the glossopharyngeal nerve at the carotid sinus was found. in another patient an us of the thyroid gland revealed a nerve tumor, which was later identified to be a schwannoma. in another case multiple neurofibroma were identified in the vagal nerve during a routine neurofibromatosis screening. us has become also important in investigations of lesions of the accessory nerve, following damage by surgery. nerve continuity and scar formation can be distinguished. lesions of the hypoglossal nerve can be caused by tumor infiltration. in one patient an infiltration of the nerve by a squamous cell carcinoma, and in another case by a low grade sarcoma were detected. in addition mri demonstrated an atrophy of the tongue. identification and assessment of the lcn from the point of exit of the skull to their endpoint can be pursued by us techniques, which have been described for the individual nerves. us is easily applicable and -in addition to the "static" image of the mri -allows assessing nerve positions during different movements, as well as detecting muscle movements as fasciculations. mri can also be used to detect not only more proximal lesions, but also changes of the skeletal muscle by denervation. grümme l , hattenhauer st , wolffram k , kleinschnitz c , mausberg ak , stettner m . university hospital essen, essen, germany; heinrich-heine-university, düsseldorf, germany. in chronic inflammatory demyelinating polyneuropathy (cidp), t cells are suspected to play a crucial role in myelin destruction. cd and cd t cells contribute to the inflammatory process, while the exact mechanism of myelin damage is still under debate. to elucidate the molecular interaction of t cells and myelin sheets, we compared neuritogenic and control cells in a live imaging in vitro model. the myelinated fibres of rat dorsal root ganglia (drg) served as model for the peripheral nervous system. drgs of embryonic (e ) lewis rats were cultured; myelination was initiated after one week in vitro and continued for two additional weeks. lewis rats immunized with p and neuritogenic t cells of the lymph nodes were obtained ten days after immunization. control t cells were prepared from healthy rats. for vital tracking, neuritogenic t cells were stained with orange cell tracker, while the control cells were labelled with cfse. myelin detection in vital cultures was assessed by incorporation of c fatty acids conjugated with a fluorophore into the myelin layer. experiments were performed in a conditioned microscope chamber, the two t cell populations were added simultaneously to the drg culture and migration was tracked using live cell imaging. we observed differing migration patterns for neuritogenic and control t cells. the velocity as well as the directionality was altered. after initial contact, the non-neuriotgenic t cells in close proximity to myelin subsequently decreased over time, while the numbers of neuritogenic t cells close to myelin remained stable. long term incubation with neuritogenic t cells affected the myelin integrity in regard to the intermodal length as well as the myelin ratio. further experiments will elucidate the specific effects of neuritogenic t cells to decipher the role of t cells during inflammation in the pns, which could be useful in developing targeted therapies. gundapaneni b , sultan mb , keohane dj , schwartz j . inventiv health inc., burlington, ma, usa; pfizer inc., new york, ny, usa. transthyretin familial amyloid polyneuropathy (ttr-fap) is a rare, life-threatening disorder caused by protein destabilizing ttr gene mutations, broadly classified as val met (the most common mutation worldwide) and non-val met genotypes. tafamidis, a highly-specific ttr-stabilizer, is the only medicine approved to delay neurologic progression in ttr-fap. the objective of this post-hoc analysis was to compare the effects of tafamidis on neuropathy progression in patients with val met and non-val met genotypes. val met patients were participants in a randomized, double-blind, placebo-controlled clinical trial of tafamidis, while non-val met patients were participants in an open-label tafamidis study. patients were grouped into three cohorts: val met tafamidis (n= ); val met placebo (n= ); and non-val met tafamidis (n= ). baseline disease severity and change in disease severity from baseline to month was assessed using the neuropathy impairment score-lower limbs (nis-ll). the effect of tafamidis in the val met and non-val met cohorts versus the val met placebo cohort was determined using a mixed-effects model for repeated measures (mmrm). at baseline, patients in the non-val met cohort were older, had longer symptom duration, and more advanced neurologic impairment than the val met cohorts. at month , the baseline-adjusted mean ± standard error change in nis-ll was comparable between the val met tafamidis and non-val met tafamidis cohorts ( . ± . and . ± . , respectively). these changes were smaller than that observed in the val met placebo cohort ( . ± . ; p= . vs val met and p= . vs non-val met) indicating less disease progression. based on predicted values from the mmrm analysis, the size of the change in nis-ll across the full range of baseline nis-ll scores was remarkably similar in the val met tafamidis and non-val met tafamidis cohorts and was consistently smaller than that observed in the val met placebo cohort. moreover, in all three cohorts, as baseline nis-ll increased, the predicted level of disease progression also increased. in conclusion, while controlling for baseline disease severity, tafamidis delayed disease progression to a comparable extent in val met and non-val met patients. the similar trajectories of disease progression across val met and non-val met patients suggest that these two genotype groups may be more similar than previously considered. clin-icaltrials.gov identifiers: nct ; nct . gutmann l , shy m . university of iowa, iowa city, ia, usa. post tetanic potentiation (ptp) is a physiological phenonmenon seen with disorders of the neuromuscular junction (nmj). it is caused by the influx of ca++ into the terminal axon during the tetanus resulting in an increased number of acetylcholine (ach) vescicles released by each axonal action potential. in myasthenic syndromes it results in improved nmj function by increasing the probability of achieving a large enough end plate potential to generate a muscle action potential. ptp has different appearances depending on whether the nmj defect is pre-synaptic or post-synaptic. in pre-synaptic defects (the most common being lambert-eaton syndrome) there is an increased amplitude of the muscle action potential after a tetanus that persists up to minutes. prolonged ptp has now been reported in disorders, one on a genetically determined neuropathy/myasthenic basis and the other on an acquired toxic origin. prolonged ptp up to minutes was reported in families with a motor neuropathy (having leg weakness and foot deformites) and a congenital myasthenic syndrome caused by a heterozygous mutation of the synaptotamin ii (syt ) gene (c t>g p.pro [p.asp ala] and c g>a [p.pro leu]). electrophysiological testing showed features of a presynaptic defect with prolonged ptp persisting up to minutes. the same phenomenon has been noted in the acquired pre-synaptic defect caused by botululinum toxin. the ptp continued up to minutes. syt is the synaptic vescicle calcium sensor in the terminal axon, allowing for fusion of ach containing vescicles with the presynaptic membrane and the synchronous release of ach. the fusion requires a complex assembly process involving snare proteins. both the syt gene mutation and botulinum toxin affect normal syt function, the mutation by altering amino acids in the calcium-binding domain and the toxin by binding to syt as well as gangliosides gd a and gt b on the neural membrane. the mechanism for the ptp prolongation remains unknown. prolonged ptp appears to be a unique physiological abnormality resulting from altered syt . this phenomenon has been decribed to occur in syt mutations causing congenital motor neuropathy/myasthenic syndrome and botulism. the abnormality may represent a physiological marker for a presynaptic nmj defect involving altered syt . hachisuka a , , senger j , curran m , chan km , . division of physical medicine and rehabilitation, university of alberta, edmonton, canada; department of rehabilitation and medicine, university of occupational and environmental health, kitakyushu, japan; division of plastic surgery, university of alberta, edmonton, canada. background: motor unit number estimation (mune) techniques are valuable tools in neuromuscular disease. among them, the multiple point stimulation (mps) is one of the most common used. contamination by distant single motor unit potentials (smups) generated by neighboring muscles is a potential confounding factor. this is particularly problematic in ulnar neuropathy, one of the most common neuropathies in humans. reason being that the ulnar nerve innervates the majority of hand muscles. the goals of this study are to test the hypotheses that ) distant smups all have an initial positive deflection and ) elimination of smups generated by distal muscles will significantly lower the mune results in the hypothenar muscles. methods: to address the first hypothesis, we tested subjects by stimulating their median nerve while recording smups simultaneously over the hypothenar and thenar muscles. for the second hypothesis, we carried out mps mune of the hypothenar muscles using multi-channel recordings placed over ulnar innervated intrinsic muscles across the hand. when a smup with an initial positive deflection was detected at the hypothenar electrodes, its original was systemically tracked through all the recording channels. results: in the first series of experiments, in accordance with the dipole theory, all smups recorded at the hypothenar recording electrodes had an initial positive polarity. in the second series of experiments, of the studies carried out in subjects, distant smups generated by muscles other than those in the hypothenar eminence represented ± . % (mean±sd) of the overall sample. mune calculated using only smups generated by the hypothenar muscles was ± , compared to ± if all smups were included (p < . ). the extent of increase in mune was highly correlated with the proportion of distant smups found in each study (r = . , p < . ). conclusion: in contrary to some studies suggesting that smups from distant muscles could have an initial negative deflection, we found all smups from distant muscles had a positive deflection. exclusion of those smups from the sample had a significant impact on the mune results. hagiwara w , konno s , kihara inoue m , fujioka t . toho university, tokyo, japan. matrix metalloproteinase (mmp) plays crucial roles in developing immune-mediated neuritis as guillain-barré syndrome (gbs) and its animal model experimental autoimmune neuritis (ean). to investigate the intraneural expression of mmps during ean and the effect of a phosphodiesterase- inhibitor cilostazol (clz) on it, ean rats were treated with either mg/kg/day of clz or vehicle from one day post immunization (dpi). to induce ean female lewis rats were immunized with synthetic peptide from bovine p protein. cauda equina (ce) were removed in several time points, total rna was extracted and reverse-transcribed to obtain cdna that was subjected to real-time pcr analysis for expression of mmp- , mmp- and tissue inhibitor of matrix metalloproteinase- (timp- ) messages. mmp- and mmp- messages peaked at dpi, that is presymptomatic phase of ean. all rats developed motor paralysis at dpi, mmp- and mmp- messages subsided at this moment. however, timp- message reciprocally increased at dpi, persisted through dpi. treatment of clz suppressed motor paralysis of ean significantly. mmp- message peaked at dpi and mmp- message peaked at dpi. on the other hand, both messages at dpi were suppressed compared to untreated ean rats. timp- message in clz treated rats peaked at dpi coincided with motor paralysis peak. both mmp- and mmp- messages might result in subsequent upregulation of timp- that finally downregulates mmps activity and inflammatory process. clz treatment suppressed and delayed expression of mmps and facilitate timp- expression, resulting suppression of ean. the precise mechanism of expression of mmps and timp- remain unclear, however, that mmp- and mmp- messages peaked at dpi suggests involvement of pro-inflammatory cytokines such as tumor necrosis factor-alpha or interleukin- . clz might suppress these cytokines resulted in mmps down regulation. mmp- less affected by clz and thus stimulated timp- expression at dpi. clz might rational treatment for immune-mediated neuropathy via mmps modulation although further investigation especially in-vivo study is needed. haidar m , de winter v , asselbergh b , bouhy d , timmerman v . peripheral neuropathy research group, vib, university of antwerp, antwerp, belgium. the small heat shock protein hspb (hsp ) gene is ubiquitously expressed and encodes for a chaperone protein with essential cellular functions. our lab was the first to identify missense mutations in hspb responsible for axonal charcot-marie-tooth neuropathy (cmt f). since then we became interested in understanding the physiological functions of hspb and its association with cmt neuropathies. we demonstrated the involvement of hspb in microtubule stability. because of the link between autophagosome formation and its intracellular transport, and microtubules stability, we believed that the macro-autophagy process could be regulated by hspb . macro-autophagy is a cellular housekeeping process during which autophagosomes target, envelop and degrade aberrant protein aggregates and damaged organelles. there is strong evidence for an essential role for autophagy in the maintenance of neuronal homeostasis; hence its impairment can lead to a neuropathic condition. our data indicate that macro-autophagy is disrupted by hspb cmt-causing mutations. combining novel microscopy and interactomics techniques we unravelled the way different cmt-causing mutations in hspb impair the autophagic pathway. our data present the impairment of autophagy as a possible pathomechanism for cmt-causing hspb mutations. hajjar h , gautier b , berthelot j , gonzalez e , gess b , young p , tricaud n . institute of neurosciences of montpelllier, inserm, university of montpellier, montpellier, france; universitätsklinikum münster, klinik für schlafmedizin und neuromuskuläre erkrankungen, münster, germany. cmt a, the most common of charcot-marie-tooth diseases, results from the duplication of peripheral myelin protein (pmp ) gene. this gene encodes for a small protein of kda, pmp , mainly produced by schwann cells and the excess of pmp leads to demyelination. there is no cure for this disease but one approach for a treatment is gene therapy. a transgenic rat model exists for cmt a, which possesses copies of the mouse pmp gene. our goal is to provide a proof of principle for gene therapy in peripheral nerves using this rat model of cmt a. our strategy is to reduce the overexpression of mouse pmp protein in rats schwann cells using short hairpin rnas (shrnas). shrnas are small non-coding rnas that specifically bind to targeted mrnas resulting in their degradation. we tested for the efficiency of several shrnas targeting mouse pmp in vitro to find two shrnas that reduce pmp levels. the shrnas have been cloned in an adeno-associated serotype (aav ) viral vector together with green fluorescent protein in order to detect infected cells. aav was selected for its high transduction rate of myelinating schwann cells, for its good diffusion and low immunogenicity. we plan bilateral injections in the sciatic nerve of control and diseased rats. the efficiency of this gene therapy will be checked by assessing muscle strength (grip test), way of walking (catwalk), mobility (rotarod) and nerve conduction velocity of treated cmt a rats versus non-treated. the process of myelination and myelin maintenance in schwann cells will be analyzed by biochemistry and electron microscopy. biochemical tests include western blot for pmp protein expression in sciatic nerve, immunohistochemistry for pmp protein expression in myelinating schwann cells and pcr for mrna pmp expression. if the therapy is successful in rats, it could possibly be later on used in clinical trials. ultrasound is a widely-used tool in diagnosing carpal tunnel syndrome (cts). several different methods for sonographical evaluation of median nerve damage exist, such as calculating the ratio of cross sectional areas (csa) of median nerves in various sites. this enables detection of actual nerve swelling proximal to the carpal tunnel as an expression of median nerve damage inside the carpal tunnel (as seen in cts). in comparison to other diagnostic methods no data exist about the prevalence of cts like changes in an unselected population. a series of non-selected fresh cadavers were examined. arms of fresh, non-embalmed whole body cadavers were examined. the medical record did not allow to obtain conclusive information on the peripheral nerves. using a regular ultrasound system with a mhz transducer, median nerves were identified and tracked along their course in the forearms. csa measurements of the median nerves were performed at two sites in each arm: .) halfway between the elbow joint and wrist, .) directly proximal to the carpal tunnel. csa ratio was calculated with the following formula: csa ratio = csa wrist (cm ) csa forearm (cm ) csa ratio < . was found in ( . %) arms, csa ratio ≥ . in ( . %) arms and csa ratio ≥ in ( %) arms. csa ratio ≥ . was detected in . % of women and % of men. the overall mean (± sd) age was . ± . years. men ( . ± . ) were significantly younger than women ( . ± . ; p = . ). a weak but significant correlation between age and csa ratio was found in women (spearman -− . ; p= . ), but not in men (p= . ). the mean bmi for csa ratio ≥ . was . ± sd . . based on a csa ratio ≥ . as a criterion for cts, the present ultrasound results are consistent with the average cts prevalence reported in previous studies, which were obtained with electrophysiological methods. this study on a large unselected series of cadavers confirms the comparability of both methods. instrumental activities of daily living (badl and iadl), falls and gait patterns in the large, prospective, population based rotterdam study. in total, participants of this study (mean age years, % women) underwent a polyneuropathy screening involving a symptom questionnaire, neurological examination and nerve conduction studies. screening yielded four groups: no, possible, probable and definite polyneuropathy. participants were interviewed about badl (stanford health assessment questionnaire), iadl (instrumental activities of daily living scale) and frequency of falling in the previous year. in a random subset of participants, gait was assessed with an electronic walkway (gaitrite). associations of polyneuropathy with badl and iadl were analyzed continuously with linear regression, and dichotomously with logistic regression. history of falling was evaluated with logistic regression and gait changes were evaluated with linear regression. we found that participants with definite polyneuropathy had more difficulty in performing badl and iadl than participants without polyneuropathy. polyneuropathy related to worse scores of all badl (especially walking) and three iadl components (housekeeping, traveling, and shopping). participants with definite polyneuropathy were two times more likely to fall, and these falls more often resulted in injury. participants with polyneuropathy had worse gait parameters on the walkway, including lower walking speed and cadence, and more errors in tandem walking. in summary, chronic polyneuropathy is strongly associated with significant impairment in daily life. recognition of polyneuropathy and related disability is very important in order to inform, support and possibly treat patients, and to prevent future falls and dependence in daily functioning. patients with polyneuropathy often suffer from tingling sensations, numbness, weakness and pain. these symptoms are used in several screening questionnaires, most of which were developed for high-risk patient groups, such as individuals with diabetes mellitus. in most tools equal weights are applied to all symptoms, while some might be more informative than others. we evaluated the diagnostic value and frequency of occurrence of individual symptoms of chronic polyneuropathy and constructed and validated a simple screening questionnaire that can reliably help to diagnose polyneuropathy in low-risk patient groups. in a multi-step procedure, we initially compiled a twelve-item questionnaire concerning symptoms of polyneuropathy. the questionnaire was completed by polyneuropathy patients and controls (headache, transient ischemic attack, multiple sclerosis). we calculated the sensitivity, specificity and likelihood ratios of each individual symptom. next, stepwise multivariable logistic regression was used to create a compact model, able to discriminate cases from controls using only the most informative symptoms. a simple scoring system was subsequently developed based on the regression coefficients of this reduced model. external validation was subsequently conducted in a population of cases with chronic idiopathic axonal polyneuropathy and controls without polyneuropathy. performance was assessed with discrimination (area under the curve, auc), and calibration. numbness and tingling feet were most frequently reported by polyneuropathy patients and had the highest sensitivity. feeling as if walking on cotton wool and allodynia of the feet had the highest specificity. multivariable logistic regression yielded a model that contained these four symptoms, complemented with balance problems and tingling hands. based on this regression analysis, the erasmus polyneuropathy symptom score (e-pss) was created, a score ranging from to . this polyneuropathy symptom score had a good performance (auc . ) in de derivation set and proved to be valid in the external population (auc . ). in this study, we created a simple, validated polyneuropathy symptom score (e-pss) that takes both the individual value of only six different symptoms and its frequency into account. this tool can be helpful as screening instrument in clinical practice and for future studies on polyneuropathy. multiple sclerosis (ms) is traditionally viewed as a central nervous system disease. to date, there is no unequivocal evidence implicating involvement of the peripheral nervous system (pns). this study aims to prove whether the pns is additionally affected and if so, to detect, localize and quantify these peripheral nerve lesions in patients with multiple sclerosis (ms) by applying high-resolution mr-neurography (mrn) with large anatomical coverage in combination with standard electrophysiological and neurological tests. we prospectively enrolled patients with confirmed ms (> years), two patients with clinically isolated syndrome (cis), and age-/sex-matched healthy volunteers. any other potential causes for a concomitant polyneuropathy were excluded. all ms patients underwent detailed neurological and electrophysiological testing. tesla mrn with large anatomical coverage from lumbar plexus and spinal nerves down to ankle level was performed in all participants by using fat-saturated, t -weighted turbo-spin-echo (tse) sequences (tr/te / ms) and a dual echo tse sequence for t -relaxometry (tr ms; te /te / ms). a d t -weighted, fat-saturated space sequence (tr ms; effective te ms) was used for imaging of the lumbar plexus. manual segmentation of spinal/sciatic/tibial/peroneal nerves was performed on a total of , axial slices. besides evaluation of nerve t w-signal, detailed quantification of nerve lesions by analyzing morphometric (nerve caliber) and microstructural markers (proton-spin-density and t -relaxation-time) was conducted. mean lesion load at thigh level was higher in ms ( . ± . ) vs. controls ( . ± . ;p< . ). nerve proton-spin-density was also higher in ms (tibial/peroneal: . ± . / . ± . ) vs. controls (tibial/peroneal: . ± . / . ± . ;p< . ). in contrast, t -relaxation time was significantly higher in controls (tibial/peroneal: . ± . / . ± . ) vs. ms (tibial/peroneal: . ± . / . ± . ;p< . ). proximal tibial and fibular nerve caliber was also significantly higher in ms (tibial: p< . ; fibular: p= . ). for the first time, pns lesions in ms patients could be visualized and quantified in vivo by high-resolution mrn. lesions are indicated by an increase of proton-spin-density and a decrease of t -relaxation-time. nerve caliber as a morphometric criterion also significantly increased. this proof-of-concept study may offer new insights into the pathomechanism of ms and might have future implications on therapeutic approaches. immunoglobulin g (igg) fc-gammars confer diverse effector functions by linking the cellular and humoral arms of the immune system that has been involved in the pathogenesis of guillain-barré syndrome (gbs). in the post-polio era, the polymorphisms of fc-gammar and their relevant knowledge have become one of the main targets for new therapeutic strategies for the treatment of gbs patients. differences in severity and frequency of gbs subtypes found between south-asian and western populations can be attributed to their genetic susceptibility. therefore, we aimed to determine fc-gammar polymorphic alleles (fc-gammariia: h /r ; fc-gammariiia: v /f ; fc-gammariiib: na /na ) and their possible link with gbs on the currently available large gbs cohort in bangladesh. fc-gamma r polymorphisms of gbs patients and healthy controls were genotyped using sequence-specific pcr. for validation, we carried out the sequencing of some samples for fc-gammariia and fc-gammariiia alleles. no significant differences were found regarding the distribution of fc-gammar genotypes and allele frequencies in gbs patients and controls. fc-gammar-h/h- genotype was significantly predominant in patients with severe disease compared to patients with mild disease (p= . , or, . ; % ci, . - . ). no other significant associations were found in gbs patients for candidate alleles and disease severity. fc-gammariiia-f/f- was found to be significantly predominant in anti-gm antibody positive gbs patients compared to anti-gm antibody negative patients (p= . , or, . , % ci, . - . ). fc-gammariiia-v alleles were significantly higher in patients with poor prognosis when compared to patients with good outcome (p= . , or, . , % ci, . - . ). no significant association of fc-gammariiib genotypes and alleles were found with gbs patients, disease severity and disease outcome. extensive subgroup analysis revealed no significant association in genotype and allele frequencies between aman and aidp subtype. in conclusion, igg fc-gammar polymorphisms do not constitute significant risk markers for susceptibility to gbs, however homozygous fc-gammariia-h might be involved in the severe form of gbs. in addition, fc-gammariiia-f/f- might play an important role in the molecular mimicry against nerve gangliosides in gbs. further studies that enroll a large number of patients (e,g. igos) are required to confirm the present findings from different geographical areas. hayes jm , o'brien pd , backus c , feldman el . department of neurology, university of michigan, ann arbor, mi, usa. peripheral neuropathy (pn) is a common complication observed in patients with impaired glucose tolerance and type diabetes. male mice fed a high fat diet (hfd) develop metabolic impairments and pn serving as an appropriate animal model to study pn development and progression. it is well documented that female mice fed a hfd display a degree of protection against hfd-induced metabolic changes with mice retaining relatively normal insulin sensitivity. this protection is attributed to differences in fat accumulation and to the anti-diabetic effects of estrogen. based on these sex-dimorphisms we hypothesized that hfd-fed female mice would also exhibit resistance to developing pn. in the present study male and female c bl /j mice were fed either a standard diet ( % kcal fat; sd) or a high fat diet ( % kcal fat; hfd) from wk. at wk, wk and wk, neuropathy phenotyping was performed on all groups complemented with longitudinal metabolic assessments including insulin tolerance testing (itt). neuropathy phenotyping consisted of hindpaw latency to heat stimulus, motor and sensory nerve conduction velocities (ncvs), and terminal intraepidermal nerve fiber (ienf) counts. assessment of insulin resistance through itt demonstrated that during early hfd feeding, female hfd-fed mice exhibited relatively normal insulin responsiveness, while male hfd mice exhibited insulin resistance. despite this finding, wk female hfd mice displayed a similar pattern of pn to that of their male counterparts, with similar fold-changes in hindpaw latency and sensory and motor ncvs. therefore, although female hfd-fed mice exhibit resistance to hfd-induced metabolic changes, they display a pn comparable to male hfd-fed mice suggesting that systemic insulin resistance does not mediate pn. further studies are underway investigating the role of insulin signaling in the peripheral nerves of female hfd-fed mice. anti-mag (myelin-associated glycoprotein) neuropathy is a disabling autoimmune peripheral neuropathy caused by monoclonal immunoglobulin m (igm) autoantibodies that recognize the carbohydrate epitope hnk- (human natural killer- ). this glycoepitope is highly expressed on adhesion molecules, such as mag, present in myelinated nerve fibers. since the pathogenicity and demyelinating properties of anti-mag autoantibodies are well established, current treatments aim at a reduction of autoantibody levels. however, the therapies applied so far are primarily immunosuppressive and lack selectivity and efficacy. we therefore hypothesized that a significant improvement of the disease condition could be achieved by selectively neutralizing the pathogenic anti-mag antibodies with carbohydrate-based ligands mimicking the natural hnk- glycoepitope. in an inhibition assay, a mimetic (mimhnk- ) of the natural hnk- epitope inhibited mag-binding by pathogenic igm antibodies from patient sera, however only with micromolar affinity. therefore, considering the multivalent nature of the mag-igm interaction, polylysine polymers of different sizes were substituted with the mimetic. with the most promising polylysine glycopolymer pl (mimhnk- ) the inhibitory effect on patient sera was improved by a factor of up to , per epitope, consequently leading to a low nanomolar inhibitory potency. since clinical studies indicate a correlation between the reduction of anti-mag igm levels and clinical improvement, an immunological surrogate mouse model for anti-mag neuropathy, producing high levels of anti-mag igm, was developed. the observed efficient removal of these antibodies with the glycopolymer pl (mimhnk- ) represents a first step towards an antigen-specific therapy for anti-mag neuropathy. hinder lm , mendelson f , backus c , feldman el . university of michigan, ann arbor, mi, usa. in the united states % of children and young adults are obese and at risk of developing prediabetes. prediabetic patients largely develop the same macro-and microvascular complications as patients with type diabetes, including peripheral neuropathy (pn). moreover, recent clinical data suggest normoglycemic obese patients develop pn. central obesity, characterized by excess fat storage in visceral white adipose tissue, leads to systemic metabolic dysfunction largely due to an imbalance between pro-inflammatory/anti-inflammatory adipokine production. subcutaneous adipose tissue is considered 'benign', but adopts a visceral-like phenotype in response to metabolic stress, with reduced thermogenicity, reduced brown adipose identity, and increased pro-inflammatory gene expression. the popliteal adipose tissue (pat) depot, corresponding to subcutaneous adipose, is adjacent to the peripheral nerve affected in pn, contains the lymph node for lymphatic drainage of the hind limb, and expands following local, sterile hind paw inflammation. the aim of the current study was to characterize pat changes in the high fat diet (hfd) mouse model of obesity and pn, and consider its contribution to peripheral nerve dysfunction. we previously reported c bl /j mice fed % hfd from - wk develop obesity, 'prediabetes' and pn; and switching mice back to a standard diet from - wk improves metabolic and pn phenotypes. at and wk pat was bilaterally dissected and the lymph node removed. the left pat was processed for histomorphometry, and the right pat for rt-qpcr. at wk hfd was associated with a significant shift in adipocyte size-frequency distribution, with a greater number of larger adipocytes. switching the hfd mice back to standard chow from - wk restored the size-frequency distribution towards age-matched controls. rt-qpcr was performed to assess changes in thermogenicity (ucp ), brown adipose identify (cidea) and sterile inflammation (saa ). at and wk hfd pat had reduced thermogenicity and brown adipose identify, and increased sterile inflammation. this switch towards a visceral-like phenotype was reversed in the hfd mice switched back to standard chow. in summary, hfd-induced changes in pat histomorphometry and adipose identity closely associate with pn phenotype. these preliminary data suggest a potential role for pat-nerve signaling in pn. hinder lm , backus c , hayes jm , feldman el . university of michigan, ann arbor, mi, usa. peripheral neuropathy (pn) is a common and debilitating complication of obesity and diabetes that triggers pain and loss of sensation. substantial nerve damage occurs in many patients prior to noticeable symptoms and no treatments are currently available; therefore, there is a critical need to identify treatment strategies that impact the underlying disease pathogenesis. our in vivo fluxomics data in the bks-db/db mouse model of type diabetes (t dm) and pn suggest that 'metabolic reprogramming' occurs in the t dm nerve to downregulate mitochondrial oxidative phosphorylation of substrates derived from glycolysis and fatty acid beta-oxidation. therefore, we hypothesize that distinct systemic metabolic alterations occur in obesity and diabetes which induce tissue-specific metabolic reprogramming within the peripheral nerve, altering fuel utilization and ultimately leading to tissue dysfunction. we contend that identifying conserved bioenergetic profiles across mouse models of pn will provide insight into key pn mechanisms. the current study utilized two mouse models of pn: the % high fat diet (hfd) mouse model of obesity and prediabetes at wk of age ( wk hfd), and the leptin receptor-deficient bks-db/db model of t dm at wk of age. mitochondrial function was determined in primary dorsal root ganglia (drg) neurons and sural nerve tissue from both models using the seahorse xf analyzer. resting mitochondrial oxidative metabolism was upregulated in drg neurons from mice with pn, with increased resting atp production and maintained mitochondrial coupling. in contrast, resting atp generation was decreased in sural nerve from mice with pn, with decreased coupling efficiency. relative spare respiratory capacity was attenuated in both drg neurons and sural nerve from mice with pn, indicating that mitochondria were less able to increase respiration in response to an energetic challenge. moreover, mitochondrial copy number was unchanged in drg neurons, but decreased in sural nerve tissue of mice with pn compared with respective controls. these data suggest a change in absolute number and function of sural nerve mitochondria, and a conserved cross-model proximal-distal bioenergetic profile in pn. we are currently exploring the relationship between these changes and pn pathogenesis. hoang ttn , umapathi t . hospital, ho chi minh city, vietnam; national neuroscience institute, singapore. ho chi minh city (hcmc) is the biggest metropolitan city in southern vietnam. its population is more than ten million. adult patients with neurological disorders are seen at six city public hospitals, including , hospital. there has been no systematic study of guillain barré syndrome (gbs) at hcmc or in vietnam in general. we are in the process of starting a prospective gbs database that we hope to expand to the other public hospitals at hcmc. here we describe our experience from . we saw gbs patients at , hospital. most of the cases were admitted in the rainy season, from late april to november, when mosquito-borne flavivirus infections are more common. patients were seen in the first week of illness and reported antecedent fever. two patients had diarrhea. diagnoses were made largely on clinical features, cerebrospinal fluid analysis and nerve conduction study. clinical findings include limb weakness, numbness and vii cranial nerve palsy. extraocular eye movements were affected in one patient. none had respiratory involvement severe enough to require artificial ventilation or intensive care. there were no pure miller-fisher syndrome cases; we suspect this might be related to the mild deficits that did not prompt hospitalization. nerve conduction studies showed typical features such as loss of f waves and abnormal blink reflex. the electrophysiology of patients' was dominated by demyelinating changes, one case was largely axonal and the remaining patient had normal electrodiagnostic study. repeat nerve conduction studies were not feasible because of limited resources. neurologists use corticosteroids as the main treatment. intravenous immunoglobulin and plasma exchange are costly and not reimbursed by medical insurance. we are currently preparing to systematically study gbs in southern vietnam, specifically with regards to possible role of antecedent flavivirus infections. we are also exploring the possibility of using low volume plasma exchange as a feasible cost-effective therapeutic modality. about % of patients with guillain-barré syndrome (gbs) treated with intravenous immunoglobulin (ivig) or plasma exchange deteriorate after initial improvement or stabilization -a phenomenon that is termed treatment-related fluctuation (trf). it is important to distinguish acute onset cidp (a-cidp) from gbs-trf during early course of the disease, because their therapeutic strategies and prognoses are different. herein, we describe a patient with gbs-trf, but with an extended progression phase that exceeds weeks. a -year-old woman was admitted due to acute onset progressive leg weakness and diplopia that had developed weeks prior (onset, d ). on neurological examination, right facial palsy was also observed. lower extremity weakness was moderate in proximal and distal muscles (mrc grade iv) with absent knee and ankle jerks. sensory examination revealed no abnormality in all modalities. she denied any recent diarrhea or upper respiratory infection, and vaccination. albumino-cytologic dissociation was noted in csf analysis; white blood cell count of / l and protein level of . mg/dl. nerve conduction study revealed demyelinating sensorimotor polyneuropathy with prolonged distal latency and conduction blocks. anti-ganglioside antibodies (gm igm/g, gd b igm/g, and gq b igm/g) were all negative. following ivig treatment, she was discharged with considerable improvement (d ). days later, she was re-admitted due to deterioration of leg weakness and hand clumsiness (d ). after another ivig treatment, she was discharged with clinical improvement (d ). days later, however, she was admitted again (d ) due to another considerable deterioration with four extremity weakness being worst at this time (mrc grade ii-iv in upper extremity, grade ii in lower extremity). a-cidp was considered given the progression phase exceeding weeks, but, we decided to give another treatment with ivig instead of a switch to corticosteroids because of uncertainty regarding distinction between a-cidp and gbs-trf. she was significantly improved following ivig treatment, and finally discharged (d ). thereafter, there has been no further deterioration during long-term follow-up of year. conclusively, this is a rare case of gbs with extended progression phase and trf. we propose that this could be referred to as subacute inflammatory demyelinating polyradiculoneuropathy (sidp) with trf. hsieh s , chao c . national taiwan university hospital, taipei, taiwan. transthyretin (ttr)-related familial amyloid polyneuropathy (fap) constitutes a major etiology of adult-onset hereditary neuropathies worldwide, in particular, a mutant ttr of ala ser (ttr-a s) in taiwan, the most common cause of acquired genetic neuropathy with adult onset (> years of age) of taiwanese patients. fap is a pan-modality neuropathy involving motor, sensory, and autonomic components of the peripheral nervous system with early involvement of small fibers as a major symptom. the early symptoms of fap are sometimes minimal and difficult to ascertain, mainly related to the fact that conventional electrophysiological examinations were not sensitive enough to detect small fiber neuropathy. skin biopsy with quantification of intraepidermal nerve fibers (ienf) has become one of the standard approaches to diagnose small fiber sensory neuropathy based on pathological documentation of nociceptive nerve degeneration. to explore the issue of early biomarkers in fap, we performed skin biopsy and compared ienf density with parameters of nerve conduction studies (ncs) and quantitative sensory testing (qst) on subjects ( men, aged . ± . years) with genetic confirmation of ttr-a s: patients and carriers. the ienf densities were significantly reduced compared to the age-and gender-matched controls in carriers ( . ± . vs. . ± . fibers/mm, p = . ) and patients ( . ± . vs. . ± . fibers/mm, p = . ). the latter was consistent with our previous report (neurology, : - , ) . the abnormal rate of ienf density was significantly higher than that of ncs and qst, respectively. in conclusion, there was significant skin nerve degeneration in carriers with ttr-a s. compared with qst and ncs, ienf density assessment had the highest abnormal rate and highest sensitivity to detect neuropathic changes in the early stage of fap. charcot-marie-tooth type p (cmt p) has been associated with frame-shift mutations in the ring domain of lrsam (an e ligase). this study describes families with a novel missense mutation of lrsam gene and explores pathogenic mechanisms of cmt p. this american family with dominantly inherited axonal polyneuropathy reveals a phenotype similar to those in previously reported non-us families. the affected members in our family co-segregated with a novel missense mutation cys arg that alters a highly conserved cysteine in the ring domain. this mutation leads to axonal degeneration in the in vitro neuronal cell-line. moreover, using protein mass spectrometry, we identified a group of rna binding proteins (including fus, a protein critically involved in motor neuron degeneration) that interacted with lrsam . the interactions were disrupted by the cys arg mutation, which resulted in reduction of intranuclear rna-binding proteins. a knockin mouse of cys arg has been created for further explorations of cmt p mechanisms and therapeutic development. together, our findings suggest that the mutant lrsam may aberrantly affect the formation of transcription machinery. given a similar mechanism has been reported in motor neuron degeneration of amyotrophic lateral sclerosis, abnormalities of rna/rna-binding protein complex may play a role in the neuronal degeneration of cmt p. supported by grants from ninds (r ns ) and the national center for advancing translational sciences (ul tr ). this double-blind, multicenter, parallel-group trial randomized ( : ) adult participants (n= ) with chronic inflammatory demyelinating polyradiculoneuropathy being treated with intravenous immunoglobulin (ivig) or corticosteroids to . mg fingolimod (n= ) or placebo (n= ) once-daily. previous treatment was discontinued (ivig) or tapered (corticosteroids). in the total trial population, there was no significant difference between the groups in the primary outcome, time-to-first confirmed worsening (≥ -point increase on the adjusted inflammatory neuropathy cause and treatment [incat] scale vs. baseline), or time-to-first any worsening (confirmed on incat assessment or unconfirmed). no significant difference between the two treatment groups was shown on secondary outcomes; change from baseline in grip strength and rasch-built overall disability scale (r-ods) at six months or trial end. analyses of pre-specified subgroups were performed for primary and secondary outcomes. this trial evaluated the efficacy and safety of fingolimod in chronic inflammatory demyelinating polyradiculoneuropathy (cidp). corticosteroids, intravenous immunoglobulin (ivig) and plasma exchange are recognized treatment options but no other immunomodulators demonstrated efficacy in a controlled trial. fingolimod has been shown to be efficacious and is approved for the treatment of relapsing multiple sclerosis. results from experimental autoimmune neuritis in rats suggested that it might show an effect in cidp. in this double-blind, multicenter, parallel-group trial, cidp participants receiving ivig or corticosteroids were randomized to once-daily fingolimod . mg or placebo ( : ). participants were stratified by inflammatory neuropathy cause and treatment disability (incat) scores and prior treatment. previous ivig treatment was discontinued after one final course before randomization. previous corticosteroid treatment was tapered over weeks. the primary outcome was time-to-first confirmed worsening (≥ -point increase on the adjusted incat score versus baseline). secondary outcomes included change in grip strength and rasch-built overall disability scale (r-ods) score from baseline to month and at trial end. the trial was stopped for futility by an independent data monitoring committee after a pre-planned interim analysis based on pre-specified criteria. in all, participants received fingolimod (ivig: , corticosteroids: ; age: . ± . years [mean±standard deviation]; male: . %); received placebo (ivig: , corticosteroids: ; age: . ± . years; male: . %). the percentage ( % confidence interval) of participants free from confirmed worsening at the trial end was not significantly different between fingolimod ( . % [ . %- . %]) and placebo ( . % ( . %- . %); p= . ). in the first days, approximately % participants experienced worsening. at trial end, approximately % participants had no worsening. there was no significant difference after six months or at the trial end (whichever occurred earlier) in the secondary endpoints. adverse events were reported in / and / participants in the fingolimod and placebo group, respectively. there were no deaths. nine participants in the fingolimod group and in the placebo group had serious adverse events. adverse events leading to trial drug discontinuation occurred in ( %) participants on fingolimod and none on placebo. no new safety signals emerged in this trial. acknowledgment: the authors consulted for or were employed by the study sponsor novartis pharma ag, basel, switzerland. myelin sheath enwraps non-nociceptive mechanoselective abeta-afferents transmitting touch/vibration sense. a prominent reduction in the mechanical stimulus required to evoke a withdrawal response in rodents, a phenomena interpreted as mechanical allodynia, arises due to peripheral nerve/myelin damage. evidence has emerged that nerve injury-induced mechanical allodynia depends on the adaptive immune/t cell activity in female but not male rodents. having previously demonstrated both the release of the cryptic - peptide regions of myelin basic protein (mbp - ) following sciatic nerve chronic constriction injury (cci) and the direct, robust and t cell-dependent ability of the pure mbp - peptides to induce mechanical allodynia after injection into the intact sciatic nerve, we hypothesized that mbp - contributes to sexual dimorphism in mechanical allodynia. the pure mbp - wild-type (wt), its histidine (his) mutant or scramble peptides were administered into an intact sciatic nerve fascicle in male and female rats or mice, followed by von frey testing. intra-sciatic mbp - -wt peptide induced robust and lasting allodynia in females. in contrast, males responded with a brief and mild decline in mechanical sensitivity for one day post-injection of both wildtype and control peptides. the algesic ability of mbp - -wt was diminished in the his mutant. we here present the molecular changes in the sciatic nerve, drg and the spinal cord after the intra-sciatic mbp - injection in male and female animals. in addition, using the biotin-labeled mbp - peptide and the hrp-labeled goat anti-rat igg/igm antibodies, we developed an elisa to quantitatively assess seropositivity for the specific anti-mbp - peptide igm/igg autoantibodies in female and male rats post-cci. human serum from female patients with multiple sclerosis was used for control. our work corroborates the findings of sexual dimorphism of mechanical hyperpathia and suggests its potentially autoimmune nature in females. iijima m , nishi r , ikeda s , kawagashira y , koike h , sobue g , katsuno m . nagoya university, nagoya, japan. non-obesity diabetic (nod) b - knockout (ko) mice are characterized by chronic and progressive neuritis and expected as models of immune-mediated neuropathies, especially cidp. hindlimb-predominant weakness due to inflammatory demyelination followed by axonal degeneration begins from around twenty week-age in all female mice until thirty week-age. to clarify the efficacy of immunoglobulins as immune-regulating therapeutics and the similarity of pathogenesis of human cidp, we injected intraperitoneally human-derived immunoglobulins (ipig, mg/mg bw/week) and saline as a control to totally forty female mice. clinical and pathological estimations in sciatic nerves were performed in time series. as a result, the ipig-treated group was protected from weight loss which could be related to axon loss followed by muscle atrophy as well as inflammatory demyelination between twenty-five week-age and thirty week-age compared to the control. in addition, the pathological findings in sciatic nerves showed that ipig apparently suppressed inflammatory infiltrates. about the subsets of inflammatory infiltrates, while macrophages (cd +) and lymphocytes (cd +) highly existed and suggested to play a main role in the neuritis until thirty week-age, only macrophages naturally disappeared after thirty week-age without any therapeutic induction. immunoglobulins effectively suppressed only macrophages although that did not suppress cd + lymphocytes. in conclusion, nod b - ko mice respond to immunoglobulins in a similar manner to human cidp and this efficacy is due to the suppression of macrophage-dominant pathogenesis. therefore, macrophage-derived pathogenesis is for the main target of immunoglobulin therapy and we should focus on the lymphocyte-derived pathogenesis which might plays an important role in non-responders to immunoglobulins. ikeda s , nishi r , kawagashira y , iijima m , koike h , katsuno m , sobue g , . department of neurology, nagoya university graduate school of medicine, nagoya, japan; research division of dementia and neurodegenerative disease, nagoya university graduate school of medicine, nagoya, japan. chronic inflammatory demyelinating polyneuropathy (cidp) is an acquired immune-mediated polyradiculoneuropathy that is characterized by heterogeneous clinical manifestations. typical cidp is defined as neuropathy manifesting in a progressive manner, stepwise manner, or with recurrent symmetrical proximal and distal weakness and sensory impairment in all four limbs. although they occur at a lower proportion than the so-called typical cidp, atypical forms, such as multifocal acquired demyelinating sensory and motor (madsam), distal acquired demyelinating symmetric (dads), pure sensory, pure motor, and focal, are considered to cidp subtypes. thus far, pathological features characterizing each clinical subtype have not been fully elucidated. we analyzed clinical and pathological correlations in consecutive cidp patients who underwent sural nerve biopsy and fulfilled the definite or probable efns/pns criteria. there were male and female patients. the age at biopsy was . ± . (mean ± sd) years, and the duration from the onset of neuropathy to biopsy was ± months. fifty-five percent (n = ) of the patients were classified as having typical cidp. regarding atypical cidp, madsam (n = , %), dads (n = , %), and pure sensory (n = , %) subtypes were the major subtypes, while pure motor (n= , %) and focal (n= , %) subtypes were rare. no significant difference was found among these subtypes in terms of sex, age at biopsy, and disease duration. sural nerve biopsy specimens revealed that the densities of large myelinated fibers significantly decreased in the madsam subtype than in the other subtypes (p = . ). in addition, the variation in nerve fibers among fascicles was more conspicuous in the madsam subtype than in typical cidp (p= . ). patients with the dads subtype tended to show the formation of onion-bulbs. in conclusion, pathological findings of sural nerve biopsy specimens were different among the cidp subtypes. further studies are needed to clarify mechanisms leading to different pathological features. small volume plasma exchange (svpe) can be an affordable and potentially effective alternative form of plasma exchange. svpe is the repeated removal of small volumes of supernatant plasma over several days via sedimentation of patient whole blood. the aim of this study is to assess the clinical feasibility and safety of svpe in patients with gbs in low-income countries. twenty adult patients with gbs diagnosed as per the criteria for gbs of the national institute of neurological and communicative disorders and stroke (ninds) were enrolled for svpe at a centre in bangladesh. serious adverse events (sae) were defined as the number of patients developing severe sepsis associated with the central venous catheter (cvc) or deep venous thrombosis in the limb where the cvc is placed for svpe. the svpe procedure was considered safe if less than of svpe-treated gbs patients have a sae, and feasible if eight litres of plasma could be removed in at least of svpe-treated gbs patients. among the cases who received svpe, ( %) patients were male and the age range between to yrs. all the patients were quadriplegic and bedbound at enrolment for svpe with a median mrc score of (iqr, - ). cranial nerve involvement, autonomic dysfunction and requirement for assisted ventilation were observed in ( %), ( %) and ( %) patients respectively. electro physiologically ( %) patients were motor axonal and ( %) patients were sensory-motor demyelinating type. during the svpe none of our patients experienced sae and one patient experienced central line associated blood stream infection. common adverse effects were transient intravenous fluid responsive hypotension during the svpe sessions in ( %), cv catheter insertion site hemorrhage in ( %) and hypersensitivity reaction to fresh frozen plasma in ( %) patients. there was no hypo-albuminemia, anemia or electrolyte imbalance observed in most patients ( %) treated with svpe. improvement in one or more grade of the gbs disability score at four weeks after the onset of svpe was observed in ( %) patients. in conclusion svpe can be a safe, feasible and cost effective alternative to standard pe in the developing countries. guillain-barré syndrome (gbs) is a descriptive disease entity defined by a set of clinical, electrophysiological and laboratory criteria. various clinical phenotypes exist that may be triggered by different antecedent infectious events. although the disease appears to affect primarily the elderly in developed countries, but, scenario is different in developing countries. bangladesh has made an impressive progress towards the eradication of poliomyelitis, and no new cases have been reported since . gbs, an acute polyradiculoneuropathy, is the most frequent cause of acute flaccid paralyis. the crude incidence rate of gbs in < years of age reported here appears to be . × to × higher than that reported in the literature. we conducted a hospital based observational study including patients fulfilling the national institute of neurological disorders and stroke (ninds) criteria for gbs patients between and in dhaka medical college hospital, dhaka, bangladesh. detailed clinical, electrophysiological, serologic and microbiological data were obtained. gbs affected predominantly in young adults males (m/f= : ) living in rural areas. antecedent events were recorded in > % of patients; frequent events being gastroenteritis (> %) and upper respiratory tract infection ( %). more than % of the patients were bed-bound (gbs disability score ) at entry and about % patients required mechanical ventilator. about % patients did not receive specific treatment either intravenous immunoglobulin (ivig) or plasmapheresis due to high expensive treatment cost. % patients had died during hospitalization. % of patients had an axonal variant of gbs and evidence for a recent c. jejuni infection ( %). c. jejuni infection was significantly associated with serum antibodies to the gangliosides gm and gd a, axonal neuropathy, and greater disability. in conclusion, the majority of the patients do not receive standard treatment with ivig in view of its high price. therefore, we developed low-cost treatment strategies and conducted a safety and feasibility trials for small volume plasma exchange (svpe) on gbs patients in bangladesh. in future, it is essential to conduct a phase ii clinical trial to assess the efficacy of svpe for low-in-come countries. prognosis of guillain-barré syndrome (gbs) has not improved in last two decades. current therapies (intravenous immunoglobulin, ivig and plasma exchange, pe) had been proved to be effective on two third of patients in developed world. unpredictable and poorly understood clinical course of gbs hamper treatment development. in bangladesh, most patients affected by gbs cannot afford specific treatments with ivig or pe instead most of them receive only supportive care. therefore, we aimed to compare the outcome of ivig treated patients with supportive care patients in improvement of gbs disability score and mrc sum score by using world's largest gbs cohort in bangladesh. we conducted a prospective observational study enrolling gbs patients between and from dhaka medical college hospital and national institute of neuroscience and hospital, dhaka, bangladesh. only gbs patients ( %) received standard ivig treatment. in current analysis, ivig treated patients and age, sex and severity matched controls (supportive care only) were considered. outcome of both groups were compared using fisher's exact or chi square test and survival analysis were performed by kaplan meier method using log rank test. among patients (cases and controls), male/female ( / ), median age years, % patients were bed-bound, one-fourth patients required mechanical ventilation and % were axonal. we did not found any significant differences of treatment outcome in both cases and control groups in gbs disability score (week : p= . , months: p= . ) and mrc sum score (week : p= . , months: p= . ). survival analysis revealed, the differences of time required for independent locomotion, improvement of one gbs disability score and improvement of mrc score were not statistically significant between treatments (ivig) and supportive care patients. in conclusion, our analysis showed that standard dose of ivig use has no considerable advantage to improve specific outcome measures among gbs patients in bangladesh. as the phenotype of gbs in bangladesh is different from developed world; therefore, an efficacy trial for ivig is needed for developing countries like bangladesh or new targeted therapeutic strategies can append beneficial effects for gbs patients. isose s , , watanabe k , omori s , sekiguchi y , beppu m , shibuya k , amino h , suichi t , misawa s , kuwabara s . graduate school of medicine, chiba university, chiba, japan; national hospital organization chiba east national hospital, chiba, japan. diabetic neuropathy is a frequent cause of neuropathic pain, suggesting the small-fiber involvement. additionally, persistent peripheral pain-related inputs could cause neuronal hyperexcitability and complex interactions of the nociceptive pathways, i.e., central sensitization. to investigate the pathophysiology of neuropathic pain in diabetic neuropathy, we studied pain-related evoked potentials (preps) after selective intraepidermal electrical stimulation (ies) to a-deltaand c-fibers in diabetes patients with neuropathic pain (n= ) and without neuropathic pain (n= ). we also conducted a longitudinal study to assess changes in preps and pain profiles in patients with neuropathic pain months after the start of treatment with duloxetine. this study is registered with the umin clinical trials registry, umin . ies was applied in the hand and foot, and preps were recorded from the cz electrode referenced to the linked earlobes. we evaluated prep latencies, amplitudes, and amplitude ratios of preps after c/a-delta -fiber stimulation. in the conventional nerve conduction studies, patients with neuropathic pain significantly showed conduction slowing and decreased snap amplitudes in the median and sural nerves compared with those in patients without neuropathic pain. in pain-related sep studies, there were no significant differences in prep amplitudes and latencies after a-delta -or cfiber stimulation between the patients with neuropathic pain and without it. prep amplitude ratios after c/a-delta -fiber stimulation tended to increase in patients with neuropathic pain compared to patients without pain. after the treatment with duloxetine, c/a-delta -prep amplitude ratios were significantly decreased after both hand and foot stimulation, and as for numerical rating scale (nrs) scores as the intensity of pain. patients with less pain relief showed the tendency of higher c/a-delta prep amplitude ratios before treatment compared to patients with better pain relief. the correlation between reduction of c/a-delta prep amplitude ratios and nrs reduction did not reach statistical significance. this pain-related sep study demonstrated that abnormal cortical response in patients with neuropathic pain could improve after the treatment with duloxetine, this might reflect the cortical hyperexcitability as a central sensitization. this study is funded by shionogi & co., ltd. the sponsors played no role in the design and management of the study, collection and analysis of data, interpretation of the results, or the writing of the writing of the report. peripheral nerve injury is commonly associated with traumatic injury which is often amenable to surgery. despite improved methods in surgical repair, functional recovery remains a challenging clinical problem that often leads to significant morbidity in patients. alternative therapies that could augment surgical repair may be beneficial in functional outcomes. neuroinflammation is a complex pathway with different cellular components and cytokines that are activated following peripheral nerve injury. macrophages are responsible for the breakdown of debris following injury as well as promotion of regenerative signals. macrophage polarization is the process by which macrophages take on phenotypically distinct functions based on the local environment and signaling cues. exercise has been shown to drive macrophage polarization from a pro-inflammatory m phenotype towards an anti-inflammatory m phenotype in numerous tissues, but remains uninvestigated in the peripheral nervous system. the purpose of our study was to identify how exercise affects macrophage polarization, motor and sensory function, and neuroregeneration following sciatic nerve crush. c bl/ mice underwent sciatic nerve crush injury and were then given access to running wheels (exercised) or not given access to running wheels (sedentary) for weeks. exercised mice ran an average of . km per night. injured exercised mice were protected from the development of thermal hyperalgesia when compared to injured sedentary mice. exercised mice had fewer paw slips on beam walk testing compared to sedentary mice. no differences were measured in mechanical sensitivity or motor coordination and balance assessed by rotarod. while motor nerve conduction velocities were significantly reduced for injured mice compared to uninjured controls, motor nerve conduction velocities from injured exercised animals were significantly higher than injured sedentary animals suggesting improved nerve recovery with exercise. injured sciatic nerves from exercised mice demonstrated increased m macrophages compared to sciatic nerves from injured sedentary mice. the behavioral changes and altered macrophage polarization correlated with increased epidermal nerve fiber density, improved myelination, and increased in vitro neurite outgrowth from injured exercised animals. therefore, exercise alters macrophage polarization towards an anti-inflammatory phenotype which improves repair and recovery of the injured peripheral nerve. jack mm , shah k , everist b , reyna j , hylton p . university of kansas medical center, kansas city, ks, usa. diffusion tensor imaging (dti) has long been used to evaluate the location and integrity of white matter tracts in the brain. dti uses quantitative data and directionality of water diffusion to determine axonal connectivity of the nervous system. the technology has only recently been utilized in limited settings in the peripheral nervous system due to challenging technical factors and lack of widespread availability. magnetic resonance (mr) neurography or peripheral neurography is a technique which uses diffusion to differentiate between intraneural and perineural tissues. it allows for fascicle patterns to be visualized particularly in the setting of peripheral nerve sheath tumors. peripheral nerve sheath tumors of various pathologies cause surrounding nerves to be involved or displaced in a range of directions. this technique helps determine the anatomic location of these nerve fibers in relation to the mass, which is particularly helpful at distinguishing neuromas from schwannomas. this data is invaluable to the surgeon to ensure a safe and low morbidity operation. while this technology has benefit particularly with surgical planning, it has been underutilized due to the challenges of requiring complex software to produce fiber tracks and the inability to translate these images into the operating room. here, we utilized brainlab software that is commonly available and utilized in surgical suites to produce images of the radial nerve fiber tracts with an associated peripheral nerve sheath tumor prior to surgical resection. while the software is commonly used in the central nervous system, it has not been reported to have been used in the peripheral nervous system. this software offers a high usability and produces anatomically correct and reliable fiber tracts. this technique overcomes the reliance on highly specialized software and extensive training required for use that most other tractography software has. utilizing peripheral neurography in this case allowed for complete surgical resection without postoperative deficits. this data offers clinicians an option to investigate peripheral nerve fibers in various pathologic states, to plan appropriate operative trajectories to peripheral nerve pathology, and to improve surgical outcomes for patients with peripheral nerve sheath tumors. jacobsen b , parry g , allen j , walk d , muley s , ortega e . barrow neurological institute, phoenix, az, usa; university of minnesota, minneapolis, mn, usa. chronic inflammatory demyelinating polyneuropathy (cidp) is an immune mediated neuropathy that is responsive to immunomodulatory agents such as glucocorticoids, intravenous immunoglobulin (ivig) and plasma exchange (pe). the specific immunopathogenic mechanisms of cidp remain unclear but there is increasing interest in nodal proteins as a site of the immune attack. even though the majority of patients respond to one of the aforementioned immunomodulatory agents there are some who are unresponsive or incompletely responsive to these first line agents and other more aggressive treatments may be necessary. cyclophosphamide and stem cell transplantation may be effective but are associated with considerable morbidity. anecdotal reports suggest that rituximab may be beneficial for some patients that fail first-line therapy, especially if they have antibodies to nodal proteins. we present four patients with intractable cidp who responded to rituximab. one of the three patients had diabetes. disease duration prior to starting rituxan was short ( months) in two patients and longer and months in the other two. all patients had failed treatment with glucocorticoids and ivig, and in two, plasma exchange and ivig-pe were also ineffective. two of the four patients were quadriparetic and non-ambulatory. two gm doses two weeks apart of intravenous rituximab were instituted in all patients. all patient tolerated the treatments well without adverse effects. all patients responded within four weeks and continued to improve at six months. other immunomodulatory agents were successfully tapered but not totally discontinued. it remains unclear whether antibodies to nodal proteins were present in these patients. in conclusion, although rituximab efficacy remains uncertain on the basis of randomized controlled clinical trials, it may be beneficial in selected patients otherwise intractable to first-line treatments. further studies are necessary to better understand which patients may benefit most from rituximab and where in the treatment algorithm rituximab should be applied. neuropathic pain is a chronic condition seen in patients suffering a direct injury to the peripheral or central nervous system or an indirect injury due to, e.g., diabetes or multiple sclerosis. current treatment options fall short of preventing or completely relieving patients of their pain. for years, research has focused on understanding the role of neurons in neuropathic pain pathogenesis while overlooking the role of supportive cells in general and satellite glial cells (sgcs) in the dorsal root ganglion in particular. these cells not only buffer the neuronal microenvironment they are also involved in controlling the electrical activity flowing through the neurons and in neuropathic pain pathogenesis. the aim of this project is to understand the role of sgcs in neuropathic pain development and thereby aid the identification of new drug targets. to purify the sgcs from adult mice we optimized a fluorescently activated cell sorting (facs) protocol. the success of our purification method was confirmed using qrt-pcr and visual inspection of the sorted cells. finally, we are running rna sequencing on sgcs after peripheral nerve injury to compare their transcriptome to that of uninjured cells at different time points. the results from our study are likely to deepen our understanding of how sgcs contribute to the development and maintenance of neuropathic pain. guillain-barrésyndrome (gbs) is an immunemediated disorder in the peripheral nervous system (pns) triggered by molecular mimicry against nerve gangliosides. one of the cell surface receptors (fas)-ligand (fasl) interaction transmits apoptotic signal to eliminate the auto-reactive b and t-cells, which generates cross-reactive antibody against nerve cells. host genetic polymorphism of fas and fasl may alter their expression and induce aberrant apoptotic response to develop gbs. therefore, we determined the single nucleotide polymorphisms (snps) of both fas receptor (− g/a and - a/g) and fasl ligand (− c/t) in gbs patients (n= ) as well as healthy controls (n= ) using the lightcycler technique. serum level of soluble form of fas and fasl was measured using commercially available sandwich elisa kit. comparison of genotype, allele and haplotype frequencies was done with the gbs subgroups based on the clinical and serological data. ag heterozygote (p= . , or= . , % ci= . - . ) and polymorphic g-allele (p= . , or= . , % ci= . - . ) of fas receptor - a/g promoter snps were significantly associated with anti-ganglioside (gm ) antibody positive gbs patients. in addition, − g-allele (p= . , or= . , % ci= . - . ) and - g/- g haplotype (p= . , or= . , % ci= . - . ) were predominantly associated with the axonal variant of gbs patients. serum soluble form of sfas (median levels pg/ml vs. pg/ml, p= . ) and sfasl (median levels pg/ml vs. pg/ml, p= . ) were found to be elevated in anti-gm antibody positive gbs patients compared to anti-gm negative patients. no significant association was found in genotypic distribution between gbs patients and healthy controls. in conclusion, fas/fasl promoter snps are not a susceptible factor for gbs but could be one of the influencing factors to develop cross-reactive anti-ganglioside antibodies in gbs patients in bangladesh. furthermore, functional studies with a larger sample size (using cohort like international gbs outcome studies-igos) are required to explain the immune pathogenic role of these snps for gbs patients. jang sy , yoon ba , shin yk , yun sh , jo yr , park ji , shin kj , kim jk , park ht . dong-a university, busan, south korea; inje university, busan, south korea. myelination is essential for the proper function of the nervous system. schwann cells, which form the peripheral myelin sheath, have the unique ability to dedifferentiate and to destroy the myelin sheath under various demyelination conditions. during schwann cell dedifferentiation-associated demyelination in wallerian degeneration after axonal injury, schwann cells exhibit myelin and junctional instability, down-regulation of myelin gene expression and autophagic myelin decomposition. however, in inflammatory demyelinating neuropathy, it is still unclear how schwann cells react and contribute to segmental demyelination before myelin scavengers, macrophages, are activated for myelin clearance. here, we show that schwann cell dedifferentiation-associated demyelination is a mechanism involved in the initial demyelination observed in a mouse model of inflammatory demyelinating neuropathy using ultrastructural, biochemical and microarray analyses. myelin uncompaction and myelin membrane instability generated by dedifferentiated schwann cells lead to autophagolysosome-dependent cytoplasmic amputation between the axon-containing myelin sheath and the schwann cell body, resulting in the formation of the "myelin corpse", thereby allowing macrophages to phagocytose the myelin corpse in the end stage of segmental demyelination. we found myelin corpse formation in inflammatory demyelination to be a process similar to the myelin rejection during wallerian degeneration, which appeared to be dependent on schwann cell autophagolysosome activation since schwann cell-specific atg knockout mice exhibited delayed myelin rejection following nerve injury. finally, lysosome inhibition in schwann cells not only prevented segmental demyelination but also delayed the progression of clinical stages by suppressing the myelin corpse formation in inflammatory demyelinating neuropathy. thus, our findings indicate that demyelination by schwann cells and macrophages might be part of a process that includes sequential divisions of labor with respect to myelin rejection and digestion, respectively. in conjunction with previous studies showing schwann cell dedifferentiation and autophagy in toxic and hereditary neuropathies, the concept of "schwann cell dedifferentiation-associated demyelination" provides insight into the development of possible therapeutic strategies to prevent schwann cell demyelination in peripheral demyelinating neuropathies. methods: electrophysiological data, the charcot marie tooth exam score (cmtes), and bmi from patients with known cmt a were obtained and analyzed. results: when controlled for age, bmi does not affect studies of ulnar motor nerve conduction in ctm a patients, but rather specific components of the cmt exam scores (cmtes, loss of pinprick sensation and motor strength in the lower extremities). discussion: bmi and clinical components of the cmtes are correlated, but it is uncertain which is the primary effect -i.e., whether the reductions in pinprick sensation and motor strength in the lower extremities lead to a higher bmi, or higher bmi results in these signs. introduction: charcot-marie-tooth disease type c (cmt c) is a rare, dominantly inherited neuropathy caused by mutations in the lipopolysaccharide-induced tumor necrosis factor (litaf) or small integral membrane protein of the lysosome/late endosome (simple) gene. methods: we present a case series comprised of patients in whom cmt c is caused by a gly ser substitution in the encoded protein. we focus on clinical presentation, electrodiagnostic analyses, and our findings in the context of previously described cases. results: the gly ser mutation causing cmt c is a mild form of cmt, as patients walked on time, had less weakness than those with charcot-marie-tooth disease type a (cmt a), had a charcot marie tooth neuropathy score (cmtns) indicative of mild disease, and had faster ulnar and median motor nerve conduction velocities compared to those with cmt a. discussion: the g s mutation in litaf seems to be clinically indistinguishable from a mild presentation of cmt a. jha mk , russell k , lee y , rothstein jd , morrison bm . johns hopkins university, baltimore, md, usa. peripheral nerves are highly dependent on metabolic energy to maintain both basic cellular functions such as axon transport, na+/k+ ion gradients, and myelination, as well as to support regeneration following injury. though glucose certainly provides some metabolic support, our recent studies have shown that monocarboxylates, such as lactate, pyruvate, and ketone bodies, also contribute to recovery from peripheral nerve injury. monocarboxylate transporters, particularly mct , are the predominate transporters for monocarboxylates in the peripheral nerve. in a recent publication, we found that mct heterozygous null mice, which express % less mct in all cells, have slowed nerve regeneration and reduced myelination following sciatic nerve crush. this study was limited by the global reduction of mct , which is widely expressed in schwann cells (sc), dorsal root ganglia (drg) neurons, endothelial cells, macrophages, and perineurial cells within the regenerating peripheral nerve. to better understand the mechanism by which mct contributes to normal nerve function and nerve regeneration, we produced and validated conditional mct null (mct loxp) mice that allow selective deletion of mct from scs, drg neurons, endothelial cells, or macrophages through mating to cell-specific cre lines. we are currently quantifying peripheral nerve development, aging, and regeneration in each of these mouse lines. following sc-, but not drg-, specific mct knockdown, sensory peripheral nerves develop demyelination by months of age, manifest by reduced myelin thickness, increased g-ratio, and reduced conduction velocity. studies are ongoing in cultured scs to determine the mechanism for demyelination. neither sc nor drg knockdown of mct impairs nerve regeneration following sciatic nerve crush. these results suggest that sc-specific mct is critical for maintaining myelin in sensory, but not motor, peripheral nerves as they age. they also suggest that mct expression in peripheral nerve cell types, other than sc and drg, is important for nerve regeneration. ongoing studies are determining the contribution of mct in other peripheral nerve cell types, particularly endothelial cells and macrophages, to normal development and regeneration following injury. our results will clarify the role of lactate and its transporter, mct , in peripheral nerve function, potentially suggesting novel targets for demyelinating neuropathies or nerve injuries. small fiber neuropathy (sfn) is a condition in which the smallest nerve fibers are affected, characterized by neuropathic pain and autonomic dysfunction. according to international criteria, sfn diagnosis is based on clinical symptoms in combination with abnormal temperature threshold testing (ttt) and/or reduced intraepidermal nerve fiber density (ienfd) in skin biopsy. skin biopsy is moderately sensitive, invasive and the process is time consuming and expensive. ttt is a widely available diagnostic tool, but lacks specificity. previous studies introduced stimulated skin wrinkling (ssw) as an objective, non-invasive diagnostic tool to detect sympathetic nerve dysfunction in sfn by means of a categorical assessment. however, our unpublished data has shown that inter-observer reliability of categorically assessed ssw is quite low. in this current study we will use a new digital method for ssw quantification: the digit wrinkle scan© (dws©). the primary study objective is to define normative values for dws© expressed as total wrinkle length per fingertip surface (mm/mm ). subsequently we investigate the applicability of dws© in patients with definite sfn, based on abnormal iefnd and/or ttt, determining the dws© sensitivity and specificity, as well as its validity. for this cross-sectional study, we will include healthy participants and patients diagnosed with sfn. eligibility is based on meeting the inclusion and exclusion criteria and providing written informed consent. skin wrinkling is induced by emla (eutectic mixture of local anesthetics) cream© application and captured by taking pictures. the primary outcome measure is total length of wrinkles per mm as shown on the photographs, which will be calculated by a new software program. patients are stratified according to age and gender. based on the results of healthy participants, normative values will be defined. inter-and intra-observer reliability will be determined. in the sfn group, additional correlation analysis will be conducted to determine the correlation between dws© and different outcome measures (sfn-symptom inventory questionnaire, visual analogue pain scale, neuropathic pain scale, sfn-rasch-built overall disability scale, ienfd and ttt). we expect to provide digitally quantified ssw (dssw©) normative values that can be used in clinical practice in the diagnostic workup for sfn. cmt , characterized by axonal degeneration, is an inherited motor and sensory neuropathy accounting for about % of total cmt patients. the cmt subtype shows on its own, a vast genetic heterogeneity with more than mutations in known genes rendering the identification of relevant drug targets and therapies very challenging. so far, only hdac inhibitors have shown promising results in mouse models for hspb mediated axonal cmt (cmt f), albeit such a single gene approach may have a limited relevance at clinical levels owing to the limited number of patients per genotype. in this study, we investigated common causative molecular players of cmt associated axonal degeneration. for this, an itraq based proteome analysis was performed on five patient's derived lymphoblasts bearing different cmt causal mutations alongwith respective age and gender matched unaffected controls. software-assisted interpretations of the obtained data led us to identify two proteins which were significantly downregulated in cmt patients compared to controls. these two proteins were then validated using western blotting and qpcr on patient derived lymphoblasts and fibroblasts. our results prompted us to unveil whether these two proteins can be used as potential biomarkers for identifying cmt patients. therefore, through a europe-wide collaboration, we constructed a cohort of cmt patients and healthy controls. these two proteins exhibited significant downregulation in this cohort suggesting a potential new role of these proteins as cmt biomarkers. remarkably, we were also able to validate the significant decrease in ineurons (neurons differentiated from patient derived ipscs) strengthening the importance of our finding and also suggesting the relevance of these proteins in the pathogensis of axonal cmt. this will be the first study involving multiple cmt causal genes at once, thereby holding the potential to offer new drug targets and potential biomarkers with wider application both clinically and pharmaceutically. mesenchymal stem cells (mscs) represents a valuable source of stem cell therapy, can differentiate into various cell types. we investigated of the neuromuscular potential of human tonsil-derived mscs (t-mscs) for neuromuscular regeneration in trembler-j mice that is considered to be a model for charcot-marie-tooth disease type a (cmt a diseases), which is involving hereditary motor and sensory peripheral neuropathies. the t-mscs differentiated toward skeletal myocytes, as evidenced by increased expression of skeletal muscle-related markers (including troponin i type , and myogenin) and the formation of myotubes in vitro. in situ transplantation of t-msc-derived myocytes (t-myocytes) into gastrocnemius in trembler-j mice, a mouse model of cmt a, enhanced motor function, as identified with recovery by a compound muscle action potential (cmap) amplitude. and the regenerated shape of the sciatic nerve and skeletal muscle by immunochemistry, without the formation of teratomas. furthermore, the expression levels of nerve growth factor (ngf) and glial cell line-derived neurotrophic factor (gdnf) were significantly increased in t-myocyte compared with t-mscs in vitro. these results indicate that the transplantation of t-myocyte can be a therapeutic option of cell therapy for the neuromuscular regeneration in hereditary peripheral neuropathy, comprising cmt a disease. kagiava a , karaiskos c , richter j , tryfonos c , lapathitis g , sargiannidou i , christodoulou c , kleopa ka , . neuroscience laboratory, the cyprus institute of neurology and genetics, nicosia, cyprus; department of molecular virology, the cyprus institute of neurology and genetics, nicosia, cyprus; neurology clinics, cyprus school of molecular medicine, the cyprus institute of neurology and genetics, nicosia, cyprus. x-linked charcot-marie-tooth disease (cmt x) is a common form of inherited demyelinating peripheral neuropathy resulting from mutations affecting the gap junction protein connexin (cx ). using a cx knockout (ko) mouse model of the disease, we have shown that targeted expression of virally delivered cx results in morphological and functional improvement. since patients with cmt x express mutant forms of cx in schwann cells, that could potentially interact with virally delivered wild type (wt) cx through dominant-negative effects, we also treated mutant mice expressing the t i, r w and n d mutations associated with cmt x on a cx ko background. all three mutants were localized in the perinuclear compartment of myelinating schwann cells consistent with retention in the er (t i) or golgi (r w, n d) with loss of physiological expression in non-compact myelin areas. following intrathecal delivery of the human gjb gene we could detect the virally delivered wt cx correctly localized in the non-compact myelin areas only in t i/cx ko mutant mice, but not in the other two mutants, suggesting dominant effects of the r w and n d mutant but not of the t i mutant. gjb treated t i/cx ko mice showed improved motor performance, along with lower ratios of abnormally myelinated fibers and reduced numbers of inflammatory cells in all tissues examined compared to mock-treated animals. in contrast, gjb treated r w and n d mutant mice showed only slight but not statistically significant improvement. this study provides additional proof of principle for a clinically translatable gene therapy to treat cmt x even in the presence of endogenously expressed cx mutants, since at least one er-retained cx mutant did not interfere with the expression of virally delivered cx allowing a therapeutic benefit similar to cx ko mice. however, golgi-retained mutants may interfere with virally delivered wt cx and other approaches besides gene addition may be needed for effective treatment. funding: muscular dystrophy association (grant mda to kak). kaida k , kadoya m , koike h , iijima m , takazaki h , ogata h , moriguchi k , shimizu j , nagata e , takizawa s , chiba a , yamasaki r , kira j-i , sobue g , ikewaki k . national defense medical college, tokorozawa, japan; nagoya university graduate school of medicine, nagoya, japan; kyushu university, fukuoka, japan; university of tokyo, tokyo, japan; tokai university school of medicine, isehara, japan; kyorin university, tokyo, japan. antibodies to a glial protein, neurofascin (nf) have recently been identified in approximately % of patients with chronic inflammatory demyelinating polyneuropathy (cidp), which are igg -predominant. igg anti-nf -associated cidp may be a distinct subtype from typical cidp in terms of clinical features and response to immunotherapy. however, a diagnostic criterion of anti-nf -associated cidp has not established yet. to develop optimal criteria and design the best treatment plan for the anti-nf -associated cidp, procedures for determining anti-nf antibodies should be simplified, prevalent, and reproducible, as well as being accurate. cell-based assay (cba) has hitherto been utilized for determining antibodies to nf in sera from patients, results of which have been confirmed by immunohistochemistry (ihc) using teased nerve fibers from rodents. these methods are the most reliable techniques, while not necessarily easy-to-use and easy to maintain in most laboratories. in the present study, we aimed to validate the diagnostic utility of a conventional enzyme-linked immunosorbent assay (elisa) for determination of anti-nf antibodies and the igg subclass. sera from patients with efns/pns criteria-met cidp were examined with elisa using human recombinant nf . to verify elisa results, ihc on rat sciatic nerves, western blot (wb) and cba using nf -transfected and naive hek cells were conducted. the human nf -based elisa clearly distinguished between anti-nf antibody-positive and -negative sera. fifteen cidp patients ( %) were igg anti-nf antibody-positive, which were confirmed by wb, ihc and cba studies. none of disease controls or healthy subjects had positive results. twenty-five sera randomly selected from anti-nf -negative cidp sera were also negative on cba. the anti-nf activities on elisa were significantly positively-correlated with those on cba (p < . ). analyses of clinical and laboratory findings showed that anti-nf -associated cidp was characterized by younger onset, distal dominant phenotype, tremor, sensory ataxia, higher protein levels in cerebrospinal fluid, and poor response to ivig, which were consistent with those in previous studies. this elisa combined with determination of the igg subclass is a simple and reliable method for initial screening for anti-nf antibodies. the genetic abnormality responsible for x-linked charcot-marie-toothy neuropathy subtype cmtx was recently identified by whole genome sequencing to be a kb insertion into chromosome xq . . the clinical profile of cmtx in childhood is not well described. we reviewed the clinical characteristics, neurophysiological profile and cmt pediatric scale (cmtpeds) assessments of children with genetically confirmed cmtx . cmtx was characterized by early onset, and early and progressive hand weakness. most affected children were symptomatic within the first two years of life. the most common presentation was with equinovarus foot deformity in the first year of life. cmtpeds analysis in these children revealed that cmtx progressed more rapidly ( . ± . points/ year, n= ) than cmt a and cmtx . grip strength in the second decade of life in most affected males was two standard deviations below age-and sex-matched normative reference values. the most severely affected individual was wheelchair bound at years of age and two individuals had no movement in the small muscles of the hand in the second decade of life. there was only a single symptomatic female identified and she had mild signs. nerve conduction studies showed a demyelinating sensorimotor neuropathy with motor conduction velocity in eight children while one child had a length-dependent sensorimotor axonal neuropathy. understanding the unique phenotype of cmtx is essential for directing genetic testing, as the cmtx insertion will not be detected on the snp microarrays, multi-gene panels or whole-exome sequencing currently used for the diagnosis of cmt. the early onset of disease coupled with rapid progression means that many children with cmtx will have severe disability within the first two decades of life and hence early diagnosis is needed for early commencement of rehabilitation. kapoor m , catania s , sarri-gonzales s , lunn mp , manji h , reilly mm , carr as . centre for neuromuscular diseases, national hospital for neurology and neurosurgery, london, uk; department of neurophysiology, national hospital for neurology and neurosurgery, london, uk. the conventional dosing of ivig in cidp and mmn is based on treatment trials that used bolus and maintenance dosing of ivig between - . g/kg. there are rare published articles reporting the efficacy of higher maintenance ivig doses. we present three cases of inflammatory neuropathies, who are currently stabilized on ivig doses of mg- mg/kg of ivig per month, refractory to standard dose ivig and other immunosuppressants. the first case is a year-old-lady with cidp who presented with episodes of ascending sensory disturbance, weakness, and diplopia. she had activity related fluctuations and pre-dose deterioration on g/kg/month ivig. she then had an acute deterioration with mrc sum score dropping from to even with additional plasma exchange. her bilateral foot drop (mrc grade - ) and fluctuations persisted with an increase of ivig to . g/kg/month. she is now clinically stable (ankle dorsiflexion mrc grade - , mrc sum score ) on mycophenolate and g ivig weekly ( . g/kg/month). case is a -year-old male fitness instructor with mmn and sjogren's syndrome. he presented with recurrent proximal and distal weakness that responded to g/kg of ivig and deteriorated with iv methylprednisolone. he had peri-dose fluctuations, intermitted proximal weakness, and persistent foot drop (ankle dorsiflexion mrc grade - ) at . mg/kg/month, worsening to mrc grade - on . g/kg/month and fluctuating between mrc grade - on . g/kg/month. an increase of ivig to g weekly ( . g/kg/month), has resulted in mmn rods scores of / , improved distal power and return to full capacity at work. case is a -year-old man with predominantly upper limb cidp. he received g/kg ivig without any benefit, had no response to doses of plasma exchange, doses of cyclophosphamide or dose of rituximab between and . since , he has received g/kg/month ivig with improvement of mrc sum score from to . these cases highlight that some patients require a much higher than conventionally prescribed dose of ivig, and that these doses are tolerated over years without serious adverse events. idiopathic rapid eye movement sleep behaviour disorder (irbd) has been identified as a precursor of alpha-synucleinopathies, such as parkinson's disease, dementia with lewy bodies, multiple system atrophy. several studies linked changes in cutaneous innervation with central nervous system pathology in neurodegenerative disorders. recently small fiber neuropathy and alpha-synuclein deposition in the skin found to be a potential biomarker in parkinson's disease. we evaluated the epidermal innervation of irbd patients and age and sex-matched controls from skin punch biopsies from the distal leg using pgp . immunohistochemistry. furthermore, a battery of clinical examinations were performed on patients and controls alike, including structured interviews, clinical motor and non-motor questionnaires and rating scales (e.g. unified parkinson's disease rating scale [updrs], non-motor symptoms questionnaire [nms-quest] and beck depression inventory, epworth sleepiness scale, evaluation of cognitive and olfactory functioning as well as blood samples. irbd patients, compared to controls, showed a significant reduction in intraepidermal nerve fiber density (p = . ), whereas the axon swelling ratio, did not differ between groups. patients with irbd reported non-motor symptoms more frequently than controls (updrs i, nms-quest). olfaction and daytime sleepiness differed between both groups, whereas there were no differences regarding cognition. these in vivo findings demonstrate small fiber neuropathy in irbd patients that are associated with non-motor symptoms indicating that peripheral abnormalities may occur early in irbd. they warrant larger scale longitudinal studies in order to investigate their prognostic value. katz j , lewis r , spatafora d . california pacific med center, san francisco, usa; cedars-sinai medical center, los angeles, usa; neuropathy action foundation (naf), santa ana, usa. multifocal motor neuropathy (mmn) is a rare condition that affects . in every , individuals worldwide and is associated with motor dysfunction and moderate to severe disability. the neuropathy action foundation conducted a global survey to determine the impact of mmn on patient quality of life (qol) and gaps in patient/provider educational needs. the first global mmn qol survey was an item internet questionnaire available between january and july , . the survey focused on three primary areas: timely and accurate diagnosis, the efficacy of treatment, and the impact of the disease on patients qol. the survey was completed by patients from countries. the majority of respondents said they were diagnosed between the ages of and years ( . %), more than % reported that it took more than one year to be diagnosed and more than % reported that it took - years or longer to be accurately diagnosed. with respect to treatment options : . % reported receiving intravenous immune globulin and . % reported receiving subcutaneous immune globulin therapy. other therapies being used to treat mmn were gabapentin ( . %), and pregabalin ( %). almost half ( . %) said that mmn often impacts their overall schedule. half of the participants reported that mmn often or always interferes with their employment; % had difficulty typing on a computer or using a telephone, . % had trouble concentrating, and . % said they had to work really hard to pay attention or else they would make a mistake. this is the first assessment of mmn from a patient's perspective. the survey highlighted critical issues relating to the diagnosis, management, and impact on the qol of individuals with mmn. the data also identified gaps and insights in provider education relating to proper diagnoses and management of the condition from a patient's perspective. katz j , levine t , dimachke m , barohn r . forbes norris center, san francisco, ca, usa; phoenix neurological institute, phoenix, az, usa; kansas university medical center, kansas city, ks, usa. in the united states, cidp cases are submitted to insurance companies to determine whether ivig therapy is appropriate. this is done using specified diagnostic criteria, which reduce diagnosis to a boolean analysis, where a disease can only be present or absent. this leaves no room for uncertainty, even when it truly exists. boolean criteria are useful for clinical trials, but fall short where real decisions are made under uncertainty and based on perceived cost/benefit analysis. this project attempts to elucidate root causes of uncertainty and to find solutions to this dilemma. we asked cidp experts to select a single diagnosis in cases where ivig was approved using the submitted case records. while there was agreement on many cases, in the five most "uncertain" cases no more than reviewers agreed on a single condition, who chose up to four separate entities. among these, at least three reviewers diagnosed an immune neuropathy in all five. the root cause of the disagreement, to a large degree was unclear documentation (aunts) which consisted of pasted, missing, and disorganized data. reviewers missed useful information, admitting it was too difficult to fully parse records. to resolve uncertainty, reviewers admitted to discounting certain reported datum to help fit the entity they suspected, such as reported therapeutic responses or certain electrodiagnostic/exam findings. other disagreement, however, reflected the complexity of neuropathy diagnosis, such as knowing if improvement was due to natural history or treatment, unawareness of rare presentations, or analyzing a true uncle (complex case). reviewers used bayesian (select most likely diagnoses from a list) and fuzzy logic (compare best fits to base cases). when the "best" diagnosis did not fit the base case, they had to re-interpret the data. improving review procedures requires eliminating aunts by collecting all key information and simplifying how records are presented. it also needs more advanced data methods to analyze common and rare borderline presentations (uncles like mama v pma, cidp v cspn, etc..), developing diagnostic algorithms that address real uncertainty, educating prescribers and patients on process, and creating systems that measure outcomes longitudinally after induction or tapering of therapy. keisuke y , miyuki m , motoi k , susumu k . department of neurology, faculty of medicine, kinki university, osaka, japan. anti-ganglioside antibodies are closely associated with clinical phenotype and specific symptoms in acute immune-mediated neuropathies. igg anti-gq b antibodies are specifically associated with miller fisher syndrome (mfs), bickerstaff brainstem encephalitis (bbe) and guillain-barré syndrome (gbs) with opthalmoplegia (gbs-op). in addition, ganglioside complexes (gscs) containing gq b also can be targets in such diseases, and might be associated with the clinical features. however, factors regulating clinical phenotype in those gq b-associated antibodies-positive diseases have not yet been known. for investigating the differences of antibody reactivities among those diseases, we examined, using combinatorial glycoarray, igg antibodies to ten individual glycolipids [gm , gm , gm , gd a, gd b, gq b, galactocerebroside (gal-c), lactosylceramide (laccer), ga , sulfatide] and glycolipid complexes consisting of two of the glycolipids listed above in sera from patients with gbs-op who were positive for anti-gq b antibody by elisa (gbs-op-gq b), patients with mfs with the clinical triad (opthalmoplegia, ataxia, and areflexia), and patients with bbe. by combinatorial glycoarray, overall sensitivity of antibodies to gq b and gscs containing gq b was . % ( / ) in gbs-op-gq b, . % ( / ) in mfs, and . % ( / ) in bbe, respectively. there were no significant differences in antibody reactivities between mfs and bbe. it is notable that antibodies to gscs containing gd b were more frequently found in gbs-op-gq b patients than in mfs or bbe patients (e.g., gd b/sulfatide: p= . and p< . , respectively). presence of the antibody reactivities to gscs containing gd b may possibly be related with clinical features of gbs-op-gq b, including frequent need of artificial ventilation. kennedy r , , , carroll k , , paterson k , ryan mm , , , mcginley jl , . royal children's hospital, parkville, australia; university of melbourne, parkville, australia; murdoch childrens research institute, parkville, australia. problems with walking and footwear fit are often reported by children and adolescents with charcot-marie-tooth disease (cmt). a cross-sectional, case controlled study of gait was conducted in children with cmt and typically developing (td) children. gait was assessed barefoot and in two types of the participants' own typical footwear; optimal (e.g. athletic shoes) and suboptimal (e.g. slip-on footwear). the aims were to determine differences in spatio-temporal (s-t) gait variables between children with cmt and td children; and to investigate the effect of footwear choices. twenty-nine independently ambulant children aged - years with confirmed genetic or clinical diagnoses of cmt, and age and gender matched td children participated (mean age . years; males). exclusion criteria included developmental disorders, other neuromuscular conditions or musculo-skeletal diseases that could affect gait, and lower limb injury or surgery in the preceding months. assessment included s-t gait patterns, footwear characteristics, metre run, and cmtpeds. gait was assessed at self-selected speed with an electronic walkway (gaitrite™), with trials for each condition. the primary gait variable assessed was speed; other variables included step length, step time, cadence, base of support width and step-to-step gait variability. across all footwear conditions children with cmt walked more slowly ( regeneration of cutaneous unmyelinated axons is known to be slowed in dm-patients and after -months, the density of intraepidermal nerve fibers (ienf) does not return to baseline levels after chemical or mechanical axotomy. however, the long-term outcome of regeneration in dm or control subjects is not known. additionally, it is not clear if the regeneration of sensory distal axons is length-dependent. here we measured the rate of axonal regeneration -months after chemical denervation using a capsaicin model in dm patients (n= / dm /dm ) without neuropathy, and controls. dm skin punches were performed at distal thigh at baseline, -hours post-capsaicin, and at , , and days. blood glucose and hgba c were measured at baseline, , and days. healthy controls had skin punches at both distal leg and proximal thigh at baseline, after capsaicin chemical axotomy, and days , , and . regeneration rate was significantly higher at the thigh in healthy controls ( . fibers/mm/day ( % ci: . - . fibers/mm/day) compared to dm (p= . ), but no difference between dm ( . fibers/mm/day % ci: . - . fibers/mm/day) or dm ( . fibers/mm/day % ci: . - . fibers/mm/day) (p= . ). comparing regeneration rate at different time intervals, showed that regeneration was significantly slowed between day and dm patients, while it continued with the same rate in controls. blood glucose or hga c had no effect on regeneration rate. ienfd returned to baseline in controls by -months ( % of baseline) while it is did not in dm subjects, %/ % (dm /dm ) of ienfd baseline, (p= . dm vs. controls). there was no difference in regeneration rate ienfd %-baseline by -months at distal leg and proximal thigh in controls (p= . ). these results suggest that the rate and outcome of regeneration is independent of the length of the axon. additionally diabetic patient have incomplete nerve regeneration after months regardless of diabetes type or the level of glycemic control. regeneration of axons slowed down over time in patients with dm and reached a plateau after days. kiessling p , lledo-garcia r , watanabe s , langdon g , tran d , bari m , christodoulou l , price g , smith b , byrnes w , brock m , jolles s . ucb pharma, monheim, germany; ucb pharma, slough, uk; ucb pharma, braine-l' alleud, belgium; ptx solutions ltd, london, uk; ucb pharma, raleigh, durham, usa; university hospital of wales, cardiff, uk. ucb is a humanised high-affinity monoclonal igg antibody developed to bind human neonatal fc receptor (fcrn), selectively inhibiting igg salvage and recycling. conditions such as myasthenia gravis (mg) are characterised by pathogenic igg autoantibodies; inhibition of fcrn may provide a suitable therapeutic approach. this phase i, double-blind, dose-escalating, first-in-human study (nct ) evaluated the safety and pharmacology of ucb . forty-nine healthy adults (mean age years, range - ) were randomised and received a single dose of intravenous (iv) or subcutaneous (sc) placebo (n= and n= , respectively), or a single dose of iv or sc ucb ( , or mg/kg; n= per dose, per administration). subjects were followed up until day . one placebo iv subject did not complete the study. twenty-seven of subjects ( %) receiving ucb , and / ( %) receiving placebo, reported ≥ treatment-emergent adverse event (teae) of mild/moderate intensity. severe teaes occurred in four subjects, all in the ucb mg/kg iv group (headache [n= ], back pain [n= ]). no serious aes occurred. incidence of infections was similar with ucb and placebo. the most frequently reported infection was nasopharyngitis. treatment-related teaes were reported by % of subjects receiving ucb and % receiving placebo: the most common in the ucb -treated groups were headache ( / ; %) and vomiting ( / ; %); these occurred more frequently with the iv than sc route. non-linear increases in ucb plasma concentration-time profile with increasing dose were observed with ucb . serum igg was reduced in a dose-depended manner with ucb iv and sc: decreases from baseline to day with ucb iv were . %, . % and . % for , and mg/kg doses, respectively, and . %, . % and . %, with ucb sc doses, respectively. these data indicated that the fcrn inhibitor ucb effectively reduced serum igg, with sc administration generally better tolerated than iv. further to these observations, the efficacy, safety and tolerability of ucb sc for chronic-intermittent treatment of moderate-to-severe mg are being evaluated in an ongoing phase ii, multi-centre, randomised, double-blind, placebo-controlled study (eudract - - middle east respiratory syndrome (mers) has a high mortality rate and pandemic potential. however, very little information has become available on this syndrome since it first erupted in . this study aimed to evaluate the frequency of neurological complications and their clinical presentations in mers. we reviewed the medical records of all patients who were diagnosed with laboratory-confirmed mers coronavirus (cov) infections and subsequently admitted to a single reference center for mers treatment during the outbreak in korea. in total, patients ( . %) reported neurological symptoms during or after mers-cov infection. the potential diagnoses in these cases included bickerstaff's encephalitis overlapping with guillain-barré syndrome, critical illness polyneuropathy or other toxic or infectious neuropathies. neurological complications did not appear concomitantly with respiratory symptoms, but were instead delayed by - weeks. neuromuscular complications were not rare in mers-cov-infected patients, and they may have previously been underdiagnosed. understanding neurological manifestations is important in an infectious disease like mers, because evaluation is frequently limited during treatment, but it can interfere with prognosis and sometimes require modification of treatment. kim hj , hyun jk , kim tu . dankook university, cheonan, south korea. the diagnosis of carpal tunnel syndrome (cts) is based on clinical symptoms, physical examinations and supported by nerve conduction study (ncs). ultrasonographic examinations can be performed to assess peripheral nerves with less discomfort and the surrounding anatomic structures. while the usefulness of ultrasonography (usg) in the cts has been reported, no study to date has compared the diagnostic utility of various usg findings for cts. we investigated the correlation of various usg findings to the clinical symptoms/signs and ncs findings in patients with cts. twenty-eight hands ( patients) with cts based on electrodiagnostic criteria and clinical symptoms such as tingling sensation or pain in the first to third fingers, burning sensation, paresthesia and weakness of hand grip power. all subjects were examined with usg. cross-sectional area (csa) and flattening ratio (fr) of the median nerve was calculated at level of radio-ulnar joint, pisiform and hamate. swelling ratio of the median nerve and palmar displacement of the flexor retinaculum was also calculated. clinical assessment was conducted using the boston carpal tunnel questionnaire (bctq) scale and historical-objective (hi-ob) scale. the analysis of correlation between usg findings and clinical symptom scales/ncs findings was performed using correlation analysis. the csa of the median nerve at level of radio-ulnar joint was significant correlated with bctq scale, hi-ob scale, distal motor latency, and conduction velocity (cv). the csa of the median nerve at level of pisiform was significantly correlated with hi-ob scale, distal motor latency, and cv. the fr of the median nerve at level of radio-ulnar joint was significantly correlated with bctq scale, hi-ob scale, distal motor latency, and cv. the swelling ratio of the median nerve was also significantly correlated with distal motor latency and cv. in patients with cts, csa of the median nerve at level of radio-ulnar joint was most closely related to ncs findings and clinical symptoms. so, csa of the median nerve at radio-ulnar joint might be a complementary tool for the diagnosis of cts. kitaoji t , tsuji y , ashida s , yamada t , ishii r , tanaka a , mizuno t . department of neurology, graduate school of medical science, kyoto prefectural university of medicine, kyoto, japan. the case was a -year-old woman. first, she noticed paresthesia in the right plantar eight months before admission and in the left plantar four months before admission. three months before admission, she developed muscle weakness in her feet. the muscle weakness and paresthesia extended to the lower legs in a few months. twenty days before admission, she experience difficulty in walking. on admission, the muscle weakness was observed in the legs, especially in the right tibial anterior muscle (ta). there was severe sensory disturbance and loss of deep tendon reflex in the legs. she had trouble walking due to the weakness and sensory aphasia. in nerve conduction study (ncs), conduction block was observed between the ankle and popliteal in both tibial nerves. the blood level of angiotensin converting enzyme (ace) was elevated. cerebrospinal fluid analysis was normal. there was no enhancement in the lumbar nerve roots shown on mri. gallium- scintigraphy showed hot spots on bilateral hilar lymph nodes and mediastinal nodes and biopsy of mediastinal nodes showed non-caseating epithelioid granuloma. therefore, we diagnosed her with sarcoid peripheral neuropathy by sarcoidosis. by using the nerve ultrasound, partial spindle-shaped nerve enlargement was observed at the part of conduction block in the left tibial nerve. we started the treatment with methyl prednisolone ( mg, days) and oral prednisolone therapy ( mg/kg/day). after treatment, the paresthesia and muscle weakness in the legs had gradually improved. the partial enlargement in the left tibial nerve also improved on the -hospital day. in ncs, the conduction block improved, however, the compound muscle nerve potential of tibial nerve decreased because of axonal damage. this partial spindle-shaped nerve enlargement by using ultrasound has never been reported in sarcoid peripheral neuropathy before. the nerve ultrasound may be useful for evaluation of therapeutic effect of sarcoid peripheral neuropathy. peripheral nerve injuries are still debating problems in the world because of poor recovery. there is absolutely a need for new therapeutic agents to improve outcome by altering nerve regeneration. there are some studies in the literature about some therapeutic agents that used in the cases of peripheral nerve injuries. despite these studies, an agent with clinical use has not been presented yet. in this experimental study, we aimed to analyze the effects of curcumin (cur) in the cases of peripheral nerve injuries. forty rats were randomly and equally divided into four groups. the first group was control group. rats in this group were not operated. right sciatic nerve injuries were performed to the other groups. the second group was operation group with no therapeutic agent. the third group was operation and local cur applied group. the fourth group was operation and systemic cur applied group. electrophysiological evaluations were performed with electroneurography (enog) before and after the surgeries. systemic use of cur although caused improvement in the enog values but could not make a positive contribution to the nerve regeneration statistically. additionally local use of cur made negative effect to the nerve regeneration statistically. according to our statistical results we could not recommend cur as a nerve protective agent. klein cj , wu y , jentoft me , mer g , spinner rj , dyck pjb , dyck pj , mauermann ml . mayo clinic, rochester, usa. intraneural perineurioma is a hypertrophic peripheral nerve tumor having immunoreactivity to epithelial membrane-antigen, negative for s- . the origin of perineurial cells is debated to be similar to meningeal cells. ip does not metastasize, but motor deficits accumulate over time from tumor growth in nerve and plexus. after schwannomas and neurofibromas, perineuriomas are the most common nerve tumor of young adults. a chromosome q deletion has been reported in one patient. we identified ip cases from our previously published clinical cohort with available flash frozen ip tissue for dna isolation. wes with cnv analysis and cgh microarray analysis (agilent x k superprintg ) were performed on extracted dna; had available germline dna (lymphocytes and buccal tissue). we compared the exome data against online and in-house control data (∼ , ) examining variants less than . frequencies, predicted damaging or nonsynonymous. wes identified three novel, heterozygous, damaging mutations in tumor necrosis factor receptor-associated factor (traf ) in of ( %) cases; p.l p (n= ), p.h r (n= ) and p.s r (n= ). mutations were within the wd domain, p.l p, p.h r within exon and p.s r within exon , and mapped to a limited region of traf with protein structure modeling. two of cases ( . %) showed macroduplications/deletions on multiple chromosomes, including chromosome , confirmed with cgh microarray analysis and cnv results from exome data analysis. four of ( %) had no discovered mutation. age of onset or severity did not correlate with type of mutations. this study provides strong evidence that traf is a specific tumor driver of ip. mutations in traf are also linked to benign intracranial meningiomas suggesting a shared pathogenesis and close origins of perineurial and meningeal cells. study supported by: mayo foundation and the mayo center of individualized medicine. klein i , , bobylev i , , lehmann hc , . university hospital cologne, cologne, germany; center for molecular medicine cologne (cmmc), cologne, germany. peripheral neuropathy is a common side effect of paclitaxel. clinical evidence suggests that the delivery mechanism of paclitaxel formulations influence time course and severity of paclitaxel induced peripheral neuropathy. in a preclinical model we studied access, distribution and toxicity of two paclitaxel formulations (nanoparticle albumin-bound paclitaxel (nab) and solvent-based paclitaxel) in the peripheral nervous system (pns). c bl/ mice were treated with mg/kg or mg/kg of nab-paclitaxel or solvent based paclitaxel. kinetics of paclitaxel in neurons was assessed by a newly established immunostaining technique. neurotoxicity was evaluated by functional assays and nerve morphology. paclitaxel accumulated mostly in dorsal root ganglia, whereas distal nerve segments showed only low uptake of paclitaxel. treatment of mice with the two paclitaxel formulations resulted in paclitaxel uptake mostly in nf + larger fiber neurons. in ib +, and cgrp+ small fiber neurons, paclitaxel was less frequently detected. nab-paclitaxel was incorporated more rapidly compared to solvent-based paclitaxel but neurons also showed a faster clearance of nab-paclitaxel compared to solvent based paclitaxel. functional assays and nerve conduction studies indicated that nab-paclitaxel was less neurotoxic compared to solvent-based paclitaxel. this is the first study that characterizes in detail the access of nab-paclitaxel and solvent based paclitaxel into the pns. our findings have important implications to understand the pathomechanisms of paclitaxel induced neurotoxicity and to develop neuroprotective strategies by preventing access of paclitaxel to the pns. the aim of our study was to investigate the etiology of neuropathy in patients with rheumatoid arthritis (ra). subjects were neuropathy patients with ra admitted to our department. laboratory investigations, nerve conduction studies (ncs) and sural nerve biopsy were performed. mean patient age was . years (range, - years), and mean disease duration was . years (range, - years). clinical diagnosis for neuropathy was rheumatoid vasculitis (rv) in patients, rv with acute motor axonal neuropathy (rv-aman) in and chronic inflammatory demyelinating polyneuropathy with ra (ra-cidp) in . rheumatoid factor ( / ) and rheumatoid arthritis particle agglutination ( / ) was high and c tended to be lower in the rv group (rv and rv-aman). anti-ganglioside antibodies were examined in patients, with positive results in . an rv-aman case was diagnosed with motor-dominant clinical presentation and the presence of anti-galnac-gd a immunoglobulin (ig)g antibody. no other cases with rv were examined for anti-ganglioside antibodies. positive results for anti-gm and gm igg antibody were seen in one ra-cidp patient. we evaluated sural/median (s/m) ratio) for sensory nerve action potential (snap). s/m ratio was low in rv cases ( / ) and high ( / ) in immune-mediated cases, suggesting a so-called normal sural abnormal median pattern in immune-mediated neuropathies. the rv-aman case showed a moderate value in s/m ratio. nerve biopsy revealed thinly myelinated nerve fibers in ra-cidp cases compatible with demyelination, while the rv group showed the typical pathology for necrotizing vasculitis. rv cases were treated with prednisolone (psl), intravenous methylprednisolone, intravenous cyclophosphamide and increased psl dose. ra-cidp and rv-aman were treated with intravenous ig. in conclusion, neuropathy in ra can be divided into vasculitic and immune-mediated groups. ncs, and the s/m ratio of snap with some laboratory parameters in particular, may be of use in differential diagnosis and deciding treatment strategies. koh s , wong shj , loh kw , chng ysk , pawa c , ei ma , lee bjh , subramaniam t , umapathi t . national neuroscience institute, singapore, singapore; lee kong chian school of medicine, nanyang technological university, singapore; yong loo lin school of medicine, national university singapore, singapore; tan tock seng hospital, singapore; khoo teck puat hospital, singapore. treatment-induced neuropathy of diabetes mellitus (dm) (tind) is an acute painful autonomic neuropathy that develops with abrupt improvement in glycaemic control. typically, type or dm patients on insulin or oral hypoglycaemic agents (ohga), present with painful neuropathy and autonomic dysfunction within weeks of rapid improvement in glucose control. current emphasis to achieve good glycaemic control rapidly may inadvertently increase incidence of tind, hence the impetus to understand risk of over-zealous glycaemic control. we therefore set out to study the occurrence of tind in a dm cohort of a tertiary hospital. we screened all patients who had two hba c measurements between and . during this period, approximately patients were seen per year. we found patient-encounters that showed hba c decrease of ≥ % over months or ≥ % over months. we then used a structured checklist of tind symptoms to shortlist cases. these case-encounters were scrutinised and classified as; 'probable tind': acute painful neuropathy and acute dysautonomia with temporal relationship to the decrease in hba c; 'possible tind': acute painful neuropathy or acute dysautonomia or uncertain temporal relationship to decrease in hba c; unlikely tind: alternative explanation exists for symptoms. only one case was deemed 'probable tind'-a middle-aged man with newly diagnosed type dm who presented to emergency department with palpitations and worsening 'frozen feet' sensation that disturbed sleep. his hba c decreased by . % in weeks. his symptoms improved within a month with neuropathic pain medications and resolved months later. he also developed maculopathy and proliferative retinopathy. ten months later, he developed significant proteinuria. four other cases were classified as 'possible tind' while the remaining were unlikely tind. our study is limited by retrospective design and reliance on hospital records. nevertheless, our findings suggest that tind is uncommon in a general cohort of dm patients. on the other hand, the number of patients with painful neuropathy and acute dysautonomia symptoms contemporaneous with rapid decline in hba c raises the intriguing possibility that forme fruste of tind exists and one should interrogate the rate of hba c decline in dm patients with these symptoms. koike h , kadoya m , kaida k , ikeda s , kawagashira y , iijima m , kato d , ogata h , yamasaki r , matsukawa n , kira ji , katsuno m , sobue g . nagoya university graduate school of medicine, nagoya, japan; national defense medical college, tokorozawa, japan; nagoya city university graduate school of medical sciences, nagoya, japan; kyushu university, fukuoka, japan. we investigated the morphological features of chronic inflammatory demyelinating polyneuropathy (cidp) with autoantibodies directed against paranodal junctional molecules, particularly focusing on the fine structures of the paranodes. sural nerve biopsy specimens obtained from cidp patients with anti-neurofascin antibodies and patient with anti-contactin antibodies were assessed. these antibodies were examined using sera obtained from patients with cidp who fulfilled the criteria of the european federation of neurological societies/peripheral nerve society. thirteen cidp patients without these antibodies were also examined to compare pathological findings. characteristic light and electron microscopy findings in transverse sections from patients with anti-neurofascin and anti-contactin antibodies indicated a slight reduction in myelinated fiber density, with scattered myelin ovoids, and the absence of macrophage-mediated demyelination or onion bulbs. teased-fiber preparations revealed that segmental demyelination tended to be found in patients with relatively high frequencies of axonal degeneration and was tandemly found at consecutive nodes of ranvier in a single fiber. assessment of longitudinal sections by electron microscopy revealed that detachment of terminal myelin loops from the axolemma was frequently found at the paranode in both anti-neurofascin and anti-contactin antibody-positive cidp patients compared with antibody-negative cidp patients. patients with anti-neurofascin antibodies showed a positive correlation between the frequencies of axo-glial detachment at the paranode and axonal degeneration, as assessed by teased-fiber preparations (p < . ). in conclusion, paranodal dissection without classical macrophage-mediated demyelination is the characteristic feature of patients with cidp with autoantibodies to paranodal axo-glial junctional molecules. koike h , ikeda s , takahashi m , kawagashira y , iijima m , misumi y , ando y , ikeda si , katsuno m , sobue g . nagoya university graduate school of medicine, nagoya, japan; kumamoto university, kumamoto, japan; shinshu university hospital, matsumoto, japan. peripheral neuropathy is the cardinal feature of familial amyloid polyneuropathy (fap), but its mechanism has not been fully elucidated. we used electron microscopy to examine schwann cells and endoneurial microvessels. sural nerve biopsy specimens from fap patients with transthyretin val met mutation were assessed. patients were consisted of early onset cases from endemic foci and late onset cases from non-endemic areas. loss of nerve fibers with or without neighboring amyloid deposition was a common feature. the amount of amyloid deposition was greater relative to the extent of nerve fiber loss in early onset cases than in late onset cases. the atrophy of schwann cells, particularly nonmyelinating cells, that were apposed to amyloid fibrils was more conspicuous in early onset cases than in late onset cases. the numbers of endothelial cell nuclei, endothelial cell profiles, and occluded microvessels were significantly increased in the fap patients compared with patients with nutritional/alcoholic neuropathies (p < . , . , and . , respectively). findings suggestive of the disruption of blood-nerve barriers, such as the loss of tight junctions and the fenestration of endothelial cells, were also more frequently found in the fap patients (p < . ), irrespective of the presence or absence of amyloid deposition. in conclusion, these findings suggest that direct insult of amyloid fibrils causes schwann cell damage resulting in the predominant loss of small-fiber axons characteristic of early onset cases. in addition, vasculopathy may also participate in the pathogenesis of neuropathy, particularly in late onset cases. kolb n , smith ag , singleton jr , beck s , howard d , dittus k , karafiath s , mooney k . university of vermont, burlington, vt, usa; university of utah health, slc, ut, usa. chemotherapy induced peripheral neuropathy (cipn) is a major cause of morbidity due to numbness, pain, and gait instability. this prospective study compares the current standard care for cipn symptom management to a new care delivery model which utilizes an automated symptom tracking program paired with a nurse practitioner led intervention triggered by moderate to severe symptoms. all participants beginning taxane or platin based chemotherapy called a telephone based automated symptom tracking program daily (symptom care at home -sch) to report chemotherapy related numbness and tingling. sch tracked the presence and severity of neuropathic symptoms and their interference with activities of daily living (adls) on a - scale. participants were randomized to two groups. the usual care (uc) group was advised to call their oncology provider for recommendations on symptom management. in the nurse practitioner (np) group, when symptom severity was ≥ participants received automated self care strategies and a call from a nurse practitioner to provide treatment recommendations based on consensus guidelines. patients participated in the study. mean duration of follow up was . ± . days with . ± . calls. the np group had fewer days with any neuropathic symptom ( . % ± . vs. . % ± . , p= . ), with moderate to severe neuropathic symptoms ( . % ± . vs. . % ± . , p< . ) or days of distress from neuropathic symptoms ( . % ± . vs. . % ± . , p= . ). on days with moderate to severe symptoms participants also reported burning ( . ± . %), weakness ( . ± . %), balance problems, ( . ± . %), and tripping ( . ± . %). there was no significant difference between groups in the interference in adls (np . ± . vs. uc . ± . , p= . ). overall the automated telephone system effectively identified neuropathy symptoms and their severity. compared to usual care in which patients must independently reach out to their care team for symptom management, sch is effective in decreasing symptom prevalence, severity and distress. kouton l , kremer l , tard c , morales r , kuntzer t , attarian s , boucraut j , delmont e . referral centre for als and neuromuscular diseases, marseille, france; neurology department, strasbourg, france; neurology department, lille, france; neurology department, montpellier, france; neurology department, lausanne, switzerland; immunology laboratory, marseille, france. antibodies against proteins of the node of ranvier have been recently described in severe chronic inflammatory demyelinating polyradiculoneuropathies (cidp). they target paranodal proteins, namely contactin (cntn ) and neurofascin (nf ). cell-based assay and elisa are available in research, but no gold standard technic is admitted for the detection in routine of these antibodies. our objective was to evaluate if flow cytometry analysis is an efficient technic to detect antibodies against ctn and nf in a large cohort of cidp patients. flow cytometry analysis were performed on a bd facs-diva. human embryonic kidney (hek) cells were transfected either with nf or cntn . sera were diluted / . antibodies anti-cntn or nf were revealed using fitc conjugated anti human igg antibodies. delta mfi (mean fluorescence intensity) was calculated as mfi of transfected cells less mfi of non-transfected cells. measures were normalized using positive controls and negative controls from healthy blood donors. sera of cidp patients from different french neuromuscular referral centres were analysed with flow cytometry. respective delta mfi were (standard deviation ) and (standard deviation ) for antibodies against nf and cntn in cidp antibodies negative patients. antibodies against nf were found in patients (respective mfi , , ) and against cntn in two other patients (respective mfi and ). isotype of these antibodies was igg in patients and igg and igg in the remaining patient. all the patient had severe cidp. four patients had poor response to intravenous immunoglobulins (ivig) and have been treated with immunosuppressive drugs. as usually reported, the patient with anti-nf antibodies had postural tremor. flow cytometry seems effective to detect antibodies against nf and cntn . compared to other assays, benefits of flow cytometry are: to analyse a large number of sera in the same time and to give objective numerical results expressed in mfi that can be compared to the results of other samples. further studies are needed to confirm that flow cytometry can be the best test to assess antibodies against cntn and nf in routine. the mechanism by which intravenous immunoglobulins (ivig) improves peripheral nerve function in multifocal motor neuropathy (mmn) is unknown. the rapid clinical improvement following ivig could be related to blocking complement deposition on gm epitopes, change in ion-channel properties of affected motor axons, or both. the present study investigated median nerve motor excitability parameters at ∘ c just before ivig administration as well as at the peak of clinical improvement in patients with mmn. the investigated nerves were characterized either by conduction block (n= ), demyelinative slowing without block (n= ), or motor axon loss (n= ). the results of motor excitability testing in mmn showed no difference between pre-and post ivig recordings. clinical assessment of apb muscle showed increase in mrc score in patients and decrease in patient after ivig administration. in patients mrc score of the apb remained the same. those findings indicate that clinical changes following ivig administration are not related to excitability parameters of affected motor axons in mmn. where impulse conduction is blocked or markedly slowed in motor axons but is normal in sensory axons. sensory symptoms or signs are usually absent but have occasionally been reported in skin areas innervated by nerves with prominent motor axon loss. although the mechanism of selective motor involvement in mmn is unresolved, it may be related to differences in antigenic properties between motor and sensory axons or differences in biophysical properties. the objective of the present study was to compare ion-channel activity in both motor and sensory axons of nerves affected by mmn. affected nerves had to have motor conduction block, demyelinative slowing on motor ncs, or motor axon loss, whereas sensory ncs had to be normal. we performed excitability tests of motor and sensory axons in affected median nerves of mmn patients and healthy controls at ∘ c. conditioning and test stimuli were delivered at the median nerve at the wrist; cmaps were recorded from the thenar muscle and snaps from the rd digit. results of motor excitability testing in mmn showed fanning-out of threshold electrotonus, decreased i/v slope, and increased superexcitability, all compatible with persistent hyperpolarization of resting membrane potential in motor axons. sensory excitability testing in mmn showed decreased subexcitability but was otherwise normal. this may indicate minimal involvement of sensory axons in mmn. krarup c , , moldovan m , , alvarez s , ciano c , pisciotta c , pareyson d . university of copenhagen, copenhagen, denmark; rigshospitalet, copenhagen, denmark; fondazione irccs istituto neurologico c. besta, (incb), milan, italy. mutations in the gene coding for myelin protein zero (mpz, p ) are associated with different forms of charcot-marie-tooth (cmt) disease. we describe a family harboring a frameshift mutation (c. dela / p.asp thrfster ) in the p gene, predicted to result in a nonfunctional p truncated very early in the extracellular domain. this offered the rare opportunity to assess the consequences p deficiency in absence of the potential gain-of-function effects of the mutations itself. conventional conduction studies and multiple measures of nerve excitability by "threshold tracking" were carried out in heterozygote parents (aged and ) and their two homozygote sons (aged and ). in the homozygous patients, all distal limb cmaps and snaps were absent. for neurophysiological assessment, the spinal accessory nerve was stimulated at the neck and cmap was recorded over the upper trapezius muscle. eight normal subjects, mean age , were used as control. the two sibs showed a severe phenotype with early onset, severe scoliosis, complete loss of distal movements and relevant proximal weakness, cmt examination score (cmtes) - / ; both heterozygous parents had very mild adult-onset neuropathy with cmtes < / . control subjects had a trapezius cmap with a latency of . ms and an amplitude of . mv. heterozygotes had a mild cmt type b phenotype, with a cmap latency of . ms and an amplitude of . mv whereas the homozygotes had a severe neuropathy with a cmap latency of . ms and an amplitude of . mv. consistently, the homozygotes had a more severe impairment in excitability with a rheobase of . ma as compared to . ma in the heterozygote and . ma in controls. deviations in excitability measures were similar to our previous reports in p +/− and p −/− mice. mathematical modeling, indicated both altered passive cable properties due to dysmyelination and depolarizing features with increased na+ currents. our data suggest that p deficiency is associated with impaired axonal na+ channel function, arguing for the translational value of na+ channel blocker treatments as found in p null mouse models. krishnarajah s , divino v , mallick r , dekoven m . csl behring, king of prussia, pa, usa; quintilesims, fairfax, va, usa. chronic inflammatory demyelinating polyneuropathy (cidp) is a rare neurological disorder of the peripheral nervous system. the objectives of this retrospective real-world study were to compare demographic and clinical characteristics among cidp cases and matched controls and to assess cidp treatment utilization. adults newly diagnosed with cidp between / / and / / were identified in the quintilesims pharmetrics plus health plan claims database (first diagnosis date termed the index date). eligibility requirements were: confirmation of cidp (second cidp diagnosis or initiation of cidp therapy) within year of initial diagnosis, continuous health plan enrollment in the months prior to diagnosis (the pre-index) and the years following diagnosis (the follow-up), and no cidp diagnosis or use of cidp therapy in the pre-index. a total of , cidp cases met the study eligibility criteria. cases were direct-matched to controls based on age, gender, region, health plan, and payer type at index, and pre-index charlson comorbidity index score. the final sample consisted of cases matched to controls (both: mean [sd] age . [ . ]; . % male; . % commercially-insured). alternative pre-index diagnoses among cases included inherited neuropathies ( . %) and chronic acquired polyneuropathies ( . %). in the pre-index, neuropathic pain ( . % vs. . %), back pain ( . % vs. . %), and use of opioids ( . % vs. . %) and anti-convulsants ( . % vs. . %) were significantly higher among cases compared to controls (p< . for all). median total pre-index healthcare costs were . x higher for cases than controls ($ , vs. $ , , p< . ). over the follow-up, median total healthcare costs were . x higher for cases than controls ($ , vs. $ , , p< . [mean $ , and $ , ] ). cidp-related therapy costs accounted for . % of total healthcare costs for cases. the majority of cases ( . %) initiated cidp therapy over the follow-up, in a mean of . ( . ) days from initial diagnosis. half ( . %) of cases initiated treatment with corticosteroids only, while . % initiated ivig only. over the follow-up, . % of cases used any corticosteroid, while . % used any ivig. our findings suggest a substantial clinical and economic burden of cidp compared to matched controls. corticosteroids and ivig were most commonly used to treat cidp. kronlage m , baeumer p, pitarokoili k , schwarz d , schwehr v , godel t , heiland s , gold r , bendszus m , yoon ms . department of neuroradiology, heidelberg university hospital, germany; department of neurology, st. josef hospital, ruhr university of bochum, germany. objective: to evaluate large coverage magnetic resonance neurography (mrn) in chronic inflammatory demyelinating polyneuropathy (cidp). methods: in this prospective study patients with cidp and healthy controls were examined by a standardized mrn protocol at tesla. lumbosacral plexus was imaged by a t -weighted d-sequence ( mm isotropic voxel size); peripheral nerves of the upper and lower extremity by axial t -weighted turbo-spin-echo sequences ( . x . mm in-plane resolution). lesions were characterized by nerve cross sectional area (csa) and t -weighted signal (nt ). additionally, t -relaxometry of the sciatic nerve was performed using a multi-spin-echo sequence. all patients received a complementary electrophysiological exam. results: patients with cidp exhibited increased nerve csa and nt compared to controls (p < . ) in a proximally predominating pattern. roc analysis revealed best diagnostic accuracy for csa of the lumbosacral plexus (auc = . ) and nt of the sciatic nerve (auc = . ). csa correlated with multiple electrophysiological parameters of demyelinating neuropathy (f-wave latency, nerve conduction velocity) of sciatic and median nerve, while nt only correlated with f-wave latency of sciatic and not median nerve. t -relaxometry indicated that mr-signal increase in cidp was due to increase in proton-spin-density (p < . ), and not increase in t -relaxation time. conclusion: both nt and csa might aid in diagnosis of cidp, but csa correlates more robustly with electrophysiological parameters. since best diagnostic accuracy was shown for proximal nerve locations, mrn may be a useful complementary tool in select cidp cases. kühnemund j , wetzel c , bégay v , moshourab r , lewin gr . mdc & bih, berlin, germany; mdc, berlin, germany; charité, berlin, germany. damage of peripheral sensory nerves due to diabetes, herpes zoster infection, chemotherapy or trauma can cause chronic neuropathic pain. common symptoms include increased pain sensation (hyperalgesia), touch-induced pain (allodynia), paresthesia and spontaneous pain. we currently have poor understanding about the underlying molecular mechanisms at the peripheral level and treatment of patients suffering from neuropathic pain is inadequate. recent meta-analysis studies show that common first-line medications only yield nnts (numbers needed to treat) between . to . . it is still unclear to what extent allodynia can be attributed to changes in the physiological properties of intact sensory afferents. in this study, we aimed to elucidate whether changes occur in intact sensory afferents that innervate the plantar skin of the hind-paw following induction of neuropathic symptoms. this question was of particular interest considering that blocking mechanotransduction in the skin can alleviate mechanical hypersensitivity in neuropathic pain models (wetzel et al nature neuroscience ( ): - ). we used the chronic constriction injury (cci) model in mice which is behaviourally characterized by robust mechanical hypersensitivity. we made electrophysiological recordings from primary afferent neurons which had intact axons passing through the constriction to innervate the plantar skin using an ex-vivo skin-nerve preparation. we were able to record from myelinated afferent fibers and unmyelinated c-fibers with receptive fields in the control uninjured plantar skin as well as plantar skin of cci mice. we will present evidence that changes in the mechanosensitivity of sensory fibers innervating the glabrous skin may contribute to the symptoms of neuropathic pain. neuropathology, national hospital for neurology and neurosurgery, london, uk; irccs foundation "carlo besta" neurological institute, milan, italy; neurogenetics unit, national hospital for neurology and neurosurgery, london, uk; nuffield department of clinical neurosciences, oxford, uk; department of clinical neurophysiology, norfolk and norwich university hospital, uk. hsn secondary to sptlc / is a rare slowly progressive neuropathy resulting in marked sensory loss, especially nociception and significant motor deficit. despite most of the patients having the same c w mutation in sptlc , there is marked heterogeneity in the phenotype. l-serine oral supplementation has been suggested as potential therapeutic candidate however the lack of outcome measures is a major limiting factor in the initiation of a clinical trial. we undertook a natural history study to identify outcome measures that are responsive enough to be used in a clinical trial. the assessments used were cmt neuropathy score (cmtns version and cmtns version rasch modified), mri of calves and thighs, computerised myometry, quantitative sensory testing (qst), comprehensive neurophysiological assessment, proximal thigh skin biopsy for intra-epidermal nerve fibre density (ienfd), plasma dsl levels and patient based questionnaires (neuropathic pain symptom inventory and sf- v ). standardised response mean, srm (mean change/standard deviation of change) was used to compare responsiveness between tests. patients were recruited: with sptlc (c w) and with sptlc mutations. when analysed as a whole cohort, proximal calf mri fat fractions showed the most significant change over months. ienfd, plasma dsl levels, npsi and sf- v showed minimal change or the change was not in the clinically expected direction. for subsets of the remaining assessments which showed the highest responsiveness, the cohort was sub-divided into mild-moderate (cmtns ≤ ) and severe (cmtns> ) subgroups. in the mild-moderate subgroup, the greatest improvement in responsiveness was seen in computerised myometry (ankle plantarflexion: srm=− . and ankle eversion: srm=− . ). in the severe subgroup, qst (vibration detection thresholds on hands: srm=− . and face: srm=− . and pressure pain threshold on the face: srm= . ) and proximal calf mri fat fractions (srm range= . - . ) showed the greatest improvement. focusing on subgroups classified according to disease severity improved the responsiveness of some tests into the highly responsive range with mri still being the best outcome measure. this will reduce the number of participants required to power a clinical trial and might be a possible solution for designing a clinical trial for a rare, slowly progressive disease with a heterogeneous phenotype. kugathasan u , clark aj , suriyanarayanan s , laurá m , wilson e , , kalmar b , greensmith l , , hornemann t , reilly mm * , bennett dlh * . hsn secondary to sptlc / mutation is a slowly progressive sensory motor neuropathy leading to profound sensory loss with variable but often severe motor deficit. the genes sptlc and encode for the essential enzyme serine palmitoyltransferase (spt) which catalyses the rate limiting step in the sphingolipid de-novo biosynthesis. mutations in these two genes alter the substrate specificity of spt leading to the synthesis and accumulation of atypical metabolites called -deoxysphingolipids ( -deoxysl). plasma levels of -deoxysl are raised in hsn patients. deoxysphingolipids have been shown to be toxic in avian and by our group, in mammalian primary drg and motor neuron cultures. firstly, this study looked at the effects of -deoxysl on the survival and neurite integrity of human ipsc derived sensory neurons following exposure to different concentrations of deoxysphingolipids. later, we determined if there was autonomous -deoxysl production in hsn patient ipsc derived sensory neurons. sensory neurons were differentiated from human ipscs using a combination of small molecular inhibitors. deoxysphingolipids were found to be neurotoxic in this model after hours of treatment. in control lines, there is a significant reduction in neuronal survival following treatment with both -deoxysphinganine ( -deoxysa) and -deoxymethylsphinganine ( -doxmethsa). a clear dose-dependent increase in the expression of the axonal injury marker, atf , is seen with both -deoxysphngoid bases. in both instances, -deoxysa is more neurotoxic than -doxmethsa, which is similar to the findings in avian and mammalian primary neuronal cultures. autonomous -deoxysl production is seen in ipsc derived neurons obtained from three different hsn patients with the levels being significantly greater than that seen in multiple control lines. this is the first study to demonstrate that human ipsc derived sensory neurons can be used as an in-vitro model for hsn , providing a great opportunity both to probe the pathomechanisms mediating deoxysphingolipid toxicity and to test potential therapeutic agents. recent studies have demonstrated an association between autoantibodies directed against antineurofascin- (anti-nfasc ) and a subpopulation of cidp patients characterized by sensory ataxia, tremor and poor response to ivig treatment. here we report on the clinical features of three patients who developed acute changes in their phenotype during the course of their neuropathy, a potential clue to recognize a neuropathy with predominantly humoral dysimmunity. case reports: our index patient had developed sensory changes over weeks, followed by irregular locomotion, and muscle weakness with general areflexia. a first run of ivig improved the patient in a week, but he relapsed within days. a second ivig course with prednisone again normalized deficits within days. ivig runs and rituximab were still necessary to treat a nd , and then a rd relapse before obtaining complete improvement. the course of the neuropathy was months. two other patients were encountered with more chronic courses but in whom periods of worsening or improvement suggested a relapsing-remitting neuropathy, either spontaneously or following immunomodulating treatments. in all three, extensive work-ups were negative, anti-nfasc igg were positive, and detailed repeat nerve conduction studies demonstrated fluctuating conduction blocks. discussion: our report underscores that in chronic cidp patients a relapsing-remitting course could be encountered as a key feature of anti-nfasc neuropathy. this not yet described characteristic course could be of value when deciding using rituximab instead of immunomodulating treatments. kusunoki s , morikawa m , kuwahara m , ueno r , samukawa m , hamada y . faculty of medicine, kindai university, osaka-sayama, japan. anti-glycolipid antibodies are often detected in sera from patients with autoimmune neuropathies, such as guillain-barré syndrome (gbs), chronic inflammatory demyelinating polyradiculoneuropathy (cidp), and multifocal motor neuropathy (mmn). not only individual glycolipid antigens but also mixtures of two different glycolipids (glycolipid complexes) are sometimes recognized by serum antibodies. to investigate antibody activities against large number of glycolipid complexes in serum samples from patients with gbs, mmn, and cidp, we examined igm and igg antibodies against glycolipids [gm , gm , gd a, gd b, gq b, galnac-gd a, lm , galactocerebroside (gal-c), asialo-gm (ga ), and sulfatide] and glycolipid complexes consisting of two different glycolipids listed above, by using combinatorial glycoarray. serum was obtained from patients with gbs, patients with cidp and patients with mmn, all in the acute or relapsing phase. serum was also obtained from healthy controls and patients with other neurological diseases. we investigated the relationships between the clinical features and presence of those antibodies. high titers of igg antibodies were detected almost exclusively in gbs patients. in contrast, igm antibodies were frequently present in mmn and gbs. among the anti-glycolipid complex antibodies in gbs, anti-gm /sulfatide, anti-ga /sulfatide, anti-gm /gd a, and anti-gq b/sulfatide igg antibodies were common ( , , , and patients, respectively). igg antibodies against antigens containing gm were significantly correlated with pure motor gbs (p < . ) and those against antigens containing gq b were significantly correlated with gbs with ophthalmoplegia (p < . ). in seven of the patients with anti-gq b/sulfatide complex antibodies, the antibodies were specific to the gq b/sulfatide complex rather than the individual gq b and suldfatide antigens. moreover, four patients did not have antibodies other than those to the anti-gq b/sulfatide complex. in patients with mmn, igm antibodies to antigens containing gm or galnac-gd a were present in % and . %, respectively. glycoarray is efficient for detecting antibodies against numerous glycolipid complexes in immune-mediated neuropathies. we need further investigations on other immune-mediated diseases using larger number of antigens. kuwabara s , misawa s , sekiguchi y , susumu kusunoki and the jet-gbs study group . department of neurology, chiba university, chiba, japan; department of neurology, kindai university, osaka, japan; japanese eculizumab trial for guillain-barré syndrome, chiba, japan. guillain-barré syndrome is a monophasic immune-mediated neuropathy, but a substantial number of patients with severe disease have poor recovery, even if treated with immunoglobulin. recent studies suggest that complement activation plays a pivotal role in gbs-associated axonal degeneration, and eculizumab is a monoclonal antibody that specifically binds to complement component and inhibits complement activation. jet-gbs is an investigator-led, phase , randomized, placebo-controlled trial conducted in hospitals, this trial aims to investigate the safety and efficacy of eculizumab for treatment of severe gbs. patients were randomly assigned ( : ) to treatment with immunoglobulin plus either eculizumab ( mg/day; n= ) or placebo (n= ) once weekly for weeks. the primary outcome measures are safety and efficacy (the proportion of subjects who regain their ability to walk independently at week ). the secondary outcome measures included the proportion of subjects who were able to walk independently at week , and other measures such as mrc sum scores, nerve conduction parameters. enrollment for the trial began in august , and follow-up of the last patient was completed in october . analyses will be made in april , and the results will be presented at this meeting. this trial is registered with clinicaltrials.gov identifier: nct , and funded by the japanese agency for medical research and development, and alexion pharmaceuticals inc. neurofascin , a paranodal protein in peripheral nerve, is a target antigen for autoantibodies in a subset of chronic inflammatory demyelinating polyneuropathy (cidp). anti-neurofascin antibody-positive cidp is characterized by onset at younger age, tremor, and refractoriness to ivig. we have treated four patients with anti-neurofascin antibody-positive cidp at kindai university hospital. anti-neurofascin antibody was detected by both elisa and cell-based assay in those patients. igg subclass was predominantly igg in all four cases. the median age of the patients at admission was . years [range: - years]. among the four patients, three had tremor, and two had severe cerebellar ataxia. cerebrospinal fluid protein levels were remarkably increased [median: . mg/dl, range: - mg/dl]. although ivig treatment was administered in all four patients, the responses were poor or partial. in contrast, plasma exchange (pe) was performed in all four patients and the clinical symptoms dramatically improved in two of them. corticosteroids were also effective in those two patients. sural nerve biopsy was performed in all four patients. although sensory nerve action potentials of the sural nerves from those patients were not evoked, the transverse semithin sections of sural nerves from three patients revealed only slight or mild loss of myelinated fibers. partial paranodal demyelination was observed in teased-nerve fibers from three patients. in addition, abnormal paranodal lesions such as loss of the transvers bands were observed by electron microscope in all four patients. those electron microscopic findings were not observed in control patients with anti-neurofascin antibody-negative cidp. anti-neurofascin igg antibody-positive cidp shows distinctive clinical and pathological features. labeyrie c , besson f , vandendries c , cauquil c , beaudonnet g , not a , durand e , adams d . neurologie adulte, chu bicêtre, le kremlin bicêtre, france; médecine nucléaire, chu bicêtre, le kremlin bicêtre, france; clinique bizet, paris, france; unité de neurophysiologie clinique, chu bicêtre, le kremlin bicêtre, france. study of the proximal portion of the peripheral nervous system (pns) is difficult because less accessible to electrophysiological exploration and biopsy. the indications of mri are increasing in proximal neuropathies to analyse morphology of the roots, plexus and proximal nerves: integrity of the nerve bundle, inflammation or infiltration of these structures. pet-computed tomography (pet-ct) can detect infiltration of the proximal segments of the pns, with hypermetabolism of roots, plexuses and large nerve trunks. pet-ct is also useful in detection of solid neoplasm which can infiltrates pns and primary nerve sheath tumors. however, spatial resolution of pet -ct scan is limited to explore the roots and plexuses for moderate hypermetabolisms. we believe that a mild hypermetabolism could be highlighted in inflammatory neuropathies or in mild tumor infiltrations. we performed a fusion of whole body pet (performed because of suspected neoplasia) and plexus mri (pet-mri) images in ten patients with a peripheral neuropathy for which we suspected proximal involvement. the pet-ct and mri were first read separately, then with merge of the images by a nuclear physician and a neuroradiologist. five out of ten patients presented with hypermetabolism of pns (hmpn+) on pet-mri: root (n= ), and/or dorsal root ganglia (n= ). median sul of lesions was . . among the hmpn+ patients: hypermetabolism was already apparent on pet-ct in cases, the merge invalidated abnormalities seen on pet-ct in patients and mri detected additional lesions, not visible on pet-ct, in one patient. all hmpn+ patients had hypersignal and or hypertrophy of pns on mri either diffuse (n= ), or multifocal (n= ). among hmpn-(no hypermetabolism) out of ( %) had abnormal mri ( multifocal and diffuse). gadolinium enhancement was found in all patients receiving gadolinium in the hmpn+ (n= ) and only in / patients in the hmpngroup. final diagnoses of hmpn+ patients were neurolymphoma in one ( %), and idiopathic cidp in the others ( %) with histological proof on nervous root biopsy in one of them. final diagnosis in hmpn-patients was cidp in out of and sequelae of neuropathy in relation to lymphoma without relapse for the last one. cidp was more disabling (onls≥ ) in hmpn+ than in hmpn-group % vs. %. pet-mri could be helpful to detect a proximal inflammation of the pns, and to plan further testing. further studies are needed to evaluate the prognostic value of hmpn+. lancaster e , li j , liem r , scherer ss . perelman school of medicine, university of pennsylvania, philadelphia, pa, usa; columbia university school of medicine, new york, ny, usa. heterozygous nefl n s/+ mutant mice are the first animal model of a charcot-marie-tooth disease e (cmt e). people with this mutation have a severe, early onset axonal neuropathy. axons in the mutant mice have reduced number of neurofilaments and decreased diameters. they also show early onset of tremor and abnormal hindlimb clasping behavior. we measured the compound action potentials (caps) from tails every weeks from the same cohort of nefl n s/+ mutant mice and their wt littermates from to weeks. even at the age of weeks, the amplitude of mutant caps was only ∼ % of wt caps ( ± . microv, n= vs ± . microv, n= ), and the caps stayed substantially smaller than those in wt mice for weeks ( ± . microv, n= vs ± . microv, n= ). the conduction velocity and the duration of caps in mutants were slower and wider compared to those of wt. separate cohorts of mice (n= mutants and n= wt) were sacrificed at different time points for analysis by light microscopy. in caudal nerve of mutant mice, the number of axons was significantly reduced compared to that of wt at weeks and, by weeks, it was reduced more than %. this model system may be useful for preclinical studies of treatments for cmt e since the animals show progressive neuropathy over weeks, which can be objectively measured electrophysiologically and anatomically. despite more than cmt genes identified today, at least % of cmt patients do not carry a mutation in any of these genes. progress in gene identification in recent years suggests that there are still many more cmt disease genes to be discovered; however, it has become rare to gather support from multiple large families that allow for conclusive linkage analysis. we have studied multiple extended dominant cmt families with linkage support for a gene at chromosome p . . originally a czech family yielded a two point lod score of . at this locus and a family from southern italy showed a lod score of . . whole exome sequencing of multiple family members identified missense mutations in the gene atpase na+/k+ transporting subunit alpha (atp a ). atp a has not been associated with human diseases thus far. in expression studies on teased fiber preparations we already confirmed predominant expression in the nodes of ranvier of peripheral nerves. through collaborative efforts in the inherited neuropathy consortium and beyond we identified five additional multigenerational families via exome or sanger sequencing resulting in a total of seven unique segregating missense changes: leu arg, ile thr, ala thr, asp phe, pro ala, pro thr and asp ala. five of these mutations fall into a remarkably narrow motif associated with the sodium binding structure of atp a , flanking the flexible hinge motif. functional studies in different model systems (mammalian cell lines, xenopus oocytes, patient fibroblast lines) are underway to determine whether a loss or a dominant gain-of-function represents the disease mechanism. taken together, we show strong support for a major new dominant cmt gene, atp a . this finding represents a new pathway and an attractive new target for therapy development in axonal cmt. laurá m , ramdharry g , , singh d , kozyra d , skorupinska m , reilly mm . mrc centre for neuromuscular diseases, ucl institute of neurology, london, uk; school of rehabilitation sciences, st george's university of london/kingston university, uk; royal national orthopaedic hospital, stanmore, uk. charcot-marie-tooth (cmt) disease is the most common inherited peripheral neuropathy. foot deformities are frequent complications and orthopaedic surgery is often required. however there are no evidence based guidelines on the type or timing of the surgery. only few studies have described the long-term results of surgical procedures and evidence regarding optimal surgical management of these patients is lacking. we prospectively studied surgical management of cmt patients attending our centre. we collected data and assessed cmt patients before and after surgery. data included: history of ankle instability, pain, skin condition, details of physiotherapy and orthotic management, assessment of lower limb strength, charcot-marie-tooth examination score (cmtes), foot posture index, ankle dorsiflexion range of movement and specific questionnaires (foot index and manchester-oxford foot questionnaire, modified fatigue severity scale and modified falls efficacy scale), details of surgical procedures. patients were assessed yearly after surgery. so far patients ( males and females, age range - ) have been evaluated prior to surgery. all patients but one had genetically confirmed cmt ( cmt a, cmtx, cmt a). patients have been assessed after year, patients after years, patients after years and patient after years from surgery. a wide range of surgical procedures were performed by one dedicated orthopaedic surgeon. preliminary results showed reduction of number of falls in / ( %) patients and improvement of callosities in / ( %) patients at year follow up. there was also significant improvement of alignment of the operated foot (p= . ) and pain (p= . ). there were no significant changes in measures of strength and ankle range of motion. further analysis on a larger number of patients will be important to determine the long-term outcome of surgery. data acquired from this study will help develop orthopaedic intervention guidelines and identify areas for further research. lavigne-moreira c , oliveira mf , marques vd , onofre ptbn , dos santos acj , nascimento ojm , barreira a , marques w jr . division of neuromuscular diseases and neurogenetics, department of neurosciences and behaviour sciences, clinical hospital of ribeirão preto, university of são paulo, ribeirão preto, brazil; department of neurology, fluminense federal university, rio de janeiro, brazil. fap associated to ttr mutations is defined as a length-dependent axonal sensory and motor polyneuropathy that at early stages affects mainly the small nerve fibers, associated to autonomic and thermo-algesic sensations. the expected emg pattern was that of an axonal sensory and motor polyneuropathy, but in fact several unexpected patterns may be found. in this study we present the results found in a brazilian population with ttr mutation. patients were divided in three groups: ttr-met of early onset, ttr-met of late onset and ttr non-met . in the first group (ttr-met of early onset), ( . %) examinations were normal, ( . %) were axonal, were demyelinating fulfilling pidc criteria, one suggested a predominately motor polyneuropathy and the final one presented a lower motor neuron disease pattern. in the second group (ttr-met of late onset), ( . %) had an axonal pattern, ( . %) had an intermediate cv, ( . %) had a demyelinating pattern, had a lumbossacral pattern and the final one had no definite pattern. among the non-ttr met , two patients had the ttr -asp tyr, one presented an axonal pattern, while the second presented initially an axonal pattern, that changed to a demyelinating pattern in the second examination. patients with ile val mutation presented an axonal neuropathy associated to cts. most patients with demyelinating or intermediate pattern were treated with corticosteroids or ivig, with no satisfactory results. this small series of patients shows clearly that fap-ttr is associated to several emg patterns in addition to the expected sensory and motor axonal polyneuropathy. this variability is present in the same family and in the same patient in different occasions. clinicians should be alert to these possibilities to do not delay diagnosis and treatment. identifying the mechanisms involved in this variability could improve our knowledge of this intriguing disease. lavin tm . greater manchester neurosciences centre, salford royal hospital, manchester, uk. subcutaneous immunoglobulin (scig) has evidence from small trials for its use following intravenous igg (ivig) loading in chronic inflammatory demyelinating polyneuropathy (cidp). potential advantages of scig include stable igg levels and reduced complication rates. scig de novo can be considered as igg levels gradually rise with subcutaneous delivery and maybe beneficial for patients for whom complications are a concern. we present cases of cidp who were initiated on subcutaneous immunoglobulin g ( g/kg/month, % scig, hizentra, csl behring) following corticosteroids; without intravenous igg loading. patient is year old with a history of ihd with a progressive lower limb sensory changes and sensory ataxia over years. neurophysiology confirmed sensory demyelinating changes. he did not respond to corticosteroids. concerns were raised about the potential risk orf adverse cardiac events with iv immunoglobulin. scig therapy was introduced at g weekly. initial therapy has been well tolerated and objective measures (rods-cidp score, jamar grip strength, hole peg) have remained stable through initiation, and at months. patient is yr old male with a past history of branch retinal vein thrombosis. he developed a sensorimotor polyneuropathy over years with neurophysiology fitting efns criteria for cidp. given concerns regarding previous thrombosis, a trial of scig was given at g/week, with resolution of sensory ataxia and improvement in objective markers (jamar grip strength, rods-cidp score, hole peg) at months. unfortunately an adverse event occurred of an urticarial skin reaction. patient is a yr old male who presented with motor predominant cidp. there was no response to corticosteroids but improvement following plasma exchange. due to a past history of transient ischaemic attack, scig was started. there has been a positive response after months with improvement in walking distances and stable objective markers (rods-cidp score, grip and pinch strength). our cohort remained neurologically stable during initiation of scig, with adverse reaction. our experience would support further trials in this area regarding the efficacy of scig compared to ivig in both the short and long term. diabetic peripheral neuropathy is the most common and debilitating complication of diabetes and it is associated to neuropathic pain and non-traumatic amputations. despite the economic burden and human costs, nowadays there is not a specific treatment to cure diabetic peripheral neuropathy. hyperglycaemia and dyslipidemia-mediated oxidative and endoplasmic reticulum stress has been linked to diabetic peripheral neuropathy, among other altered pathways. in order to study in more detail the molecular mechanisms that lead to the development of diabetic peripheral neuropathy we set up in vitro models of the disease using nsc- (motoneurons) and med . (sensory neurons) cell lines or primary cultures of dorsal root ganglia and motoneurons exposed to saturated fatty acids. it has been reported that palmitic acid is able to induce endoplasmic reticulum stress and oxidative stress in multiple cell types including schwann cells and myenteric neurons, resulting in a good model of dyslipidemia-mediated stress. here we found that palmitate induces upregulation of the molecular chaperone bip/grp and the ccaat-enhancer-binding protein homologous protein (chop) mrnas and a dose-dependent downregulation of the apoptosis marker bcl- in primary cultures. moreover, palmitic acid induces loss of neuron dendrites and cell death at high doses and upregulation of heme oxygenase (ho- ) and chop at lower doses in the nsc- cell line. we are currently characterizing multiple molecules implicated in oxidative stress, endoplasmic reticulum stress and inflammation pathways in these cell types to find new therapeutic targets to treat type diabetic sensorimotor polyneuropathy, that will be subsequently validated in the db/db mouse model by pharmacological or gene therapy strategies. lee bjh , ohnmar o , wong j , koh sj , umapathi t . lee kong chian school of medicine, nanyang technological university, singapore; national neuroscience institute, singapore. treatment-induced neuropathy of diabetes mellitus (dm) (tind) is an acute painful peripheral neuropathy and autonomic dysfunction that occurs within weeks of tight glycaemic control. therapy with either insulin or oral hypoglycaemic agents (ohga) may result in tind. the quantum and rate of decline in hba c predicts development and severity of tind. both type i and ii dm patients are prone to this iatrogenic complication. besides the expected morbidity associated with painful somatic and autonomic neuropathy, tind patients also develop life-threatening eye complications such as maculopathy. with greater awareness, we picked up at least typical cases of tind in recent few months. however, there was a fourth possible tind case, whom we feel deserves special attention. the circumstances surrounding this case are common and may go under-recognised in acute hospitals. a year-old man with -year history of poorly controlled type ii dm was admitted with a partial left middle cerebral artery stroke. one month before admission, his hba c was . %. his hospitalization was prolonged because of his considerable disability that required rehabilitation. he stayed weeks. his blood sugar was difficult to control with hyperglycaemic episodes requiring ohgas and insulin. the highest capillary blood glucose recorded was mmol/l. he also had episodes of hypoglycaemia. three weeks into hospitalization, he developed severe orthostatic hypotension. he came to our attention two months later when he was sent for autonomic screening tests for severe postural hypotension, in spite of therapy with fludrocortisone and midodrine. his hba c was . %. he had marked orthostatic hypotension suggestive of sympathetic dysfunction. we were not able to discern if he had a painful neuropathy because of his aphasia. there was no recent ophthalmology review. we suggested a diagnosis of possible tind. he was discharged with lower doses of ohga. however, day after discharge, he attended the emergency department for a syncopal episode. this case raises intriguing questions on the safety of glucose control paradigms commonly employed in patients with acute stroke and myocardial infarction as well as the possible role of major fluctuations in blood glucose in the development of tind. lee hs , kim sm . presbyterian medical center, jeonju, korea; yonsei university college of medicine, seoul, korea. the occurrence of peripheral neuropathy by a tumor within or compressing a nerve in neurofibromatosis (nf) type and is relatively well known. however, nf presenting with demyelinating polyneuropathy unrelated to tumor masses is rarely reported. we report a rare presentation of an nf patient with demyelinating polyneuropathy of subacute onset. a -year-old woman was referred to our hospital with paresthesia on both limbs months before. she was healthy and had no family history. the symptoms worsened over the next months, tremor and weakness in both limbs occurred. although she treated as a chronic inflammatory demyelinating polyneuropathy (cidp) with intravenous steroid and immunosuppressant in another hospital, symptoms were getting worse. bifacial numbness and left eyeball pain occurred weeks ago and she visited our hospital. on neurologic examination, bilateral facial sensory hypoesthesia and symmetrical both limbs weakness (mrc grade iv+) were observed. decreased touch and pinprick sensation on both limbs were observed like stocking-glove distribution. the reflexes were sluggish. on nerve conduction study, sensorimotor demyelinating polyneuropathy with conduction blocks and temporal dispersions was observed. bilateral r , r responses were prolongation on facial blink test. mri of cervical spine and brain revealed contrast enhancing tumor-like enlargement of multiple nerve roots and cranial nerves. nerve biopsy was performed on right supraorbital nerve, neurofibromatous changes were observed. the symptom deterioration was stopped without treatment. gene test dose not revealed nf type and . on review of the literature, polyneuropathy in nf patient can result from tumor masses within the proximal nerve roots, or along the peripheral nerve, or in the extramedullary lesion affecting neighboring nerve roots. thus, axonal type polyneuropathy and focal amyotrophy have been reported in nf. demyelinating polyneuropathy has not been reported before in our knowledge. although the etiology of demyelinating polyneuropathy in nf requires further clarification, some authors claim that unknown local toxic or metabolic influences of the endoneurial pathological cells on adjacent nerve fibers. in this patient, atypical symptoms were observed in cidp such as cranial nerve involvement and stocking-glove sensory distribution. in this case, a nerve biopsy can be helpful the accurate diagnosis. lee jy , yoo jh , kang dk , bae js . department of neurology hallym university, seoul, korea. acute disseminated encephalomyelitis (adem) is an uncommon post-infectious inflammatory demyelinating disorder of central nerve system, while guillain-barre syndrome (gbs) is a prototype of acute post-infectious peripheral neuropathy. previous reports regarding the coexistence of these relatively rare diseases suggest that certain immunogenicity within central and peripheral nerves may share a common autoimmune process during the disease course. a previous healthy years old man was admitted because of fever, headache, nausea and myalgia in department of infectious disease. two weeks before admission, he suffered from watery diarrhea for days and spontaneously recovered. at initial presentation, he had high fever( ∘ c), headache and myalgia and intermittent horizontal diplopia. a few days after admission, he began to complain of drowsy mentality, bilateral extremities weakness, especially lower limbs, dysarthria, bilateral facial paralysis, urinary retention, dyspnea. on neurologic examination, he had mildly drowsy mentality, symmetric muscle weakness scoring of on bilateral hip, knee flexion and finger extension, but he had no sensory symptoms. he showed gazed evoked nystagmus with no extraocular muscle palsies. deep tendon reflexes were not present. pulmonary function test revealed a severe restrictive pattern. csf studies disclosed a dissociative increase of protein contents ( mg/dl) without pleocytosis. anti ganlioside antibody assay identified an anti-gt a igg positivity in his serum. nerve conduction study (ncs) showed prolonged motor terminal latencies and slow motor conduction velocity on multiple nerves. in contrast, sensory ncs revealed no abnormal findings. imaging studies unexpectedly revealed apparently symmetrical lesions across bilateral brainstem and basal ganglia suggesting a diagnosis of adem. after both ivig and high dose steroid treatment, he remarkably recovered from disturbed mental state and motor weakness. about month after the symptom onset, he could walk with assistant aid and discharge to other hospital for rehabilitation. our case suggest that certain component of autoimmunity simultaneously result in both cns and pns inflammation. specific immunological mechanism is remained to be elucidated. although we could not conclude whether cellular component or humoral component is dominant for our case, the presence of anti gt a antibody suggest a role of humoral mechanisms. the aim of this study is to evaluate whether peripheral neuropathies and headaches affect the same subgroups of patients with ibd. since , we have established a cohort study to evaluate the prevalence and incidence of neurological diseases in patients with ibd. over a period of years, all patients with ibd (either crohńs disease or ulcerative colitis) were invited to participate in a study designed to evaluate the risk factors for the presence of headaches and peripheral neuropathy in ibd. a separate group of control patients (age-matched relatives of ibd patients) was also formed. after a clinical interview and neurological examination, patients were invited to undergo skin wrinkling test (swt) to evaluate small fiber function and/or electromyography. headaches were present in . % of the patients with ibd, and were more common in patients with ulcerative colitis than in control patients (p< . ). migraine comprised . % of all cases of headache and was more prevalent in patients with crohńs disease than control patients (p< . ). tensional headaches were also common affecting . % of the ibd patients. electromyography was abnormal in . % of the ibd patients tested ( / ). swt was abnormal in . % of the ibd patients tested ( / ). . % of the ibd patients had abnormal swt but had no neuropathy symptoms. patients with abnormal swt or emg were not more likely to have headaches (p= . and . , respectively). overall, patients with symptomatic polyneuropathy were not more likely to have headache (p= . ). patients with abnormal swt or emg were also not more likely to have migraine (p= . and . , respectively). patients with abnormal swt or emg were also not more likely to have tension-type headache (p= . and . , respectively). in summary, although highly prevalent in this population of brazilian ibd patients, primary headaches and neuropathy do not affect the same subgroups of ibd patients. further studies are necessary to understand the mechanisms of both conditions in ibd patients. leitao amf , , araújo df , marques h , pamplona l , , souza mh , , nbraga ll , , gondim faa , . the aim of this study is to evaluate whether peripheral neuropathies and headaches affect the same subgroups of patients with ibd. since , we have established a cohort study to evaluate the prevalence and incidence of neurological diseases in patients with ibd. over a period of years, all patients with ibd (either crohńs disease or ulcerative colitis) were invited to participate in a study designed to evaluate the risk factors for the presence of headaches and peripheral neuropathy in ibd. a separate group of control patients (age-matched relatives of ibd patients) was also formed. after a clinical interview and neurological examination, patients were invited to undergo skin wrinkling test (swt) to evaluate small fiber function and/or electromyography. headaches were present in . % of the patients with ibd, and were more common in patients with ulcerative colitis than in control patients (p< . ). migraine comprised . % of all cases of headache and was more prevalent in patients with crohńs disease than control patients (p< . ). tensional headaches were also common affecting . % of the ibd patients. electromyography was abnormal in . % of the ibd patients tested ( / ). swt was abnormal in . % of the ibd patients tested ( / ). . % of the ibd patients had abnormal swt but had no neuropathy symptoms. patients with abnormal swt or emg were not more likely to have headaches (p= . and . , respectively). overall, patients with symptomatic polyneuropathy were not more likely to have headache (p= . ). patients with abnormal swt or emg were also not more likely to have migraine (p= . and . , respectively). patients with abnormal swt or emg were also not more likely to have tension-type headache (p= . and . , respectively). in summary, although highly prevalent in this population of brazilian ibd patients, primary headaches and neuropathy do not affect the same subgroups of ibd patients. further studies are necessary to understand the mechanisms of both conditions in ibd patients. the classic guillain barré syndrome (gbs) is characterized by motor weakness, hyporreflexia, but limited sensory deficits. sensory variants involving either small or large fibers or both are unusual and represent a diagnostic challenge. we described patients presenting with the sensory variant of gbs and retrospectively analyzed the clinical and electrophysiological findings of patients fulfilling the criteria for sensory gbs according to oh et al. criteria. six patients were identified (mean age years: range - years). four had a previous infection. they all consulted due to distal painful paresthesias and allodynia. on examination the patients presented normal strength and normal cranial nerves through the course of the disease with reduced knee and ankle reflexes in patients. distal hyperesthesia to pinprick was identified in and one of them additionally had hyperhidrosis and constipation. two additional patients presented hypoesthesia to pinprick and temperature. one patient had distal proprioceptive sensory loss with sensory ataxia. csf albumin cytological dissociation was present in patients. nerve conduction studies (ncs) identified a sensory motor demyelinating neuropathy in patients. among the with normal ncs, had abnormal cold and warm threshold in their qst evaluation. all patients received symptomatic treatment for the neuropathic pain and only two ivig therapies. longstanding pain, fatigue or both were persistent findings in patients after a mean follow up of months. in conclusion the sensory variant of gbs is both an infrequent presentation and a diagnostic challenge. longstanding pain and fatigue are common persisting findings. the epidemic of zika virus (zikv) throughout the americas and asia, and the subsequent rise in reported cases of guillain-barré syndrome (gbs) caused worldwide concern. as of january , countries have reported evidence of mosquito-borne zikv transmission and in of these countries, a sudden increase of gbs has been reported. moreover, case studies and a case-control study further indicate that zikv may trigger gbs. however, accurate diagnosis of both zikv and gbs in many of these studies is disputed, and a comprehensive description of the clinical phenotype of gbs related to zikv is lacking. the international gbs outcome study (igos) is a prospective observational study on the factors determining the onset, clinical course and outcome of gbs. at present, a research consortium of centers from countries has included patients in igos. our aim is to investigate zikv-related gbs in igos as is already occurring in colombia. in igos-zika, data on clinical features and ancillary investigations will be collected in zikv endemic areas according to the igos protocol with some modifications. first, igos-zika has a case-controlled study design to define the association between gbs and zikv and other arboviruses. second, urine samples will be collected and additional questions on preceding events will be asked, focusing on arbovirus infections. third, a more limited follow-up is required. our aim is to recruit additional centers via the inflammatory neuropathy consortium (inc) and centers in all arbovirus endemic regions that are willing to participate. the focus of igos-zika will be on the accuracy of the diagnosis of both gbs and zikv and on defining the associated clinical phenotype, course and outcome. igos-zika provides the opportunity to combine data and biobanks from various geographical regions using a standardized protocol and to compare these data with data and biosamples already collected in igos. studying these cases will help to optimize diagnostics and care for gbs patients in arbovirus endemic countries and provides a unique opportunity to further understand the pathogenesis of gbs. moreover, this study design and network can be used to adequately respond to other future viral epidemics related to gbs. lerat j , cintas p , dzugan h , , magdelaine c , , sturtz f , , lia as , . service de biochimie et génétique moléculaire -chu de limoges, limoges, france; service de neurologie et d'explorations fonctionnelles -chu de toulouse, toulouse, france; ea -université de limoges, limoges, france. pharc syndrome is an autosomal recessive neurodegenerative pathology leading to demyelinating polyneuropathy, hearing loss, cerebellar ataxia, retinis pigmentosa and early-onset cataract. these various symptoms can occur at different ages, so that pharc syndrome can be a differential diagnosis of charcot-marie-tooth disease (cmt) associated with deafness. only abhd mutations have been reported in patients. we described the th mutation and compared our results to the literature data. we analysed by next generation sequencing (ngs) strategy using a targeted cmt and associated neuropathies -gene panel the dna of a -year old male who has suffered from demyelinating sensory and motor polyneuropathy and ataxia since the age of . bilateral sensorineural deafness was diagnosed at the age of five. bilateral congenital cataracts were operated on at the age of . a new large complex homozygous mutation, with one deletion of seven base pairs and one insertion of base pairs, was detected. by analyzing our patient data and those of the literature, we evaluated that, in pharc syndrome, sensorineural deafness always occurs as the first feature in late teens. the ophthalmological symptoms are cataracts that occur at a mean age of yo and then retinis pigmentosa at a mean age of . demyelinating sensory-motor polyneuropathy is the most variable characteristics, which occurs in the thirties. we report the first large complex homozygous mutation in pharc syndrome, which is certainly under-diagnosed. therefore, it seems interesting to include abhd in the panels of the five symptoms, especially deafness ones. chronic inflammatory demyelinating polyradiculoneuropathy (cidp) is a chronic disabling disease that often improves with immune therapy. to date, the most reliable diagnostic criteria for cidp are the efns/pns revised criteria, with a reported sensitivity of % and specificity of %. we implemented a web-based database to collect data from patients with cidp followed by italian centers with expertise on cidp to determine the frequency and characteristic of cidp and it variants, the diagnostic criteria used for their diagnosis, the possible evolution into typical cidp, the association with specific anti-nerve antibodies, and their response to therapy. all the patients were evaluated at the time of inclusion and will be followed for two years to monitor their outcome and response to therapy. by february we included patients with cidp and variants ( men, women), aged - years (median ) with a mean disease duration of . years (range . - years). based on clinical symptoms, cidp was defined as typical in % and atypical in %. the diagnosis of typical cidp fulfilled efns/pns criteria in % of the patients while nerve conduction studies were not diagnostic in % (grouped as clinical cidp) or not available in %. we analyzed the frequency of supportive criteria for the diagnosis of cidp in patients with clinical cidp and found that increased csf proteins, demyelination or cell infiltration on nerve biopsy and imaging abnormalities consisting with cidp on us or nmr were present in %, % and % of the patients, respectively. a relapsing course was present in % of patients with clinical cidp, increasing the reliability of the diagnosis for cidp. in addition an improvement after one or more therapies was reported by % of the patients, with a positive response to ivig in %, steroids in % and plasma exchange in %, similarly to what observed in patients fulfilling efns/pns criteria. in % of the patients with clinical cidp two or more supplementary criteria for cidp were present. this study on a large population of patients is providing useful information that may help to revise the current diagnostic criteria for cidp. li j , cannell m , suragani r , pearsall r , kumar r . acceleron pharma inc, cambridge, usa. charcot-marie-tooth (cmt) is the most common hereditary peripheral neuropathy and is characterized by demyelination and/or axonal damage of peripheral nerves and muscle weakness. foot drop, steppage gait, and foot deformities are a typically seen in cmt patients. consequently, falls are commonly reported in these patients. improvement of dorsiflexor muscle function to prevent falls may improve quality of life and activities of daily living in patients with cmt. ace- , a locally-acting ligand trap that binds growth and differentiation factors (gdfs) and activins, has previously been shown to increase muscle mass and force in both duchene muscle dystrophy (dmd) and amyotrophic lateral sclerosis (als) mouse models. in the current study, we evaluated the therapeutic effects of ace- to improve muscle strength in the trembler (tr-j) mouse model of cmt a. these mice harbor a mutation in the peripheral myelin protein (pmp ) known to cause cmt a. seven-month old (b .d -pmp tr-j /j) mice were administered ace- ( g, twice weekly) intramuscularly to one of the unilaterally tibialis anterior (ta) muscle for weeks. the contractility of the ta muscle was evaluated during isometric contraction. all data were compared to the uninjected contralateral control hind-limb. after weeks of ace- treatment, ta muscle mass was increased by % (p< . ) and its physiological cross-sectional area was increased by % (p< . ). the increase in muscle mass correlated with an increase in strength, with maximum tetanic force and twitch force improved by % (p< . ) and % (p< . ), respectively. in addition, temporal properties during isometric contraction, such as maximum rate of contraction and relaxation, were accelerated by % and % respectively (p< . ) in the ace- -treated ta muscle compared to its contralateral hind-limb. pathological and biochemical assessment of ace- -treated mice showed enlarged myocyte area (+ %, p< . ) and reduced atrogin- mrna expression (− %, p< . ). together, these results demonstrated that ace- attenuates the degree of muscle atrophy and also improves muscle function in a mouse model of cmt a. the current study provides proof of concept for the use of ace- as a therapy for cmt to improve dorsiflexor muscle function and alleviate foot drop. we have generated a rat model of charcot-marie-tooth disease a (cmt a) harboring the p.arg trp mfn mutation, whose human counterpart results in a severe, early-onset axonal neuropathy. the mutation was made using zinc finger nuclease-mediated genome editing in fertilized rat eggs. a large cohort of mutant and wt littermates were characterized behaviorally and found to develop multiple motor deficits that worsened over time. nerve conductions of the tail (caudal nerve) was performed on a separate cohort of mutant (n= ) and wt littermates (n= ) every weeks from to weeks. mutant rats showed a progressively decline in the amplitude of the compound action potential after weeks, whereas the amplitude progressively increased in their wt littermates. separate cohorts of rats were sacrificed at , , and weeks and analyzed by light microscopy. in mutant rats, there was a reduced density of myelinated axons and active axonal degeneration in distal but not proximal nerves, and in the fasciculus gracilis of the cervical spinal cord at and weeks. these findings were not present in the -week-old cohort of mutant rats, or in wt rats at or weeks. a genetically authentic animal model of cmt a that develops a progressive, length-dependent axonal neuropathy will be a valuable tool for examining the pathogenesis and treatment of cmt a. lindborg ja , niemi, jp , defrancesco a , zigmond re . case western reserve university, cleveland, usa. traditionally the role of immune cells in nerve degeneration and regeneration has focused on the infiltration of inflammatory monocytes into the distal nerve after nerve injury and the phagocytosis by the resulting macrophages of myelin and axonal debris, thereby clearing a path for regenerating axons. therefore, it was surprising when we discovered that in ccr knockout (ko) animals, in which the entry of these inflammatory monocytes does not occur, that wallerian degeneration precedes normally. we now report that the reason for this is that neutrophils and schwann cells compensate for the decrease in macrophage accumulation. furthermore, nearly complete depletion of circulating neutrophils by systemic injection of an antibody to ly g leads to an inhibition of myelin clearance both in ccr ko and in wild type animals. on the other hand, we have demonstrated a second site of macrophage accumulation in wild type animals, namely around axotomized sensory neurons in dorsal root ganglia (drgs). blockade of that accumulation, for example as occurs in ccr ko animals, leads to a dramatic impairment of nerve regeneration. to examine the relationship between macrophages and regeneration further the monocyte chemokine ccl was overexpressed in drg neurons in intact animals by viral infection using an aav containing the ccl coding sequence. the resulting overexpression of ccl led to the accumulation of macrophages in drgs even though no injury had taken place and subsequently to an increase in the intrinsic growth capacity of the sensory neurons. examination of changes in gene expression in the drgs in these animals revealed increased expression of the cytokine leukemia inhibitory factor and an increase in its downstream signaling pathway that involves the phosphorylation and nuclear translocation of stat . strikingly, pharmacological blockade of stat activation inhibited the increase in the neurons' growth capacity produced by the virus. these results reveal unexpected interactions between immune cells and neurons facilitating nerve degeneration and regeneration and could lead to therapies to improve regeneration after injury or in disease. lin j , , qiao k , , huang j , , zhao cb , , lu jh , . institute of neurology, fudan university, shanghai, china; department of neurology, huashan hospital, fudan university, shanghai, china. we used terminal latency index (tli) as a tool in differentiation between poems syndrome and chronic inflammatory demyelinating polyradiculoneuropathy (cidp). comparison of median and ulnar nerve conduction studies including motor conduction velocity (mcv), distal motor latency (dml) and terminal latency index (tli) were studied in poems patients, matched cidp patients and normal controls. in this cohort, the average age at evaluation was . ± . years old in poems group and that of cidp patients was . ± . years old. except the ulnar terminal latency index in cidp group, poems and cidp patients demonstrated prolonged distal latencies, low conduction velocities and increased terminal latency indexes compared with the normal group. reduced conduction velocities and higher terminal latency indexes in poems group than in cidp group was found. increased tli was demonstrated in . %(median nerve) and . %(ulnar nerve) poems and that in cidp patients was . %(median nerve) and . %(ulnar nerve). decreased tli was found in . %(median) and . %(ulnar) cidp patients and none in poems. temporal dispersion (td) and conduction block (cb) were more often seen in cidp patients with increased tli than that in poems. compared with cidp and poems showed greater slowing of the intermediate nerve segments and relatively more uniform demyelination. about % cidp demonstrated more distal conduction slowing and more td and cb especially in those with increased tli. terminal latency index combined with td and cb may be helpful in differentiating poems from cidp. lin y , sung j , chang t , jowy t . department of neurology, taipei municipal wanfang hospital, taipei, taiwan. the purpose of our study is to exam whether electrophysiology changes could be detected in prediabetes patients and to discover the possible mechanism of nerve injury in prediabetes stage. we analysis and compare the nerve excitability test data between prediabetic patients and age-matched normal control subjects. prediabetes is defined by american diabetes association (ada) as one of the three following: hba c . % to . %, fasting glucose mg/dl to mg/dl, and hour oral glucose tolerance test to mg/dl. patients with radiculopathy, myelopathy, entrapment neuropathy such as carpel tunnel syndrome, and polyneuropathy were excluded. the strength-duration time constant (sdtc) and superexcitability showed significant difference (p< . ) between two groups. we also find increased threshold electrotonus in depolarization (ted) and reduced relative refractory period (rrp) and refractoriness in . msec. these early changes in prediabetic patient are similar in nerve excitability feature of diabetic patients. however, the above changes are not found in motor axonal excitability test. our data supports that nerve excitability test may be a useful, non-invasive, and less time dependent tool to detect peripheral nerve injury in prediabetic stage. the sensory axons are more vulnerable than motor axons. superexcitability is the most sensitive parameter in prediabetes. transthyretin-related familial amyloid polyneuropathy (ttr-fap) is an autosomal dominant disorder caused by mutations of ttr gene and is associated with variable penetrance. ttr-fap is rare, except for endemic areas. this is a retrospective study of ttr-fap patients diagnosed at our center between - . we identified four families with different ttr mutations. in one family with v a mutation, nine family members over four generations diagnosed with ttr-fap was followed since . in the other families the index cases with different mutations were identified between - . affected family members with v a mutation developed severe progressive polyneuropathy with cachexia, with onset of the disease between ages and . three patients presented with marked visual symptoms (one patient underwent vitrectomy). nine patients died to years after disease onset. two patients (sisters) underwent liver transplantation -one died after years of disease at age , second is years old and wheelchair-bound as her symptoms continue to progress. the ttr mutations diagnosed in the index cases of three other families are: d v, f l and v m. they all presented with similar clinical picture of late-onset ttr-fap with predominant progressive axonal sensory, motor and autonomic polyneuropathy. all three index cases were men, the onset of symptoms was between - years with numbness and paresthesia in the feet followed by weakness and autonomic dysfunction. all had excessive weight loss resulting in cachexia and were diagnosed with cardiomyopathy. no patient suffered from visual symptoms. all three patients progressed to stage ii of ttr-fap -walking with assistance. time to diagnosis was . - years. due to advanced stages of their disease these patients were not suitable for therapy with tafamidis or the liver transplantation. the ttr d v (p.d v) was confirmed as a de novo mutation, which is uncommon in ttr-fap. in the remaining families carriers of ttr mutations were identified and are followed up. pedigree analysis of the family with f l mutation revealed affected members who with high probability died from ttr-fap. our study suggests that patients with ttr-fap in poland exhibits clinical and genetic heterogeneity. liu x , fan d . department of neurology, peking university third hospital, beijing, china. objective: to identify the gene mutation of chinese charcot-marie-tooth pedigrees and investigate the correlation among the clinical manifestation, electrophysiology and mechanism of different genotype. methods: we included pedigrees with cmt enrolled in our hospital from january, to december . we recorded clinical features, cmtns and electrophysiological data at diagnosis. the patients underwent mutation analysis of pmp , cx , mpz, mfn , hspb , hspb using mlpa, dhplc and sanger gene sequencing. results: we found pmp duplication pedigrees ( . %), cx pedigrees ( . %), mfn pedigrees ( . %), mpz pedigrees ( . %) conclusions: in chinese han population, the proportion of pmp duplication is relatively low, the majority of clinical manifestation is classical cmt. axonal cmt can show isolated lower extremity injury, with central nervous system involvement. hmn may be an underestimated clinical types, the identification should be done with caution in differential diagnosis. liu y , liu b , sebastian b , wozniak km , wu y , slusher b , polydefkis m . johns hopkins school of medicine, baltimore, usa. chemotherapy-induced peripheral neuropathy (cipn) is a common dose-limiting toxicity in the treatment of many cancers. most cipn studies preferentially focus on sensory fiber loss and dysfunction. here, we compared the structural and functional recovery of autonomic fibers in sweat glands (sweat gland nerve fiber density, sgnfd) and sensory fibers (intra-epidermal fiber density, ienfd) in mouse footpads after exposure to a maximum tolerated dose (mtd) of several common chemotherapy agents. additionally, we assessed footpad sweat production as a functional correlate to sgnfd reductions. female balb-c mice ( -animals/group) were treated with a mtd of four anti-tubulin drugs: paclitaxel (pca, mg/kg), ixabepilone (ixa, mg/kg), eribuline (erib, . mg/kg), vinoelbine (vino, mg/kg), or corresponding placebo given intravenously, mwf for two weeks. recovery was assessed at -hours, , , , , and weeks following the last dose. footpads were processed to visualize epidermal nerve fibers using pgp . and autonomic nerve fibers with tyrosine hydroxylate and pgp . . ixabepilone-treated mice experienced significant reductions in sgnfd at hrs, while ienfd nadir occurred at a later time point, -weeks. the recovery to baseline levels occurred more quickly for ienfd ( -weeks) than sgnfd ( -weeks). in contrast, vinorelbine and eribuline treated mice experienced a maximum deficit in sgnfd and ienfd at hrs and sgnfd recovery was slower ( -weeks) compared to ienfd ( -weeks). pca-treated animals showed more severe ienfd and sgnfd deficits compared to the other agents with both ienfd and sgnfd not recovering completely until -months. reductions in th-sgnfd were comparable or more pronounced to decreases in pgp . -sgnfd for all agents and timepoints. pca-treated animals demonstrated reductions in footpad sweat droplet number thereby providing a functional correlate. together, these data indicate that in mouse models of cipn, autonomic nerve fibers are affected more severely than sensory nerve fibers, and also recover more slowly than intraepidermal nerve fibers. autonomic dysfunction may be an important and under-appreciated consequence of chemotherapy exposure. the pi -kinase vps (pik c ) synthesizes phosphatidylinositol -phosphate (pi p), a lipid critical for both endosomal membrane traffic and macroautophagy. human genetics have implicated pi p dysregulation, and endosomal trafficking in general, as a recurring cause of demyelinating charcot-marie-tooth (cmt) peripheral neuropathy. here, we investigated the role of vps , and pi p, in mouse schwann cells by selectively deleting vps in this cell type. vps -schwann cell knockout (vps scko ) mice show severe hypomyelination in peripheral nerves. vps −/− schwann cells interact abnormally with axons, and there is a delay in radial sorting, a process by which large axons are selected for myelination. upon reaching the promyelinating stage, vps −/− schwann cells are significantly impaired in the elaboration of myelin. nerves from vps scko mice contain elevated levels of the lc and p proteins, indicating impaired autophagy. however, in the light of recent demonstrations that autophagy is dispensable for myelination, it is unlikely that hypomyelination in vps scko mice is caused by impaired autophagy. endosomal membrane traffic is also disturbed in vps −/− schwann cells. we investigated the activation of the erbb / receptor tyrosine kinases in vps scko nerves, as these proteins, which play essential roles in schwann cell myelination, are known to traffic though endosomes. in vps scko nerves, erbb was hyperphosphorylated on a tyrosine known to be phosphorylated in response to nrg exposure. the overall level of erbb was also decreased during myelination. our findings suggest that the loss of vps alters the trafficking of erbb / through endosomes. abnormal erbb / signaling may contribute to the hypomyelination observed in vps scko mice. lombardi r , devaux j , cortese a , dacci p , benedetti l , demichelis c , lauria g . irccs foundation "carlo besta" neurological institute, milan, italy; aix-marseille université, marseille, france; irccs c. mondino national neurological institute, pavia, italy; university of genoa and irccs aou san martino-ist, genoa, italy. the recent identification of igg anti-neurofascin (nfascin) antibodies in a group of patients has widened the spectrum of presentation for chronic inflammatory demyelinating polyradiculoneuropathy (cidp). these patients can be distinguished by disabling tremor, poor response to intravenous immunoglobulin and distal and sensory disturbances. cell-adhesion molecule nfasc and cntn are expressed on the paranodal junction (pnj) of nodes of ranvier, and play key roles on sodium channel clustering and glia-axon interactions. quantification of unmyelinated intraepidermal nerve fibers (ienf) is a useful parameter employed in small nerve fiber pathology diagnosis. in addition the immunohistochemistry evaluation of dermal nerve fibers allows to examine morphological changes of myelin sheath and ranvier nodes structure. we performed immunofluorescent colocalization studies using antibodies to visualize axons (protein-gene-product . , neurofilament, tubulin), sheath of myelin (myelin-basic-protein) and specifically nodal/paranodal/juxtaparanodal structures (pannfascin, nfascin , nfascin , caspr, cntn , potassium and sodium channels) in skin tissues from seronegative and seropositive cidp patients. we analyzed axon and myelin sheath damage, abnormal nodal-paranodal-juxtaparanodal architecture and morphometric parameter as internodal length of ranvier nodes. our results on skin biopsies from three igg nfasc -positive cidp patients revealed complete loss of nfasc staining at the paranodes, asymmetrical paranodes and widening of the nodes of dermal myelinated nerve fibers. one igg cntn -positive cidp patient showed abnormal nodal/paranodal immunostaining with different features as compared with igg nfasc -positive patients suggesting specific changes. however, such alterations were not found in four seronegative cidp patients. our data support the hypothesis that examining specific axonal and myelin markers could provide diagnostic and prognostic clues on nodo-paranodopathies. the goal of this study is attempt a possible correlation between the presence of serum autoantibodies and structural changes in nodal/paranodal regions of dermal nerve fibers in cidp patients. knowledge of autoantibodies expression in the peripheral myelinated nerves of cidp patients could serve for stratifying patients and potentially guiding personalized treatments. lunati a , lerat j , dzugan h , , rego m , magdelaine c , , bieth e , calvas p , cintas p , gilbert-dussardier b , goizet c , journel h , magy l , toutain a , urtizberea j , sturtz f , , lia as , . charcot-marie-tooth disease is one of the most frequent inherited peripheral neuropathies ( / ). so far, mutations in more than genes have been identified causing either the demyelinating form (type ) or the axonal form (type ). duplication of pmp gene is the most frequent cause of autosomal dominant demyelinating form. autosomal recessive demyelinating form is often due to sh tc gene mutations. patients suffer then from early severe neuropathy starting in the first decade. scoliosis and deafness are often observed. we analysed patients suffering from peripheral neuropathy, by multiplex-ligation-dependant-probe-amplification (mlpa), followed by targeted next-generation-sequencing (ngs) using a -gene custom panel designed for the diagnosis of charcot-marie-tooth and associated neuropathies. mutations of interest were verified by sanger sequencing. diagnosis was positive for patients. as expected, the most frequent mutation was the pmp duplication detected in patients. deletion of pmp was observed in patients and pathogenic point mutations were detected in patients. sh tc gene appeared to be the most frequently mutated with nine patients diagnosed. associated with known mutations, four new mutations have been identified: two nonsense mutations and two missense mutations. all these patients presented deafness and/or scoliosis. sh tc appears to be an important gene involved in charcot-marie-tooth disease, often associated with deafness and /or scoliosis. it is important to pay attention to these associated symptoms in charcot-marie-tooth patients in order to guide their diagnosis and to improve their medical care. lupo v , , frasquet m , , sánchez-monteagudo a , , barreiro m , alberti ma , casasnovas c , quintáns b , , , camacho a , domínguez c , sedano mj , pelayo al , pardo j , sobrino t , sobrido mj , , , sevilla t , , espinós c , . mme (membrane metalloendopeptidase) mutations, inherited in an autosomal recessive fashion, have been recently identified in japanese probands (higuchi et al. ) . thus, mme has been included in the list of cmt genes as a new autosomal recessive axonal form, cmt t (mim ), and moreover, it is considered a strong candidate for the genetic diagnosis of unsolved late-onset cmt cases. in fact, few months later auer-grumbach et al. ( ) reported european probands with autosomal dominant late-onset cmt and mutations in mme. we have investigated a clinical series of patients diagnosed of motor or sensory-motor peripheral neuropathy using an updated version of our custom gene panel, which includes mme. in this study, we report probands with cmt , intermediate cmt or dhmn/cmt and homozygous or compound heterozygous mutations in mme, and proband with cmt and a heterozygous mutation in mme. we have identified different type of mutations: novel splice donor variant, frameshift, nonsense and missense mutations. the two nonsense changes, p.trp * and p.arg *, and the splice donor variant c. + g>a, were detected in homozygous or compound heterozygous state in patients, while the frameshift mutation, p.pro leufs* , was detected in homozygous or heterozygous in the remaining patients. strikingly, the two nonsense and the frameshift mutations had been previously reported as causative for autosomal-dominant cmt t (auer-grumbach et al. ) . out of three missense mutations, one is novel (p.his tyr), and two are reported in control databases (p.asn lys and p.arg trp). this study shows that the autosomal recessive cmt t is common in spanish population, and moreover, it suggests that screening of mme using gene panel testing could help to improve diagnosis of unclarified inherited peripheral neuropathies cases. funds: isciii (pi / , pi / ); fundació per amor a l' art. inherited peripheral neuropathies (ipns) encompass a group of disorders highly heterogeneous, clinically and genetically. charcot-marie-tooth (cmt) disease is closely related to distal hereditary motor neuropathy (dhmn) or distal spinal muscular atrophy (dsma), and some patients show additional signs associated with amyotrophic lateral sclerosis (als). targeted gene panel and exome sequencing are considered to be powerful and cost-effective tools for diagnosis of these disorders. we have investigated a clinical series of patients diagnosed of motor or sensory-motor peripheral neuropathy: families were investigated by exome sequencing and, cases were tested using different updated versions of a gene panel . each version comprises , or ipn genes, respectively and it shows a high coverage performance: percentage of analyzable target base with > coverage was , %. both exome and gene panel capture libraries were based on sureselect capture technologies (agilent technologies), and sequencing was performed in miseq or hiseq illumina equipment. we have identified novel genes and novel mutations in known genes, broadening the phenotypical spectrum associated with ipns. exome sequencing has allowed us to identify causative gene in % of familiar or sporadic cases: morc , aars, bscl , kif a, gars, egr , fig , dnajb , drp , ighmbp , dao, sod , fig . gene panel testing has been mostly performed in sporadic cases, and it has allowed us to identify either disease-causing or candidate mutations in % of cases: kif a and bicd were the most common genes mutated. update gene panels neuro and neuro have revealed novel mutations in genes recently associated to cmt and cmt disease: mme and pmp , respectively. in sum, both strategies have helped us to achieve a more accurate clinical and genetic reclassification of these disorders, an impossible challenge using conventional sequencing methods. our study expands the clinical phenotype previously associated to known ipn causing-gene, and emphasizes that gene panels should be considered as a first diagnosis method for unclarified ipn patients. funds: isciii (pi / , pi / , pi / ); fundació per amor a l' art. magy l , mathis s , goizet s , tazir m , vallat j-m . department and laboratory of neurology, national reference center for rare peripheral neuropathies, chu limoges, france; department of neurology, chu bordeaux, france; department of medical genetics, chu bordeaux, france; department of neurology, chu algiers, algeria. charcot-marie-tooth (cmt) disease is a hereditary neuropathy with a relatively homogeneous phenotype but is genetically heterogeneous. moreover, nerve conduction studies distinguish different forms, adding another level of complexity. the current classification of cmt being difficult to understand for physicians, scientists and patients, we presented and published a proposal for updating this classification, based on inheritance, nerve conduction findings and gene/mutation involved. inputs from colleagues prompted us to conduct a survey in order to try to reach some consensus about our proposals. we conducted an internet survey between october and december . the link to complete the survey was sent several times by email with an introduction to more than people. participants were contacted through the emailing list from the last cmt meeting in venice (september ) and additional physicians and scientists who are involved in cmt care and research were contacted as well. one hundred seven people from various countries (mainly france, italy and the usa) answered the survey. most ( %) of the participants were between and years of age, % being physicians and % being scientists. the vast majority ( %) considered the proposal constituted an improvement over the historical classification whereas % wanted to keep the old one. about the order of information, % of participants thought the mode of inheritance should come first, whereas % felt the phenotype should be placed at the beginning. ninety-one percent of people thought cmt should be kept as a generic name for hereditary sensory and motor neuropathy. for pure sensory neuropathy, % favoured hsn over hsan although % thought the opposite and % of participants felt dhmn should be kept for distal motor neuropathy. about nerve conduction findings, % of participants thought the intermediate phenotype has to be kept and % favoured our proposal to replace " " by "de" (for demyelinating) and " " by "ax" (for axonal). finally, % of responders thought that genetic information should be included in the classification of cmt. overall, our proposal of a new classification received a very good appreciation from physicians and scientists implicated in the care of patients with hereditary neuropathy. mallik r , hubsch a , gaida a , barnes d . csl behring, kop, usa; csl behring, bern, switzerland; csl behring, ottawa, canada. the risk of hemolytic events (hes) with intravenous immunoglobulin (ivig) therapy appears to be linked to the isoagglutinin (anti-a and anti-b) level of the specific ivig product. using published anti-a and anti-b titers for seven ivig products and corresponding he rates reported to the eudravigilance database, we developed a mathematical model to predict the risk of he to patients receiving ivig products of given anti-a and anti-b levels. modeling was performed separately for the risk to patients with blood groups a, b, ab and o and the overall population risk was estimated assuming a blood group distribution of % a, % b, % ab and % o. applying the prediction model, we calculated the he risk for an ivig product produced via a chromatographic process (privigen ® , csl behring) a) without any isoagglutinin reduction measures ( ) ( ) ( ) ( ) ( ) ( ) ( ) , b) with an anti-a donor screening program eliminating approximately % of donors with high anti-a titers ( ) ( ) ( ) , c) incorporating an anti-a/anti-b specific immunoaffinity chromatography (iac, igisolo tm ) step in the manufacturing process (since ) and d) with both measures (b and c) combined; as well as for an ivig product produced with a cohn-like cold ethanol fractionation process (carimune ® nf/sandoglobulin ® , csl behring). isoagglutinin titers in ivig products, measured by european pharmacopoeia direct assay, were provided by dr c bellac, swissmedic, bern, switzerland. the predicted risk was highest with the chromatographically purified ivig without isoagglutinin reduction ( . cases expected per kg ivig used). anti-a donor screening reduced the predicted risk to . cases/ kg. a greater risk reduction was predicted with the iac isoagglutinin reduction step ( . cases/ kg). the combination of both methods produced little benefit ( . cases/ kg) versus iac alone. the predicted hemolytic risk with ivig produced by cohn-like ethanol fractionation was low ( . cases/ kg). an observational cohort study to confirm these hemolytic risk reductions is in progress. at present, the observed hemolytic risk for anti-a donor screening appears consistent with the prediction calculated by the model; results for iac isoagglutinin reduction are expected in . the cmt infant scale (cmtinfs) is an outcome measure of functional ability for young infants and children aged < years. cmtinfs aligns with the cmt pediatric scale and cmt neuropathy score to measure disease severity across the lifespan. to measure gross motor and fine motor function, cmtinfs comprises of two subscales: gross motor (e.g. head control, crawling, walking, jumping and hopping) and fine motor function items (e.g. grasping, reaching, tearing paper and buttoning). overall and subscale-specific function is expressed as a z-score based on normative reference values (positive z-scores indicate poorer function). a total of controls aged - months (mean age , sd m) have been assessed across australia (n= ), thailand (n= ) and usa (n= ). total cmtinfs z-scores did not differ significantly between sites (australia vs thailand) (p= . ) or gender (p= . ). data collection is ongoing and infants aged < years are eligible for inclusion. to date, infants ( % male) aged - months (mean age , sd m) with a range of cmt subtypes ( cmt a, cmt d, cmt c, cmt x and unidentified gene) have been assessed with cmtinfs. mean total z-score for infants with cmt ( . , sd . , range: − . - . ) was significantly higher than controls ( . , sd . , range: − . - . , t=− . , p= . ). differences between affected infants and controls were larger in infants older than months. infants with cmt a (cmtinfs z-score . , sd . ) and cmt c (z-score . ) were less affected than cmtx (z-score . ) and cmt d (z-score . ). the gross motor function subscale differed significantly between cmt cases and controls ( . , sd . vs . , sd . ; p=. ) and a significant difference was also observed for the fine motor function subscale ( . , sd . vs . , sd . ; p= . ). reliability, factor and rasch analysis of the cmt-infs is underway to assess validity. initial results support the sensitivity of cmtinfs in distinguishing between infants with and without cmt. preliminary analyses also suggest the scale is sensitive to genetic subtype. with increased power, cmtinfs promises to become a useful outcome measure of disease severity and function in infants with cmt. manso c , querol l , mekaouche m , illa i , devaux j . aix-marseille université, marseille, france; universitat autónoma de barcelona, barcelona, spain. contactin- , contactin-associated-protein- (caspr ), and neurofascin- (nfasc ) are essential for the formation of paranodal axoglial junctions. igg autoantibodies to contactin- , caspr , and nfasc are associated with subsets of patients with chronic inflammatory demyelinating polyradiculoneuropathy (cidp) presenting with common clinical features. anti-contactin- igg autoantibodies have been shown to be pathogenic and to affect the paranodal axoglial junctions in vivo and in vitro. by contrast, the pathogenic effect of anti-nfasc igg have not been demonstrated. here, we purified anti-nfasc igg from cidp patients' plasma and investigated their effects after passive transfer. to determine whether these antibodies can pass the paranodal barrier, we performed intraneural injections of anti-nfasc igg autoantibody. by contrast to anti-contactin- igg , anti-nfasc did not penetrate the paranodal regions after intraneural injections, but bound to the surface of the schwann cell. to perform chronic exposure, lewis rats were implanted with intrathecal catheter and anti-nfasc igg were administrated in a daily manner during three weeks. igg to nfasc , but not control igg , induced progressive clinical deteriorations characterized by gait ataxia and hindlimb paraparesis. these deteriorations were associated with nerve activity loss in motor spinal nerves and with a selective loss of the paranodal specialization characterized by the disappearance of the caspr /contactin- /nfasc complex at paranodes. the passive transfer of anti-nfasc igg thus seem to induce similar pathogenic effects as the anti-contactin- igg . however, the pathogenic mechanisms leading to paranode disappearance appear different. our findings indicate that igg directed against nfasc are pathogenic and further show that these antibodies are reliable biomarkers of a specific subset of cidp patients. better fit the needs of the consortium and improve patient experience. these enhancements include creating mobile friendly webpages, updating enrollment form content, access to a customized dashboard, and the ability of registrants to explore their data in comparison to other registrants. we will review these enhancements in depth, and demonstrate their impact on the growth and development of the rdcrn inc contact registry. martinez c , hubsch a , watson dj , shebl a , wallenhorst c , simon tl . institute for epidemiology, statistics and informatics gmbh, frankfurt, germany; csl bering ag, bern, switzerland; csl behring llc, king of prussia, usa; csl bering gmbh, marburg, germany. hemolytic anemia (ha) is a complication of intravenous immunoglobulin (ivig) treatment, particularly in patients receiving high dose ivig for immune modulation, such as guillain-barré syndrome or chronic inflammatory demyelinating polyneuropathy. the primary mechanism for the increased risk is believed to be passive acquisition of anti-blood group a and b antibodies (isoagglutinins) from the ivig product. to reduce the quantity of isoagglutinins, an anti-a donor screening was implemented for the ivig privigen ® from - and donors with high titers were excluded from contribution to pooled plasma. anti-a donor screening was replaced since with an immunoaffinity chromatography step, which decreases isoagglutinins to a greater extent, but no data are available to test its clinical effectiveness. to test the effectiveness of the donor screening, two cohorts of patients treated with privigen ® before and after start of donor screening were identified from a hospital-based administrative database of us hospitals with in-and outpatient discharge diagnoses, procedures, drug utilization and laboratory tests between / and / (period ) and between / and / (period ). privigen ® dose per kg body weight was estimated from the daily quantity administered and age-and sex-specific us population body weight estimates. ha within days of privigen ® use was assessed from manual records review and the incidence rate of ha in the two periods compared. incidence rate ratios (irr) of ha were adjusted for sex, age, treatment setting, indication and dose per kg body weight using period as reference. the incidence rate of ha was . / , person-days ( % confidence interval: . - . ) in period ( has in , person-days) and . ( . - . ) in period ( has in , person-days). the adjusted irr was . ( . - . ). significantly less ha risk was found with high dose (≥ . g/kg body weight) privigen ® , irr . ( . - . , p= . ). we conclude that anti-a donor screening and exclusion of donors with high anti-a titers from plasma pools is associated with a decreased risk of ha with ivig. matsumoto a . department of neurology, keijinkai jozanki hospital, sapporo, japan. subacute myelo-optico neuropathy (smon) is the intoxication of clinoquinol with main clinical symptoms of paresthesia and spasticity of legs. these symptoms have been considered to be elicited by the disturbance of spinal cord and peripheral nerve as the intoxication of clinoquinol. however, as to the patients with smon who have been still living after the onset of disease, the examination of nerve conduction velocities are in normal ranges and the clinical symptoms of peripheral neuropathy are not observed now. in order to investigate whether the peripheral neuropathy were observed in the early stage of smon, we investigated the longtidunal changes of electrophysiological results in patients who could examine the nerve conduction studies from early stage of smon until the present time. as to the disturbance of pyramidal tract functions (myelopathy) in smon patients, the central motor conduction times were calculated by transmagnetic stimulation of motor cortex, cervical roots and lumbar roots. the peripheral nerve conduction velocities of sensory nerve were examined with the sural nerves. as the results, in patients with smon who could examine the electrophysiological examination from the early stages of smon until to years later, the central motor conduction times of leg muscles from motor cortex to lumbar roots were prolonged in the smon patients compared to the normal cases. these results suggest the presence of disturbances of conduction velocities of spinal cord. conduction velocities of sensory nerve velicities (sncvs) showed the delayed sncvs of sural nerves( - m/sec) at the first examination from the onset of - years. however from to years later, sncvs of these cases were covered to - m/sec. from these electrophysilogical examinations, it was suggested that the presenting main symptoms of smon were the disturbance of myelopathy, and the disturbance of peripheral nerve function had been recovered after onset of smon being elapsed a long time, natural killer (nk) cells are part of our innate immune system with regulatory and effector functions. they comprise the first line of defence in the recognition and destruction of virus-infected and pathologically altered cells. different studies suggest that the treatment with intravenous immunoglobulins (ivig) has an immunomodulatory effect on nk cells. ivig is a first-line treatment for various autoimmune diseases in particular in chronic inflammatory demyelinating polyneuropathy (cidp). the lack of a predictive marker for ivig responsiveness in cidp avoids the early preservation of non-responding patients. to better understand the effect of ivig in patients with cidp, we tested whether ivig treatment altered the nk cell status. additionally, we analysed if the alteration in the populations may serve as a surrogate marker in predicting the outcome of ivig treatment. using semi-quantitative pcr and flow cytometry in the peripheral blood of patients with cidp, we analysed the effects of ivig on the nk cell population before treatment initiation and h after first dose and correlated the changes with the reponsiveness to ivig. ivig administrations induced a reduction in the expression of several typical nk cell genes. interestingly, this ivig-induced reduction of nk cells was reversible four weeks after the ivig treatment. flow cytometry data revealed that ivig reduced the cytotoxic cd dim nk cell population, while regulatory cd bright nk cells remained almost unaffected or were even increased. interestingly, we found that the observed effects on nk cells almost exclusively occurred in cidp patients who responded to ivig therapy. correlation between the changes in the nk cell population and treatment efficiency suggests a crucial role for nk cells in the immunomodulatory mechanism of ivig. further studies are warranted to investigate whether the differences in the nk cell status of patients with cidp represent a reliable surrogate marker in predicting the outcome of ivig therapy. mccray b , sullivan j , woolums b , aisenberg w , lloyd t , sumner c . johns hopkins university, baltimore, usa. mutations in transient receptor potential vanilloid (trpv ), a calcium-permeable non-selective ion channel, cause charcot-marie-tooth disease type c (cmt c). trpv is unique in that it represents the only membrane-expressed ion channel in cmt and thus a potential therapeutic target. previous work has suggested that trpv mutations lead to gain of channel function and toxicity in cultured cells. neuropathy-causing mutations of trpv largely cluster in the cytosolic ankyrin repeat domain (ard) that is known to mediate protein-protein interactions, suggesting that pathogenesis may be related to disruption of such interactions. in order to identify trpv -interacting proteins, we performed two unbiased proteomics screens and identified multiple cytoskeletal-modifying proteins including syndapin- , a neuronal protein known to promote axonal outgrowth by influencing the actin cytoskeleton. in cultured cells, we have shown that trpv and syndapin- co-localize to highly dynamic actin-rich cellular processes and together stimulate robust neurite extension, but this facilitation of neuritogenesis is impaired by disease-causing mutations in trpv . we have also shown that over-expression of syndapin reduces trpv -mediated calcium influx in cultured cells and rescues toxicity of mutant trpv . in addition, syndapin over-expression suppresses mutant trpv phenotypes in a drosophila model of trpv -related neuropathy. further, we have demonstrated that treatment of drosophila with a specific trpv channel antagonist ameliorates trpv mutant toxicity. together, our data highlight the importance of trpv interaction with cytoskeletal proteins such as syndapin- in the pathogenesis of cmt c. specifically, our results suggest that mutations in trpv disrupt the normal role of trpv in regulation of cytoskeletal dynamics and that interactions with the cytoskeleton reciprocally modulate trpv channel function and influence toxicity of mutant trpv . mcgonigal r , yao d , barrie ja , crawford c , willison hj . university of glasgow, glasgow, uk. guillain-barré syndrome (gbs) is in part mediated by anti-gm ganglioside antibodies induced by preceding infections. anti-gm antibodies target plasma membrane gm that is extensively distributed in both glial and axonal membranes, particularly at the node of ranvier. antibodies deposited at this site in models of gbs are associated with complement deposition, conduction block, structural disruption of ion channels and macrophage infiltration. the wide distribution of the gm ganglioside target leads to unwanted complexity in ascribing pathological outcomes to injury of cell-specific membranes, in particular unravelling the consequence of paranodal schwann cell membrane injury on axonal function, and vice versa. to overcome this impasse, we have generated transgenic mice through glycosyltransferase manipulation that express gm exclusively in neurons or glia, thus allowing us to very specifically target and injure axonal or glial membranes with a single anti-gm ganglioside antibody. through this route we can create mouse models of both the axonal and demyelinating forms of gbs, induced by a single anti-gm antibody, thus creating otherwise highly comparable conditions. here, we show anti-gm antibody binding is restricted to the nodal axolemma in galnact −/− -tg(neuronal) mice and conversely to paranodal loops in galnact −/− -tg(glial) mice. when anti-gm antibody and a source of complement is added to a nerve-muscle ex vivo injury paradigm, there is a loss of axonal integrity (i.e. loss of neurofilament immunolabeling) when the neuronal membrane is targeted in galnact −/− -tg(neuronal). conversely, axonal integrity is maintained when the paranodal membranes are decorated by antibody and complement products ex vivo in galnact −/− -tg(glial) mice. in a passive immunisation model in vivo, galnact −/− -tg(neuronal) mice acutely develop weakness, respiratory dysfunction, associated complement deposition, and degenerative pathology in distal axons. in contrast, galnact −/− -tg(glial) mice have significantly fewer abnormalities under the same acute conditions. these data indicate the high vulnerability of axonal membranes to acute injury and underline the importance of developing specific axonal protection strategies. in summary, targeting the nodal axolemmal or glial membranes allows us to study associated nodal pathology, and determine the downstream consequences on function and axon fate, currently a major area in gbs clinical research. memon a , madani s , schultz l , grover k , arcila-londono x , sripathi n , ahmad bk . neuromuscular division, department of neurology, henry ford hospital, detroit, michigan, usa. objective: to differentiate sensory electrophysiology, tli and treatment response in patients with paraproteinemic cidp. background: low tli has been reported as a useful electrophysiological marker for mag-cidp. to our knowledge comparison of sensory electrophysiology and tli of paraproteinemic cidp subgroups have not been previously reported. methods: retrospective review(january -december ) of patients with cidp fulfilling electrophysiological criteria(aan ad hoc subcommittee and albers and colleagues).cidp patients with diabetes(n= ) were excluded. patients were divided into idiopathic (n= ) and paraproteinemic cidp(n= ). paraproteinemic cidp sub-groups: mag( ), non-mag( ) and igg( ) were compared to idiopathic cidp( ). these groups were compared for demographics, history of cancer, csf protein, sensory conductions, tli measurements and response to treatment using chi-square tests for binary and categorical variables and t-tests for continuous measures. results: there was a higher proportion of females in idiopathic-cidp compared to non-mag-cidp ( % vs %). idiopathic group having a higher proportion of patients on monotherapy( % vs %) and combination therapy( % vs %) compared to non-mag. higher mean csf protein compared to mag-cidp(p= . ) was seen in the idiopathic. the difference between idiopathic and igg-cidp was significant for overall rx response(p= . ) and rx response in patients with follow-up(p= . ). for both variables, patients in the idiopathic group had a higher proportion of patients on combination therapy and lower proportion of no treatment offered compared to patients in the igg-cidp. % of non-mag-cidp patients had a history of cancer vs % of mag-cidp. none of the other differences were significant. there were no group differences in sensory electrophysiology and tli. conclusions: sensory electrophysiology and tli may have no value in differentiating paraproteinemic cidp. csf protein is higher in idiopathic cidp compared to mag-cidp. idiopathic-cidp has a higher proportion of females compared to non-mag-cidp and a higher proportion of patients on combination therapy compared to igg-cidp. cancer screening should be considered in patients with non-mag-cidp. memon a , madani s , ahmad bk , schultz l , grover , arcila-londono x , sripathi n . department of neurology, henry ford hospital, detroit, michigan, usa. introduction: sensory electrophysiology and terminal latency index (tli) differences have been described in various cidp sub-groups. objective: evaluate electrophysiology, tli and treatment response in idiopathic and diabetic cidp. methods: retrospective review of patients with cidp who underwent electrodiagnostic evaluation (january -december . patients fulfilled electrophysiological criteria described by ad hoc subcommittee of american academy of neurology (aan) and albers et al. we excluded patients( ) with acute inflammatory demyelinating neuropathy, hereditary sensorimotor neuropathy, vasculitis and polyneuropathy with paraproteinemia. patients were divided into idiopathic( ) and diabetic( ) groups. these groups were compared for age, sex, history of cancer, csf protein, response to treatment, sensory response abnormalities and tli measurements using chi-square tests for binary and categorical variables and t-tests for continuous measures. all testing was at the alpha= . level. results: group differences for age, sex, history of cancer, csf protein and treatment response were not significant. comparing tli values in measurable responses, the difference between the two groups for tibial tli was significant (p= . ), with idiopathic group having a lower mean as compared to the diabetic. tli values differences for median, ulnar and peroneal nerves were not significant. the difference in abnormal rates of sensory responses was significant for the sural nerve with the idiopathic group having a lower rate compared to the diabetic group ( % vs %, p< . ). no differences were noted for the ulnar, median and radial nerves. tibial tli and sural sensory responses have some value in differentiating the two groups. larger prospective studies are needed to confirm our findings. ivig is an important treatment option for cidp. although recommended by treatment guidelines, little is known about the consequences of temporary ivig withdrawal to assess ongoing immunoglobulin need. path is a randomized, double-blind trial of the subcutaneous immunoglobulin (scig) igpro (hizentra ® , csl behring) in cidp. before scig randomization, subjects underwent periods of ivig withdrawal ( weeks or until pre-determined indications of clinical deterioration) and ivig restabilization (igpro ; privigen ® , csl behring). subjects not showing deterioration during withdrawal period were withdrawn from study. to proceed to scig randomization, subjects had to achieve "cidp stability" (no relevant change in incat score at last two restabilization visits and at least the same total score as at screening). subjects entered the ivig withdrawal period. ( %) of these qualified for igpro restabilization; subjects ( %) were not ivig dependent, and ( %) were withdrawn for other reasons. one subject withdrew consent before igpro dosing. at the end of the igpro restabilization period, cidp stability was achieved in % of subjects ( did not reach stability, were withdrawn for other reasons). post-study follow-up information was available for / subjects who did not reach stability: ( %) had improved to baseline clinical status and had not, meaning at least % of the subjects improved to their pre-study status. during the restabilization period, / subjects ( %) improved in at least one of the predefined outcome measures. on average, subjects improved by . points in incat total score, . points in i-rods centile score, kpa in mean grip strength (dominant hand), and . points in mrc sum score. improvement occurred with a median of days after the first igpro dose in one or more efficacy outcome measures and in % of cases after the third igpro maintenance infusion. headache and nasopharyngitis were the most frequently reported adverse events (aes) during restabilization. aes deemed causally related were mostly mild or moderate. no unexpected aes or laboratory or vital sign findings associated with igpro occurred during the study. in summary, igpro reversed neuromuscular disability and improved activity/participation after previous clinical deterioration during an ivig withdrawal period. pmp duplication is the most frequent cause of charcot-marie-tooth disease (cmt). since it discovery, more than genes have been identified to be potentially responsible for cmt disease. however only single nucleotide variations (snvs) or small indels have been described. this could be due to the new sequencing strategy (ngs), especially ngs by amplicon sequencing, for whose few convenient tools are available and easily usable to detect cnvs responsible for inherited disease. to overcome this problem, we designed "cov'cop", a user-friendly tool able to detect cnvs among amplicons sequencing data. using the run's coverage file provided by the sequencer, "cov'cop" simultaneously analyzes all the patients of the run using a two-stages algorithm containing correction and normalization levels and provides an easily understandable output, showing with various colors, potentially deleted and duplicated amplicons. we validated our method on several datasets, including those of our targeted ngs panel screening genes known to be involved in cmt and close pathologies. cov'cop detected easily pmp duplication and deletion in our patients, confirmed by mlpa. in addition, cov'cop permitted the detection of new cnvs different from the pmp duplication, in cmt patients. we confirmed these cnvs by quantitative pcr and cgh array. we present here one of these cnvs: the duplication of aars gene detected in cmt patients and we discuss the pathogenicity of this new cnv. additional cnvs responsible for cmt disease are probably still to be discovered and we believe that cov'cop will help molecular geneticists to rapidly identify them. poems (polyneuropathy, organomegaly, endocrinopathy, m-protein, and skin changes) syndrome is a rare cause of demyelinating neuropathy associated with plasma cell dyscraisia and vascular endotherial (vegf) overproduction. although number of therapeutic interventions for plasma cell dysorders have been applied to poems syndrome, there have been no randomized clinical trials. this phase / double blind, randomized, placebo comtrolled trial was performed to investigate the safety and efficacy of thalidomide for patients with poems syndrome who are not eligible for stem-cell transplantation. the primary endpoint was the reduction rate of serum vegf concentrations at weeks in intention to treat analysis. additional outcomes of long-term extension study included progression-free survival. twenty-five poems patients were randomly assigned to either thalidomide plus dexamethasone or placebo plus dexamethasone from nov , , to july , . one patient in the placebo group was excluded from analyses because of a protocol violation. the adjusted mean serum vegf reduction rate at weeks was . (sd, . ) in the thalidomide group compared with − . ( . ) in the placebo group (p= . ). the kaplan-meier rate of progression-free survival at months was . in the thalidomide group, as compared with . in the placebo group (hr, . ; % ci, . to . ). in the randomized study period, mild sinus bradycardia was more frequent in the thalidomide group than in the placebo group ( % vs %; p= . ). thalidomide suppresses serum vegf concentrations and lengthened pregression-free survival in poems patients who are ineligible for stem cell transplantation. although thalidomide treatment has a risk of bradycardia, the benefits would exceed the risk. this study is registered with the umin clinical trials registry, umin . montes-chinea ni , coutts m , vidal c , courel s , rebelo a , abreu l , zuchner s , saporta, ma , . department of neurology, university of miami, miami, usa; department of human genetics, university of miami, miami, usa. autosomal dominant mutations in synaptotagmin- (syt ), a synaptic vesicle protein that functions as a calcium sensor for neurotransmission, have been previously linked to presynaptic neuromuscular junction (nmj) dysfunction and motor neuropathy in two families. both pathogenic mutations (asp ala and pro leu) were located in the c b domain of syt , which is essential for neurotransmitter release at the nmjs. we report a family with a new missense mutation in the c b domain of syt and a similar phenotype characterized by a slowly progressive, predominantly motor neuropathy and evidence of presynaptic nmj dysfunction on nerve conduction studies. the index case is a year-old woman with gradually progressive weakness of her extremities. she had normal developmental milestones, but was found to have bilateral high arched feet and hammertoes and occasional falls around the age of . she gradually developed progressive leg weakness, worsening bilateral hand cramping, weak handgrip, and only mild paresthesias on distal extremities. family history is remarkable for similar symptoms reported by her maternal grandfather, two maternal uncles, her mother and a younger sister. her neurological exam revealed inability to walk on heels or toes, significant distal lower extremity weakness and absent ankle deep tendon reflexes. cranial nerve examination and coordination were normal and there were only non-specific sensory changes in the lower extremities. emg/ncs revealed normal sensory responses throughout; however, motor nerve evaluation demonstrated globally reduced amplitudes with a > % increment after brief isometric contraction. further electrophysiological evaluation with slow ( hz) repetitive nerve stimulation of the right ulnar motor nerve revealed a % decremental response in amplitude and a > % increase in amplitude immediately after a one-minute period of sustained muscle contraction, which rapidly extinguished after one minute. voltage-gated calcium channel (vgcc) antibodies and a chest ct were normal. targeted sanger sequencing revealed an ile lys mutation in syt , which is located in the c b domain and is predicted to impair protein function. syt -related neuropathy is a rare disease, but should be suspected in patients presenting with a combination of pre-synaptic nmj dysfunction (resembling lambert-eaton myasthenic syndrome) and a predominantly motor neuropathy, especially in the context of a positive family history. charcot-marie-tooth (cmt) disease affects roughly in , individuals and is described as an inherited peripheral neuropathy primarily affecting distal muscles. limited studies detail patient-reported impact of muscle weakness on functional activities. this anonymous survey was developed with input from clinical experts and patient interviews and aimed to better understand the prevalence and impact of various cmt clinical manifestations on patients' lives. the survey was administered online to the hereditary neuropathy foundation's (hnf) patient contact database and is ongoing through june . here we present preliminary data on patient characteristics and disease impact for cmt patients collected february - , . respondents were mostly female ( %) and mostly from the us ( %). median age (range) at symptom onset was years ( - years), at diagnosis was years ( - years), and at present was years ( - years). the sample was representative of all cmt types (cmt , , , ,and x). the most common physical and clinical manifestations of cmt were problems with balance ( %), ankle weakness/foot drop ( %), loss of feeling or abnormal sensation in the lower leg/foot ( %), and hand muscle weakness ( %). maintaining balance, walking long distances, and climbing up and down stairs were key challenges associated with ankle weakness/foot drop. foot drop was considered by % to be the primary factor contributing to falls, which averaged . falls to ground per month. of those with foot drop, % had bilateral weakness. a majority of respondents ( %) used some form of assistive device for mobility, including ankle-foot orthotics/below-the-knee leg braces ( %), canes/walking sticks ( %), and custom foot orthotics/inserts ( %). the most common drug therapy included pain and anti-inflammatory medications ( %). foot surgery was the most common surgical procedure received ( %) and toe surgery was the most common surgery considered ( %). key symptoms that affected quality-of-life "very much" included problems with balance ( %), ankle weakness (foot drop) ( %), and fatigue ( %). these data suggest a high prevalence of lower leg muscle weakness; therefore, therapies aimed at improving ankle weakness and the resulting foot drop and imbalance may be beneficial to patients' daily functioning and quality of life. morano m , , gambarotta g , ronchi g , , cillino m , fornasari be , , fregnan f , , tos p , cordova a , moschella f , geuna s , , raimondo s , . department of clinical and biological sciences, university of turin, orbassano (to), italy; neuroscience institute of the "cavalieri ottolenghi" foundation (nico), university of turin, orbassano (to), italy; plastic and reconstructive surgery. department of surgical, oncological and oral sciences, university of palermo, palermo, italy; hand microsurgery and surgery, gaetano pini hospital, milan, italy. nerve fiber regeneration and complete functional recovery after peripheral nerve injury do not always occur and can be influenced by many factors including patient age, gender, lesion site, injury severity, size of the gap between damaged nerve stumps and time interval that elapses before performing surgical repair. the poor outcome occurring after a long delay can be due to loss of the neuron ability to regenerate, loss of the schwann cell ability to support regeneration and, of course, progressive muscle atrophy. the aim of this study was to investigate the nerve regeneration after delayed repair and to study the degenerative processes of the denervated distal nerve stump and denervated muscle. in particular, the analyses were focused on the role of nrg/erbb system, that is expressed both in nerve and in muscle tissue, during degenerating and regenerating processes. functional recovery analysis performed after nerve repair showed that only the group repaired immediately and not the groups repaired with a delay of or months, recovered partially. nevertheless, morphological analyses demonstrated that, despite the delay, the nerve fibers are still able to regenerate, even if they are fewer and smaller than the immediate repaired group. moreover, the analysis of the nrg /erbb system showed a significant decrease of soluble nrg in both degenerating and delayed-repaired nerves. the poor outcome after delayed nerve regeneration might be explained by schwann cell impairment and the consequent ineffective support for nerve regeneration. as regards denervated muscle analysis, results showed that erbb receptors expression is related to the innervated state of the muscle, with an upregulation of erbb clearly associated with denervation state. interestingly, nrg isoforms are differently regulated depending on the type of nerve injury. future experiments will be needed to address the in vivo efficacy of different isoforms of nrg both in injured nerve and denervated muscle. we planned a multicenter, prospective, randomized, single blind, controlled study to evaluate the efficacy and safety of an innovative rehabilitation protocol based on the use of treadmill training in a cmt a population. the protocol required that subjects were blindly randomized into two treatment groups, spe (three months of respiratory, proprioceptive and stretching exercises) or trespe (the same treatment plus aerobic training at the treadmill). subjects were evaluated at baseline (t ), after three month of treatment (t ) and further three months of follow up free of therapy (t ). the full assessment included: -mwt (primary outcome measure), -mwt, walk- , short physical performance battery (sppb); lower limbs dynamometric strength evaluation; berg balance scale (bbs); cmt neuropathy score; medical outcomes study short form (sf ). a total of subjects (mean age of . ± . years) were recruited. at t we found a significant improvement in both groups in the -mwt (p< . ), -mwt (p< . ), bbs (p< . ) and sppb (p< . ), while at t only the -mwt was still significantly improved (p< . ) in the spe group. no significant differences between groups were observed for any of the outcome measures. performances on walk did not significantly change during follow-up (p= . ). concerning the sf , we did not observe consistent changes during follow-up or consistent differences comparing the two treatments. in conclusion, this multicenter, prospective, randomized, single blind, controlled study shows that the combination of respiratory, proprioceptive and stretching exercises has a positive impact on the performance of cmt patients, especially regarding walking tests. the aerobic exercise at the treadmill, is well tolerated but apparently does not add any further improvement to the conventional treatment. we speculate that the relatively low clinical severity of the patients, due to the selection criteria, may have prevented a positive effect of treadmill exercise. müller m , dohrn m , romanzetti s , reetz k , gess b . university rwth aachen, department of neurology, aachen, germany. muscle mri is increasingly used in neuromuscular patients to detect changes in muscle volume, muscle fat infiltration and edema. muscle mri are mostly analyzed by qualitative means as quantitative analysis is time-consuming and not well established. here, we developed a novel method for semi-automated segmentation of muscle mri data sets. based on axial t -weighted dixon mri stacks, muscle volumes were quantified by an adapted water-shed algorithm. muscle volumes of thighs and calves were determined separately and the ratio of thigh/calf was calculated. myopathy, neuropathy patients and healthy controls were included in the study. muscle volumes determined by semi-automated segmentation were very similar to manually segmented data sets, differences being < %. this was the case for patients as well as healthy controls. the time-saving effect of automated segmentation was very strong ( vs min. per patient). muscle volumes of the thigh and also of the calf of myopathy patients showed a highly significant difference (p< . ) compared to healthy subjects. in neuropathy patients there was a just significant difference (p< . ) of muscle volumes compared to healthy patients that did not sustain in bonferroni's multiple comparison test. the ratio of thigh/calf muscle volume was significantly different comparing patients with myopathy and neuropathy (p< . ). subgroup analyses of different groups of myopathy patients showed highly significant differences (p< . ) in myositis, limb-girdle-muscular dystrophy and metabolic myopathy, compared to healthy patients, but no significant differences in-between these groups. taken together, the data shows that automated segmentation of muscle mri allows for exact and fast quantification of muscle volumes in neuromuscular patients. higher patient numbers are necessary to test differences between specific disease groups. further studies should also address the possible use as a marker of disease progress for clinical studies or therapy monitoring. murakami t , nishimura h , nagai t , hemmi s , kutoku y , sunada y . department of neurology, kawasaki medical school, kurashiki, japan; department of pathology, kawasaki medical school, kurashiki, japan. familial amyloidotic polyneuropathy (fap) is an autosomal dominant hereditary systemic amyloidosis caused by mutation of transthyretin (ttr) gene, and usually shows sensory dominant polyneuropathy and autonomic neuropathy at the initial stage. the pathogenesis of neuropathy is not well understood, and explained by several mechanisms, including such as mechanical compression, vessel occlusion, ttr toxicity and schwann cell dysfunction. we describe a sporadic patient with late-onset fap due to ttr e k. she noticed dysesthesia first in the foot at age . the symptoms were slowly progressive, and abnormal sensations were extended up to the both upper arms and the both knees at age . distal muscle weakness and atrophy was also observed in the extremities. she noticed difficulties in walking and frequent diarrhea. echocardiogram revealed diffuse left ventricular hypertrophy, suggesting cardiac amyloidosis. amyloid deposits were not detected in the endoneurim or perineurium of the sural nerve years after the onset of the disease, but a marked loss of myelinaed and unmyelinated nerve fibers was observed in it. ttr-derived amyloid deposits were confirmed in the peroneous brevis muscle, salivary gland and heart tissue. dna analysis revealed the heterozygote mutation, p.e k (e k)/c. g>a, of ttr gene, and she was diagnosis as fap. these findings suggest that the proximal parts of peripheral nervous system might be strongly involved by ttr aggregates or amyloid fibrils. blood-nerve barrier in the distal part of peripheral nerves could be preserved until later in the patient. several biopsy sites other than nerve may be helpful and necessary for diagnosis of ttr amyloidosis in mild or late-onset fap as our case. amyloidgenic element (cae) encoded by the ' utr. this study also identified a de novo c. _ dup frameshift mutation predicting p.lys glnfs* in nefh from a cmt family with atypical clinical symptom of proximal dominant weakness. this mutation is located near the previously reported frameshift mutations, suggesting a mutational hot spot. these relatively frequent deletion/duplication events with this resign might be caused by the putative hairpin structure. patient's lower limb mri revealed a marked hyperintense signal changes in the hip muscles than those in the thigh or lower leg muscles. this study also observed an anticipation pattern of earlier onset ( yrs old for mother to yrs old for daughter) and more severe symptoms in later generation. therefore, this study suggests that the stop loss and translational elongations by the ' utr of the nefh mutations may be relatively a frequent genetic cause of axonal peripheral neuropathy with the specific characteristics of proximal dominant weakness and an anticipation pattern. neil j , haghi ashtiani b , choumet v , musset l , léger jm . department of immunology, pitié-salpêtrière hospital (ap-hp), paris, france; department of neurology, national referral center for rare neuromuscular diseases, pitié-salpêtrière hospital (ap-hp), paris, france; institut pasteur, emerging diseases epidemiology unit, paris, france. the myelin-associated glycoprotein (mag) is a transmembrane glycoprotein localized in periaxonal shwann cells and oligodendroglial membranes of myelin sheaths. mag contains a carbohydrate epitope (hnk- ) that is a target antigen in autoimmune peripheral neuropathy associated with monoclonal igm gammopathy. in these neuropathies, numerous studies report the absence of correlation between the titers of anti-mag antibodies and the disease course. anti-mag titers and igm level at diagnosis are not always associated with disease severity and there is not good correlation between pre-and post-treatment anti-mag titers in patients who respond clinically to immunomodulators. mag belongs to siglec- a family and the linkage of sialic acid to the underlying sugars is an important determinant of siglec binding. mag shows high affinity for alpha- , -linked sialic acid ( , -sa).moreover, human monoclonal igm possesses heavy chain glycosylation sites at asn , , , and with sialylated olidgosaccharides and high-mannose type oligosaccharides. igm may bind to mag via these glycan epitopes as an alternative and additional route of antigen binding other than through the fab v regions. this mag-glycans igm interaction may be clinically neutral but could lead to an overvaluation of the biological results. in this study, we analyzed sera from patients with igm reactivity against mag: of them had an anti-mag neuropathy with various degrees of severity, and the last one had igm monoclonal gammopathy, strong serum anti-mag reactivity but no neurological disease. igm were extracted and purified from these sera by affinity chromatography. for each batch, an aliquot was digested by jack bean alpha-mannosidase and anti-mag reactivity was performed by elisa and indirect immunofluorescence (iif), before and after demannosylation. these extracts, tested in an iso quantitative way with regard to the original serum, showed a decrease of activity (elisa) and intensity (iif) after demannosylation. furthermore, elisa anti-mag was carried out in sera from patients with igm monoclonal gammopathy without neurological impairment: of them ( . %) showed a significant biological response. taking into account the fact that anti-mag antibodies are pathogenic (in animals models), these results support the hypothesis of neutral intermolecular interactions between igm and mag. ng cjb , ng jph , tay lb, t , umapathi . yong loo lin school of medicine, national university of singapore, singapore; lee kong chian school of medicine, nanyang technological university, singapore; national neuroscience institute, singapore. recent developments have validated non-invasive means of measuring central arterial blood pressure (casp) and have shown that casp and peripheral blood pressure (pbp) are unidentical entities. patients with postural orthostatic tachycardia syndrome (pots) have marked tachycardia with no associated decrease in pbp. we asked if the reflex tachycardia, which corresponds to postural dizziness in these patients, could be a result of a decrease in casp. two male patients, and years of age, with clinical features typical of pots went through a complete battery of autonomic screening tests. the sympathetic and parasympathetic responses were normal other than a heart rate increase of and beats per minute, respectively, on standing. there was no significant decrease or increase in pbp on standing for and minutes. casp was measured non-invasively by a device bpro r that imputes the measured radial waveform onto the brachial blood pressure to generate a pressure waveform from which a numerical casp value is derived. the casp measurements for both patients did not decrease on standing for and minutes. our preliminary observation suggests that the basis of tachycardia in pots patients may not be a decrease in central blood pressure. we are proceeding to systematically study more pots patients to corroborate the above observation. we are also trying to compare the difference between pbp and casp in pots and age, gender-matched normal controls. the major limitation of the study is the model-based mathematical derivation, rather than direct measurement, of casp. we are proceeding to systematically stud y more pots patients to corroborate the above findings. ng jph , ng cjb , t umapathi . lee kong chian school of medicine, nanyang technological university, singapore; yong loo lin school of medicine, national university of singapore, singapore; national neuroscience institute, singapore. recent developments have validated non-invasive means of measuring central arterial blood pressure (casp) and have shown that casp and peripheral blood pressure (pbp) are unidentical entities. orthostatic hypotension (oh) is a prominent component of autonomic dysfunction (ad), the consequent hypoperfusion of vital organs responsible for considerable morbidity and mortality. these structures are exposed to casp rather than pbp. we sought to understand the relationship of casp to peripheral blood pressure (pbp) in patients with autonomic dysfunction exposed to orthostatic stress. we reviewed autonomic function tests of patients tested at our laboratory over a -year period. the patients were divided into cohorts: ( ) no ad and no oh ( ) no ad, with oh ( ) mixed ad ( ) parasympathetic dysfunction ( ) sympathetic dysfunction. casp was measured non-invasively by a device, bpro r , that imputes the measured radial waveform onto the brachial blood pressure to generate a pressure-wave form from which a numerical casp value is derived. the difference and ratio of casp to pbp was recorded at rest and after minutes of standing. out of patients had complete data and a definitive final diagnosis. cohorts - had , , , , patients respectively. mean casp-pbp difference in cohorts - were − . , − . , − . , − . , − . respectively at minutes, and − . , − . , − . , − . , − . respectively at minutes. mean casp/pbp ratio in cohorts - were . , . , . , . , . , . respectively at minutes, and . , . , . , . , . respectively at minutes. there was no significant difference in the response of casp and pbp to orthostatic stress across abnormal cohorts to and in comparison with the "normal" cohort (p= . to . ). there was also no relationship to symptoms, namely postural dizziness. in conclusion, autonomic dysfunction does not seem to affect the casp-pbp relationship as measured by non-invasive means. the absence of true normal controls, the exclusion of significant number of patients because of incomplete data and the model-based mathematical derivation rather than direct measurement of casp are limitations that we aim to address in follow-on studies. niu jw , guan hz , cui ly , guan yz , liu ms . the department of neurology, peking union medical college hospital, chinese academy of medical sciences, beijing, china. we aimed to explore the correlation between afterdischarges in motor nerve conduction studies and clinical motor hyperexcitability in patients with voltage-gated potassium channels (vgkc) antibodies. six patients with positive serum antibodies to contactin-associated protein-like (caspr ) or/and leucine-rich glioma-inactivated protein (lgi ) were recruited, including with autoimmune encephalitis, and with cramp-fasciculation syndrome. electromyography (emg), nerve conduction studies (ncs) and f waves were performed, and afterdischarges were assessed. one patient was followed up. five patients had clinical evidence of peripheral motor nerve hyperexcitability (myokymia or cramp), and four of them had abnormal spontaneous firing in concentric needle electromyography. prolonged afterdischarges following normal m waves were present in all six patients, including the two patients who had no emg evidence of peripheral nerve hyperexcitability (pnh). in the patient who was followed up, afterdischarges disappeared after treatment with intravenous immunoglobulin (ivig). afterdischarges in motor nerve conduction study might be more sensitive than needle electromyography for detecting peripheral motor nerve hyperexcitability in patients with vgkc antibodies, and could disappear gradually in accordance with clinical improvement and reduction of antibodies. in our research, multiple sites measurement of cross sectional areas (csa) by ultrasound was performed to differentiate charcot-marie-tooth type a (cmt a) and chronic inflammatory demyelinating polyradiculoneuropathy (cidp). twenty-eight patients with cidp, patients with cmt a, and healthy controls (hc) were recruited prospectively. consecutive ultrasonography scanning was performed from wrist to axilla on median and ulnar nerves. csas were measured at predetermined sites of each nerve. cmt a had significantly larger csas at all sites of median and ulnar nerves (all p< . ). in cmt a, csas increased gradually and homogeneously from distal to proximal along the nerve, except potential entrapment sites. cidp displayed three different morphological patterns, including mild enlargement in patients, prominent segmental enlargement in , and slight enlargement in one, among which different treatment responses were observed. all patients with mild nerve enlargement treated with intravenous immunoglobulin (ivig) were responsive ( / ), while less than half of those with prominent segmental enlargement ( / ) were responsive (p< . ). the patterns of csa enlargement were different in cmt a and cidp patients. consecutive scan along the nerve and multiple sites measurement by ultrasound could supply more detailed morphological feature of the nerve and help to differentiate cidp from cmt a. guillain-barre syndrome (gbs) mainly consists of acute inflammatory demyelinating polyradiculoneuropathy (aidp) and acute motor axonal neuropathy (aman). in aman, conduction block (cb) could be reversible or followed by axonal degeneration. we aimed to identify the correlation between existence of cb and the functional outcome for patients with gbs. gbs patients were prospectively recruited for serial electrophysiological tests and disability evaluation. all patients received treatment of intravenous immunoglobulin (ivig), and their disabilities were evaluated on the hughes functional grading scale before and month after treatment. patients were classified into aidp, aman, equivocal or normal according to electrodiagnostic criteria described by rajabally et al. aman patients who had follow-up nerve conduction studies were further classified into three groups. group was typical aman without conduction block, group had reversible conduction block, group had conduction block and subsequential axon degeneration. electrophysiological study results showed aidp, aman, equivocal and normal. probable or definite conduction block was observed in aidp patients and aman patients. aman with cb had higher reduction of hughes grade at one month ( . ± . vs . ± . ,p= . ), and lower percentage of patients with slow recovery (unable to walk independently at six months) ( % vs %, p= . ) compared with aman without cb. there were no significant differences between aidp with cb and without cb, in the reduction of hughes grade at one month. among the aman patients who were followed up, were typical aman without cb (type ), had reversible cb (type ), had cb and subsequential axon degeneration (type ). hughes grades at nadir were similar, while patients with reversible cb (type ) had the largest hughes grade reduction at one month (type - . vs type - . vs type - . ). none of the patients with axon degeneration (type ) showed rapid recovery, while % of those with reversible cb (type ) had rapid recovery (improvement by two or more hughes grades within four weeks after onset). electrodiagnosis of aman with conduction block, especially reversible conduction block, might be a marker of good recovery. we report a follow-up study of nerve ultrasound in a patient with primary neurolymphomatosis. a -year-old female presented with -months history of asymmetric limb pain, paresthesia, and weakness. electrodiagnostic studies and spinal cord mri showed an axonal neuropathy involving cervical and lumbosacral root, brachial plexus and left median nerve. detection of malignant b lymphocytes by cytology and flow cytometry of cerebral spinal fluid confirmed the diagnosis of b-cell non-hodgkin lymphoma. nerve ultrasound showed dramatic enlargement of upper, middle and lower trunks of left brachial plexus (cross sectional area-csas mm , mm , mm respectively), middle trunk of right brachial plexus (csa mm ), and proximal part of left median nerve (csa - mm ). five months later, after five chemotherapy of rituximab and high-dose methotrexate, and intrathecal injection of cytosine arabinoside and dexamethasone, the patient had clinical improvement. nerve ultrasound also showed alleviation of nerve enlargement. the csas of upper, middle and lower trunks of left brachial plexus were mm , mm , mm respectively; the csa of middle trunk of right brachial plexus was mm ; the csa of proximal part of left median nerve was - mm . peripheral nerve ultrasound could help locate the distribution of nerve involvement, and reveals disease progression. nolano m , provitera v , stancanelli a , caporaso g , saltalamacchia am , borreca i , lullo f , califano f , lanzillo b , iodice r , manganelli f , barone p , santoro l . irccs "salvatore maugeri" foundation, institute of telese terme (bn), italy; "maugeri" clinical and scientific institutes irccs, institute of telese terme (bn), italy; center for neurodegenerative diseases (cemand), department of medicine and surgery, neuroscience section, university of salerno, italy. a peripheral nerve involvement has been demonstrated in pd with the evidence of a small fiber pathology as possible intrinsic feature of the disease and a higher occurrence of large fiber neuropathy in patients longtime treated with l-dopa. however the role that disease itself and ldopa have on small and large fiber pathology in pd is still debated. we studied morphology and function of cutaneous innervation, in idiopathic pd patients ( male, aged . ± . ), including naïve and l-dopa treated subjects without electrophysiological signs of neuropathy, with the aim to assess and characterize small and large fiber involvement and the effect of l-dopa on it. all patients underwent a screening to rule out potentially neurotoxic conditions such as glucose intolerance, dysendocrinopathies, vitamin e, b and folic acid deficiency, hepatic or renal failure, hiv or connective tissue disorders. skin biopsies were obtained from thigh, leg and fingertip from the more affected side and bilaterally from thigh and leg in patients. samples were processed with indirect immunofluorescence technique using primary antibodies to mark different sensory and autonomic fiber populations. density of intrapapillary myelinated endings (ime), meissner's corpuscles (mc) and epidermal nerve fibers (enfs) was obtained as well as a semi-quantitative assessment of sudomotor, pilomotor and vasomotor innervation. further evaluation included sympathetic skin response, quantitative sensory testing and dynamic sweat test. morphological and functional findings were compared with data extracted from our age and sex stratified normative dataset. ienf, ime, mc densities were lower (p< . ) compared to controls in both naïve and l-dopa treated patients without differences between them except for mc density that was lower in l-dopa treated subjects ( . ± . vs . ± . /mm ). a loss of autonomic nerves was also found in both groups compared to controls. significant abnormalities (p< . ) of thermal sensory thresholds, tactile thresholds, mechanical pain perception and reduced sweating output were present and similar in both groups. our work confirms in pd an intrinsic peripheral nerve pathology involving both small and large fibers. small fiber pathology isn't affected by l-dopa treatment while sensory large fibers involvement, already present in naïve patients worsens with ldopa treatment. noto y , garg n , li t , timmins hc , park sb , shibuya k , kiernan mc . brain and mind centre, the university of sydney, sydney, australia. the diagnosis of amyotrophic lateral sclerosis (als), a progressive, fatal neurodegenerative disorder defined by combined upper and lower motor neuron involvement, remains clinically based. the purpose of this study was to determine the ultrasound appearance of peripheral nerves in als patients, and to investigate whether parameters such as distal/proximal ratios of nerve cross-sectional areas (csas) may effectively differentiate disease mimics from als. nerve ultrasound of the median, ulnar, and tibial nerves was performed in als patients compared to mimic patients ( patients with peripheral nerve hyperexcitability syndromes (pnhs) and patients with multifocal motor neuropathy (mmn)). comparison of nerve and the distal/proximal ratios was undertaken by ultrasound and compared across clinical and neurophysiological parameters.compared to normal controls, csa of the median nerve at the upper arm was decreased in als (p < . ). in comparison to als mimic disorders, csa at the proximal site of the median, ulnar and tibial nerve and the forearm/upper arm ratio of the median and ulnar nerves had diagnostic values. in addition to csa of the median, ulnar, and tibial nerves, the median and ulnar nerve forearm/upper ratios may provide a useful marker in for the diagnosis of als. approximately in , individuals are diagnosed with charcot marietooth (cmt) disease, making it the most common hereditary peripheral neuropathy. there is no documented cure for cmt, however, many of those affected, report difficulty with mobility, imbalance, and weakness of the feet and hands. in the general population, patients reporting difficulty walking, falls and/or fear of falling, and poor strength are often referred to physical (pt) and occupational therapists (ot) to skillfully address the impairments and help restore function and quality of life (qol). for patients diagnosed with cmt this is unfortunately not the norm, often leaving patients without any skilled guidance on managing their functional impairments. patients ( males) with a mean age of . years ( - ), went through a progressive and skilled pt intervention over the course of months. the program included: therapeutic activities and exercise, neuromuscular reeducation, and manual techniques to address the documented deficits. patients were progressed through the program based on the borg scale. each patient was assessed prior to and post the commencement of the program with the berg balance scale, minute walk test, timed up and go, sit to stand in seconds, foot self selected and fast gait speed, the lower extremity functional scale, activities balance confidence form, upper extremity functional index, oswestry, and the sf- qol measure. the patients were seen by the same skilled pt - a week for weeks. all but patients improved in all measures taken, indicating an improvement in function and overall quality of life. participants reported a total of falls in the months prior to the initiation of the study and only fall was reported during the month pt intervention. this study makes a strong case for the utilization of skilled pt to address deficits in patients with cmt. additionally, the utilization of objective, valid and reliable outcome measures in this population may help healthcare practitioners establish baseline function and response to change. a large randomized control trial is recommended to study the effects of a specific pt intervention on outcome measures in patients with cmt. ogata h , fujita a , yamasaki r , matsushita t , kira ji . department of neurology, neurological institute, graduate school of medical sciences, kyushu university, fukuoka, japan. clinical features of chronic inflammatory demyelinating polyneuropathy (cidp) patients with autoantibodies against neurofascin (nf) , one of the paranodal proteins, have been elucidated while the relation between anti-nf antibody levels and long-term clinical course in these patients still remains elusive. we retrospectively collected clinical, electrophysiological and immunological data of three anti-nf antibody-positive cidp patients. they were all males and their ages at onset were , , and years old. their clinical severity was evaluated by deep tendon reflexes (dtrs), grip strength and hughes functional scale. anti-nf antibody levels were measured by flow cytometry using hek cell lines stably expressing human nf . after immunotherapies of various combinations, including intravenous immunoglobulin, plasmapheresis, corticosteroids and other immunosuppressants, were introduced, their clinical parameters were gradually improved. decreased or absent dtrs were normalized and grip strength was increased by more than kg. hughes functional scale scores were decreased by at least one point compared with those at nadir. ncs findings of all three patients also showed obvious amelioration. for example, their f wave latencies in the right ulnar nerve were improved from to ms, from to ms, and from to ms, respectively. anti-nf antibody levels after treatment were decreased in two patients whose pre-and posttreatment sera were available. when dose of oral prednisolone was being tapered, they experienced re-exacerbation of clinical parameters, especially dtrs and grip strength. their ncs findings and serum anti-nf antibody levels were also deteriorated. exacerbation of these laboratory data in one patient preceded his clinical fluctuation, which suggests that ncs and serum anti-nf antibody levels could be used as early disease activity markers. in this case series, not only clinical but also laboratory data support a notion that anti-nf antibody-positive cidp patients were reactive to combined immunotherapies including corticosteroids. even though various treatments were administered to them, efficacy of oral corticosteroids seemed to be dose-dependent. optimal disease activity markers and immunotherapies for long-term maintenance of remission in anti-nf antibody-positive cidp should be identified. evaluated by deep tendon reflexes (dtrs), grip strength and hughes functional scale, after starting immunotherapies, ohnmar o , kamyw , ng lfp , t umapathi . university of medicine , yangon, myanmar; singapore immunology network, a*star, singapore; national neuroscience institute, singapore. singapore's zika virus (zikv) outbreak started in late august . over a period of months, we studied patients enrolled into our institution's prospective guillain-barré syndrome (gbs) database for relationship to zikv infection. we also studied gbs controls that were seen before the established outbreak and non-gbs controls. the index cases tested negative for zikv pcr in blood and urine. we proceeded to test zikv igg, igm, dengue virus (denv) igg and igm, and neutralization assays against zikv and denv. one patient with anti-gq b igg positive miller fisher syndrome had detectable zikv igm and zikv igg. the serum showed low titre denv igm and denv igg. follow-up serum at about months showed increase in zikv igg. we believe this patient has zikv-gbs. one patient with acute motor sensory axonal neuropathy and another with acute inflammatory demyelinating polyneuropathy had high zikv igm but low denv igm and igg. another patient with mfs showed high levels of zikv and denv igm but low igg. the latter two patients had gbs before the zikv outbreak in singapore. we suspect these patients could have zikv-gbs, but are awaiting convalescent sera for confirmation. two patients seen during the outbreak had detectable levels of zikv igg but serial testing showed a decline after a period of - months. the initial and follow-up sera showed raised denv igm and igg levels in one and raised igg levels in the other. in addition, both had stronger neutralizing capacity against denv than zikv suggesting that the initially detectable zikv igg levels was due to cross reactivity with previous denv infection. four patients, gbs control and non-gbs controls also showed serological response consistent with previous exposure to denv. one normal control showed nil exposure to both viruses. in summary, using various overlapping serological methods we diagnosed definite and suspect zikv gbs cases. our findings highlight ) insensitivity of blood and urine pcr to diagnose zikv-gbs ) the problems of interpreting zikv serology from cross-reaction with denv ) serial serology increases diagnostic accuracy. okar sv , ergunay k , bekircan-kurt ce , , erdem-ozdamar s , , tan e , . department of neurology, hacettepe university, ankara, turkey; virology unit, department of medical microbiology, hacettepe university, ankara, turkey; neuromuscular disease research laboratory hacettepe university, ankara turkey. guillain-barré syndrome (gbs) is an acute monophasic immune-mediated polyradiculoneuropathy. it is believed that acute inflammatory demyelinating poliradiculoneuropathy is caused by t-cell mediated autoimmune response targeting peripheral nerve myelin. molecular mimicry plays a role in the pathogenesis of some gbs cases. this mechanism has been well demonstrated in the acute motor axonal neuropathy (aman) variant, in which autoantibodies to camphylobacter jejuni share epitopes with peripheral nerve gangliosides. this molecular mimicry mechanism can be attributed to some cases with atypical triggers such as zika virus or west nile virus infections. moreover there are accumulating clinical data for vector borne viral infections triggering gbs. we evaluated vector-borne viral infections in our gbs and aman patients. eight patients with gbs, two patients with aman and as a control group, seven patients with normal pressure hydrocephalus were included. gbs and aman was diagnosed with clinical, electroneuromyograpic and cerebrospinal fluid (csf) findings. cerebrospinal fluid serum and urine samples were examined for vector borne viral infections via generic flavivirus and phlebovirus pcr. we also documented our patients prognostic scores such as modified erasmus gbs outcome score (megos) and modified erasmus gbs respiratory insufficiency score (megris). the mean age of the patients was , ( - years) , six of them were female. all csf, serum and urine samples of our patients and control patients were negative for flavivirus and phlebovirus families. the preliminary results of our study in this our small cohort did not show any correlation between the vector-borne viral infections and gbs. further studies with broad number of patients are needed for more suggestive results. neuromyotonia (nmt) consists of spontaneous motor unit activity that reflects increased peripheral nerve excitability, leading to involuntary, persistent muscle activity, visible as muscle twitching at rest, with generalized, easily provoked cramps. since the first electrophysiological (emg) description of nmt by denny-brown and foley ( ) , there has been discussion about the origin of the abnormal electrical activity recorded in needle emg studies. we studied two patients. patient 's nmt is aggravated by cold, and he has an associated non-progressive mild polyneuropathy with demyelinating features. he is now -year-old and has been followed in our centre for years. he is negative for anti-vgkc antibodies. firstly, he was treated with carbamazepine and phenylhydantoin with poor response, but he has shown major improvement on intravenous immunoglobulin (ivig) during the last years. patient is a year-old man with nmt, followed for year, with high titters of anti-vgkc antibodies ( pmol/l; normal< ). he improved on ivig during the last months. screening for neoplasia was unremarkable in both patients (negative anti-neuronal antibodies, in particular anti-hu, anti-yo and anti-ri antibodies; normal computerized tomography scan of the chest and abdomen). in addition to routine studies, we tested synchronicity to spontaneous discharges in different motor units in simultaneous recordings made with two needle electrodes in the first dorsal interosseus muscle. time-locked fasciculations in these double recordings would represent abnormal ectopic activity initiated in a nerve trunk with ephaptic stimulation of a nearby axon. in patient , this research protocol was applied once, years after regular ivig treatment. patient was investigated before and year after ivig. both patients improved after ivig, mirrored by a striking decrease in the amount of spontaneous activity on emg. moreover, our technique did not detect synchronous spontaneous activity (time-locked fasciculations) on the second assessment, although this was predominant before treatment in patient . in nmt, abnormal discharges originate both in distal axonal branches and in more proximal segments. it appears that ivig is more effective in blocking antibody activity in proximal axonal segments, perhaps related to factors such as blood-nerve barrier, temperature or differing ion channel distributions. celiac disease (cd) is a chronic, multisystem and immune-mediated disorder characterized by small-bowel sensitivity to dietary gluten in genetically predisposed individuals. neurological manifestations may occur in about % of patients, including peripheral nerve involvement. recent growing evidence strongly suggests that peripheral neuropathy in cd may be autoimmune and associated with anti-ganglioside antibodies. a -year-old woman presented with slowly progressive weakness of her right hand and fingers extensors. medical and family history were unremarkable. on examination, muscle strength (medical research council-mrc) was scored for right wrist and finger extensors, for right abductor pollicis longus and for right ankle dorsiflexion. right triceps brachii and brachioradialis reflexes were weak, but normal elsewhere. the remainder of the neurological examination was normal. neuroaxis magnetic resonance was unremarkable, specifically with no gadolinium-enhancing lesions. motor and sensory nerve conduction studies were normal. no conduction block or abnormal temporal dispersion was found. needle electromyography showed severe neurogenic changes with abnormal spontaneous activity in right radial-innervated muscles, and chronic neurogenic changes in homolateral tibialis anterior, peroneus longus and extensor digitorum brevis. ganglioside antibody testing was positive to igg anti-gm antibody, but negative to anti-gm and other anti-ganglioside antibodies. additional blood tests were unremarkable, in particular cryoglobulin testing was negative. intravenous immunoglobulin improved weakness, as right extensors of the wrist and fingers scored (mrc). a monthly treatment was initiated, which after months was changed to every weeks to preserve function. a diagnosis of mama was established. later, cd was diagnosed in her daughter due to chronic diarrhoea. our patient underwent anti-tissue transglutaminase antibodies determination and small-bowel biopsy after years disease' duration, and a diagnosis of cd was made. gluten-free diet was started, but her neurological picture did not change after six months. in our case the presence of igg anti-gm antibody may support a causal link between mama and biopsy-confirmed cd, and the lack of response to gluten-free diet may be explained by chronic axonal injury induced by memory t-cells. this case broadens our knowledge about neurological manifestations in cd, raising a probable association with purely axonal multifocal motor neuropathies and anti-ganglioside antibodies. Õunpuu s , , pogemiller k , acsadi g , pierz k , , . center for motion analysis, connecticut children's medical center, farmington, ct, usa; school of medicine, university of connecticut, farmington, ct, usa; division of neurology, connecticut children's medical center, farmington, ct, usa; division of orthopaedics, connecticut children's medical center, farmington, ct, usa. orthopaedic surgical intervention of the foot and ankle is performed in persons with charcot-marie-tooth (cmt) for improving foot pain, ankle instability, orthosis fitting/comfort issues and shoe wear. the impact of these surgeries on ankle function during gait is not known. therefore, the goal of this study was to measure gait changes in ankle function following surgical intervention by means of computerized motion analysis. fourteen patients with cmt ( ± years pre and ± years post-operative) with bilateral orthopaedic surgery were included. all patients had a plantar fascia release plus some combination of other soft-tissue (posterior tibialis and tendo-achilles lengthenings; extensor hallucis longus, peroneus longus and anterior tibialis transfers) and bony procedures (metatarsal and cuboid osteotomies). all patients completed two gait analyses (pre and on average . years post-surgery) during barefoot walking using a standardized d motion analysis protocol. the changes in ankle kinematics and kinetics and temporal-spatial parameters were analyzed in reference to a control group of patients with cmt without intervening surgeries with . years between gait analyses as well as normal reference data. the surgical group showed a significant increase in height between the pre and post-operative analyses and no changes in walking velocity (pre: ± , post: ± , normal: ± cm/sec). similarly, the ankle kinematics and kinetics showed no changes as a result of surgery. however, there was a trend for increased peak ankle dorsiflexion (pre: ± , post: ± , normal: ± degrees). as in the surgical group, the control group showed an increase in height but no simultaneous increase in walking velocity (test : ± , test : ± cm/sec). the control group also showed no changes in ankle kinematics and kinetics suggesting that the impact of the disease is, for the most part, not noticeable over . years. the results show that surgical intervention that primarily addresses foot alignment does not negatively impact ankle kinematics and kinetics during gait. the comparison with the control group supports this finding. however, there are some other findings such as the increase in peak dorsiflexion during stance in some patients that will need to be examined further in larger cohorts. Õunpuu s , , pogemiller k , pierz k , , , acsadi g , . center for motion analysis, connecticut children's medical center, farmington, ct, usa; school of medicine, university of connecticut, farmington, ct, usa; division of orthopaedics, connecticut children's medical center, farmington, ct, usa; division of neurology, connecticut children's medical center, farmington, ct, usa. ankle-foot-orthoses (afos) are commonly prescribed for patients with charcot-marie-tooth (cmt) to improve gait and reduce ankle instability and falling. there are no studies that examine bracing outcomes using objective evaluations. the purpose of this study was to examine the impact of various afo designs on gait parameters in children and adolescents with cmt. we predicted that the afos would improve excessive and delayed peak dorsiflexion in stance and equinus in swing. fifteen patients (mean age ± years) were analyzed barefoot and with their prescribed afos by means of a standardized motion analysis protocol. a full clinical examination was also completed including strength and passive range of motion measures. the afos included solid, hinged and posterior leaf spring (tapered, less supportive) designs. sagittal plane ankle kinematics and kinetics and temporal-spatial parameters were analyzed in comparison to normal controls. walking velocity improved from ± to ± cm/sec demonstrating the functional benefits of afos. ankle plantar flexion angle at initial contact improved from − ± to − ± degrees demonstrating improvement in drop foot in swing and at initial contact reducing the risk of tripping. however, the degree of peak ankle dorsiflexion in stance remained the same and excessive at ± degrees barefoot and ± degrees with afos suggesting that in many patients the afo design was not sufficiently supportive. peak ankle plantar flexor moment showed improvement from . ± . to . ± . nm/kg highlighting the improved base of support provided by the afos that compensate for ankle plantar flexor weakness. however, peak power generation was reduced from . ± . to . ± . w/kg indicating that some of the available ankle strength was impeded with the afos. the results of this study suggest that orthoses can provide improved gait outcomes which will improve overall function. however, there are individual differences in patient impairment (strength, range of motion and bony deformity) and associated gait presentation that need to be accounted for in afo design. afos do not always function as intended due to the complex interaction between patient impairment, orthosis stiffness and orthosis design. motion analysis can assist in identifying the specific afo needs for an individual with cmt. painous c , lópez-pérez ma , illa i , , querol l , . neuromuscular diseases unit, neurology department, hospital de la santa creu i sant pau, barcelona, spain; hospital san pedro, logroño, la rioja, spain; centro para la investigación biomédica en red en enfermedades raras (ciberer), madrid, spain. chronic inflammatory demyelinating polyradiculoneuropathy (cidp) is an autoimmune neuropathy with a heterogeneous clinical spectrum. specific autoantibodies define different clinical phenotypes. cidp with nf antibodies constitutes a specific cidp subset in which a high incidence of postural and intention tremor has been described and that responds poorly to immunoglobulins. we report a patient with an anti-nf positive cidp that presented head, voice and limb tremor that improved with immunotherapy. a -year-old man with unremarkable medical history, presented at the age of with progressive distal weakness and paraesthesia. numbness, gait ataxia and action tremor involving voice, head and limbs appeared sequentially. the emg showed features of acquired demyelination fulfilling cidp diagnostic criteria. a first course of intravenous immunoglobulins was ineffective. the weakness, ataxia and tremor worsened significantly, needing two walking aids first and becoming wheelchair bound later on. he received six plasmapheresis cycles that were also ineffective and oral corticosteroids ( mg/kg) were started with mild improvement. after corticosteroid tapering the patient developed a severe relapse and was referred to our centre. five plasma exchange cycles followed by rituximab ( mg/m , doses) were added to the corticosteroids. three months later the weakness, ataxia and tremor, including the head and voice tremor, started to improve significantly. six months later the patient presented a significant improvement and was able to walk unaided. the anti-nf antibody titres fell from / pre-rituximab to be undetectable. limb tremor is known to occur in patients with inflammatory neuropathies and, specifically in anti-nf + cidp patients but, to our knowledge, this is the first report of a cidp patient presenting with head and voice tremor ever reported. the improvement of tremor with immunotherapy strongly suggest that anti-nf autoantibodies are involved in its pathogenesis, expanding the phenotype of anti-nf specific clinical features. palaima p , peeters k , l. pelayo-negro a , garcía a , gallardo e , garcía-barredo r , de vriendt e , infante j , berciano j , jordanova a . vib and university of antwerp, center for molecular neurology, molecular neurogenomics group, antwerp, belgium; university hospital "marqués de valdecilla", santander, spain. charcot-marie-tooth disease type g is an autosomal dominant and slowly progressing inherited neuropathy which was first described over years ago. it has been attributed to a single spanish family consisting of individuals with affected members spanning four generation. initially, the genetic defect was linked to a . mb region in q -q . . however, extensive sequence and structural variant analyses using whole genome sequences (wgs) of three affected individuals did not reveal any known or novel genetic causes within the region. over the last decade, serial clinical re-evaluation of the entire pedigree was performed leading to changes to the affection status of seven individuals redefining the disease-linked region to chr q . -q . (z max = . at theta = ). additional family members were then submitted for whole exome sequencing. this has led to the identification of a novel missense variant in the e ubiquitin-protein ligase lrsam (p.cys tyr) that was previously not covered by wgs. the variants co-segregated with disease and were absent from controls. other mutations that are known to disrupt the ring domain of lrsam have been previously reported to cause both autosomal dominant and recessive cmt type p (cmt p). unlike prior reports, we demonstrated that the mutation does not influence overall protein levels of lrsam , nor of its ubiquitylation target tsg in patient derived lymphoblasts. transcriptomics analysis identified significant upregulation of another e ubiquitin-protein ligase (nedd l) and of a key regulator of axonal degeneration (tnfrsf ). notably, magnetic resonance imaging of lower-limb musculature systematically showed fatty atrophy in both clinical and subclinical mutation carriers emphasizing its use for the identification of mildly affected members. our findings demonstrate that the isolated genetic entity cmt g is caused by a missense mutation in lrsam and should be reclassified as cmt p. moreover, we reveal novel molecular players associated with lrsam dysfunction, and highlight pathways and therapeutic targets shared with amyotrophic lateral sclerosis and alzheimer disease. damage to peripheral nerves is a prerequisite for neuropathic pain. however, it remains unclear why some neuropathy patients have pain, but others with identical nerve conduction, qst and ienfd do not. we propose to examine the distribution of trpv and its co-localization with cgrp and sp in epidermal nerve fibers in patients with and without neuropathic pain. we aimed to define the expression pattern of trpv in normal healthy subjects first, and study the co-localization of trpv with cgrp and sp in normal controls and patients with painful neuropathy. skin biopsies from neuropathy patients and normal subjects were utilized. anti-trpv antibody generated in our university with support from ninds-funded dept. of neuroscience monoclonal core (ns ) was used. combined immunohistochemistry were performed to identify co-expression of trpv with cgrp, sp and pgp . . the distribution of trpv in controls revealed a proximal to distal gradient similar to that observed for ienf labeled by pgp . . trpv staining was more intense in nerve terminals in the epidermis. combined immunostaining revealed that % of pgp . labeled fibers in the epidermis were trpv +, while % of cgrp+ fibers trpv +. patients with pain had a higher density of trpv + fibers compared to that of patients with numbness. a greater proportion of cgrp+ fibers ( %) in the painful patients were trpv +. expression of trpv in controls exhibits a distal to proximal gradient. trpv expression and co-localization with cgrp were altered in neuropathic pain patients, suggesting that this receptor plays an important role in pathological states. activation of the nop-receptor (nop-r) by its endogenous ligand nociceptin/orphanin fq or non-peptide agonists modulates nociception and analgesia in neuropathic pain models. the wide distribution of nop-r and its endogenous ligand represents an attractive treatment target. since pain is the most prominent feature in pc, we defined expression of the nop-r in plantar skin biopsies and assessed whether alterations exist in pc-affected vs pc-unaffected and anatomically matched control skin. skin biopsies from k a pc and control subjects were immunohistochemically stained for nop-r. combined immunostaining for nop-r with pgp . , neurofilament h (nfh) and cgrp was used to define nop receptor expression in the epidermis and upper dermis. robust nop-r was detected in epidermal keratinocytes and a subset of pgp . + fibers in both epidermis and dermis. staining was inhibited through pre-incubation with a nop-r blocking peptide and western blot analysis using homogenized human skin tissue demonstrated a band at ∼ kd consistent with nop-r molecular weight. nop-r expression occurred in dermal nfh+ a beta-fibers in all groups though no cgrp+ fibers co-expressed nop-r. pc-affected skin had slightly lower nop-r expression than in pc-unaffected skin and a similar pattern in anatomically matched locations from healthy control subjects was observed. nop-r is expressed in human plantar skin epidermal keratinocytes as well as a subset of epidermal and dermal nerve fibers. these fibers are pgp . +, cgrp-and many co-express nfh. nop receptor is a viable pharmaceutical analgesic target in pc patients irrespective of its slight down-regulation as compared to pc-unaffected skin. this work was supported by grünenthal gmbh. pareyson d , stojkovic t , leonard-louis s , reilly mm , laurà m , parman y , battaloglu e , tazir m , bellatache m , bonello-palot n , sacconi s , guimarães-costa r , attarian s , latour p , megarbane a , schenone a , ursino g , sabatelli m , luigetti m , santoro l , manganelli f , quattrone a , valentino p , murakami t , scherer ss , dankwa l , shy me , bacon cj , herrmann dn , pisciotta c , previtali s , bolino a . milan, italy; paris, france; london, united kingdom; istanbul, turkey; algiers, algeria; marseille, france; nice, france; lyon, france; genoa, italy; rome, italy; naples, italy; catanzaro, italy; kurashiki, japan; philadelphia, usa; iowa city, usa; rochester, usa. cmt b and b are characterized by recessive inheritance, early onset, severe course, slowed nerve conduction, myelin outfoldings, association with loss-of-function mutations in myotubularin-related protein- and − (mtmr , mtmr /sbf ), respectively, involved in the metabolism of ptdins p and ptsins( , )p phosphoinositides, key regulators of membrane trafficking. in a multicentre retrospective study to better characterise cmt b, we collected a minimal dataset of information including cmtes/cmtns on cmt b patients, cmt b ( unrelated families) and cmt b ( families). cmt b patients were younger and with earlier onset than cmt b : last visit was performed at a mean age of years (sd . ; range - ) for cmt b and years ( . ; - ) for cmt b ; disease onset occurred at a mean age of . years ( . ; - ) in cmt b as compared to . years ( . ; - ) in cmt b ; delay in motor milestones occurred in / cmt b and / cmt b subjects. eleven cmt b patients became chair-bound, whereas all cmt b subjects but one are still ambulant, although with afos for patients and requiring unilateral support in two cases. both disease types are characterised by vocal cord involvement ( / cmt b and / cmt b ); respiratory involvement was seen almost exclusively in cmt b patients (n= , four requiring non-invasive ventilation and one tracheostomy, as compared to one cmt b patient on niv at age ); two cmt b subjects and an affected cmt b relative not included in the present study died of respiratory complications. glaucoma (n= ) and buphthalmos (n= ) occurred only in cmt b . cmtes/ cmtns scores were higher in cmt b patients in spite of their younger age, indicating more severe disease: cmt b = cmtes mean . (n= ; sd . ; range - / ), cmtns mean . (n= ; sd . ; range - / ,; cmt b = cmtes mean (n= ; sd . ; range - / ), cmtns mean (n= ; sd . ; range - / ). our data confirm that cmt b is more severe than cmt b . interestingly, mtmr interacts with mtmr . mtmr is a catalytically active phosphatase, whereas mtmr is a catalytically inactive protein, known to increase mtmr enzymatic activity. thus, in cmt b nerves a residual enzymatic activity of mtmr may result in a less severe clinical phenotype as compared to cmt b . the charcot-marie-tooth disease (cmt) national registry is fully operative (https:www.registronmd.it) with collection of clinical/genetic information (minimal dataset) and reporting of clinical scales; cmt patients have registered thus far and have chosen one of the reference centers; information collected during the ad hoc visit have been entered in the registry for of them. registered patients have the chance to participate to a study that requires filling online self-reported questionnaires related to five important issues: disease course and complications during pregnancy; use, efficacy and tolerability of orthotics and assistive devices; outcome of surgery for skeletal deformities; safety of anesthesia; occurrence of sleep disorders (including evaluation of fatigue, anxiety and depression). by february , patients and relatives/friends (as healthy controls) have filled the questionnaires. we are performing a first explorative analysis of results, but data collection on all questionnaires will be prolonged until novemebr , , to obtain a larger sample. pregnancy: / cmt women had at least one pregnancy; complications ranging from mild to severe occurred in / pregnancies vs / in controls. cmt worsened in pregnancies ( patients) with no recovery in instances. prenatal diagnosis was performed in / pregnancies. satisfaction related to surgical procedures for foot deformities, assessed with vas (score - ), was . ± . (n = ). repeat surgery was required in / instances. sleep: the epworth sleepiness scale questionnaire revealed abnormalities of sleep in / cmt patients ( %) and in / controls ( %). the vast majority of cmt subjects ( / ; mean . ± . ), but also of controls ( / ; . ± . ) were not good sleepers according to the pittsburgh sleep quality index (psqi) (range - , good sleep). fatigue: scores of modified-fatigue impact scale (range - , no fatigue) were higher for cmt (mean ± . ) than controls (mean . ± . ). hospital scale for anxiety and depression: / cmt subjects had mild-to-severe anxiety and / mild-to-severe depression as compared to / and / controls, respectively. data analysis on orthotics and anesthesia is ongoing. in conclusion, the first data analyses confirm that there are problems related to all the five domains explored, that will need to be specifically addressed in patients' care. supported by telethon-uildm grant gup . charcot-marie-tooth disease (cmt) is the most frequent motor and sensory peripheral neuropathy and is known to have the uniform demyelination. the traditional definition of conduction block is the reduction of negative peak of compound muscle action potential (cmap) of proximal segment relative to adjacent distal segment more than %. in this study, we tried to find the frequency of conduction block in cmt a patients and to investigate the differences of the clinical manifestation. we enrolled unrelated cmt a patients ( males and females) with pmp duplication and undertook nerve conduction studies from to . stimulation sites were wrist, elbow and axilla for median nerve study. eleven patients ( . % of all enrolled patients) had ncs features suggestive of conduction block. compared to cmt a patients without conduction block, functional disability scale was significantly higher in cmt a patients with conduction block (p < . ). however, onset age and disease duration were not different between cmt a patients with and without conduction block. in addition, conduction block was more frequently observed in distal segments than proximal segments. we suggest that the frequency of conduction block in cmt a patients is not low, and there is some heterogeneity of demyelination in cmt a patients. also, in cmt a patients, the conduction block might have relationship with clinical disability. park jg , park ms . yeungnam university college of medicine, daegu, korea. the subacute combined degeneration (scd) is diagnosed by a characteristic clinical manifestation, spinal mri, and decreased serum vitamin b levels. we report a case of scd with elevated homocysteine and methlymalonic acid level in the situation of spurious elevation of vitamin b concentration. an years old man presented with progressive gait disturbances and sensory disturbances. about a year ago, he felt both hands and feet paresthesia and gait disturbances. four months before the visit, nerve conduction tests were performed elsewhere due to symptoms. polyneuropathy was found. the laboratory test showed megaloblastic anemia. however, serum vitamin b concentration was increased to pg / ml (normal: - pg / ml). his symptoms progressed gradually. at presented, neurological examination showed spasticity of the lower limb without weakness, and vibration and position sensation were decreased in both lower limbs, and showed ataxic gait. spinal cord mri showed a lesion with a long t high signal intensity from c to t in the posterior column of the spinal cord. further laboratory test were added, then while folate was normal level but homocysteine at . umol/l (normal: - umol/l), and methylmalonic acid at . um / l (normal: - . um / l) were increased. finally, scd caused by vitamin b deficiency was diagnosed. in addition, gastric endoscopy was performed to find the cause of vitamin b deficiency and chronic atrophic gastritis was found. after cobalamine treatment for months, hemoglobin level was improved and his symptoms were all improving with a little gait disturbances. false-elevation of vitamin b level could lead to delayed diagnosis and cause irreversible changes in the nervous systems. one of the most commonly used methods to measure vitamin b concentrations is competitive-binding assay, which may result in normal levels even with vitamin b deficiency due to the effect of anti-intrinsic factor antibodies. when vitamin b deficiency is suspected, even if the vitamin b concentration is normal, additional tests of homocysteine and methylmalonic acid should be considered. parman y , durmus h , deymeer f , oflazer-serdaroglu p , battaloglu e . istanbul university, istanbul faculty of medicine, department of neurology, istanbul, turkey; bogazici university, istanbul, turkey. hereditary motor and sensory neuropathies, also called cmt neuropathies, are the most common group among the hereditary neuropathies. cmt subtypes are grouped by axonal, demyelinating or intermediate phenotype, or by autosomal-dominant (ad), autosomal-recessive (ar) or x-chromosomal inheritance. cmt- is considered axonal and characterized by distal muscle wasting, mild sensory loss and normal or near-normal nerve conduction velocities. mutations in more than genes are known to be able to cause autosomal dominant (ad) or recessive (ar) cmt- to date. the genetic heterogeneity in charcot-marie-tooth (cmt) is a challenge for genetic diagnostics. clinical clues and frequencies of mutations in cmt genes from large cohorts may help to develop strategies for efficient genetic testing. here, we present the clinical, electrophysiological and genetic features of patients from turkey, diagnosed as genetically confirmed cmt- in the department of neurology, istanbul faculty of medicine our clinic between and . genetic testing was performed for gdap by dna sequencing and samples from patients were exome sequenced (wes). twenty-one male and ten female patients from unrelated families were investigated. segregation was ar in eight, ad in six families and two were isolated cases. intraand interfamilial variability in the age of onset with a range of - (mean . ± . years) and disease progression rate were striking. slowly progressive weakness and atrophy of distal muscles in the feet and/or hands were the most common presenting symptoms. mfn was found in four unrelated ad kinship and in unrelated ar kinships and was most common gene mutated among whole cohort. gdap was the most commonly mutated gene among ar families ( / ). wes revealed further mutations in aars, nefl, kif b and hspb , however, the causative mutation could not be identified in known cmt genes in about % of patients. our data indicates the marked intra-and inter-familiar phenotype variability in cmt- as previously described in literature. many more genes causing arcmt- remain to be discovered. pasnoor m , veerapaneni k , murphy r , statland jm , kimple d , hamasaki a , glenn md , herbelin l , barohn rj , jawdat o , dimachkie mm . department of neurology, neuromuscular division, the university of kansas medical center, kansas city, ks, usa. electrodiagnostic (edx) studies involving electromyography/nerve conduction study (emg/ncs) are useful for diagnosis of neuromuscular disorders. although these are safe procedures, emg and ncs often evoke anticipated pain and anxiety. there are no published research studies to support the notion that providing detailed information to patients prior to these procedures would reduce procedural pain and ameliorate anxiety levels afterwards. the objective of this study was to perform a prospective survey to assess anticipated pain and anxiety in patients presenting for edx studies, design a detailed patient education form, and assess the change in perceived pain and anxiety pre and post procedure in the standard of care (soc) education versus the printed detailed education instrument group. after completing a brief pain/anxiety questionnaire, patients were randomly assigned to either soc verbal education group or to read the detailed education form. another brief questionnaire was completed post procedure. seventy-eight patients were enrolled at the time of abstract submission, in intervention and in soc groups. mean age of patients enrolled was ± years. pain was anticipated by % patients as a visual analog scale (vas) score mean of . ± . with no significant difference between both groups (p= . ). post-procedural pain was reported in % of patients with mean pain score of . ± . and no significant difference between the two groups (p= . ). anxiety pre-procedure was reported by % patients with a mean likert-like score of . ± . score in all cases (p= . between both groups). post-procedural anxiety frequency was reduced to % with mean level of . ± . (p= . between both groups). most patients reported pain with both emg and ncs ( %). we found that edx testing evokes moderate pain in most and in some cases moderate anxiety level. the detailed education intervention did not attenuate the frequency or severity of pain. post-procedural anxiety was expectedly reduced in severity and frequency in both groups with a suggestion that anxiety severity is lesser in the detailed education group but numbers were small. further studies with more detailed questionnaire and perhaps web-based education in larger population may be useful to reduce pain/anxiety in patients presenting for edx studies. pasnoor m , roach c , barohn rj , statland j , jawdat o , dick a , glenn m , dimachkie mm . department of neurology, neuromuscular division, the university of kansas medical center, kansas city, ks, usa. diagnostic criteria for chronic inflammatory demyelinating polyneuropathy (cidp) have been designed for use in clinical trials. there is limited data on the comparative diagnostic utility of these criteria in the clinic setting and it is unknown if some of these criteria are better for predicting treatment response. the objective of this study is to compare the sensitivity of various diagnostic criteria and review treatment response. after obtaining local irb approval, we performed a retrospective chart review of cidp patients seen at the university of kansas medical center between and . we abstracted the clinical, electrodiagnostic, and treatment information. we determined the frequency of patients fulfilling each of the following criteria: efns , aan, saperstein and incat. we defined treatment response based on treating physician's impression of change, patient-reported functional improvement or one point grade change in the mrc grade. fifty-three cidp patients charts were reviewed, were excluded due to missing data. mean age was . , and ( %) were female. elevated csf protein was seen in / ( %). twenty-eight ( %) fulfilled efns definite criteria, ( . %) efns probable, ( . %) aan, ( . %) incat, and ( . %) the saperstein criteria. treatment response in patients who fulfilled efns definite/probable criteria included / to ivig, / to iv or oral corticosteroids, / to mycophenolate mofetil; among patients who fulfilled aan criteria, these were respectively / , / and / ; among those meeting incat criteria / , / and / ; and for saperstein criteria it was / , / and / . half to two-thirds of patients responded to plex based on different criteria. while all cidp criteria can similarly predict ivig treatment response, the efns criteria are most sensitive for the clinical diagnosis of cidp. pellegatta m , canevazzi p , forese mg , podini p , quattrini a , taveggia c . division of neuroscience and inspe, axo-glia interaction unit, san raffaele scientific institute, milan, italy; division of neuroscience and inspe, experimental neuropathology unit, san raffaele scientific institute, milan, italy. axonal nrg type iii is an essential instructive signal for pns myelination, since its expression determines whether axons are myelinated and also the thickness of the myelin sheath. previous studies have shown that secretases' cleavage controls nrg type iii activity at post-transcriptional level. specifically, the beta-secretase bace- cleavage of nrg type iii promotes myelination, whereas the alpha-secretase tace inhibits pns myelination by inactivating nrg type iii. after a damage, the axon located distally to the site of injury degenerates and loses the myelin sheath, following a process termed as wallerian degeneration. unlike the cns, axons in the pns can regenerate and regrow. several studies have shown that regeneration is favored by the trans-differentiation of schwann cells, which start to create a permissive environment for axonal regrowth. in addition, it has been shown that nrg regulates the early stages of the dedifferentiation process and is essential for creating a permissive environment to regeneration. similarly, the beta secretase bace- promotes pns regeneration and remyelination. in the present study, we analyzed the role of the alpha-secretase tace during wallerian degeneration. our data indicate that tace is upregulated in sciatic nerves after injury, distally to the site of damage. since tace is expressed in schwann cells and axons, we analyzed the role of both glial and neuronal tace during degeneration and regeneration processes. thus, we performed crush injury in sciatic nerves of two different transgenic lines carrying a conditional deletion of tace either in schwann cells (p -cre//tace flox/flox ) or in neurons (chat-cre//tace flox/flox ). the analyses of the different phases of the wallerian degeneration in these animals suggest a role of glial tace during the early stage of the process. in fact, we observed an increased number of myelinated axons only in p -cre//tace flox/flox mice, while we did not detect substantial differences in mutant chatcre//tace flox/flox mice. these results suggest that even during regeneration tace has an inhibitory role, as deletion of tace in schwann cell likely induces the activation of a neuro-protective program that we are currently investigating. péréon y , nizon m , küry s , besnard t , quinquis d , boisseau p , magot a , mussini jp , mayrargue e , barbarot s , bézieau s , isidor b . reference centre for neuromuscular disorders; dept. of genetics; dept. of paediatric surgery; dept. of dermatology, university hospital, nantes, france. the hereditary sensory and autonomic neuropathies (hsan) constitute a clinically and genetically heterogeneous group. hsan are associated with sensory dysfunction, altered pain and temperature perception with varying degrees of autonomic dysfunction, and abnormal small fibers neurodevelopment. more than ten genes have been described so far in the hsan group. original classification encompassed four entities, but additional subgroups continue to be described. hereditary sensory neuropathies (hsan) type ii are characterized by autosomal recessive inheritance, onset at birth and self-mutilating behavior. until now, one homozygous frameshift variant, c.[ _ del], p.(lys phefs* ), was reported in arl ip (adprribosylation-like factor -interacting protein ) in a consanguineous family. patients presented with spastic paraplegia, diffuse sensory and motor polyneuropathy and acromutilation. the disorder was classified as autosomal recessive spastic paraplegia spg . here, we described a new patient with congenital insensitivity to pain, sensory neuropathy, self-mutilation, and spastic paraplegia. whole exome sequencing showed a homozygous frameshift variant c. [ _ del], p.(lys phefs* ) in arl ip . the protein harbours reticulon-like short hairpin transmembrane domains and has a role in endoplasmic reticulum shaping. the variant causes an additional c-terminus hydrophobic domain which could alter its function. arl ip interacts with atlastin- responsible for spg a and hsan type d. this report highlights the role of arl ip in pathophysiology of insensitivity to pain and spastic paraplegia. péréon y , nguyen a-l , leclair-visonneau l , fayet g , nguyen j-m , magot a . laboratoire d'explorations fonctionnelles, hôtel-dieu, nantes, france; département de statistiques médicales, hôtel-dieu, nantes, france. carpal tunnel syndrome (cts) is responsible for sensory and/or motor symptoms that may be increased by wrist flexion or extension (phalen sign). previous studies have shown that short duration (e.g. min or less) flexion or extension was not responsible for significant changes of median nerve conduction parameters. the objective is the study was to determine how prolonged extension (reverse phalen's test) affects median and ulnar nerve conduction parameters in normal subjects. after providing informed consent, normal subjects ( females, age rank - years) underwent motor and sensory testing of both median and ulnar nerves from the dominant side. edx testing was performed using standard techniques with wrist in neutral position, then during passive wrist extension ( ∘ ) for minutes, with sequential recording of both motor action potential (cmap) and sensory action potential (snap) latencies and amplitudes every minutes after extension onset. ulnar nerve conduction parameters remained unchanged in all the subjects. regarding median nerve, groups of subjects could be individualized: subjects with no changes; subjects with only significant decrease of snap amplitude (− %); subjects with both snap amplitude and velocity decrease; subjects with both cmap and snap significant changes. when present, changes did not appear before min, with snap decrease being the earliest observed abnormality. prolonged wrist extension was responsible for median nerve edx parameter modifications in / normal subjects. sensory fibers were firstly affected, corresponding to the chronology clinically encountered in cts. based upon these results, the same protocol will be used in patients presenting with mild clinical cts, in order to try and identify an additional edx technique being useful in the diagnosis of cts. one could also wonder whether the subjects with the most important changes would be more prone to present cts in the future. perez-siles g , , drew a , , ellis m , kidambi m , takata r i , speck-martins c e , hagerman k a , siskind c e , day j w , ginzberg m , nicholson g , , , kennerson m l , , . northcott neuroscience laboratory, anzac research institute, sydney, australia; sydney medical school, university of sydney, sydney, australia; molecular medicine laboratory, concord repatriation general hospital, sydney, australia; sarah network rehabilitation hospitals, brasilia, df, brazil; department of neurology, stanford health care, stanford, ca, usa; pediatric neuromuscular unit, wolfson medical center, holon, israel. mutations in the atp a gene cause of x-linked hereditary distal motor neuropathy (dhmnx). to date, missense mutations (t i and p s) in this copper transporting atpase are the only confirmed mutations causing dhmnx in two independent families. next generation sequencing (ngs), including whole exome and whole genome sequencing, is increasing the rapid detection of variants in genes known to cause disease, however the absence and size of additional families, make it challenging to determine the pathogenic or benign status of variants identified. we have recently identified new variants in atp a in patients with progressive peripheral neuropathy, suggesting further genetic heterogeneity of dhmnx. two of these new variants, pe v and pm v, are located at highly conserved amino acids within domains of atp a (a-domain and p-domain, respectively) that are critical for the catalytic cycle of the copper transporter. we have also identified a third variant (c. - a>g) located bases upstream exon that is predicted to abolish a conserved branch-site, a consensus intronic sequence necessary for the processing of immature rna during splicing. our recent investigations using both patient fibroblasts and an atp a conditional knock in mouse model for dhmnx expressing atp a t i , the orthologue of the human atp a t i mutation, showed reduced atp a protein levels and defective retrograde trafficking of atp a, as pathological hallmarks of dhmnx atp a causative mutations. to elucidate if the newly identified pe v, pm v and c. - a>g atp a variants are pathogenic, we have systematically assessed patient fibroblasts harbouring these mutations for altered parameters previously found in the pathogenic t i atp a mutation. we predict that functional characterisation of atp a using patient fibroblasts harbouring newly identified variants will provide the evidence to ascertain whether these variants are disease causing. establishing a systematic functional readout for atp a variants will improve accuracy of genetic counselling and patient management of dhmnx in those cases where genetic evidence is limited. this study represents a complementary and necessary approach to the use of ngs, for validating the pathogenic status of variants identified and for expanding the genetic heterogeneity of dhmnx. month of birth (mob) have been defined as a risk factor for more than diseases. for instance, susceptibility for multiple sclerosis (ms) seems to be associated with being born in may, while lower risk of ms is observed in those born in november. there are no studies that assessed potential association between mob and a risk for guillain-barré syndrome (gbs). we sought to determine if the risk of gbs is associated with the mob. study included gbs patients diagnosed in serbia, montenegro and republic of srpska in the period from january , until december , . mob of patients and of general population were compared. patients with gbs had tendency to be born in october ( % increase compared to general population, p= . ) and were less likely to be born in june ( % decrease, p= . ). when consider specific seasons, gbs patients were more likely to be born in winter months ( % increase, p< . ). no associations were found between month/season of birth and disease severity. results of this pilot study showed that gbs patients are more likely to be born in cold months, and less likely to be born in june. this might be explained by higher exposure to different pathogens during pregnancy in cold months. in accordance with this, it is well known that early exposure to infective agents reduces risk of allergic and autoimmune diseases. further studies are needed to test our findings in different cohorts and in regions with different climate. these results may shed new light on the disease pathogenesis. majority of patients with guillain-barré syndrome (gbs) tend to have a successful recovery, but in number of them significant long-term consequences may negatively affect their quality of life. aim of this research was to analyze the outcome of the disease one year after the acute episode of gbs. among patients diagnosed with gbs in seven tertiary centers in serbia, montenegro and republic of srpska during , subjects were retested after one year ( % males, mean age ± years). functional disability of patients was estimated based on the gbs disability scale (gds). severe form of the disease (gds score - ) was registered in % of patients at admission, % at nadir, and % on discharge. after one year follow-up period, % of patients had no symptoms of gbs, % had mild symptoms, % was able to walk but not to run, % needed unilateral support during walking, while % was wheelchair bound or bedridden. lethal outcome was registered in three patients during acute phase of gbs and in four more during one-year follow-up. paresthesias were present in % of gbs patients, musculoskeletal pain in %, and fatigue in % one year after acute phase of the disease. factors associated with the worse functional outcome (gds grade above ) after one year were: age above , preceding respiratory infection, and worse gds on discharge. one year after the onset of the disease, significant number of our gbs patients had neurological impairments including sensory symptoms, pain, fatigue and muscle weakness which may significantly affect patients' everyday functioning. phetteplace je , saade d , bacon c , shy me . university of iowa hospitals and clinics, iowa city, ia, usa. charcot-marie-tooth (cmt) disease, also known as hereditary motor and sensory neuropathy, is a heritable peripheral neuropathy caused by genetic mutations in many different genes. cmt type a is the most common form of cmt. individuals affected with cmt a commonly have distal muscle atrophy, foot deformities, abnormal gait, and reduced nerve conduction velocities caused by demyelination of the peripheral nerves. cmt a is known to be caused by a duplication of the pmp gene at p . . the proposed disease mechanism of cmt a is believed to be increased gene dosage of the pmp gene, although the exact function of pmp is not known. there have been previous reports in the literature of individuals who carry a homozygous duplication of pmp , therefore having four copies of the gene. however, many of these reports have focused on adult patients who symptoms may not vary significantly from individuals who harbor only a duplication of pmp . a month old male presented to the university of iowa hospital due to a family history of cmt a and concern for delay in independent ambulation. he was known to have both a maternal and paternal family history of cmt a, although the families were believed to be unrelated. on exam he was unable to walk independently, but could take a few steps when his hands were held. per report he began crawling and scooting at months of age. he was not found to have any structural abnormalities or atrophy in his upper or lower extremities. electrodiagnostic testing revealed a demyelinating neuropathy. only one nerve was tested, as the patient was unable to tolerate additional shocks. the peroneal nerve was found to have a nerve conduction velocity of m/s. based on the clinical presentation, electrodiagnostic examination and family history deletion and duplication testing for pmp was performed. this testing revealed a homozygous duplication of pmp , which has been previously reported to cause cmt a. this case supports the gene dosage disease mechanism, as our patient appears to be more severely affected than a typical infant or toddler affected with cmt a. piscosquito g , saveri p , provitera v , stancanelli a , ciano c , magri s , taroni mpz mutations are associated with the demyelinating early-onset charcot-marie-tooth (cmt) type b and with the axonal later onset cmt i/cmt j. paresthesias/dysesthesias and pain have been already reported in some cmt types and also in cmt i/j. we report patients ( from families, sporadic cases,) carrying the mpz c. dela mutation (p.asp thrfster ). this is predicted to be a loss-of-function mutation, leading to p haploinsufficiency. most of the subjects have genetic ancestry from puglia region (southern italy). two patients carried the mutation in homozygosity, showing a severe phenotype: onset at birth, severe scoliosis, proximal weakness, distal limb plegia, no autonomous walking, cmt examination score (cmtes) - / . all the other heterozygous patients had mild adult-onset (mean age , range - ) neuropathy, walked without aids or ankle-foot orthoses, had cmtes < / . five showed mild foot deformities, / had foot and / hand weakness (mrc never less than / ), / sensory loss in lower limbs (ll). paresthesias/dysesthesias (mostly tingling and burning in type) localized in hands and ll were reported by / subjects, neuropathic pain by / . in the homozygous patients, all cmaps and saps were absent. in all other subjects, motor conduction velocities (cv) were > m/s (range - m/s) and sensory cv > m/s (range - m/s). cmaps as well as saps were normal or moderately reduced in amplitude, indicating only slight axonal loss. we confirm that heterozygosity is associated with very mild cmt, whereas homozygosity causes a very severe neuropathy. our data suggest that paresthesias and neuropathic pain are very common and should be considered as part of the phenotype. although the clinical picture suggests a small fiber neuropathy, no such evidence is provided in the current literature. in the attempt to further investigate this field, we found in a -year-old male patient of our series that all thresholds were increased at quantitative sensory testing, and several abnormalities of small nerve fibers were present in skin biopsy. apparently, p aneuplody causes neuropathy and small fiber involvement through a mechanism different from other mpz missense mutations. poitras t , chandrasekhar a , singh v , martinez j , zochodne dw . neuroscience mental health institute, and division of neurology, department of medicine, university of alberta, edmonton, alberta, canada. a microarray mrna analysis of dorsal root ganglia examined in long-term diabetic mice yielded an unexpected upregulation of a unique set of proteins known as major urinary proteins (mups & ). originally, this family of barrel shaped proteins was described as including mediators of pheromone secretion in the urine of rodents, apparently unconnected to other functions. we identified its unanticipated expression in sensory neurons of adult mice and rats and explored its potential impact on the properties of these neurons. analysis of rat and mouse sensory neurons showed widespread and pan-neuronal cytosolic mup expression, not only in the cell body, but also in distal sensory projections located in the dermis of the footpad. to assess the role that mup might offer in the growth behaviour of adult neurons, we examined sirna-induced knockdown of mup on pre-injured dissociated drg primary cultures. mup knockdown in both species showed a significant increase in neurite outgrowth following mup sirna treatment when compared to a scrambled sequence control. mice treated with streptozotocin (stz) model features of human type diabetic polyneuropathy, including decreases in multi-fiber motor and sensory measurements, and changes in thermal sensation in the extremities. to explore the potential role of mup upregulation specifically in diabetes, we examined the impact of non-viral intranasal injection of mup sirna on indices of neuropathy in chronic type diabetic mice. following treatment, mice treated with mup sirna showed improvement in both motor and sensory nerve conduction velocities compared to scrambled controls. taken together, this data suggests that mup plays a growth-suppressive role in both diabetic and non-diabetic neurons and may also contribute to the electrophysiological and behavioral abnormalities associated with diabetic polyneuropathy. the repurposing of mups in sensory neurons identifies an interesting role for a supposed pheromone protein. [supported by cihr, cda and adi] enhancement of their outgrowth properties (singh et al, ) . here we asked whether similar activation, using low dose capsaicin, might similarly ramp up the regenerative activity of sensory neurons. using rat adult primary sensory neurons, we identified a dose dependent relationship between capsaicin exposure and their outgrowth with enhancement at lower doses and expected neurotoxicity at higher doses. doses that enhanced outgrowth were nonetheless associated with rises in intraneuronal calcium. we next tested whether a similar impact of trpv activation in vivo might exist. we used a high sciatic crush injury mouse model to assess the impact of capsaicin at low ( um) or high ( mm) doses applied directly at the site of axon outgrowth after injury. by days following the single application of capsaicin, low doses of capsaicin showed more rapid recovery of thermal, but not mechanical sensation, whereas high dose capsaicin showed no significant difference compared to vehicle treated mice. in parallel with the neurotoxicity observed in vitro, the high dose capsaicin resulted in a decrease in sensory nerve conduction velocity, while the low dose showed no significant difference when compared to the vehicle treated animals. there was no impact on motor axon recovery. taken together, subtoxic trpv activation with intraneuronal calcium mobilization, as applied to regenerating sensory axons, enhances their outgrowth after injury, and improves behavioural recovery similar to that following extracellular electrical stimulation. [supported by cihr] hereditary transthyretin (hattr) amyloidosis is a rapidly progressive, life-threatening disease caused by ttr gene variants, resulting in ttr misfolding and amyloid deposition in multiple organs, including peripheral nerves. hattr amyloid polyneuropathy has prominent small fiber involvement characterized by neuropathic pain and dysautonomia. measurement of intraepidermal and sweat gland nerve fiber density (ienfd, sgnfd) in skin biopsies has been useful in identifying small fiber abnormalities in hattr. we report the effect of patisiran, an investigational rnai therapeutic for the treatment of hattr, over a -month period on ienfd, sgnfd and dermal amyloid content from the phase open-label extension (ole) study. skin biopsies (distal leg, distal thigh) were obtained every months for up to years within the phase ole study (patisiran . mg/kg iv, q w, nct ) and analyzed in a blinded manner by a central laboratory. all analyses are exploratory; nominal p-values are reported without adjustment for multiple testing. twenty-seven patients enrolled; preliminary data indicated patisiran was generally well tolerated; resulted in sustained mean serum ttr lowering of ∼ % for > months and a mean . -point decrease in mnis+ (n= ). twenty-four patients underwent serial skin punch biopsies. at baseline, mean ienfd was . and . fibers/mm, while mean sgnfd was . and . m/mm for distal thigh and distal leg, respectively. amyloid was detected in ∼ % of skin biopsies, mean baseline dermal amyloid content . % and . % for distal thigh and distal leg, respectively, which inversely correlated with ienfd and sgnfd. overall, ienfd was stable throughout the -year treatment. sgnfd increased over time relative to baseline, reaching statistical significance at , , and months for distal thigh (p< . , all time points) and at months for distal leg (p= . ). dermal amyloid content decreased over time and reached statistical significance at , and months for distal thigh (p< . , all time points) and at , , , and months for distal leg (p< . , all time points). in summary, improvements in sgnfd and dermal amyloid content observed over a -year period suggest that these parameters have the potential to serve as biomarkers of response to patisiran treatment. polydefkis m , neuhaus s , doherty l , ebenezer gj . department of neurology, johns hopkins university, baltimore, md, usa. misdiagnosis and delayed identification of an etiology for sensory neuropathies hampers adequate management and delays initiation of therapy. we present several cases that illustrate variable presentations of amyloid neuropathy (an) and an complicated by amyloid arthropathy. a -year-old former college athlete developed painless difficulty walking. he was unable to keep up with family members during routine outings and subsequently was unable to navigate uneven ground during a hike, something he had previously excelled at. balance decreased, making bicycling difficult. neurological evaluation -months after symptom onset led to a diagnosis of peripheral neuropathy. a reversible neuropathy panel was normal though a c was elevated ( . %). over several months, his strength/sensation deteriorated despite diet improvement, losing lbs and a c improvement ( . %). upon referral, emg revealed a sensorimotor neuropathy with markedly reduced/absent sural, peroneal and tibial motor amplitudes. there was mild orthostasis. nis was . skin biopsies revealed severe ienfd, sgnfd reductions and positive congo red staining, confirmed with birefringence. a sural nerve biopsy confirmed amyloid deposits. genetic testing revealed the ttr-fap variant leu his. there was no history or suspicion for a family history of amyloid. a -year-old male with a history of controlled diabetes x years developed abrupt onset of rls months after a lymphoma diagnosis. treatment with rituximab led to radiographic resolution of the lymphoma though the patient developed progressive peripheral neuropathy confirmed by ncv/emg. new-onset early satiety, mild orthostasis and ed emerged. skin biopsies demonstrated a lichenoid pattern of amyloid deposition consistent with aa-amyloid. a -year old woman with leu his ttr-fap since developed progressive leg weakness, reduced ability to walk and low back pain. emg demonstrated progression of her sensorimotor neuropathy and superimposed multilevel radiculopathy. spine mri demonstrated severe lumbar stenosis requiring surgical decompression. postoperatively, she regained strength, walking more easily. congo red staining of vertebral bone demonstrated widespread positive staining with birefringence consistent with amyloid arthropathy. these cases illustrate to wide sprectrum of amyloid neuropathy presentation, an example of amyloid arthropathy-induced spinal stenosis and the utility of skin biopsy to diagnose and manage amyloid neuropathy. the differentiation between hereditary neuropathy and chronic inflammatory demyelinating polyneuropathy (cidp) in children is especially significant because of completely different treatment possibilities and prognosis in these conditions. the aim of the study was to compare electrophysiological abnormalities in a group of children and young adults with demyelinating neuropathy of chronic or subacute onset. retrospective analysis of clinical and nerve conduction study (ncs) data included children and young adults with charcot-marie-tooth neuropathy x type (cmtx ), children with charcot-marie-tooth neuropathy type a (cmt a) and children with cidp. in our study / cmtx had both axonal and demyelinating changes in ncs study. the aan and efns electrophysiological cidp criteria were fulfilled in / cmtx , / cmt a and / cidp patients. additionally patients with cmtx are classified with efns criteria as "probable/possible cidp". a distal compound muscle action potential (dcmap) was > ms in all cmt a and / cidp patients but none with cmtx . abnormal median/normal sural snap (amns) parameter was observed in // cidp and / ctmx patients but not any cmt a patient while abnormal sural/normal median snap (asnm) parameter was found in / patients with cidp. a difference between conduction velocities (cv) of two corresponding nerves > m/s was seen in / cmtx and / cidp patients but no one with ctm a. one patient with cmtx had especially conspicuous difference between nerve conduction in lower limbs, with axonal neuropathy and demyelinating features, and upper limbs with no changes. one -years-old patient with genetically confirmed cmtx had no abnormalities in ncs. electrophysiological data of cmtx , cmt a and cidp indicate diffuse demyelination, however in cmtx axonal changes coexist, seen in / patients, and asymmetrical abnormalities between corresponding upper and lower limb were observed in / patients. our study has showed that duration of dcmap is useful not only in diagnosing an inflammatory neuropathy but also in differentiating cmtx from cidp. however presence of the not homogenous abnormalities in ncs in patients with cmtx may mimic inflammatory neuropathy. prada v , mori l , francini l , accogli s , ursino g , gemelli c , schizzi s , grandis m , bellone e , mandich p , schenone a . department of neurosciences, rehabilitation, ophthalmology, genetics and maternal and child health, university of genoa, genoa, italy. the overwork weakness (ow) problem in cmt disease has been debated for long time. it has been reported that the non-dominant hand (ndh) of patients with cmt disease is stronger than the dominant hand (dh) as a result of ow and some authors verified this hypothesis using mrc on different muscles (van pomeren, ). more recently, piscosquito et al. ( ) found that the ow phenomenon does not exist using a dynamometer and the hole peg test, a dexterity test. we recruited cmt patients and healthy controls. we evaluated the strength of the -pinch and of the hand-grip with a dynamometer, the opposition ability with the thumb opposition test (tot) and applied an instrumental testing of hand function using the sensor engineered glove test (segt), which previously demonstrated its sensitiveness to measure severity of hands dysfunction in cmt patients. tot was significantly higher in the ndh compared to dh (ndh= , ± , ; dh= , ± , , p< . ) in cmt patients, instead there was no difference in dh and ndh in healthy controls. in the evaluation of -pinch and of the hand-grip, ndh performed slightly but not significantly better than the dh ( -pinch: dh= , ± , n; ndh= , ± , n; ± , n; ndh= , ± , n, p:ns) . in normal controls we confirmed the % rule (noguchi & demura, ). finally, segt results were similar between the ndh and dh in cmt patients but in normal controls there was a better performance in the dh. in conclusion, this study supports the existence of the overwork weakness in cmt, evident in every measurements. dexterity and overall ability of the hands impaired in the dh, probably because of compensating movements, compared with the healthy controls in the weaker hand. finally, our results support the importance of avoiding supramaximal exercises and educating the cmt patients to prevent incorrect movements, which may overload the hand muscles. prasad k , ohnmar o , teng a , cheng yj , umapathi t . national neuroscience institute, singapore; yangon general hospital, yangon, myanmar; yong loo lin school of medicine, national university of singapore, singapore. antecedent infections that have been linked to guillain-barré syndrome (gbs) include campylobacter jejuni, haemophilus influenza, epstein-barr virus, cytomegalovirus, mycoplasma pneumoniae and influenza a virus. in south-east asia, the burden of mosquito-borne flavivirus infections is considerable. even in a small country like singapore, with a population of only . million and in spite of excellent sanitation and public health measures, dengue virus (denv) infections can exceed , a year. both symptomatic and asymptomatic denv infections are associated with gbs. zika virus (zikv) infections were detected in singapore in late august . doctors working in south-east asia anecdotally report that gbs cases increase after rainy season when mosquitos breed. we are currently planning studies to estimate the hitherto unknown burden of gbs associated with denv, zikv and other mosquito-borne viruses in this region. as a preliminary step, we reviewed the gbs cases seen at our institution in for evidence of denv and zikv. three out of the tested cases were positive for denv serology. one of these was also positive for denv pcr. all these patients had symptomatic dengue. two had acute inflammatory demyelinating polyneuropathy (aidp) and acute motor axonal neuropathy (aman) subtype of gbs. none the patients tested were positive for zikv pcr in serum and urine. one patient, with miller fisher syndrome (mfs), had serological evidence of recent zikv. he did not have clinical zikv symptoms. in mfs cases, the initial detectable zikv igg was later proven to be due to cross reactivity with previous denv infection. in cases ( amsan, aidp, mfs) the initial zikv igm was raised. we await analysis of convalescent sera to decide if they indeed had zikv or the results were related to previous and co-infection with denv. our preliminary findings indicate that flavivirus infections may account for at least some of the gbs cases in singapore. the lack of symptoms in some cases and the interactions between zikv and denv antibodies make accurate diagnoses challenging. prior r , , benoy v , , vanden berghe p , van den bosch l , . ku leuven-university of leuven, department of neurosciences, experimental neurology and leuven research institute for neuroscience and disease (lind), leuven, belgium; vib-center for brain & disease research, laboratory of neurobiology, leuven, belgium; laboratory for enteric neuroscience, translational research center for gastrointestinal disorders, k.u. leuven, leuven, belgium. charcot-marie-tooth disease (cmt) is the most common inherited neurodegenerative disorder of the peripheral nervous system. it is divided into two main subtypes, a demyelinating subtype (cmt type ) and an axonal form (cmt type ). cmt is a length-dependent disease, in that it effects the longest neurons in the body, thus the muscles in the peripheral regions are affected first and foremost. moreover, the majority of cmt patients share a classical phenotype with shared pathological hallmarks, such as distal muscular atrophy, reduction in nerve conductions, etc. but also molecular pathological hallmarks, like the breakdown in the transport of organelles and vesicles in neurons in a process called axonal transport. currently, there is no cure or effective treatment available to cmt patients. histone deacetylase (hdac ) has been shown to be a key regulator in axonal transport. moreover, inhibiting hdac has been demonstrated to stabilize microtubules, which act as molecular tracks for motor proteins and facilitates axonal transport of cargos. our labs current focus is on cmt type a, the main cause of cmt, which is caused by a duplication of a segment of chromosome p . containing the gene encoding peripheral myelin protein (pmp ). pmp is mainly expressed by schwann cells, the cells that myelinate neurons in the peripheral nervous system. in the work presented, the commercial mouse schwann cell-line, sw cells, was transfected to overexpress pmp using a lentivirus vector system to mimic that of cmt a patient schwann cells. the overexpression of pmp was confirmed using immunofluorescence and western blot techniques. these transfected sw schwann cells were then co-cultured with primary mouse dorsal root ganglion neurons (drgs) isolated from adult mice. these co-cultures where then analysed after weeks in vitro for axonal transport. the investigated groups were: a co-culture of drgs + sw cells, a co-culture of drgs + sw cells transfected with pmp , and a co-culture of drgs + a sw cell-line transfected with green fluorescent protein using a lentivirus vector system, and a monoculture of drgs. furthermore, this work demonstrates that the overexpression of pmp in schwann cells can impair axonal transport in co-cultured drgs in comparison to the other co-culture groups. moreover, these axonal transport defects were able to be rescued by the treatment of a hdac inhibitor, tubstatin a. to conclude, selective hdac inhibitors have been shown to be a beneficial treatment for a number of cmt subtypes in preclinical studies in our lab and offer as a viable treatment for a currently, untreatable debilitating disease. provitera v , caporaso g , stancanelli a , piscosquito g , di caprio g , saltalamacchia am , santoro l , nolano m . "maugeri" clinical and scientific institutes irccs, institute of telese terme (bn), italy; department of neurosciences, reproductive and odontostomatological sciences, university 'federico ii' of naples, naples, italy. the observation of rate and patterns of cutaneous nerves regrowth after mechanical or pharmacological distal axonotmesis, has proven to be an excellent tool to study human nerve regeneration in normal and pathological conditions. most of the observations, however, are referred to small fibers, possibly due to the availability of excellent models of reversible distal cutaneous small fiber axonopathy. no such model is available to study the regeneration of myelinated fibers in human. we studied regrowth of cutaneous large fibers in fingertip of patients with carpal tunnel syndrome after surgical decompression. we recruited patients (m/f / ; age . ± . years) with carpal tunnel syndrome candidate to surgery. patients underwent clinical and electrophysiological evaluation, quantitative evaluation of discriminative threshold at rd fingertip. in the same site, patients also underwent mm punch skin biopsy. skin sections were stained by immunohistochemical techniques and cutaneous innervation was analyzed by confocal microscopy. meissner corpuscles and their myelinated afferences were assessed following previously published procedures. twelve months after surgery, patients repeated functional evaluation and underwent a second skin biopsy two mm apart from the first one. mean density of mcs/mm was . ± . at time and . ± . at follow-up, mean density of myelinated endings was . ± . at time and . ± . at follow-up. however, not in all patients regeneration occurred. based on the variation of mc density between time and follow-up we were able to identify patients in which active regeneration had occurred. in this subgroup mean density of mcs/mm was . ± . at time and . ± . at follow-up (p< . ) with a mean delta of + . . in the same group, mean density of myelinated endings was . ± . at time and . ± . at follow-up (p< . ) with a mean delta of + . . we describe morphological patterns associated to nerve regrowth in the biopsies of patients in which nerve regeneration occurs. we propose an in vivo model to study regeneration of large myelinated fiber endings in human skin. in addition to the count of nerve endings, the identification of patterns associated to nerve regeneration can increase the diagnostic yield of skin biopsy. the most common type of charcot-marie-tooth disease is caused by a duplication of pmp , leading to dysmyelination, axonal loss and progressive muscle weakness (cmt a). currently, no approved treatment for cmt a patients is available. among others, preclinical therapeutic approaches aim to correct the pmp overexpression in order to ameliorate axonal loss and muscle weakness. we previously reported that the novel polytherapeutic drug pxt , a low-dose combination of baclofen, naltrexone and sorbitol, improved dysmyelination and axonal loss after long-term application in adult pmp transgenic rats, a known animal model of cmt a. interestingly, after short-term application in young cmt a rats we observed a long-lasting prevention of muscle weakness as well but without obvious effects on dysmyelination and axonal loss. improved distal motor latencies in the electrophysiological recordings and a shift in the axonal diameter distribution raised the hypothesis that therapy may improve the neuromuscular endplate pathology as another therapeutic target for cmt a. here, we report a preclinical trial in adult cmt a rats treated from postnatal week for consecutive weeks as the most effective regimen in order to facilitate a deeper understanding of the mode-of-action of pxt . long-term therapy effects were confirmed by an ameliorated behavioral phenotype, improved distal motor latencies and also nerve conduction velocity in the electrophysiological recordings. histological analysis revealed an increased number of neuromuscular endplates, which were lowered to wildtype level after pxt treatment. further investigations include detailed analysis of peripheral nerve myelin thickness, internodal and nodal length, terminal axonal sprouting at the neuromuscular endplate and muscle fiber subtyping in treated cmt a rats. charcot-marie-tooth disease (cmt) is a rare hereditary neuropathy for which novel treatments are being developed and urgently needed. only few clinical trials and natural history studies have been performed. evaluation of intervention efficacy is hampered by slow progression and lack of sensitive outcome measures. the interindividual disease variability is high and prognostic disease measures are not established for cmt patients. previously, we have identified skin-derived disease and progression biomarkers in a large european and us-based cmt a cohort. within the german charcot-marie-tooth disease network (cmt-net, www.cmt-net.de) we aim to establish easier accessible biomarkers in blood of cmt a patients. blood analysis is less invasive and can be repeatedly performed during clinical trials and routine patient care. we have started clinically assessing approximately young, adolescent and adult cmt a patients at clinical centres (münster, münchen, göttingen) including a large set of clinical outcome measures (cmtnsv , onls, mwt, mwt, walk , hpt, sf- , fss, psqi, ess, bdi-ii). we will sample blood and skin tissue once a year at , and months for an observational period of years. tissue samples will be analyzed on the transcriptional, translational and epigenetic level. we envision that the diagnostic and progression biomarkers may be used to measure therapeutic effects within clinical trials and later in clinical routine monitoring. this is the first trial testing "circulating" biomarkers from blood in a prospective observational trial in cmt a patients. igm peripheral neuropathy is a slowly progressive and heterogeneous disease with symptoms ranging from mild foot numbness and minor imbalance to severe neuropathic pain and sensory and motor dysfunction. international consensus regarding assessment and treatment of patients with igm peripheral neuropathy is lacking. this might be caused by the repeated use of suboptimal outcome measures, the small trial sizes with low numbers of treated patients, the indolent disease course needing a longer follow-up period to capture relevant changes, or the possibility that administered treatments were not aggressive enough. the imagine study is an international, multi-centre, prospective, observational cohort study, which will result in a unique collection of a large number of prospectively collected and highly standardized clinical data, and a biobank from a large population of well-defined patients with igm peripheral neuropathy. the main objective is to describe in detail the variation in clinical subtypes, clinical disease course, past and current practice of treatment, antibody titres, and clinical picture at the various levels of assessing outcome. patients being at least years, and fulfilling the international criteria for igm peripheral neuropathy are eligible. exclusion is primarily based on concomitant diseases influencing peripheral nerve function. several study parameters measuring weakness, sensation, activity and participation, ataxia, pain, and quality of life are of interest. in february an enmc kick of meeting is organized, bringing together an igm peripheral neuropathy study group. the meeting will focus on the development of a core set of outcome measures to be used in future studies in igm peripheral neuropathy. the imagine study started in the netherlands in september , and to date patients were included. the imagine study starts in the united kingdom, italy, and france in the beginning of . centres recruiting at least patients with igm peripheral neuropathy are eligible to participate in the study. during the pns global recommendations from the enmc meeting, as well as the first results of the imagine study, will be presented. puget s , paolantonacci p , burlot l lfb biomédicaments, les ulis, france; lfb biotechnologies, les ulis, france. in dysimmune neuropathies patients (mmn, cidp, gbs), ivig have become the gold standard due to their efficacy and tolerability. acute renal impairment, a rare but serious adverse event, can be induced by all ivig. its incidence is not determined precisely for each ivig. it mostly occurs in patients at risk, with pre-existing conditions (prior renal insufficiency, diabetes, mellitus, arterial hypertension, elderly > years old, dehydratation, hypervolemia, sepsis, paraproteinemia or concomitant use of other nephrotoxic drugs) and treated by immunomodulatory doses. as the number of these patients increases over the years, the choice of ivig in association with the precautionary measures will be decisive to reduce or avoid the occurrence of this adverse event. from s to s, the nephrotoxicity of ivig has been explained by tubular toxicity related to osmotic nephrosis. sucrose, a stabilizer of some ivig, has been implicated as one of the causes of this. even if several new ivig without sucrose are used, renal impairment cases have been described and studies have highlighted that sucrose is not the only ivig stabilizer associated with tubular damage. however, in a recent study, renal impairment cases ( / ) have occurred in cidp elderly patients treated by free-sucrose ivig. the occurrence of renal failure seemed to be low (only / ) for patients treated with sucrose-ivig in association with precautionary measures (hydratation, adaptation of dosage according body mass index, rate infusion). otherwise, since s, cases of renal impairment secondary to hemolysis have been increased with some ivig but would be rare for full ethanolic fractionated products as they have been identified to generate very low occurrence of hemolysis. the occurrence of renal impairment related to ivig seems to be multifactorial, need to find out all causes (mechanisms of different stabilizers, hemolysis, and concentration of ivig). registries would be helpful for physicians to define the incidence, relative risk of ivig-related renal impairment and the right ivig in association with precautionary measures in these patients at risk. the published ultrasound (us) studies on chronic inflammatory demyelinating polyradiculoneuropathy (cidp) report diffusely increased cross-sectional area (csa) of nerves. these data have not been correlated with histological patterns. to date, no further information about us ultrastructural nerve modification has been provided because of limited frequency range ( - mhz) of the us probe. the aim of this preliminary study is to evaluate the correlation between histological findings from sural nerve biopsies and us patterns found with uhfus ( mhz) from sural nerve at the ankle. four patients with cidp underwent uhfus nerve evaluation of clinically affected sural nerve before undergoing a sural nerve biopsy. us findings included: cross-sectional area of the nerve, connective tissue depth and changes in echogenicity of fascicles. those data were then compared to the histological findings obtained in transversal and longitudinal sections. in all patients, uhfus nerve changes were as following: csa was increased; connective tissue was thickened and in two of the four patients hyperechogenicity of fascicles was observed. also, thanks to the ultra-high-resolution of the probe, a direct correlation of the histological and us images was possible, so as a direct measurement of internal microstructure of the nerve. uhfus may be of adjunctive diagnostic value in cidp assessment. more detailed images of sural nerve can be obtained compared with high-frequency us, allowing a better evaluation of the internal structure of the nerve. the increased csa observed in all our subjects seems to relate to an enlargement of connective tissue, as confirmed by the histological study. in particular, we have observed a hyperechogenicity of fascicles in most severe patients; in those cases, histology confirmed an increase of endoneurial depth. we speculate that those findings may explain a preliminary involvement of connective tissue in the pathogenesis of the cidp; our findings of nerve enlargement may be tool to monitor disease activity in cidp, and better understand disease pathogenesis. further studies are needed to confirm these findings and additional data are being processed and will be presented during the meeting. puma a , cambieri c , panicucci e , desnuelle c , raffaelli c , sacconi s . high-resolution ultrasound (hfus, mhz) of peripheral nerves is a valuable non-invasive, painless complement to neurophysiology, especially in the workup of cidp. nevertheless, the current spatial resolution of echographic images doesn't allow a detailed study of the nerves. ultra-high frequency ultrasound (uhfus, mhz) is a new tool with a - times higher spatial resolution than traditional hfus. the aim of this preliminary study is to evaluate sensory and motor nerves structural characteristics found with uhfus in patients with definite cidp. seven patients with cidp underwent uhfus nerve evaluation of median, ulnar, peroneal and sural nerves, bilaterally. us findings included: cross-sectional area of the nerve, connective tissue depth, nerve vascularization and changes in echogenicity of fascicles. patients also underwent electroneurography (eng) and plexus mri. in all patients, uhfus nerve changes were as following: csa was increased; connective tissue was thickened. two of the seven patients presented an epineural hypervascularization, observed at the doppler evaluation; none of them was treated by iv immunoglobulines. echographic changes were present even in the absence of mri abnormalities (root hypertrophy). eng characteristics correlated with the us patterns. uhfus may be of adjunctive diagnostic value in cidp assessment. more detailed images of nerves can be obtained compared with high-frequency us, allowing a better evaluation of the internal structure of the nerve. the increased csa observed in all our subjects seems to relate to an enlargement of connective tissue. in particular, uhfus allows a more detailed study of nerves, demonstrating that the structural abnormalities hit connective tissue, while -conversely to previous studies -fascicles anatomy seems to be spared. we did not show nerve vascularization except in non-treated patients. we speculate that those findings may explain a preliminary involvement of connective tissue in the pathogenesis of the cidp; our findings of nerve enlargement may be tool to monitor disease activity in cidp, and better understand disease pathogenesis. further studies are needed to confirm these findings and additional data are being processed. purcell l , , wojciechowski e , , gibbons p , , jamil k , , menezes, m , , burns j , . sydney children's hospitals network (randwick and westmead), new south wales, australia; university of sydney, new south wales, australia; universiti kebangsaan, kuala lumpur, malaysia. - % of children with cmt are reported to have hip dysplasia. we aimed to investigate the relationship between radiological hip dysplasia indicators and walking pattern in children with cmt. thirty children ( female; . ± . yrs; ± . cm; ± . kg cmt a, cmtx , cmtx , cmt f, cmt a) underwent d gait analysis ( dga), and had an anterior-posterior pelvis radiograph within months of assessment. radiographs were reviewed by two orthopaedic surgeons, and the reliability of measures of dominant limb hip health via radiograph was assessed. of the measures, measures had an intraclass correlation coefficient > . between raters, and the more experienced surgeon's measures were used for further analysis. the measures of acetabular index (ai), centre edge angle (cea), neck shaft angle (nsa), medial joint space, head width, lateral uncoverage, migration percentage and triradiate were used to investigate correlations with kinematic and kinetic dga variables of the pelvis and dominant limb hip, knee and ankle in planes, temporal spatial parameters and gait profile score. dga data were captured with an -camera vicon nexus motion capture system using the lower body plug-in-gait model. gait data were compared to typically developing children ( female; . ± . yrs, ± . cm, ± . kg). five of affected children had a migration percentage > ∘ , representing % of our sample. maximum hip abductor moment in terminal stance was significantly lower than normative reference values, and was moderately correlated with of the radiographic measures (ai r=− . , p= . ; nsa r=− . , p= . and medial joint space r=− . , p= . ). walking speed (normalised to leg length) was correlated with medial joint space (r= . , p= . ) head width (r=− . , p= . ) and triradiate (r=− . , p= . the ganglionopathies are a unique group of disorders with a varied etiology which includes autoimmune disorders, paraneoplastic syndromes and toxin induced causes. it has been observed that despite extensive investigations the cause of a sensory neuronopathy is often idiopathic in approximately - % cases. electrodiagnostic criteria to diagnose a possible ganglionopathy requires at least one sensory action potential absent or three sensory action potentials < % of the lower limit of normal in the upper limbs plus less than two nerves with abnormal motor nerve conduction study in the lower limbs. ulnar sensory-motor amplitude ratio values (usmar) lower than . is useful in differentiating ganglionopathy from axonal length-dependent neuropathy. we performed a retrospective analysis of patients who were either admitted or evaluated in the outpatient department in department of neurology, nizam's institute of medical sciences, with a possible ganglionopathy as per the diagnostic criteria proposed by camdessanchéet al. consecutive patients who sought treatment during a year period with a clinical pattern of sensory neuronopathy were analysed retrospectively. we reviewed the electrodiagnostic studies of patients and calculated the ulnar sensory-motor amplitude ratio values in comparison with patients with a clinical and electrophysiological diagnosis of diabetic axonal sensorimotor neuropathy. the clinical profile of a ganglionopathy from the indian subcontinent comprised of a prominent sensory ataxia as the initial presenting clinical manifestation with a predilection towards involvement of large-fiber sensory modalities. electrophysiologically a pattern of absent snaps was characteristically encountered with a significant value of usmar less than . , enabling differentiation from axonal length-dependent neuropathy. rahman im , jahan it , nahar s , khalid mm , jahan i , hayat s , , , islam z . guillain-barré syndrome (gbs) is a post-infectious autoimmune polyradiculoneuropathy where immune response is triggered by molecular mimicry between glycolipid antigens expressed by an infective agent such as campylobacter jejuni (c. jejuni) and human peripheral nerve gangliosides. cd molecules are mhc-like structures specialized in capturing and presenting a variety of glycolipids to antigen-specific t lymphocytes. the objective of this study was to investigate the possible role of coding region polymorphisms of cd genes in the pathogenesis of gbs in bangladeshi population. single nucleotide polymorphisms (snps) of exon of cd a (* /* ) and cd e (* /* ) in well defined gbs patients and healthy controls were studied to delineate their effect in developing gbs. we genotyped exon of both cd a (cys/tryp) and cd e (gln/arg) genes through pcr-rflp. to validate these findings, direct sequencing of pcr product was performed for at least samples for each position. we found no differences in genotypes and allele frequencies of both genes in gbs patients compared to controls. however, compared to control individuals with cd a* /cd e* haplotype were . times more likely to develop gbs, whereas individuals with cd a* /cd e* haplotype had a reduced relative risk by . times. a positive association of cd a* /cd e* haplotype was observed only in axonal form of gbs ( . % vs. . %, p = < . ). haplotype cd a* /cd e* was prevalent among anti-gm antibody positive gbs patient compared to anti-gm antibody negative patients ( . % vs. . %) though it was not statistically significant. snps in cd a and cd e were not associated with antecedent c. jejuni infection, disease severity and disease outcome at months of follow up. in conclusion, cd polymorphisms are not a susceptibility or disease causing factor in gbs. conversely, increasing knowledge of this field may offer new dimension for the research to elucidate better answer for disease pathogenesis and also contribute to conduct high power meta-analysis. extensive genetic testing was performed on a unique patient, who received national media attention due to her severe cmt phenotype. the index patient was never able to walk independently, had difficulty breathing and swallowing and demonstrated aspiration by a barium swallow study. nerve conduction velocity testing revealed velocities of m/s in her upper extremity. she required continuous positive airway pressure (cpap) for an upper respiratory infection and developed bilateral vocal cord paralysis. we used the combined brief assessment of motor function (bamf) scale to evaluate her disability. her fine motor scale was a / , her upper extremity gross motor scale was a / and her lower extremity gross motor scale was / . unfortunately, she died at age in her sleep, presumably from respiratory arrest. the proband's father was asymptomatic, however, his neurological exam showed pes cavus bilaterally and mild atrophy of the first dorsal interossei muscles in his hands. his nerve conduction velocities were slowed to m/s in the upper extremities and his cmt neuropathy score (v ) was / . we performed whole exome and subsequently whole genome sequencing in the trio. comprehensive structural variant analysis for copy number variations, large deletions, and recombinations was completed by a combination of software tools. known cmt genes were excluded as the underlying cause and the only viable candidate gene remaining was sh tc . we showed expression of sh tc in peripheral nerve and schwann cells. sh tc is a paralogue to sh tc , which causes the recessively inherited dysmyelinating form cmt c. sanger sequencing confirmed the variants in our family, p.v m (c. g>a, chr : ) and p. a p (c. g>c, chr : ) , and showed the segregation of the heterozygous variations. we hypothesize that the heterozygous paternal allele had a minimal effect and let to a very mild or subclinical form of peripheral neuropathy. of interest, the recessive sh tc gene has also been shown to cause mild aberrant forms of peripheral nerve degeneration in carriers of heterozygous disease alleles. in summary, this paper will present genetic and molecular evidence from an extensive n= study proposing a novel cmt gene. charcot-marie-tooth (cmt) is an important cause of morbidity worldwide. it is a heterogeneous disease manifesting as progressive weakness, wasting and loss of feeling in a length-dependent pattern. there are an increasing number of cmt-related genes in the literature. more recently, recessive mutations in the hint gene have been reported as causative of predominant motor axonal neuropathy associated with neuromyotonic discharges on emg. one of the characteristics of autosomal recessive cmt is it varying frequency in different populations and ethnic groups. we sought to evaluate the frequency of mutations in the hint gene in a brazilian cohort with axonal hereditary neuropathy. all patients included in this study born within south east area of brazil. the group consists of consecutive patients with axonal neuropathy screened for recessive or sporadic axonal neuropathy in the neurogenetics laboratory of clinical hospital of ribeirão preto. direct sequencing of the coding region of hint gene was done. among patients screened, were suspected of having recessive axonal neuropathy without neuromyothonic discharges, and two have axonal neuropathy associated with neuromyothonic discharges on emg. we did not find any disease causing mutations among our patients. some previously reported studies reported a high frequency of mutations in the hint gene among recessive axonal neuropathies in some european countries. our results demonstrated that frequencies of mutation underlying genetic hereditary neuropathies are different between different ethnic groups and have implications for the organization of services management of cmt, for genetic counseling, and for gene flow in different world populations. funded by cnpq, fapesp, faepa, pronas (ministry of health). rodriguez-menendez v , ballarini e , malacrida a , , ceresa c , semperboni s , , meregalli c , cavaletti g , nicolini g . school of medicine and surgery, experimental neurology unit, university of milano-bicocca, monza, italy; phd program in neuroscience, university of milano-bicocca, monza, italy. bortezomib (btz) is a proteasome inhibitor widely used for multiple myeloma treatment. btz induced peripheral neuropathy (bipn) is the most frequent adverse effect. bipn in humans, is a dose dependent painful sensory neuropathy characterized by nerve axonopathy and a tendency to recover in the follow-up period after btz withdrawal. bipn affects principally dorsal root ganglia (drg) and different rodent models have shown alterations in sensory neurons, small unmyelinated axons, large myelinated axons, axonal mitochondria and schwann cells. in this work, we evaluated the effects of btz in vitro on drg neurons isolated from adult mice. our interest focused on dystonin, a protein able to interact with all the three components of cytoskeleton (microtubules, microfilaments and intermediate filaments) and able to bind map b (a mt-associated protein) through which can influence golgi apparatus morphology. there are different neuronal isoforms of dystonin and in particular dystonin-a is able to modulate tubulin acetylation and stability through interaction with map b. it is noteworthy to underline that map b expression in the mature nervous system is restricted to sensory neurons. western blot analysis demonstrated that a treatment with nm btz induces a statistically significant decrease in tubulin acetylation. this result does not go along with our previous study where we observed a tubulin polymerization increase after btz treatment. therefore, we have decided to focus our interest on soma organelle organization that is well known to be dependent from cytoskeleton structure. immunofluorescence images showed an altered distribution of acetylated tubulin in soma cytoplasm after hour treatment. moreover, confocal analysis of cis golgi (gm ) demonstrated that in btz treated neurons the normal golgi structure is lost showing a spot-like non perinuclear labeling distribution. additionally, dystonin distribution seemed comparable to that of cis golgi apparatus suggesting that btz could induce a change in dystonin localization which in turn affects golgi organization, probably through map b.these data suggest that the cytoskeleton alterations, induced by btz, could probably cause wrong maturation and trafficking alteration of golgi vesicles consequently impairing the correct sensorial function. romão tt , aleixo bfl , wedemann d , herculano fgn , prado h , cal h , pupe c , bittar c , nascimento ojm . universidade federal fluminense (uff), rio de janeiro, brazil. acute motor and sensory axonal neuropathy (amsan) is a clinical variant of guillain-barré syndrome (gbs) which has rarely been reported in association with human immunodeficiency virus (hiv) and neurosyphilis. we describe a case of a -year-old woman who started with muscle weakness in the left leg followed by weakness in the right leg and in upper limbs in one month. motor symptoms were followed by urinary and fecal incontinence. no preceding symptoms, as diarrhea or fever were referred. neurological examination showed global areflexia with impairment of vibratory and tactile modalities, as well as loss of proprioception. pinprick sensation was moderately compromised. no impairment of higher mental functions was observed. other causes of neuropathies were ruled out. cerebrospinal fluid (csf) examination showed cell/mm , increased protein level, normal glucose level and negative vdrl test. blood analysis showed hiv and positive serology tests, vdrl : and positive t. pallidum hemagglutination assay. igm cytomegalovirus antibody was negative, cd was in normal range and hiv load was undetectable. cranial and spinal cord magnetic resonance imaging revealed extensive involvement of the posterior spinal cord tracts which supports the diagnosis of neurosyphilis. nerve conduction studies showed a significant reduction in compound motor action potentials amplitudes, particularly at lower limbs, and absent sural nerve responses. electromyography revealed positive waves and fibrillation at lower limbs. treatment with methylprednisolone, human intravenous immunoglobulin and ceftriaxone has been settled, resulting in improvement of upper limbs paresis and sphincters dysfunction. antiretroviral therapy was initiated. this amsan case is associated with central nervous system involvement, encompassing an encephalomyeloradiculopathyrelated to hiv/t. pallidum co-infection. c.jejuni is the main etiological agent associated with amsan, but there are some reports of hiv/cmv co-infected patients who presented this gbs variant. facing a patient with amsan, mainly when cns involvement is present, it is of crucial importance to undergo investigation of an ongoing infectious process, such as hiv and syphilis, considering the impact of early treatment on prognosis. roodbol j , , yiu e , doets a , , de wit mcy , monges ms , van nes s , catsman-berrevoets ce , van den berg b , , jacobs bc , and on behalf of the igos-kids consortium. only a few prospective cohort studies so far have investigated the clinical presentation and course of guillain-barré syndrome (gbs) in children using age-adjusted outcome scores. in we started a study based on the igos protocol but adjusted for children with gbs (igos-kids). (pediatric)neurologists from argentina, australia and the netherlands joined forces to determine the clinical and biological determinants of disease progression and recovery in gbs in children from different geographical areas. for each age category specific pain scales are used including the comfort score for children < years old, pain faces revised age - years old and numerical rating scale in children ≥ years old and outcome measures. a new strength score was developed: gbs kids score. this score will be used and validated in addition to the mrc-sum score. the onls, r-ods and fss are also be used in igos-kids. age-dependent quality of life questionnaires were added to the igos-kids protocol, namely the pedsql and the pedsql multidimensional fatigue scale. these scales are available for children ≥ years old. an activity score validated for neuromuscular disorders for children ≥ years old was also added. currently there are children included in igos-kids, eight children from australia and five from the netherlands. additional clinicians and researchers interested in gbs in children are most welcome to participate in igos-kids. prognostic models have been developed to predict the highly variable clinical course of guillain-barré syndrome (gbs) in adults. the clinical course of gbs is equally variable in children, but the current prognostic models have not been validated in children. in this study, we aimed to identify in children with gbs the characteristics at hospital admission that predict the clinical severity and outcome. the study was conducted in two patient cohorts from europe: one (largely) german cohort of children and one dutch cohort of children. clinical information was obtained regarding preceding infection, first symptoms, neurological deficits at admission and nadir, results of additional investigations (cerebrospinal fluid and nerve conduction studies). clinical severity, course and outcome was defined by the gbs disability score, especially the ability to walk unaided, at a follow-up of month, months, months and months after onset of symptoms. univariate and multivariate regression analyses were performed initially on the two separate cohorts. combined the cohorts consisted of children (age median years, range - years) including boys ( %). the median duration between onset of symptoms and hospital admission was days (range ). pain at admission was remarkably frequent and present in ( %) children. in the combined cohorts, children ( . %) developed respiratory failure and one child died. multivariate regression analysis showed that in both cohorts strong predictors of respiratory failure available at hospital admission were cranial nerve involvement, a higher gbs disability score and a shorter period in days between onset of symptoms and admission. this information was used to develop and validate a prognostic model for children with gbs that will be presented at the conference. in conclusion, based on the analysis of two independent cohorts of patients the predictors of respiratory failure and clinical recovery were identified and validated. similar factors were identified for adult patients, although the prognosis in children in general is better than in adults. this information will be used to develop a simple prognostic model for current clinical practice to predict the chance of respiratory failure and outcome in children with gbs. the negative trials of vitamin c in cmt a have highlighted the lack of sensitive outcome measures in charcot-marie-tooth disease (cmt). neurofilaments are abundant neuronal cytoskeletal proteins and their concentration in blood is likely to reflect axonal breakdown. we therefore examined plasma neurofilament light chain (nfl) concentration as a potential biomarker in cmt. blood samples were collected from patients with cmt and age matched healthy controls over a -year period. disease severity was measured using the weighted cmt examination and neuropathy scores. plasma nfl concentration was determined using an in house developed simoa assay based on the nfl antibodies from the nf-l light elisa kit (umandiagnostics). plasma nfl concentrations were significantly higher in cmt patients (median: . pg/ml; iqr: . - . ) than in controls (median: . pg/ml; iqr . - . , p< . ) and correlated with disease severity as estimated by the weighted cmt examination (n= , r= . , p< . ) and neuropathy scores (n= , r= . , p= . ) . concentrations were also significantly higher when subdividing cmt patients by genetic subtype; cmt a (n= , p< . ), sptlc (n= , p< . ) and gjb (n= , p= . ) or into demyelinating, cmt (n= , p< . ) or axonal, cmt (n= , p< . ) forms compared to healthy controls. there was no significant difference in the plasma nfl concentration after year in patients with cmt (n= , mean difference − . pg/ml, % confidence interval − . - . ) or healthy volunteers (n= , mean difference − . pg/ml, % confidence interval . - . ) which is unsurprising as cmt is a slowly progressive disease in which the rates of axonal degeneration are likely to be constant and elevated. in summary, we have shown that plasma nfl levels are significantly raised in patients with cmt and that they correlate with disease severity. this is of relevance not only for the field of cmt but for peripheral neuropathies in general, and suggests that plasma nfl holds promise as a biomarker of peripheral neuropathy in both routine practice and clinical trials. neurolymphomatosis (infiltration of the peripheral nervous system by lymphoma cells) is a rare and usually devastating condition belonging to the spectrum of lymphoma-associated neuropathies. cerebrospinal fluid examination with cytologic examination, flow cytometry and clonality testing by pcr may show malignant cells especially when nerve root involvement is prominent. however, nerve biopsy remains a useful tool to confirm the presence of malignant cells invading the nerve. neuropathological features are important and pcr-based immunoglobulin or t-cell receptor clonality testing on nerve fragments may add notable value for the diagnosis of neurolymphomatosis, although this has not been systematically investigated. we retrospectively studied clinicopathological data and clonality results of nerve biopsy samples in patients with nl from centres, performed between and . among patients with nl, we found % of b-cell lymphoma and one t-cell lymphoma. nl was the first manifestation in , % of patients. the main clinical pattern was symmetrical progressive sensorimotor polyneuropathy in % of patients and pain was a prominent feature in %. clonality testing showed a monoclonal rearrangement in ( %) cases, oligoclonal rearrangement and no amplification in ( %). the main histological pattern was perivascular infiltration of predominant b-cells in the epineurium, without signs of vasculitis. the extent of axon loss was highly variable between patients. various chemotherapeutic regimens were used and the median overall survival was months. only one case showed a monoclonal pattern among control nerve samples from patients with other types of neuropathy including vasculitis and cidp. overall, we found that clonality testing on nerve biopsy specimens may provide decisive information on the presence of neurolymphomatosis, with a sensitivity of . %, a specificity of . %, a positive predictive value of . % and a negative predictive value of . %. we confirm the utility of nerve biopsy for the diagnosis of nl and show the great yield of pcr-based clonality testing to assess the malignant feature of peripheral nervous system lymphoid infiltrates. despite an accurate diagnosis, neurolymphomatosis still remains a devastating disease with an overall poor prognosis. in the last years, cumulative data have shown that patients with amyotrophic lateral sclerosis (als) and mouse models of the disease present loss of small epidermal and dermal nerve fibers and sensory dysfunctions, in addition to the classical motor symptoms. our objective is to characterize this small fiber neuropathy and to clarify if axonal loss involves all sort of fibers equally, or if there is some specificity. for this purpose, we performed an immunohistochemical characterization of total intraepidermal nerve endings (protein gene product; pgp . ), peptidergic (calcitonin gene-related peptide; cgrp) and nonpeptidergical nerve epidermal endings (isolectin b ; ib ) of the sod g a mouse at different stages: presymptomatic stage ( weeks), disease onset ( weeks) and in symptomatic stage ( weeks). the sympathetic sweat gland innervation was immunolabeled for vasoactive intestinal peptide (vip) from very early stage ( weeks) to disease onset ( weeks). the results showed a marked reduction of the intraepidermal nerve fibers already in the presymptomatic stage compared to the wildtype littermates (p< . ). this axonal loss affected more markedly the nonpeptidergic axons from the disease onset stage ( % axonal loss, p< . ), whereas no significant differences were found in the cgrp positive fibers ( . % axonal loss). a reduction of the sympathetic innervation of the sweat glands was also found from the disease onset stage ( % axonal loss, p< . ). in summary, we have found that nonpeptidergic and sympathetic innervation of the skin are predominantly affected in the sod g a mouse model. these findings suggest that this specificity could be used as an accessible biomarker for the disease. hereditary and inflammatory neuropathies are peripheral nerve disorders of different pathophysiology whose identification is crucial for therapeutic approach. diagnosis of cmt is easy when there is a family history, disease course is slowly progressive, neurophysiological findings are homogeneously abnormal. cases of cmt patients with inflammatory-like phenotypes leading to a misdiagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (cidp) have been described. the presence of "red flag signs", such as slowly progressive decline, mild sensory symptoms, minimal electrophysiological progression and no response to therapy should prompt re-evaluation of the diagnosis of cidp. the introduction of nerve neuroimaging has contributed to the diagnostic work-up. we describe cmt patients ( men, women, mean age . ± . yrs, mean neuropathy duration . ± . yrs) with genetically confirmed cmt, who were initially diagnosed with cidp. neurophysiology showed demyelinating features in patients, the remaining patients had axonal features. csf analysis showed albumin-cytological dissociation in patients, oligoclonal igg bands were present in patient. nerve ultrasound in patients with demyelinating neuropathy showed diffuse increased cross-sectional area. mr-neurography in one patient confirmed diffuse nerve hypertrophy and increased signal intensity, supporting the hypothesis of a overlap syndrome. all patients were treated with immunomodulatory therapies. among patients with demyelinating features, patients underwent ivig for months, without benefit; the remaining were treated with steroids, showing temporary improvement. the patients with axonal neuropathy complaining of a progressive history, underwent ex adjuvantibus plasma exchange and ivig, without benefit. given the lack of benefit from therapies, screening for hereditary neuropathies was performed. among patients with demyelinating neuropathy, had cmt a, cmt b, cmt d. among the patients with axonal neuropathy, one was diagnosed with cmt k. in patients an overlap syndrome was present. several clinical and laboratory features (csf protein elevation), might contribute to the misdiagnosis of cidp in cmt patients. refractoriness to immune-modulatory treatment should rise the suspicion of a hereditary neuropathy. an overlap cmt/cidp syndrome may be considered, in front of acute/subacute deterioration and/or proximal muscles involvement. two patient with an overlap syndrome showed benefit after either steroids or ivig. ruiz m , tripodi sm , campagnolo m , zara g , salvalaggio a , ruggero s , toffanin e , anglani m , briani c . neurology, department of neuroscience, university of padua, padua, italy; neuroradiology, padua hospital, padua, italy. facial diplegia is a rare regional subtype of guillain-barrè syndrome characterized by rapidly progressive bilateral facial palsy in absence of other cranial neuropathies, ataxia or limb weakness. the diagnosis is based on history, clinical examination, laboratory data. the outcome of this variant appears to be better than that of classical gbs. although about % of gbs patients clinically exhibit facial nerve involvement, there are only few reports that demonstrate mri gadolinium facial nerves enhancement. a -year-old previously healthy man sought neurological advice for the acute onset of right perioral paresthesias and hyposthenia at the extensor hallucis longus bilaterally. in the previous month, during a trip to china and japan, he had suffered from gastroenteritis. at neurological examination he presented with bilateral extensor hallucis longus hyposthenia. ankle jerk reflexes were absent. one week later, he developed bilateral facial palsy. neurophysiology disclosed absence of activity in the facial nerves innervated muscles bilaterally and signs of mild partial denervation at right l metamer. csf analysis showed increased protein levels ( mg%) and . leucocytes/ l. serological tests for infectious agents were negative and serum levels of angiotensin converting enzyme were normal. antibodies to monosialoganglioside gm of igg isotype were positive ( / ). t brain mri showed, after gadolinium administration, marked bilateral enhancement of the facial nerves in their extra-and intra-canalicular segments. t lumbosacral mri scan ruled out the presence of disc diseases as well as signal modifications within conus medullaris and cauda equine nerve roots. the patient was treated with iv immunoglobulins ( . g/kg/die for days) with benefit on facial weakness. at follow-up examination months later, the patient presented a further improvement of the facial diplegia and neurophysiology disclosed a partial recovery of activity in the facial nerves, with persistent axonopatic damage. bilateral extensor hallucis longus hyposthenia persisted. in conclusion, we report on a regional subtype of guillain-barrè syndrome with the curious association of facial diplegia and bilateral extensor hallucis longus hyposthenia, and igg anti-ganglioside antibodies, that are not commonly described in facial diplegia. moreover, we provide t brain mri evidence of facial nerve involvement. rumora ae , tabbey ma , lograsso g , dolkowski j , haidar j , lentz si , feldman el . department of neurology, university of michigan, ann arbor, usa; department of internal medicine, division on metabolism, endocrinology and diabetes, university of michigan, ann arbor, usa. diabetic neuropathy (dn) is the most common complication of diabetes affecting up to % of diabetic patients. the pathogenesis of dn in type diabetes is directly related to the metabolic syndrome associated with the western diet composed of elevated levels of long chain saturated fatty acids (sfas) and low levels of medium chain sfas. long chain sfas are associated with insulin resistance and dyslipidemia while medium chain sfas have been associated with decreased lipid accumulation and improved mitochondrial function. since dn is primarily a disorder of the sensory dorsal root ganglion (drg) neurons, we sought to evaluate the impact of sfa hydrocarbon chain length on mitochondrial trafficking mechanisms that are critical for distributing atp throughout drg axon to provide energy for synaptic transmission. we hypothesize that sfas with longer hydrocarbon chains will impair mitochondrial trafficking whereas medium length sfas will not impact mitochondrial movement along the drg axon. in this study, we examined the impact of sfa hydrocarbon chain length on mitochondrial trafficking, directionality and velocity in primary mouse drg neurons. drg neurons were treated with increasing concentrations of long chain sfas, stearate and palmitate, or medium chain sfa, laurate, ranging from . to micromolar for twenty-four hours. drg neurons treated with long-chain sfas, palmitate and stearate, showed a significant decrease in the percentage of motile mitochondria whereas medium chain sfa, laurate, does not alter mitochondrial motility. we next assessed whether motile mitochondria in drg neurons treated with palmitate or stearate exhibited altered directionality or velocity of mitochondrial trafficking. palmitate and stearate treatments resulted in a trending decrease in the number of mitochondria trafficking in both anterograde and retrograde directions. furthermore, . to micromolar palmitate and stearate induced a significant decrease in mitochondrial velocity. laurate treatment, on the other hand, retained directionality and velocity of mitochondrial trafficking. these results suggest that hydrocarbon chain length of saturated fatty acids plays an important role in regulating mitochondrial trafficking mechanisms in dorsal root ganglion neurons. impaired mitochondrial trafficking in drg neurons exposed to elevated levels of long-chain sfas may play a critical role in the progression of dn. dyslipidemia is a critical factor that contributes to the development of diabetic neuropathy (dn). the progressive nerve damage associated with dn correlates with the dyslipidemic state characterized by elevated circulating levels of harmful saturated fatty acids (fas) and low levels of beneficial unsaturated fas. in dn, primary sensory dorsal root ganglion (drg) neurons exhibit energy dyshomeostasis and mitochondrial dysfunction, however, little is known about the differential impact of saturated and unsaturated fas on mitochondrial mechanisms in drg neurons. mitochondrial trafficking is an essential mechanism for transporting mitochondria throughout drg axons to provide cellular atp for neuronal function and neurotransmission. since mitochondrial trafficking is regulated by metabolic flux, we sought to determine whether saturated fa, palmitate, and unsaturated fa, oleate, have differential effects on mitochondrial trafficking in drg neurons. we evaluated mitochondrial trafficking patterns and the mitochondrial membrane potential (mmp) in primary drg neurons treated with physiologically relevant concentrations of palmitate, oleate, and combinations of both fas. primary drg neurons treated with . to micromolar palmitate induced a significant and dose-dependent reduction in the percentage of motile mitochondria. these palmitate treatments also induced a dose-dependent reduction in mitochondrial velocity but did not impact the directionality of mitochondrial movement. alternatively, . to micromolar oleate treatments did not impair the percent of motile mitochondria, the direction of mitochondrial movement, or mitochondrial velocity. since palmitate and oleate have differential effects on mitochondrial motility, we next assessed whether oleate could counter the inhibitory effect of palmitate on mitochondrial trafficking. surprisingly, oleate/palmitate mixtures at ratios of : or : prevented palmitate-induced impairment of mitochondrial trafficking. we assessed the impact of palmitate and oleate on mmp by staining palmitate and oleate-treated drg neurons with tetramethylrhodamine methyl ester. drg neurons treated with micromolar palmitate exhibited an increase in the percentage of depolarized mitochondria while mitochondria in oleate-treated drg neurons retained mmp. interestingly, drg neurons treated with : oleate/palmitate mixtures also maintained polarized mitochondria. these results suggest that saturated and unsaturated fas have a distinct impact on mitochondrial trafficking mechanisms in drg neurons and that equimolar ratios of oleate/palmitate can prevent impairment of mitochondrial trafficking. of g alpha- in m r overexpressed sensory neurons significantly reversed the m r-induced reduction in relative levels of total neurite outgrowth (mean±sd: . ± . (control) vs . ± . (g alpha- knockdown), p< . , n= neurons). further, treatment of m r overexpressing neurons with mt or pirenzepine sequestered g alpha- / proteins at the m r and significantly reversed the impaired cytoskeleton-mediated reduction in total neurite outgrowth (mean±sd: . ± . (control), ± (+ nm mt ), ± . (+ micromolar pirenzepine); n= , and neurons, respectively; for treated groups p value= . vs control by one-way anova). mt and pirenzepine also significantly restored mitochondrial trafficking and abundance of mitochondria in the distal neurites. our findings suggest a novel mechanism in which modulation of m r influences tubulin polymerization, mitochondrial distribution in nerve terminals and controls axonal outgrowth and regeneration. funded by cihr and nih. muscarinic receptors are a group of five g-protein coupled receptors (gpcrs) that are targeted by drugs for the treatment of several human pathophysiological conditions. we have recently shown that selective (pirenzepine) and specific (muscarinic toxin : mt ) antagonists of the muscarinic acetylcholine type receptor (m r) induced elevated neurite outgrowth and protected from small and large fiber neuropathy in adult sensory neurons in various animal models (calcutt et al., ) . one of the major cellular effectors activated by gpcrs is extracellular signal-regulated kinase (erk). the erk signaling cascade regulates a variety of cellular processes including growth and proliferation. both g protein and beta-arrestin mediated signaling pathways can lead to erk activation by phosphorylation through different kinases. activated erk in turn can phosphorylate about cellular substrates, thereby mediating diverse functions. in this study, we have analyzed beta-arrestin recruitment, as part of the receptor internalization process induced by agonist/antagonist binding. in addition, we studied phosphorylation of erk by mt and pirenzepine using isoelectric focusing with phospho-erk specific antibodies and a variety of cell-based assays including beta-arrestin and g protein (gnas/gnasl/gnaq/gna /gna /gna ) knockout cell lines. our study revealed that beta-arrestin is recruited to the m r upon mt and pirenzepine treatment. treatment with nm mt and micromolar pirenzepine significantly increased the dual phosphorylation of tyr and tyr residues of erk / in primary rat sensory neurons (p< . ) in comparison to muscarinic agonist carbachol ( micromolar) and general antagonist atropine ( micromolar). we have identified multiple distinct phosphorylation events on the m r by isoelectric focusing that are specific to mt and pirenzepine induction. further, we have shown that mt and pirenzepine-mediated erk phosphorylation is dependent on both g protein and beta-arrestin recruitment to m r. finally, we reveal that increased erk phosphorylation by mt and pirenzepine significantly (p= . and . , respectively) increased phosphorylation of camp responsive element binding protein (creb) at ser . these results show for the first time that antagonists of the m r can activate the erk signaling pathway and possibly drive phenotypic change in adult sensory neurons. funded by cihr # mop- . charcot-marie-tooth disease (cmt) is representative of inherited neuropathies affecting an estimated in people. the immense advances in gene discovery gained from next-generation sequencing (ngs) projects have revealed the extent of cmt's genetic heterogeneity, with over loci already identified. this knowledge is rapidly translated into clinical comprehensive gene testing panels, often containing over genes. such a large genomic space will invariantly yield variants of uncertain clinical significance (vus) in nearly any person tested. this rise of the number of vus creates major challenges for genetic counseling. in addition, less individual mutations in already known genes are being published as the academic merit is decreasing, and most such testing now happens in clinical laboratories. we propose to capture more of this data in the cmt field to gain a more complete collection of alleles in cmt genes, ideally in conjunction with detailed phenotypic data. this represents a rational approach to eventually reduce the number of vus. thus, we have created a unique, community-driven variant database for cmt researchers and clinicians. the inherited neuropathy variant browser provides simple, user-friendly access to currently reported cmt variation, including patient-level genotypic and phenotypic information. we have also designed an interactive rating system of genetic variation to assist the community with interpretation of vus. for the initial release, we have collected genetic variation, along with genotypic and phenotypic data when available, from published literature, clinical lab reports, and our in-house database. we highly encourage new submissions of not only observed pathogenic variation, but also variation of unknown significance. the goal is to provide a platform for the cmt community to store, share, and discuss genetic data in order to resolve variation of uncertain significance as a joint-effort. with active participation, we aim to provide the community with a more complete mutational spectrum in cmt genes to assist allelic interpretation and patient diagnosis. neurofilaments are strictly neuron-specific intermediate filaments crucial for maintaining axonal architecture. pathogenic mutations in nefl, which encodes the light chain of neurofilament, cause dominantly and recessively inherited charcot-marie-tooth neuropathy (cmt). the nefl-associated neuropathy can be either axonal (type e) or demyelinating (type f). most pathogenic nefl variants are dominantly inherited missense mutations, which are thought to cause disease by inducing nefl aggregation, leading to the disruption of axonal transport. however, investigation of disease mechanisms caused by the mutations has been complicated by the neuronal specificity of nefl. we identified a homozygous nefl variant c. c>t predicting a nonsense change p.arg * in a patient with early-onset cmt. to elucidate the disease mechanism, we used pluripotent stem cells, reprogrammed from patient's skin fibroblasts, to differentiate patient-specific spinal motor neurons. the motor neurons revealed a near complete loss of nefl mrna, and absence of nefl protein. our results establish that nefl is not essential for the development of human nervous system but its absence causes progressive axonal neuropathy. we currently profile the transcriptomic alterations of the motor neurons lacking nefl using single cell rna sequencing to identify compensatory pathways. friedreich's ataxia (frda) is the most common autosomic recessive ataxia, due to a trinucleotide expansion within the frataxin gene. within the wide phenotype, frda patients present also with an axonal neuropathy whose pathological mechanisms are not completely known. eight patients ( women, mean age . yrs, range - ) with genetically confirmed frda underwent neurophysiological and nerve ultrasound evaluation at four limbs bilaterally. echogenicity and cross-sectional area (csa) of median, ulnar, radial, peroneal, tibial, and sural nerves were recorded. mr neurography and diffusion tensor imaging (dti) analysis were performed in one patient; fractional anisotropy (fa), radial (rd) and axial (ad) diffusivity of median, radial and ulnar nerve were calculated at proximal, intermediate and distal sites. all patients presented with sensory axonal neuropathy. seven patients ( %) presented with increased csa of median and ulnar nerves at arm and axilla. mean median nerve csa at mid-upper arm was . mm (normal values < mm ), mean ulnar nerve csa at mid-upper arm was . mm (normal values < mm ). mean median nerve csa at axilla was . mm (normal values < mm ), mean ulnar nerve csa at axilla was . mm (normal values < mm ). mr neurography (performed in one patient) confirmed diffuse swelling and signal hyperintensity of median and ulnar nerves at the arm and dti analysis showed abnormal values of fa, ad and rd along the whole course of evaluated nerves thus suggesting a wide alteration of nerves structure. frda patients presented with an axonal neuropathy characterized, at ultrasound, by a nerve enlargement strictly limited to mid-upper limbs in all patients, findings that cannot be solely explained by a dying-back axonopathy, as suggested by several authors. neither a dorsal root ganglia neural loss could explain by itself our findings, because a diffuse csa reduction would have been expected. on the whole, these findings represent a peculiar feature in frda, but its pathophysiologic meaning remains unclear. inherited peripheral neuropathies are an important health concern for which there is currently no disease-modifying therapy. dogs are affected by a variety of peripheral neuropathies that are breed-specific, indicating a strong genetic component. the use of in-bred populations, such as pure-bred dogs, is advantageous for genetic dissection of disease. acquired peripheral neuropathy (apn) is an inherited late-onset generalized polyneuropathy with high prevalence in labrador retrievers. the most prominent features of apn, laryngeal paralysis and pelvic limb weakness, are associated with the longest peripheral motor nerves in the dog. the pathologic features of apn are similar to human peripheral neuropathy. our aim is to understand the genetic and pathologic features of apn for development of this condition as a naturally occurring large animal model for human disease. we performed a genome-wide association study (gwas) and short-read high-depth whole genome sequencing (wgs) to investigate the genetic underpinning of apn in the labrador. our gwas data indicates that apn is an autosomal dominant disease. the initial analysis from the wgs study resulted in a potential causal variant with an autosomal dominant pattern; this variant is associated with an axonal gene. the neuropathologic progression and histologic features of apn are poorly defined. using genetic markers from our gwas study, we are able to confidently identify labradors with pre-clinical apn, from which nerve biopsies can be obtained. preliminary analysis of biopsies from labradors suggest apn is an axonopathy. further histologic data from preclinical and symptomatic dogs is being obtained to further define the pathogenesis in this model. mutations in morc lead to an axonal form of neuropathy (cmt z). to date, nine families have been published with mutations in the morc gene, showing that this gene is frequently involved in cmt. while the recent genetic data clearly established the causative role of morc in cmt z, its phenotypic consequences in patients and role in neuronal biology remains to be clarified. therefore, we aim to look for altered genetic and biochemical pathways with a transcriptomic approach in order to investigate the role of morc in hereditary peripheral neuropathy. we have performed transcriptomic analysis using a human gene expression microarray (v x k, agilent technologies), in three hek- t cell lines: control, morc knock-down (kd) and the overexpression of the most common morc mutation, the p.r w (np_ ) (kr). differential gene expression assessment was carried out using limma moderated t-statistics. standard analysis techniques perform one test for each gene. thus, for each gene, a t-test statistic is reported together with its corresponding p-value. in this analysis we have used the conventional multiple testing p-value correction procedures proposed by benjamini hochberg to derive adjusted p-values. the preliminary results reveals that kd shows up-regulated genes involved in transmission of nerve impulse and cilium metabolism, suggesting that morc might act at this level in the peripheral nervous system. otherwise, kr shows a major alteration of main axonal metabolic pathways, including the overexpression of genes related to the generation of neuronal action potential, transport through the axon and its targeting in synapse formation. kr also shows a marked alteration of gene expression related to organization, assembly and cilium movement and with the axonemal dynein complex assembly. this study provides an important step towards understanding the pathomechanism underlying to morc p.r w and its role in cmt z. aifm encodes a mitochondria associated apoptosis inducing factor. mutations in aifm lead to a wide spectrum of neurodegenerative disorders: cowchock syndrome; a combined oxidative phosphorylation deficiency (coxpd ) with severe encephalomyopathy; x-linked deafness with peripheral sensory neuropathy; spondyloepimetaphyseal dysplasia (semd) with mental retardation; and an infantile motor neuron disease. previous studies showed severe defects in mitochondrial metabolism, related to redox function, mitochondrial fragmentation, and respiratory deficiencies. in addition, some mutations impair the protein expression of aifm and cause an increase in caspase-independent apoptosis. by targeted next-generation sequencing, we detected the aifm c. c>t (p.phe ser), in a year-boy. this mutation was confirmed in his year-old affected brother. electromyography and nerve conduction velocities studies revealed an axonal polyneuropathy with exclusive involvement of motor fibers, with an early childhood-onset. both children currently show normal cognitive and cranial nerves functions. the in silico structural modeling of human aifm showed that the mutation of a phenylalanine to serine at position disrupts the hydrophobic interaction between phe and pro , and consequently, it destabilizes an alpha-loop domain. cartoon of protein superposition between two different human aifm structures suggest that a lack of constraints in this region could affect the interaction between - helix and the - -hairpin regions, a very important stage for the functional activity of the aifm protein. patient-derived fibroblasts were used to investigate the pathological effect of the p.phe ser mutation: fibroblasts from patients show a similar mrna but different protein expression of aifm compared to healthy control fibroblasts. however, they have an aberrant morphology, from fibroblastic to polygonal shape, and they are larger than control fibroblast; mitochondria from mutant fibroblasts are markedly fragmented compared to controls; the viability of the patient's fibroblasts is lower, but it does not correlate with an increase in apoptosis. instead, it seems to be caused by an increase in the expression of genes activating the senescent program, like p and p . our study confirms that variable effect of different mutations on the protein function may contribute to the clinical variability observed in aifm patients. funds: isciii (pi / ); fundació per amor a l' art. sango k , takaku s , niimi n , yako h . diabetic neuropathy project, tokyo metropolitan institute of medical science, tokyo, japan. coculture models of neurons and schwann cells have been utilized for the study of myelination and demyelination in the peripheral nervous system; in most of the previous studies, however, these cells were obtained from the primary culture with embryonic or neonatal animals. because it is recognized that some biological properties of both neurons and schwann cells change with maturation and aging, culture systems of adult animal cells appear to mimic peripheral nerve degeneration and regeneration better than those of immature animal cells. we have established spontaneously immortalized schwann cell lines from long-term cultures of adult fischer rat peripheral nerves. one of these cell lines, designated ifrs , has been shown to retain distinct schwann cell phenotypes, such as spindle-shaped morphology with expression of glial cell markers, synthesis and secretion of neurotrophic factors and cytokines, and fundamental ability to myelinate neurites in cocultures with adult rat dorsal root ganglion neurons and nerve growth factor-primed pc cells. our current investigation focuses on the establishment of the coculture system of ifrs cells and nsc- motor neuron-like cells. nsc- cells were seeded at a low density ( x /ml) and maintained for a week in serum-containing medium supplemented with non-essential amino acids and brain-derived neurotrophic factor (bdnf, ng/ml). after overnight exposure to mitomycin c (mmc, micro g/ml), nsc- cells were cocultured with ifrs cells ( x /ml) and maintained in serum-containing medium supplemented with bdnf ( ng/ml), ciliary neurotrophic factor (cntf, ng/ml) and coenzyme q ( micro m). under this culture condition, overgrowth of nsc- cells was prevented and gradual movement of ifrs cells toward the neurites emerging from nsc- cell bodies was observed. double-immunofluorescence staining carried out at day of the coculture showed myelin protein zero-immunoreactive ifrs cells surrounding the beta iii tubulin-immunoreactive neurites. this coculture system can be a beneficial tool to study the pathogenesis of motor neuron diseases (e.g. amyotrophic lateral sclerosis, charcot-marie-tooth diseases and immune-mediated demyelinating neuropathies) and novel therapeutic approaches against them. santos pp , torezani gs , maciero l , pagliarini lfd , romão tt , abunahman ms , ferreira is , bittar c , pupe c , nascimento ojm . universidade federal fluminense (uff), rio de janeiro, brazil. zika virus (zikv) is a flavivirus related to dengue, yellow fever and west nile viruses, and has been recently associated to the occurrence of neurological complications in children and adults. previous studies have linked zikv to the development of guillain-barré syndrome (gbs), myelitis, meningoencephalitis and ophthalmological manifestations in adults. guillain-barré syndrome (gbs) encompasses a spectrum of post-infectious neuropathies characterized by different distributions of weakness and sensory impairment. serum anti-ganglioside antibodies are often found and are related to different clinical patterns. recently we have encountered patients in rio de janeiro, brazil, with distal edema in lower limbs, acute weakness, pain and sensory disturbances during the acute stage of an acute febrile exanthematous illness. the symptoms persist for up to days, with complete resolution afterwards, without specific therapy. blood concentrations of muscle enzymes show normal values, and electromyography and nerve conduction studies (emg/ncs) are usually unremarkable. of note, all cases have had positive rt-pcr for zika virus, indicating an illness that occurred during the viremic phase of this arbovirus infection, and complete recovery within the expected timeframe for the resolution of the systemic viremia. there is a subset of patients who developed acute weakness very early after the initial viral symptoms, with clinical, laboratorial and electrophysiological findings that substantially differ from gbs. we describe three cases with similar features suggestive of an acute infective polyneuritis (aipn). one might hypothesize that zikv might lead to a direct neurotropic injury, significant enough to cause weakness and sensory complaints, but not severe enough to cause permanent damage, resolving in conjunction with decreasing blood viremia. we consider that these patients differ from classical gbs because their illness begins during the acute febrile stage of an infective illness and the clinical course is more rapid leading to complete resolution in a few days. savransky a , mozzoni j , massaro sanchez mp , reisin r , monges ms . department of neurology, hospital de pediatria j.p. garrahan, buenos aires, argentine; department of physical therapy, hospital de pediatria j. p garrahan, buenos aires, argentine; department of neurology, britain hospital, buenos aires, argentine. our objective is to describe a series of children with guillain barré syndrome (gbs) included in the igos protocol. as part of the igos multicenter protocol, pediatric patients meeting gbs diagnostic criteria, who consulted within the first weeks of symptom onset and had parental consent to participate in the study were included. patients were also offered to participate in the extended -year protocol. all patients were evaluated according to the igos protocol. patients were recruited between october and june . twenty-four patients, eight girls, participated. ages ranged from months to years (mean . years). all patients agreed to participate in the extended protocol, which was completed by of them. eight patients completed the -year follow-up and are still under evaluation. five patients were lost to follow-up.twenty-two had the classic variant of gbs and two miller fisher. radicular pain in the back or lower limbs was reported by %. twenty-three patients underwent lumbar puncture and albumin-cytological dissociation was found in . in all cases, csf was stored for proteomic studies. all patients underwent emg showing aidp in , and amsan and aman in each. one patient with aidp developed to cidp. in patients full-spine mri was performed and cauda equina enhancement was found in every case. three patients required ucip, two with invasive and one non-invasive ventilation. all patients were treated with gammaglobulin, with a second dose at weeks in cases with a poor response. all patients who followed the protocol were evaluated with the gbs disability score. median score was at baseline and between and at the -year assessment. we describe a series of children with gbs as a part of an international protocol including patients of different ages. pain was a frequent and early symptom and could be determined despite the young age of our patients. most patients fully recovered. we were invited to participate in igos kids to better assess this age group. saysavath k , somchit v , t. umapathi . mittaphab hospital, vientiane, lao pdr; setthathilath hospital vientiane; national neuroscience institute, singapore, singapore. laos people democratic republic is a country of . million people in south east asia. largely agricultural, its capital and metropolis is vientiane. adult neurological services are concentrated at mittaphab hospital, vientiane serviced by three neurologists. on the average about six cases of guillain-barré syndrome (gbs) are seen per year. it is believed that most patients do not seek medical attention. cases appear to cluster during the rainy season. most patients present late, often at the second week of illness when recovery is unapparent after seeking treatment from traditional medicine doctors and at district hospitals. a substantial number of patients seek treatment at hospitals across the border, in neighboring provinces of thailand. common antecedent symptoms are viral prodrome and diarrhea. miller fisher syndrome appears to be rare, possibly because of the mild deficits that do not prompt patients to seek medical attention. diagnosis is made largely from clinical features and from spinal fluid analysis. nerve conduction studies are not available. patients are often treated with steroids by internists. intravenous immunoglobulin and plasma exchange are not available. common complications include pneumonia, autonomic dysfunction (fluctuating blood pressure), pressure sores and depression. patients who develop respiratory failure are nursed at a twelve-bedded intensive care units. plans are afoot to set up a prospective gbs database, systematically study antecedent infections, including of flaviviruses, and develop low-volume plasma exchange as a feasible therapeutic modality. a gene therapy approach for treating cmt c neuropathy schiza n , markoullis k , richter j , tryfonos c , kagiava a , sargiannidou i , christodoulou c , kleopa ka , . neuroscience laboratory; department of molecular virology; neurology clinics, cyprus institute of neurology and genetics and cyprus school of molecular medicine, nicosia, cyprus. charcot-marie-tooth type c (cmt c) is the most frequent form among recessively inherited demyelinating neuropathies and results from mutations in the sh tc /kiaa gene. sh tc mutations cause loss of function of the sh tc protein suggesting that gene replacement therapy may be useful for treating cmt c. sh tc −/− mice develop all major aspects of the human pathology including early onset progressive peripheral neuropathy with hypo-and demyelination along with decreased motor and sensory nerve conduction velocities, offering a relevant model for testing treatments for cmt c. in order to develop a gene replacement strategy for cmt c, we generated a novel lentiviral vector, lv-mpz-sh tc .myc, to drive expression of the human sh tc cdna under the control of the myelin protein zero (mpz/ p ) promoter specifically in myelinating schwann cells. a c-terminus myc tag was included to facilitate expression analysis. a control vector (mock) was also produced in which the sh tc cdna was replaced by the egfp reporter gene. we first confirmed expression of hsh tc in hela cells transfected with the pcdna -cmv-sh tc .myc vector. immunofluorescence analysis confirmed a strong expression of sh tc specifically at the plasma membrane with additional localization in a dotted pattern intracellularly. for in vivo gene delivery we used both intraneural and intrathecal injections of the lv-mpz-sh tc .myc vector in -week to -month old sh tc −/− mice. expression of virally delivered hsh tc was assessed weeks after injection. immunofluorescence analysis showed hsh tc immunoreactivity in perinuclear schwann cell cytoplasm in sciatic nerve teased fibers of sh tc −/− mice following both intraneural and intrathecal delivery, while lumbar intrathecal gene delivery resulted additionally in expression of hsh tc in the lumbar roots. real time pcr analysis confirmed hsh tc mrna expression in both lumbar roots and sciatic nerves. thus, we have developed a novel lentiviral vector for schwann cell targeted gene delivery to treat cmt c and for testing possible therapeutic effects in the mouse model of the disease. hereditary neuropathies are a group of disorders which are characterised by the systemic impairment of peripheral nerves. more than neuropathies are associated with causative gene defects [ ]. charcot marie tooth (cmt a) neuropathy is the most frequent hereditary neuropathy, triggered by a mutation in the peripheral myelin protein gene (pmp ). cmt a leads to a primary loss of myelin sheath and afterwards to a degeneration of axons [ ] . symptoms appear with the degeneration of axons, whereas demyelination is thought to be largely asymptomatic. for that reason, we investigate in the mechanisms of axonal degeneration. for our analysis, we used purified axoplasma without detectable myelin proteins of the sciatic nerves of weeks old pmp -c mice. in this early stage of the axonal degeneration sarm was significantly increased. the nad + concentration in the axoplasma was dramatically reduced. this correlates to the previous finding that sarm promotes axonal degeneration by cleavage of nad + . additional studies showed an increase of the nad + -dependent axonal protective factor sirt in pmp -c sciatic nerves. nmnat- , known as the active component of the wallerian degeneration slow gene, was unaffected in axoplasma of pmp -c sciatic nerves. summarised, these results indicate that the pathway of sarm , nad + and sirt may play a critical role in axonal degeneration in neuropathy. we report two unrelated czech patients with cmt b , both sporadic cases in the family. patient is a year old man with congenital glaucoma after ophthalmological surgeries. his early motor development was normal. at the age of years parents noted gait problems, first neurological examination was at the age of years, when emg showed diffuse motor and sensory neuropathy with severely decreased ncv ( - m/s). he developed foot deformities (pes cavovarus) and underwent corrective orthopedic surgeries at the age of years. after several dna tests for demyelinating cmt the sfb gene was sanger sequenced and a novel missense mutation p.ile asn was found in homozygous state in the patient and in heterozygous state in both parents. the patient was later tested also by ngs of a panel of all genes to be causal for hereditary neuropathies and no other potentially causal variants were detected. patient is years old man, with normal early motor development. at the age of years parents noted gait problems with distal leg weakness which progressed into distal leg plegia at the age of years. hand weakness was noticed since the age of years. he has severe atrophies of distal muscles of all extremities, is self ambulant. at the age of , emg showed unrecordable responses from nerves of lower limbs and ncv was measurable only on ulnar nerve and was m/s. at the age of years increased intraocular pressure was diagnosed and he uses anti glaucoma eye drops. after many single gene tests for demyelinating cmt, we used ngs of a panel of genes known to be causal for hereditary neuropathies and two novel heterozygous, probably pathogenic variants affecting invariant splice sites were detected: c. - a>g and c. - _ del, both confirmed by sanger sequencing. the first variant is also in the father, but the second is probably de-novo (not detected in parents, despite correct parentity). sekiguchi y , kikuchi si , konno si , sekiguchi m . department of orthopaedic surgery, fukushima medical university school of medicine, fukushima, japan. carpal tunnel syndrome (cts) is the most common entrapment neuropathy. ultrasonography can be used to detect anatomic changes in cts. more recently, it has been shown that doppler ultrasonography can detect increased intraneural blood flow in cts. the purpose of this study was to determine the most suitable finding of pre-and postoperation in cts by ultrasonography. a total of wrists of patients with nerve conduction study (ncs) proven cts were evaluated with ultrasonography. we measured the median nerve's cross-sectional area (csa) and intraneural blood flow of median nerve by ultrasonography. the correlation between these ultrasonographic measurements, ncs severity and duration of clinical cts symptoms was analyzed. the csa (mean, mm ) was no significantly reduction after successful carpal tunnel release. morphologic median nerve changes may persist for a longer period regardless of successful surgery and clinical improvement. however, intraneural blood flow is increasing after successful carpal tunnel release. we conclude that doppler ultrasonography results strongly correlate with post operated cts improvement. hence doppler ultrasonography is a useful method for functional improvement of pre-and post cts operation. senger jl , chan km , olson jl , webber ca . university of alberta, edmonton, canada. the beneficial effects of a preinjury crush conditioning lesion (cl) on peripheral nerve regeneration is well-documented in animal models. no human studies have been attempted to date, given the ethical dilemma of deliberately injuring an intact nerve, and the difficulty in predicting the timing of a nerve injury. recent studies demonstrate that hour of electrical stimulation (es) produces effects similar to cl in neuronal cultures. this, coupled with a surgical environment favoring nerve transfers, in which an intact nerve is deliberately cut to reinnervated a denervated muscle, means that es may be clinically translatable to enhance regeneration. this study hypothesizes that es prior to nerve injury will enhance nerve regeneration. twelve sprague-dawley rats were divided into four groups based on conditioning-type to the mid-common peroneal (cp) nerve: es ( ), crush ( ), sham-es ( ), and naïve ( ). one week following conditioning, they underwent a cut/coaptation of the cp nerve at the sciatic trifurcation. post-cut day , nerves and dorsal root ganglia (drgs) were collected. axonal counts of nerves stained with nf- revealed similar regeneration between es and crush ( . vs. . mm, p= . ) that was superior to sham-stimulation ( . mm) or no-conditioning ( . mm, p< . ). a greater number of axons at the distal tip were present in animals that received either type of conditioning compared to the unconditioned cohorts. drgs were stained with neuronal injury marker growth associated factor- (gap- ), and satellite cell glial cells with glial fibrillary acidic protein (gfap). significant increase in gap- expression at three days was observed in es and crush cohorts compared to sham or naïve (p< . ) cohorts. the satellite glial cells of es and crush conditioning showed a significant increase in gfap expression ( . % and . % respectively) compared to sham ( . %) and naïve ( . %) drgs. by demonstrating similar improvements in axon regeneration, this proof of principle project suggests that es conditioning may produce regenerative outcomes comparable to the classical crush injury model. in turn, this suggests that es may be a promising method for delivering conditioning lesions in clinical trials for conditioning nerves prior to surgical intervention. we report a unique case of newly developed waldenstrom's macroglobulinemia (wm) in a patient with chronic inflammatory demyelinating polyneuropathy (cidp) with antibodies against myelin-associated glycoprotein (mag) and sulfatide who was undergoing treatment with intravenous immunoglobulines (iv-ig). subsequent rituximab infusions did not have a positive impact. patients with wm can develop demyelinating and axonal polyneuropathies and few patients have anti-mag and/or anti-sulfatide antibodies. anti-mag antibodies ( % of wm) are associated with sensorimotor axon loss and demyelination and anti-sulfatide ( % of wm) with sensory axonal loss. rarely, both antibodies can be present, with a more severe clinical phenotype. cidp associated with anti-mag and anti-sulfatide antibodies can represent independent entities, not associated with wm. there are no reports to date of patients with cidp associated with anti-mag and anti-sulfatide antibodies that developed wm during immunomodulatory therapy with iv-ig. in addition, subsequent rituximab infusions after the iv-ig were stopped have not been proven beneficial, as has been previously reported for anti-mag cidp patients. seventy-six year old right-handed gentleman presented with persistent numbness in his left foot, three months following artificial disc placement in his lumbar spine. gradually he developed sensory ataxia. no radicular signs were present on exam or impingement on serial spine mri's. ncs/emg studies were consistent with a cidp variant with severely prolonged distal motor latencies. serum anti-mag and anti-sulfatide antibodies were elevated. chronic therapy with iv-ig was able to partially stabilize the symptoms; however, six years later he newly developed wm. subsequent infusions with rituximab, after iv-ig was stopped, did not improve the clinical picture or the ncs/emg findings. wm can newly develop in an autoimmune setting, such as cidp associated with anti-mag and anti-sulfatide antibodies. in this particular case, there was an ongoing immunomodulatory therapy for our cidp patient, as he had monthly iv-ig infusions. this may reflect a possible induction of pathological b cell clone proliferation during the iv-ig treatment. subsequent rituximab infusions, after the iv-ig was stopped, did not improve the symptoms or the demyelination features on ncs/emg. he continues to be symptomatic despite efforts. charcot-marie-tooth disease (cmt) is an inherited neuropathy without known cure (prevalance: : ). duplication of the gene encoding the peripheral myelin protein of kda (pmp ) underlies the most common subtype cmt a. severely affected cmt patients suffer from sensory and motor symptoms with wheelchair-boundness. the clinical phenotype is highly variable and is determined by the amount of axonal loss, but the molecular mechanisms of the disturbed neuron-glia interaction are poorly understood. risk factors have not been investigated. therefore, cmt-net, a german network funded by the german ministry of education and research (bmbf, bonn, germany) includes interdisciplinary expertise from molecular biology, neurology, neuropathology and human genetics in order to identify genetic and non-genetic risk factors of disease severity of cmt by: (i) examining the mechanisms of the disturbed axon-glia-interaction and neuronal vulnerability, (ii) identification of genetic modifiers and (iii) novel therapeutic targets, (iv) validating outcome measures in children and adults, (v) establishing a biobank and (vi) exploring the disease burden via an internationally harmonised patient registry. cmt-net includes three service structures cmt-net will focus on cmt a, but also includes rarer subforms. we will provide the scientific basis for the development of translational approaches to therapy in patients. our approach bridges cutting edge molecular screening techniques, transgenic animal models of altered axon-glia interactions (fly, chick, mouse, rat), state-of-the-art genomic technologies and human patient trials in order to understand and treat the disease aggravation in cmt. sezer g , tekol y , sezer z , . erciyes university, betül ziya eren genome and stem cell centre, kayseri, turkey; erciyes university, school of medicine, pharmacology department, kayseri, turkey; erciyes university, good clinical practice and research centre, kayseri, turkey. analgesic effects of antidepressant drugs are well known for a long time, however, their systemic side effects limit their usage as an analgesics. venlafaxine is an antidepressant drug that has different structure. our purpose was to investigate whether systemic analgesic effect has been proved drug, venlafaxine, has local peripheral antinociceptive action. we applied vanlafaxine ( μl , , , μg) to male, sprague-dawley rats' paws by intraplantar injection and also by intraperitoneal route ( , , , mg/kg) in formalin test, a model for acute and tonic pain. we also pretreated another groups of rats with mg/kg naloxone (opioid receptor antagonist), mg/kg cpt (adenosine a receptor antagonist) or saline (ip.) before μg/paw venlafaxine injection. to check the effect is local or not, we determined the blood levels of venlafaxine in at different time points after both the local and systemic applications by gc-ms method. datas were expressed as number of flinches and total time for biting/licking of the injected paw over phase ( - min) or phase ( - min) and analyzed using the student's t-test. venlafaxine induced antinociception at , and μg concentrations by the local peripheral application and at , mg/kg doses by the systemic application in formalin test and the effects were comparable. pretreatment with naloxone diminished the effect of venlafaxine in the both phases, however, it was not statistically significant. pretreatment with cpt decreased venlafaxine induced antinociception only in phase . neither naloxone nor cpt changed formalin induced nociceptive behaviors alone. this is the first that determines the peripheral antinociceptive actions of venlafaxine in rat formalin test. with roles of opioid and adenosine a receptors in this action. our results suggest that venlafaxine has local peripheral antinociceptive effect and such an activity may led to trials for to use this drug as a cream-gel formulation for analgesia in clinics in the future. topical application might permit the attainment of higher and more efficacious concentrations in the region of the sensory nerve terminal, with limited systemic side effects. shah a , hoffman em , klein cj , staff np . mayo clinic, rochester, usa. cipn is a common dose-limiting complication for patients with cancer. the long-term disease burden of cipn is compounded by increasing cancer survivorship, yet there are minimal data on long term outcomes following onset of cipn, especially in population-based studies. we utilized the rochester epidemiology project to examine incidence and disease burden of cipn among individuals of olmsted county, minnesota with neurotoxic chemotherapy exposure between and . clinical records were queried for the presence of neuropathic signs, symptoms and icd- diagnostic codes as well as for patient provided information on impairment with activities of daily living and use of pain medications. a total of individuals with incident exposure to neurotoxic chemotherapy agents between and were identified. based on aan criteria for identifying peripheral neuropathy, ( . %) of these individuals were determined to have cipn, while ( . %) controls did not. the median time from incident exposure to reported symptom onset was days (iqr . - ). patients with cipn received a neuropathy icd- diagnosis in merely cases ( . %). median survival following incident chemotherapy exposure among all cases and controls was . years with a significantly longer mean survival in cases with cipn as compared to that of controls ( . years vs. . years, p< . ). in addition to acute effects in cipn, individuals surviving greater than years following exposure to neurotoxic chemotherapy continue to self-report increased symptoms of numbness (or . , % ci . - . ) and pain (or . , % ci . . . ) of the extremities. through utilization of patient provided information, our study was able to collect data on long-term impairment associated with previous history of exposure to neurotoxic chemotherapy. our results are consistent with previous reports of the high incidence of cipn in the first two years following incident exposure. additionally, our results provide evidence of high incidence of cipn independent of individual chemotherapeutic agent used. additionally, our results indicate icd- -cm diagnostic code attribution may dramatically underestimate the magnitude of cipn. increased survival following exposure to neurotoxic chemotherapy and its long-term disease burden necessitates further study of among survivors. the utility of quantitative muscle ultrasound as a marker of disease severity in charcot-marie-tooth (cmt) disease subtypes was investigated. muscle ultrasound was prospectively performed on individual muscles from cmt patients ( cmt a, cmtx , cmt a) and compared to muscles from age and gender-matched controls. muscle ultrasound recorded echogenicity and thickness in representative muscles including first dorsal interosseus (fdi) and tibialis anterior (ta charcot-marie-tooth (cmt) disease is the most frequent inherited peripheral neuropathy, and there is currently no available cure. the most common subtype of cmt, cmt a, is completely associated with duplication of the pmp gene, which encodes peripheral myelin protein of schwann cells. previous studies of cmt a mainly relied on rodent models, and it is not yet clear how pmp overexpression leads to the phenotype in patients. based on induced pluripotent stem cell (ipsc) technology, we herein developed a brand new in vitro cell model of cmt a, called cmt a-hipscs, in the hopes of simulating the developmental progress of the disease and gaining new insights into its pathogenesis. here, we efficiently derived ncscs from cmt a-ipscs and assessed the potential of the isolated cmt a-neural crest stem cells (ncscs) to differentiate into peripheral neurons and schwann cells using defined media. we found that, unlike normal control ncscs, cmt a-ncscs rarely generated schwann cells. instead, cmt a-ncscs produced numerous endoneurial fibroblasts in the schwann cell differentiation system. we further established a pmp -overexpressing ipsc model, and obtained similar results when pmp -ncscs were subjected to schwann cell differentiation. these results suggest that the development of schwann cells in cmt a patients is interrupted by the duplication of pmp . with the exception of the demyelination-remyelination process, developmental disabilities of schwann cells should be considered as an underlying cause of cmt a. shimoi t , yamada t . international university of health and welfare, tochigi, japan, cmt japan, tokyo, japan. charcot-marie-tooth (cmt) disease is the most common hereditary motor and sensory neuropathy. our preliminary report suggests that a certain cmt patient has the recruitment disorder of motor units during muscle fatigue and this disorder may be a factor of "super fatigability" in motor neuropathy patients. if the "super fatigability" occurs, we would expect patients with this characteristic to become slower in recovery from muscle fatigue than patients without this characteristic. in order to verify this hypothesis, we measured characteristic of recovery from muscle fatigue in charcot-marie-tooth patients with electromyographic study. twenty three participants were asked to maintain their % of maximal voluntary isometric contraction (mvc) of elbow flexor until exhaustion as the fatigue exercise. in addition, the participants asked to perform s of their % of mvc at , , , , , , , , , s after the fatigue exercise as recovery tasks. the surface emg (semg) signals of biceps brachii muscle were determined during the exercise and tasks. muscle force, median power frequency (mdpf) and the root mean square of semg amplitude (rms) were used as objective parameters of muscle fatigue. borg scale was used as a subjective parameter of muscle fatigue. six of twenty three participants showed significant decrease of rms during the fatigue exercise. in consideration of this result, we compared alteration of mdpf in recovery task between six participants with decrease of rms (abnormal group) and seventeen participants with increase of rms (normal group). as the result, the abnormal group had at least s as the recovery time from muscle fatigue in contrast with s of normal group. the recovery time from muscle fatigue in subjective parameter was shorter than the time in objective parameters in each group. our data support the "super fatigability" hypothesis. and that hypothesis may induce "hidden muscle fatigue". comparison between complex regional pain syndrome type and based on electrophysiologic, imaging and clinical findings shin jy , moon jy , sung jj . seoul national university hospital, seoul, republic of korea. complex regional pain syndrome (crps) is a constant regional neuropathic pain characterized by various kinds of motor, sensory, and autonomic changes. conventionally, the crps is divided into type i and ii according to the absence and presence of nerve injury. but the pathogenesis of crps is not fully understood yet. and there is still no systematic comparative study between crps type i and ii. we compared between crps type i and ii using multimodal approaches including electrophysiologic, imaging, and clinical findings. the patients ( type i and type ii) diagnosed with crps using the international association for the study of pain (iasp) diagnostic criteria were included. type i and ii were divided by electromyography and nerve conduction study. we obtained clinical information such as continuing pain, allodynia, hyperalgesia, edema, temperature, skin color, sweating, trophic change from patients. all patients were evaluated by bone scan, thermography, quantitative sudomotor axon reflex test (qsart), quantitative somatosensory test (qst). the ratio of qsart and temperature threshold abnormality in type ii was higher compared to type i ( . % vs . %, . % vs . % respectively, p = . and . ), among clinical symptoms, sweating change significantly high in type ii compared to type i ( . % vs . %, p = . ). other electrophysiologic and imaging, clinical findings were not significantly different in both type. in this study, we identified that crps type i and ii are distinguished not only by the nerve injury but also by the sudomotor function, and qsart can serve as a good technique to differentiate between crps type i and ii. it is estimated that there are two distinct pathogenesis in crps. our results may be helpful to diagnose crps correctly and understand the pathogenesis of crps. sjogren syndrome (ss) is an autoimmune inflammatory disorder of exocrine glands resulting in xerophthalmia and xerostomia. ross syndrome is a rare entity characterized by tonic pupil, hyporeflexia, and segmental anhidrosis. we present a -year-old hispanic woman with debilitating sensory and autonomic neuropathies, and persistently elevated anti-ss-a and anti-ss-b antibodies, without the classic sicca complex. she initially developed diarrhea and an ear infection, then felt toe and later leg numbness, which eventually spread to her cheeks and tongue, over few months. four years later, her thumbs and index fingers started tingling. also, she developed orthostatic lightheadedness, tachycardia, segmental hypohidrosis of the right abdomen, and hyperhidrosis of the remaining trunk, intermittent erythema, chronic diarrhea, and a -pound weight loss. her exam demonstrated orthostatic hypotension, bilateral tonic pupils and light-near dissociation, sectoral palsy of the right iris sphincter, stocking-distribution diminished sensation to all modalities, pseudoathetosis, areflexia, dysmetria, intention tremor, romberg, and sensory gait ataxia. mri of neuraxis demonstrated t -weighted hyperintensity in the dorsal spinal cord from c to the lower thoracic level, with mild atrophy. electrodiagnostic testing was consistent with moderate-to-severe, length-dependent, asymmetric, sensory polyganglionopathies. csf showed oligoclonal bands. serology showed elevated antinuclear antibody ( : , reference < : ), ss-a ( , reference < u), ss-b ( , reference < u), and rheumatoid factor ( , reference < iu/ml) titers. the remaining workup was negative for infection (syphilis, hiv, htlv, hepatitis, lyme disease), paraneoplastic syndrome (anti-hu and ganglionic nicotinic acetylcholine receptor antibodies), pyridoxine intoxication, malignancy (chest/abdomen/pelvis ct, breast ultrasound, axillary lymph node flow cytometry, colon and esophagus biopsy), celiac disease, vitamin deficiency, autoimmune disease (anti-aquaporin and anti-gq b antibodies), and adrenoleukodystrophy. the patient received ivig and steroid with some gait improvement and currently takes mycophenolate. midodrine and fludrocortisone resolved her dizziness. this case highlights an important, treatable sensory ganglionopathy and systemic autonomic neuropathy due to sjogren syndrome, and illustrates the overlapping clinical triad of ross syndrome, which may guide future management. siles am , , assylbekova d , , diaz-manera j , , rojas-garcia r , , cortes e , , gallardo e , , illa i , , querol l , . neuromuscular diseases unit, neurology department, hospital de la santa creu i sant pau, univeristat autònoma de barcelona, barcelona, spain; centro para la investigación biomédica en red en enfermedades raras (ciberer), madrid, spain. inflammatory neuropathies are a heterogeneous group of peripheral nerve diseases that respond to immune-therapies. chronic inflammatory polyradiculoneuropathy (cidp) and multifocal motor neuropathy (mmn) are two chronic inflammatory neuropathies responding to intravenous immunoglobulins (ivig). b lymphocytes are involved in their pathogenesis. while widely used in clinical practice, ivig's mechanism(s) remain not completely understood. ivig are reported to lead to b-cell anergy and to increase regulatory t-cell function and frequency. regulatory b cells (bregs) are a rare subset of b lymphocytes that suppress immunopathology acting upon several target cells in the immune system. impaired breg yields have been described in a plethora of autoimmune conditions. the presence of regulatory b cells in inflammatory neuropathies and the effect of ivig therapy on their frequencies has not been studied. the aim of this study is to describe the frequencies of bregs in cidp and mmn and the effect of ivig on their frequencies. patients fulfilling diagnostic criteria for cidp or mmn and matching controls were included. pbmcs were obtained by gradient centrifugation before ivig infusion and one week after treatment. b-cells were isolated with negative selection magnetic beads, cultured and activated with the tlr agonist odn and anti-human igg+iga+igm. il- secretion capacity was assessed by flow-cytometry. twenty-eight patients were included of whom where cidp and mmn. of all patients included, received ivig and were suitable for pre and post ivig breg frequency comparisons. breg frequencies did not differ in patients (before ivig treatment) and controls (p= . , mann whitney test, two-tailed). however, the frequencies of bregs significantly increased one-week after treatment with ivig (p= . , wilcoxon matched pairs test, two-tailed). when stratifying by disease subtype, breg frequencies increased in cidp patients after ivig (p= . , wilcoxon matched pairs test, two-tailed) and in mmn (p= . , wilcoxon matched pairs test, two-tailed) although results did not reach statistical significance in mmn. this is the first study that studies the breg frequencies in cidp and the first study that addresses the effect of ivig on breg frequencies. our study provides the proof of principle that bregs could become a biomarker for response to ivig but this would need a larger and prospective study. siles am , , martínez-hernández e , diaz-manera j , , rojas-garcia r , , gallardo e , , illa i , , graus f , querol l , . paraneoplastic neuropathies (pn) are rare, immune-mediated disorders of the peripheral nerve with important prognostic implications. ectopical expression of neural antigens in the tumor leads to the development of onconeural antibodies. several autoantibodies associate to pn, including anti-hu, anti-caspr or anti-cv antibodies but a significant proportion of pn lack identifiable antigens. adhesion molecules that are autoantigens in other neuropathies, like contactin- , are present in several types of tumors. our study proposes a systematic screening of autoantibodies against neural cell-adhesion molecules and neural structures to detect novel antigenic reactivies in pn. thirty-five patients followed in our centre and at the neuroimmunology-multiple sclerosis unit at hospital clínic de barcelona, with pn fulfilling diagnostic criteria of possible (n= ; . %) and definite (n= ; . %) paraneoplastic disease were included. serum samples were obtained and tested by immunocytochemistry against contactin- (cntnt ), neurofascin (nf ) and the cntn /caspr complex. primary cultures of dorsal-root ganglia (drg) and rat schwann cells were incubated with patients' sera to detect antibodies targeting neural structures. ten individuals ( . %) presented with a tumor and a neuropathy involving both sensory and motor symptoms. the remaining patients ( . %) presented with a tumor and a classical sensory neuronopathy without anti-hu or any other onconeuronal antibody. among the latter, ( . %) patients were diagnosed with small-cell lung carcinoma. the rest of the individuals ( . %) associated diverse malignancies. we did not detect any sera reacting against cntn , nf or the cntn /caspr complex. in igg antibody screening experiments, patients ( . %) reacted against drg neurons, of them ( . %) reacting strongly, and patients ( . %) reacted mildly against rat schwann cells. in igm experiments, patients ( . %) reacted slightly against drg neurons and patients ( . %) against rat schwann cells, of them ( . %) featuring strong staining. experiments screening antibodies against motor neurons and immunoprecipitation assays are ongoing. overall, % of patients reacted strongly against either neurons or schwann cells. our study did not detect antibodies against the neural adhesion molecules cntn , nf and the cntn /caspr complex in patients with pn. however, a significant proportion of pn patients harbour antibodies targeting neural structures, which suggests that novel neoplasm-associated antigens remain to be discovered. simmons m , tao f , abreu l , zuchner s , li j . department of neurology, vanderbilt university school of medicine, nashville, tennessee, usa; hussman institute for human genomics, university of miami, miami, florida, usa. objective: despite of a shared genetic mutation of the trisomy of chromosome p (c p ), patients with charcot-marie-tooth type- a (cmt a) present with a high variability of their disease severities. the underlying cause for the variability is still unclear. in this study, we tested a hypothesis whether a second genetic mutation known to damage the nervous system is also present in cmt a patients with early onset and severe phenotypes. methods: from a cohort of patients with cmt a mutation (chromosome p duplication), we identified patients with an early onset (< or = years of age) of the disease. four of the eleven also had dna testing for a panel of known cmt-related genes and sequencing of mitochondrial dna in addition to the dna testing for c p duplication. results: besides the c p duplication, we identified three additional mutations in the four patients with early onset. the mutations were a missense mutation of arg his in mpz gene, an a g mutation in mitochondrial trna for glycin and a homozygous mutation of c p duplication. three of the four had symptomatic onset at birth. one showed symptoms at years of age. conduction velocities were severely reduced in all four patients (from to m/s). interpretation: traditional approaches to identify genetic modifiers, including snp association, assume that those modifiers are clustered in a small region of human genome and shared by the studied patients. however, our study suggests that genetic modifiers in cmt a may be highly diverse and scattered throughout the genome, which could make the conventional approach via the genetic variants association difficult. supported by grants from ninds (r ns ) and the national center for advancing translational sciences (ul tr sjogren's syndrome(ss) is a systemic auto-immune disease that apart from exocrine glands may affect any organ. involvement of peripheral nervous system results in wide spectrum of neuropathic manifestations. the aim of our study was to evaluate the clinico-electrophysiological patterns and pathological characteristics of neuropathy in sjogren's syndrome (ss) patients presented to neuromuscular clinic in a tertiary hospital from south india. this is a retrospective study from the departments of neurology, rheumatology and pathology from nizam's institute of medical sciences. twenty one patients with diagnosis of ss and peripheral neuropathy between to were analysed. clinical records, conventional nerve conduction studies, lip and nerve biopsy reports were collected.in patients with ss associated neuropathy,male to female ratio was : . in ( . %) neuropathy was the initial manifestation,while in ( %)exocrinopathy preceded neuropathy. the patterns of neuropathy included mononeuropathy multiplex(mnm) in patients ( %),ganglionopathy in ( %),length dependant, trigeminal, autonomic neuropathy and cidp in ( %)and cranial neuropathy in ( %).eighteen( %) were seropositive..schirmer's test was positive in ( . %).nerve biopsy showed vasculitis in patients, demyelinating and axonopathy in patients each.we conclude that neuropathy is frequently the initial presentation of ss.mnm is the common pattern followed by ganglionopathy. pattern of neuropathy helps in arriving at the diagnosis of ss. confirmation of ss is not by mere serology. schirmer's test and lip biopsy are equally essential for the diagnosis especially in seronegative patients when clinical index of suspicion is high. siskind ce , tesi rocha c . stanford health care, palo alto, ca, usa; stanford university, stanford, ca, usa. here, we report the first case of a human found to have a homozygous, presumed disease causing variant in the arl ip gene, causing charcot marie tooth disease (cmt) with central nervous system findings. the proband was born at term with apgars of and at and minutes. he was found to have iugr and was hospitalized for days for weight gain. he developed respiratory distress during the admission and was intubated. due to inability to extubate, he was transferred to stanford children's hospital, where he remained for three months. noted during admission was hypotonia, areflexia, minimal voluntary movment, sinus tachycardia, and dysautonomia. brain mri found polymicrogyria and cerebral underdevelopment with generally normal-appearing brainstem, with moderate ventriculomegaly. ncs found length dependent polyneuropathy with axonal degeneration. follow up muscle and nerve biopsy found immature muscle and amyelinating neuropathy the patient had normal plasma amino acid, acylcarnitine, lactate, pyruvate, urine organic acid testing, opththalmology exam, newborn screen, and normal array cgh. genetics ordered whole exome sequencing through baylor genetics laboratory (houston, tx, usa), which found a homozygous nonsense variant in arl ip : c. c>t, p.r x. a second child had been identified by baylor with two variants in this gene. that child had hypotonia, respiratory distress and seizures, and a muscle biopsy consistent with sma. the parents of that child chose to withdraw care at months of age. our patient's parents continued with aggressive therapies, including tracheostomy and g-tube for feedings. he had several subsequent hospitalizations for respiratory distress, possible seizure activity, and buldging anterior fontenelle, but now, at two years of age, has made developmental progress and is living at home with his family. he is able to smile, reaching for toys and swatting objects. he has little voluntary movement, and no longer responds to light touch stimuli. overall, this is the first picture of a child affected with a severe amyelinating form of cmt that causes weakness, hypotonia, and possible seizures, with the main concerning feature being the severe respiratory distress that may be life threatening, but can be managed with extreme care. charcot marie tooth (cmt) disease is the most common inherited peripheral neuropathy. patients frequently ask whether pregnancy will affect their cmt, whether cmt will affect their pregnancy, the optimal delivery and whether they or their child will have a higher risk of complications during pregnancy or delivery. so far few studies address these questions. currently no guidelines exist for the management of pregnancy, delivery and postnatal care in cmt patients. the aim of the study is assess the impact of pregnancy on cmt and assess how cmt affects pregnancy, delivery and care of the new born baby. we designed a retrospective questionnaire with expert help from an obstetrician with a special interest in pregnancy in patients with medical conditions. the questionnaire is divided into four parts (prior, during, after pregnancy and delivery) and includes questions on impairment, falls, pain, fatigue and respiratory complications during those periods; type of delivery, possible complications, details of anaesthesia and difficulties looking after the baby in the first months postpartum. so far women ( pregnancies) with cmt and related disorders have answered the questionnaire. % of patients had cmt a, the remaining had various subtypes of cmt and related disorders. patients reported deterioration of cmt symptoms during pregnancy in % of pregnancies with resolution of symptoms after pregnancy in % of pregnancies. of symptoms questioned walking ( %), balance ( %), and hand function ( %) deteriorated the most. there was an increased use of orthoses and walking aids during pregnancy. the majority of women ( %) had natural delivery, % were assisted and % had caesarian sections which was similar to the uk population ( %). no complications with anaesthesia were reported. the survey is currently ongoing. we plan to survey consecutive patients. data acquired from this survey will provide valuable information on current practice and will inform future guidelines and standard of care in charcot marie tooth disease. multifocal motor neuropathy (mmn) is a slowly progressive disorder in adults, characterized by asymmetrical limb weakness, mainly affecting the arms. despite beneficial effect of immunoglobulins, weakness gradually progresses. a major determinant of muscle weakness is the degeneration of affected motor axons. treatments aiming to reduce loss of motor axons require objective tools to quantify such an effect. therefore, we applied the compound muscle action potential (cmap) scan, which is an electrophysiological method that, with increasing transcutaneous stimulus-currents, successively activates all motor units (mus) in a muscle. it captures the contribution of enlarged mus due to reinnervation by the presence of relative large discontinuities in the scan. the aim of the present study was to identify pathophysiological changes of mu-loss and reinnervation in mmn patients by means of the cmap-scan. recordings were obtained from mmn patients. cmap-scan recordings were performed in the median nerve at the wrist where motor responses were recorded from the thenar muscle. we determined the number of largest cmap-scan discontinuities by means of a novel marker, d , where a low number is indicative of mu-loss and enlarged mus. furthermore, we applied the recently developed method of professor hugh bostock for obtaining a mu-number estimate from the cmap-scan. the median peak cmap amplitude was . mv (range . - . mv) and median d was (range - ). in three mmn patients with a normal maximum cmap amplitude (> mv) a reduced d (< ) was found indicative of mu-loss and enlarged mus. furthermore, d and the estimate of mu number were significantly related (r = . , p < . , n = ). the findings suggest that the cmap-scan is a sensitive tool in detecting the underlying pathological changes of reinnervation and mu-loss in mmn, more so than standard maximum cmap amplitude. it is quick and easy to perform and has the potential to be useful for follow-up studies. smith ag , thurgood b , revere c , hauer p , aperghis a , singleton jr . university of utah, salt lake city, utah, usa. corneal confocal microscopy (ccm) directly and quantitatively assesses corneal innervation including nerve fiber length (nfl) and density (nfd). ccm has shown promise as a diagnostic test. we have previously demonstrated that ccm has a diagnostic performance for diabetic neuropathy (dpn) similar to skin biopsy with assessment of intraepidermal nerve fiber density (ienfd) and nerve conduction studies (ncs). the responsiveness of these surrogate measures to dpn progression and their relation to clinically meaningful outcomes has not been well explored. diabetic patients undergoing annual retinopathy examination were recruited. each underwent ccm, ienfd, ncs including sural sensory and peroneal motor responses, the utah early neuropathy score (uens), the norfolk quality of life -diabetic neuropathy (nqol-dn, a validated neuropathy specific qol scale), and a minute walk test ( mwt). with dpn based on symptoms ( %) or signs underwent repeat testing at months and at months. at baseline, nqol-dn correlated with sural sensory amplitude (ssa) (− . , p< . ), peroneal motor conduction velocity (pcv) (− . , p< . ) and ienfd (− . , p< . ). no ccm metric was related to qol. mwt distance correlated with ssa ( . , p< . ), nfl ( . , p< . ) and nfd ( . , p< . ). over months, there was a significant worsening in dpn signs assessed by the uens (increase . +/− . , p< . ). ssa declined . uv (p< . ) and ienfd . fibers/mm (p< . ). there was no change in any ccm metric, pcv or nqol-dn. these findings suggest measures of distal axonal integrity are most sensitive to neuropathy progression, with ienfd having the greatest responsiveness. in contrast, ccm was not responsive to dpn progression. both ncs and ienfd (but not ccm) were significantly correlated with neuropathy-specific qol, whereas ncs and ccm measures correlated with physical functioning. the responsiveness of ienfd and ssa, and their relationship to qol support their selection as endpoints in dpn clinical trials. chronic inflammatory demyelination polyradiculoneuropathy (cidp) affects in , people, and is marked by chronic autoimmune infiltration of peripheral nerves and destruction of the myelin sheath. with current therapies, only % of cidp patients achieve complete remission. to produce more effective, mechanism-based therapies, we study mice with a partial loss of function g w substitution in the autoimmune regulator (aire) gene on the non-obese diabetic (nod) background (nod.aire gw/+ ) that develop spontaneous autoimmune peripheral polyneuropathy (sapp) resembling cidp. autoimmunity can result from defective immunosuppression. the potent, immunosuppressive cytokine interleukin (il- ) is increased in the peripheral blood mononuclear cells (pbmcs) of active phase cidp patients relative to remission phase patients. further, pbmcs from cidp patients produce il- in response to the myelin protein p . despite these findings, whether il- is important for cidp pathogenesis is not known. thus, we sought to determine the role of il- in sapp. il- was highly upregulated in sciatic nerves of nod.aire gw/+ mice with sapp, suggesting it may play an immunosuppressive role in pathogenesis. however, genetic ablation of il- in nod.aire gw/+ mice lead to a paradoxical delay in disease development. age-matched il- -deficient nod.aire gw/+ mice exhibited no sciatic nerve infiltrate and no reduction in nerve conduction during electrodiagnostic studies. interestingly, the delay in sapp was specific, since the incidences of five other autoimmune manifestations in il- -deficient nod.aire gw/+ mice were unchanged relative to il- -sufficient nod.aire gw/+ controls. importantly, il- -deficient nod.aire gw/+ mice did not have colitis, which is consistent with previous studies of il- deficiency on the nod background. il- is known to perform effector functions in autoimmunity by promoting b cell secretion of immunoglobulins. however, genetic ablation of b cells did not affect neuropathy development in nod.aire gw/+ mice, suggesting b cells are dispensable for pathogenesis and unlikely to mediate the protective effect of il- deficiency. il- -deficient nod.aire gw/+ cd + t cells, which are sufficient to transfer sapp, exhibited increased activation, increased interferon gamma secretion, and preserved nerve-specific t cell activation. these data suggest t cell activation and priming are unperturbed and not the mechanism of protection. in summary, our data showed that il- was paradoxically an effector cytokine in sapp. long exercise test (let) has been used especially in myotonic syndromes and muscle channelopathies. marked decrement in compound muscle action potential (cmap) amplitude after prolonged exercise was previously reported in patients with paramyotonia congenita, hyperkalemic or hypokalemic periodic paralysis. we describe a patient with secondary hypokalemic paralysis who showed abnormal let results. a -year-old man presented with ascending flaccid paralysis which evolved in a hyperacute fashion. the patient became quadriplegic after two hours. initial laboratory evaluation revealed severe hypokalemia, with normal thyroid function. we performed electrodiagnostic studies including long exercise test as proposed by mcmanis et al. nerve conduction study was normal, but marked decrement in cmap amplitude (up to % decrease after minutes) was noted after prolonged exercise. despite oral and intravenous potassium replacement, serum potassium level was not corrected as expected. the unusual clinical course prompted for evaluation of secondary etiologies. abdomen computed tomography scan revealed a . x . cm-sized mass in the left adrenal gland. aldosterone to renin ratio was elevated, suggestive of primary hyperaldosteronism. genetic study for cacna s mutation turned negative. after receiving laparoscopic adrenalectomy, the patient experienced no further attacks, and also was able to stop his antihypertensive medication. let may show abnormal results in condition with reduced membrane excitability, even without true channelopathy. according to international criteria, the diagnosis small fiber neuropathy (sfn) is based on clinical symptoms in combination with a reduced intraepidermal nerve fiber density (ienfd) in skin biopsy and/or abnormal temperature threshold testing (ttt). the sensitivity of skin biopsy is moderate to good, although ienfd is normal in about % of patients with sfn complaints. furthermore, ttt is a widely available diagnostic tool, but lacks specificity. corneal confocal microscopy (ccm) has been described and is used in clinical practice as an objective, non-invasive diagnostic tool to detect small nerve fiber damage in patients with diabetes mellitus. this study examines the applicability of ccm in patients with sfn, and the value of ccm as an additional diagnostic tool in sfn. we will include healthy participants to compare the results with the recently published ccm normative values, and patients referred to the sfn center maastricht with the clinical picture of sfn. corneal nerve fiber density (cnfd), branch density (cnbd), fiber length (cnfl), and the tortuosity coefficient (cnft) will be determined in all participants. the results will be compared with the ienfd and ttt. preliminary results will be presented. southanalinh k , university of health sciences, vientiane capital, lao p.d.r. located in south east asia, lao pdr is a landlocked country with a population of about . million inhabitants. the health indicators are among the lowest in south east asia. the total health caregivers in consisted of , persons corresponding to a ratio of . health workers per inhabitants. the main network for health care service provision remains the public system. its health care facilities consist of four central teaching and referral hospitals; five regional hospitals, including one teaching hospital; provincial hospitals; district hospitals, and about health centers. only one in seven sick people receives modern health care treatment. most people rely on self-medication and/or reliance on self-healing. neurological care is a very new field. knowledge of common neurological disorders among both the lao population and medical staff is only beginning to be spread. there are three neurologists in the country. six neurology residents are currently being trained in a three-year program supported by the association pour la promotion des neuro-sciences au laos (association for the promotion of neuro-sciences in laos) and the asean neurological association. indeed, resources are scarce. in the peripheral nerve diseases domain for example, we have only one electromyography machine that was only temporary used when emg experts from france and from singapore came to teach residents. a significant mismatch between the provision of specialized neurologic services and the needs for them exists, especially in rural areas. also, health insurance is not available for the majority. as a consequence, patients have to bear the costs themselves, which constitutes a limit to the access of available healthcare facilities. neurologic training centers, laboratory facilities and equipments are limited. optimizing available human resources, integrating primary, secondary, and tertiary healthcare tiers and making medical treatment more affordable are need to improve neurologic care in the developing world. in certain low-income countries with limited human and financial resources, it may be difficult for governments to apply some of these recommendations on their own. in these circumstances, it is suggested that countries work with international agencies, nongovernmental organizations or other partners to put their plans into practice. spina e , topa a , iodice r , tozza s , dubbioso r , ruggiero l , santoro l , manganelli f . department of neuroscience, odontostomatological and reproductive sciences, university of naples "federico ii", naples, italy. chronic inflammatory demyelinating polyradiculoneuropathy (cidp) is a disabling disease and about % of patients may become persistently disabled over time. our aim was identify clinical prognostic factors of long-term disability in a large series of cidp patients. we collected data from cidp patients with definite diagnosis according efns/pns criteria and positive response to first-line therapies (immunoglobulin or corticosteroids) including sex, age of onset, phenotype, disease duration, course of disease (monophasic/relapsing-remitting or chronic progressive) and disability at the time of diagnosis assessed using the modified rankin scale (baseline mrs). all patients had clinical assessment of disability through mrs within the last months (last mrs). ordinal logistic regression model was applied to evaluate the relationship among the clinical parameters and last mrs, considered as ordinal outcome ( - ). anova test for repeated measures was applied to test the overall effects of different course on disability accumulation while t-test was performed to evaluate inter-group differences for parametric variables. we found a significant relationship between last mrs and the course of disease [p< . , z= . , or: . ]. disability accumulation was greater in patients with chronic progressive course than those with monophasic/relapsing-remitting course of disease [p= . ]. moreover, patients with progressive course were older [p= . ]. our data suggest that chronic progressive course of disease may be a major negative prognostic factor for long-term disability in cidp patients. to note that a chronic progressive course of disease is also associated with an older age from the beginning and a more pronounced worsening over the course of disease. sprenger a , lichtenstein t , henning t , lehmann hc . department of neurology, university hospital of cologne, cologne, germany; institute of diagnostic and interventional radiology, university hospital of cologne, cologne, germany; department of neurology, university hospital of cologne, cologne, germany. an unresolved problem in the treatment of inflammatory neuropathies is the lack of valid and reliable diagnostic biomarkers to evaluate axonal damage. we investigated if "diffusion tensor imaging" (dti) and mri t w multi echo dixon imaging are eligible methods to determine proximal nerve injury in chronic inflammatory demyelinating polyneuropathy (cidp). in this prospective observational cohort study the sciatic nerve of cidp patients and age matched healthy controls was investigated. all subjects underwent multimodal mri imaging to determine fractional anisotropy (fa) and muscle fat fraction of the biceps femoris and quadriceps femoris muscle. patients were evaluated by mri, clinical examination and nerve conduction studies at baseline and after six months. the mean fractional anisotropy (fa) value was significantly lower in the sciatic nerve from cidp patients compared to controls. fat fraction of the biceps femoris and quadriceps femoris muscle were significantly higher in cidp patients compared to controls. mri outcome parameters remained unchanged after six months. our study demonstrates the utility of mri imaging to differentiate between "healthy" and functional constricted proximal nerve segments. we postulate that dti and dixon mri might be eligible methods to assess proximal nerve damage in cidp. the presence of peripheral myelin protein (pmp ) has been known for decades, but its functional role was uncovered only recently. recent characterization of pmp -deficient mice revealed a role of pmp in the lipid homeostasis of myelinating schwann cells. in this study, we analyzed the functional impact of pmp on myelination. to decipher the role of pmp , experimental demyelination was performed in myelinating dorsal root ganglia cultures, and in vivo re-myelination was assessed after experimental peripheral nerve damage. we used the myelinating dorsal root ganglia (drg) model in pmp -deficient schwann cell cultures, combined with an established de-and remyelinating protocol in order to analyze myelination in vitro. we also performed experimental nerve crush in pmp -deficient mice. morphometric parameters were defined for the in-vitro experiments and functional parameters such as nerve conduction velocity and the clinical score were additionally measured for the in vivo experiments. structural analyses of the drg cultures revealed fibers expressing myelin basic protein (mbp) and pmp , as well as fibers positive for mbp alone. in contrast to our previous in vivo data, we were also able to detect myelin segments that stained positive for pmp , but were negative for mbp. pmp -deficient drg-cultures demonstrated slightly greater nodal lengths than the control cultures. this trend was significantly augmented after in vitro de-and remyelination, which also resulted in decreased internodal lengths only now, while conserving an intact myelin structure. concomitantly, in vivo nerve crush gives rise to a more severe phenotype in pmp -deficient mice than in wild-type controls. consistent with this, nerve conduction studies showed a delay in remyelination, and analysis of semi-thin sections demonstrated an altered fiber structure in the peripheral nerve biopsies. together, these data suggest that in addition to its role in glial cell lipid homeostasis, pmp also plays a role in remyelination of the injured peripheral nervous system. anti-mag neuropathy remains a difficult diagnosis to treat given its limited therapeutic options. of all interventions, rituximab has emerged as the most effective, although its effect has been with mixed results, especially in patients with advanced axonal loss. lenalidomide is another promising immune modulating therapy, whose effect has been well demonstrated in neuropathy associated with poems (polyneuropathy, endocrinopathy, organomegaly, m-spike protein, and skin changes) syndrome, a condition that has several striking parallels to anti-mag neuropathy. the use of lenalidomide has not been previously described in anti-mag neuropathy. herein, we describe a case of lenalidomide-responsive anti-mag neuropathy in a patient with advanced axonal loss. suichi t , misawa s , sato y , beppu m , sekiguchi y , shibuya k , watanabe k , amino h , kuwabara s . department of neurology, graduate school of medicine, chiba university, chiba, japan; clinical research center, chiba university hospital, chiba, japan. polyneuropathy, organomegaly, endocrinopathy, m-protein, and skin changes (poems) syndrome is a rare cause of demyelinating neuropathy associated with plasma cell dyscrasia and vegf overproduction. several diagnostic criteria for the disorder have been published, but sensitivity/specificity analyses, and their validation have never been performed. the aim of this study is to establish valid diagnostic criteria for poems syndrome. consecutive poems patients, seen at chiba university hospital since , were screened. of these, we have set a gold standard group of poems syndrome, based on treatment response and exclusion criteria during -year follow-up, and patients was diagnosed as having definite poems syndrome. we also collected patients with cidp (demyelinating neuropathy control) and with multiple myeloma, primary amyloidosis, or mgus (m-protein control). criteria for poems syndrome was defined as having two of the three major criteria (polyneuropathy, m-protein, and elevated serum vegf level) and at least two of the four minor criteria (extravascular volume overload, skin changes, sclerotic bone lesions, and thrombocytosis) which were determined by logistic regression analyses. according to the criteria the sensitivity was %, and the specificity was %. our results indicate that the proposed criteria have an excellent diagnostic accuracy, and are useful in clinical practice, presumably leading to early diagnosis and treatment. intraepidermal electrical stimulation (ies) is a new technique to that assesses the function of a-delta fibers in the epidermis. using this technique, we previously reported that the epidermal pain threshold was two-hold in asymptomatic diabetic patients than in normal subjects (muscle nerve : - , ). subsequently, we reported that the elevated pain threshold negatively correlated with intraepidermal nerve fiver density (jpns : s , ). empirically, it is known that lowering the skin temperature makes it less likely to feel pain. therefore, it is necessary to investigate whether the results of ies are affected by skin temperature. the aim of this study was to investigate the influence of a low skin temperature on pain threshold. we recruited subjects with a mean age of . years. for nociceptive stimulation, we used an ies method with a concentric micro-needle electrode that was developed specifically for the selective stimulation of cutaneous a-delta fibers. we placed the ies electrode onto the extensor digitorum brevis and began stimulation with intensity strong enough for the subject to feel a pricking sensation, then reduced the current in steps of . ma until no sensation was felt. we defined pain threshold as the minimum electrical intensity at which a subject felt a pricking sensation. firstly, we measured pain threshold at skin temperature above degrees celsius. then, we put an ice pack on the extensor digitorum brevis for min to lower the skin temperature, and measured pain threshold at skin temperatures below degrees. mean pain threshold values above degrees and below degrees of skin temperature were . and . ma (p< . ), respectively. our data indicated an elevated pain threshold in epidermis with a low skin temperature. one of most common methods for nociceptive stimulation is painful co laser stimulation. some co laser stimulation studies reported pain threshold increased with a low skin temperature. our result is similar to that of co laser stimulation. pain threshold using ies is very easy and non-invasive technique. it may be useful for the evaluation of small fiber neuropathy. svačina mkr , röth p , bobylev i , sprenger a , zhang g , sheikh ka , lehmann hc . department of neurology, university hospital cologne, cologne, germany; department of neurology, university of texas, houston, usa. intravenous immunoglobulins (ivig) are an effective treatment in guillain-barré-syndrome (gbs). in most patients, the optimal ivig dose and regime is unknown. in serum and ivig preparations, immunoglobulin (ig) g form igg dimers, which are assumed to consist of idiotypic/anti-idiotypic antibody pairs. however, data about kinetics of igg dimer formation in gbs are lacking. to study igg dimer formation, c bl/ mice were injected with ivig and anti-gd b antibody or pbs. blood sera were collected h, h and week post injection. a third cohort received an anti-gd a/gt b antibody and blood was collected h post injection. igg was extracted and subtyped into polymeric, dimeric and monomeric fractions using the Äkta fplc system. dialysed dimeric and monomeric igg fractions were examined for the presence of anti-ganglioside antibodies by anti-ganglioside antibody elisa. further, blood samples from gbs patients were collected before (pre-ivig) and after treatment with ivig (post ivig). serum samples were examined for igg dimers and monomers using the Äkta fplc system. in the mouse model, a maximum peak of igg dimer formation was observed h post injection. in gbs patients' samples, igg serum levels and igg dimer content was significantly higher after treatment with ivig. we demonstrate here the feasibility to assess igg dimer formation in an animal model and in gbs patients' samples after treatment with ivig. h after ivig treatment appears to be the optimal time point to assess igg dimer formation. further studies are warranted to determine the utility of igg dimer formation as surrogate marker for treatment response in gbs. svaren j , moran jj , wu x , gutmann l , shy m . university of wisconsin-madison, madison, wisconsin, usa; university of iowa, iowa city, iowa, usa. development of outcome measures for clinical trials in cmt a is a major challenge given the slowly progressive nature of the disease. outcome measures can be used to measure a) target engagement for a given therapy, as well as b) disease process and c) disease burden. several candidate therapies have been shown to reduce pmp levels in cmt a rodent models and thereby ameliorate the symptoms of pmp overexpression. measuring pmp mrna reduction in human trials has so far been limited to analysis of skin biopsies by qrt-pcr, which did not demonstrate clear elevations of pmp mrna during, nor a reduction following, ascorbic acid trials. the analysis of skin biopsies is hampered by variable amounts of schwann cells (sc) in skin biopsies, as well as the variable amount of pmp in sc as previously established by immuno-em in cmt a skin biopsies (katona et al., ) . therefore, it is important to develop optimal normalization criteria to address the variability inherent in skin biopsy analysis. ideally this will employ normalization to sc-specific genes that are not altered by cmt a status. to optimize normalization, we have performed rna-seq analysis of skin biopsies from patient and control skin biopsy samples. analysis of these data after normalization to read depth indicated that pmp levels were . fold higher in cmt a patient samples compared to control skin biopsies. however, there was significant variability in pmp levels particularly in cmt a samples, which may be due to variable amounts of schwann cells in cmt a skin. using a combination of sc-specific genes for normalization, we were able to reduce the apparent variability and optimize the differential levels between cmt a and control skin biopsy samples. we also identified other sc-specific genes that were apparently induced in cmt a skin biopsies relative to control. these studies provide a new framework for gene expression analysis in skin biopsies, enabling more precise evaluation of pmp levels in clinical trials for cmt a as a measure of target engagement. in addition, the normalization framework may also be applicable to other types of cmt. chronic inflammatory demyelinating polyneuropathy (cidp) is the most common chronic autoimmune neuropathy, with an estimated prevalence of between and per , people. it can cause temporary disability in the affected individuals and may eventually lead to permanent disability or death. cidp is commonly treated with intravenous immunoglobulin (ivig) therapy or corticosteroids. octagam ® % is licensed for cidp in france, while octagam ® % is licensed for cidp in germany and belgium. this analysis presents data from three open, multicenter, non-interventional, single-arm, non-controlled studies of a post-authorisation safety surveillance (pass) program for the subset of patients receiving octagam ® % or % for neurological indications, focusing on patients with cidp. briefly, data from in-and out-patients in austria, france, germany, and uk treated with octagam ® for neurological disorders were collected by physicians and analyzed to assess safety and tolerability of the treatment. of patients included in the three studies, patients ( . %) received octagam ® for neurological indications, of which patients ( . %; mean age . years [range - ]) had cidp. the mean dose of octagam ® per course was . g/kg bw for patients with cidp; for the other neurologic indications, the dose ranged from . (for multiple sclerosis) to . g/kg bw (for guillain-barré syndrome). premedication was not needed in . % of these patients. the development of clinical appearance since last observation (mean: every . months) was assessed for of the cidp patients by their treating physicians. the majority of observations ( . %) assessed the patients as stable and . % showed even an improved clinical appearance. only . % of the observation periods resulted in deteriorations. adverse drug reactions were rare: of the infusions received by patients with neurological disorders, . % of infusions were associated with an adr ( . % of infusions in cidp patients). overall, treatment with octagam ® was effective and well-tolerated in patients with cidp. these results are consistent with data for the overall patient population (including patients with primary and secondary immunodeficiencies, dermatological and other diseases). szepanowski f , szepanowski lp , kleinschnitz c , kieseier bc , stettner m . department of neurology, medical faculty, university duisburg-essen, essen, germany; department of neurology, medical faculty, heinrich-heine-university, düsseldorf, germany. lysophosphatidic acid (lpa) is a pleiotropic signaling lipid that acts as ligand for at least six specific g protein coupled receptors. schwann cells (sc) are known to mainly express the lpa receptor subtype. an emerging body of in vivo evidence has linked lpa with injury induced peripheral nerve demyelination as well as neuropathic pain. however, the molecular mechanism underlying its demyelinating effect has remained largely unclear. myelinated dorsal root ganglia (drg) cultures were treated either with lpa, lpa + am (lpa antagonist) or vehicle. we assessed myelin basic protein, tumor necrosis factor alpha (tnf-alpha) as well as the sc differentiation marker sox by immunocytochemistry. additionally, myelin was investigated by sudan black staining. to better understand the relevance of lpa signaling for demyelination in vivo, we performed sciatic nerve crush in c bl/ mice treated with am at mg/kg in order to study schwann cell expression of tnf-alpha, sox and sox , a marker for sc dedifferentiation, by immunohistochemistry. in drg cultures, lpa caused a significant reduction of myelin as demonstrated by both sudan black staining and immunocytochemical analysis of myelin basic protein. demyelination was paralleled by an upregulation of tnf-alpha as well as downregulation of sox . lpa mediated effects were found to be blocked by addition of the lpa receptor antagonist am . in c bl/ mice, am treatment prior to crush injury increased sox expression in scs in the distal nerve stump while reducing the number of cells expressing sox . these data indicate that lpa may be a critical factor to shift scs towards an injury-associated phenotype and contribute to the onset of wallerian degeneration. szepanowski lp , szepanowski f , kleinschnitz c , stettner m . department of neurology, university hospital essen, essen, germany. glyphosate-based formulations comprise the world's most commonly used herbicides. in non-resistant plants, glyphosate exerts toxic effects most likely via inhibition of aromatic amino acid synthesis by interfering with the shikimate pathway. while glyphosate is the active ingredient, herbicidal formulations contain several adjuvants, including polyethoxlated alkylamines (poeas). although glyphosate has long been considered safe for use in humans and animals, several studies have implicated glyphosate and/or the commonly used adjuvants in cytotoxicity, carcinogenicity and endocrine disruption. furthermore, glyphosate-based herbicide has been reported to mediate neurotoxicity in immature rat hippocampus involving glutamate excitotoxicity. however, it remains unclear whether glyphosate alone or in combination with its adjuvants may have detrimental effects on myelin integrity in the peripheral nervous system. myelinated dorsal root ganglia (drg) cultures were treated over the course of ten days with either pure glyphosate or a glyphosate-based herbicide at concentrations of . %, . % and . %. the concentration of the glyphosate-based herbicide was matched with regard to glyphosate content ( %). controls were treated with equal amounts of vehicle adjusted for the ph. subsequently, cultures were stained with sudan black and myelin content was assessed by determining the number of internodes per neurons. while glyphosate, regardless of its concentration, did not show any effect on myelin content, the glyphosate-based herbicide caused significant demyelination in a concentration-dependent manner. notably, at . %, drg cultures were completely devoid of myelin and appeared severely necrotic. these data raise the possibility that not glyphosate itself, but rather the adjuvants in glyphosate-based herbicide formulations may cause demyelination. the open question whether demyelination is a direct effect of the adjuvants or a consequence of increased cellular glyphosate uptake due to permeabilization warrants further investigation. tan cy , tan mp , yeoh ky , goh kj , shahrizaila n . department of medicine, university of malaya, kuala lumpur, malaysia. in guillain-barré syndrome (gbs), autonomic dysfunction is common and accounts for significant morbidity and mortality. there have been many studies investigating the electrodiagnosis of gbs but few have studied autonomic dysfunction in gbs. the current study comprehensively investigates quantitative autonomic function in patients with gbs and its variant. ten gbs patients were prospectively recruited and the results were compared to age-and gender-matched healthy controls. a series of autonomic function tests including computational (power spectrum analysis of heart rate variability (hrv) and baroreflex sensitivity (brs) at rest) and challenge tests (deep breathing, eyeball compression, active standing, valsalva manoeuvre, isometric exercise and ice-water hand immersion) were performed. parasympathetic function was represented by high frequency (hf) hrv, heart rate responses to deep breathing, eyeball compression, valsalva manoeuvre and active standing. sympathetic function was represented by low frequency (lf) hrv, blood pressure responses to active standing, sustained handgrip and ice-water hand immersion. in the frequency domain analysis of hrv, low frequency (lf: . ± . vs . ± . ; p= . ), high frequency (hf: . ± . vs . ± . ; p= . ) and total power spectral densities (psd: . ± . vs . ± . ; p= . ) were significantly reduced in patients compared to controls. the mean up slope ( . ± . vs . ± . ; p= . ), down slope ( . ± . vs . ± . ; p= . ) and total brs slope ( . ± . vs . ± . ; p= . ) were significantly lower in the gbs group. the diastolic rise in blood pressure upon ice-water hand immersion was significantly lower in gbs group compared to controls ( . ± . vs . ± . ; p= . ). our findings suggest that computation dependent tests (hrv and brs) were sensitive at detecting autonomic dysfunction and baroreceptor reflex insensitivity in gbs patients. in contrast, ice-water hand immersion was the only reliable challenge test making it useful as a bedside measure of autonomic function in gbs patients. sjögren's syndrome (ss) is an autoimmune disease that affects both east and west. nevertheless, we still have limited knowledge of how autoantibodies in ss affects the peripheral nervous system. in this study, we investigated the peripheral neuropathy in ss and sicca complex using the nerve excitability test, to elucidate how peripheral nerves are affected. we have enrolled a total of patients with ss or sicca complex. of these, two patients were excluded due to co-morbid carpal tunnel syndrome. each patient received clinical evaluation, examination for ssa/ssb antibodies titer, the nerve excitability test, conventional thermal quantitative sensory test, and conventional nerve conduction study. compared to normal control subjects, motor nerve excitability test of ss patients with positive ssa or ssb antibodies (n = ) were found to have increased rheobase (p< . ), increased relative refractory period (rrp) (p< . ), increased refractoriness at . ms (p< . ), increased accommodation toward depolarizing current in threshold electrotonus (te) (p< . ), and decreased superexcitability (p< . ). the sensory axonal study in seropositive ss also revealed increased rrp (p< . ), increased refractoriness at . ms (p< . ), and increased accommodation toward hyperpolarizing current in threshold electrotonus (te) (p< . ). meanwhile, in seronegative ss and sicca complex (n = ), we found no significant axonal properties changes. the present study revealed that peripheral nerves are affected differently in seropositive ss and in seronegative ss/sicca complex. in seropositive ss, motor axons tended to be depolarized, and both sensory and motor axons have increased refractoriness. the findings suggested that ssa and ssb antibodies might play a role in the inactivation of transient sodium channels. the effects of the antibodies on transient sodium channels might be the basis of peripheral neuropathies and even cardiac arrhythmias and heart block in ss. charcot-marie-tooth disease type a (cmt a), caused by the pmp duplication on chromosome p . , is the most common subtype of inherited peripheral neuropathies and affects in , individuals worldwide. while sharing the same genetic cause, cmt a patients often present great variability in their phenotypic presentation and disease severity. the cause of the phenotypic variability is largely unclear. in this study, we performed genome-wide association study (gwas) to identify novel genetic modifiers of various phenotypes in cmt a. dna samples from cmt a patients were genotyped on illumina omniexpress platform. after standard quality control, the dataset includes k markers in individuals ( individuals from european ancestry, and individuals from asian ancestry). we focused our analyses on the european population. logistic regression in plink was used to analyze the association between the clinical outcomes and patients' genotypes in an additive model. for cmt neuropathy score (cmtns), the analysis was performed using linear regression in plink, adjusting for patients' age. the analyses yielded several suggestive association signals. an association peak on chromosome was identified in difficulty with eating utensils (lead snp rs , chr : , p= . e- , odds ratio= . ). the peak is located within a non-coding gene linc . hearing loss showed an association peak on chromosome (lead snp rs , chr : , p= . e- , odds ratio= . ), located in an intergenic region near the megf gene. in foot plantar flexion, an association signal was identified in the dscam gene on chromosome (lead snp rs , chr : , p= . e- , odds ratio= . ). cmtns showed an association signal on chromosome (lead snp rs , chr : , p= . e- , beta= . ), located within an intergenic region close to dffb, c orf , and linc . while these suggestive signals require further validation, our study provides novel insights into the genetic architecture of cmt a. novel genetic modifiers may serve as potential targets for therapeutic interventions in the future. teng a , ohnmar , kalpana p , chai yh , umapathi t . yong loo lin school of medicine, national university of singapore, singapore; department of neurology, national neuroscience institute, singapore. we present an intriguing diagnostic puzzle, that was eventually cracked serendipitously. a -year-old man was seen for bilateral ptosis. evaluation for myasthenia gravis was negative. nevertheless, a diagnosis of ocular myasthenia gravis was made and he was put on pyridostigmine. he did not respond. the ptosis progressively worsened. he sought a second opinion. at this evaluation, he was noted to have complex ophthalmoplegia without diplopia, bilateral facial weakness and mild bulbar weakness. he had no sensory complaints. the limb examination was remarkable for slightly reduced reflexes, normal strength, and other than increased vibration threshold at the toes, intact sensory examination. repeat serological and electrodiagnostic work-up for myasthenia gravis was negative. a myopathic disorder such as chronic progressive external ophthalmoplegia was considered. serum creatine kinase and lactate were normal. he underwent biceps muscle biopsy which showed increased cox-negative and sdh positive fibers, supporting the then clinical impression of a mitochondrial cytopathy. at this point, he underwent blepharoplasty to improve his vision. routine histological examination of the levator palpebrae muscle showed amyloid deposits. this prompted a review of the earlier biceps biopsy, which revealed amyloid deposits that were not appreciated before. at this point, the significance of the patient and his son's history of lattice corneal dystrophy became apparent. he also reported that his late mother had similar facial appearance as his. the patient's nerve conduction study showed length-dependent sensory axonal polyneuropathy, right carpal tunnel syndrome and bilateral facial neuropathy. he had no definite symptoms of autonomic neuropathy. cardiac evaluation was unremarkable. the final diagnosis of familial gelsolin amyloid polyneuropathy was made. genetic confirmation for the patient and his family is being planned. we highlight the key clinical features of gelsolin neuropathy. the symmetric cranial neuropathy can resemble a muscle or neuromuscular junction disorder and the relative sparing of the cardiac muscle, somatic and autonomic nerves contrasts with transthyretin-related amyloid polyneuropathy. neuropathy is one of the most common long-term complications of diabetes. furthermore, % to % of diabetic neuropathy patients will develop neuropathic pain. the pathophysiology of neuropathic pain in diabetic peripheral neuropathy is complex and not fully understood. a potential mechanism is a change in voltage gated sodium channels, such as nav . . loss of function mutations in this channel cause insensitivity to pain, whereas gain of function mutations have been linked with different pain syndromes including small fiber neuropathy. in a cohort of patients with diabetic peripheral neuropathy we investigated whether mutations in nav . were associated with diabetic neuropathic pain. twelve nav . variants were identified in nine participants all within a cohort of participants with painful diabetic peripheral neuropathy. five of these variants were previously associated with pain disorders: v l, m l; w r, r h, l v. among the other variants two of them met the criteria of potential pathogenicity based on predictive algorithms and were further studied. functional analysis by whole cell patch clamp showed that one of these variants (m t) drastically impairs the inactivation of the channel by shifting the steady-state fast-inactivation towards more depolarizing potentials. there were no phenotypic difference between those participants with pathogenic variants and those participants without pathogenic variants. no rare nav . variants were found in participants with painless diabetic peripheral neuropathy. these observations suggest that mutations in nav . may contribute to painful diabetic peripheral neuropathy. tholance y , rosier c , f bouhour , psimaras d , kuntzer t , taieb g , créange a , delmont e , camdessanché jp , antoine jc . university hospital, saint-etienne, france; university hospital, lyon, france; university hospital, paris, france; university hospital, lausanne, switzerland; university hospital, montpellier, france; university hospital, creteil, france; university hospital, marseille, france. dysimmune sensory neuronopathies (snn) encompass paraneoplastic snn and snn associated with systemic autoimmune diseases such as sjögren syndrome, lupus or inflammatory bowel or rheumatic diseases but also a number of apparently idiopathic cases. biomarker antibodies are well-known in paraneoplastic snn but are lacking in non paraneoplastic cases. from a mono-center retrospective study we identified in anti-fgfr antibody as a potential biomarker of dysimmunity in patients with idiopathic or systemic autoimmune disease associated sensory neuropathy. the identified patients were more frequently women and had a non lenthg dependent neuropathy suggestive of snn. anti-fgfr antibody was the only immunological marker in / of cases at initial work-up although / of patients eventually developed with time systemic autoimmune disease. to confirm the incidence and the clinical pattern of patients with anti-fgfr antibodies we launched a prospective multicenter french study including patients with a sensory neuropathy suspected to be a snn of no paraneoplastic, genetic or metabolic origin. we present here the results on the first included patients compared to healthy blood donors. anti-fgcr antibodies were searched by elisa using the trk intracellular domain of the protein (invitrogen©). we found patients positive for anti-fgfr antibody ( . %). these patients were women and men aged . years as a mean ( - ). the neuropathy was acute and subacute in one patient respectively and progressive in the others. six patients fulfilled the diagnosis criteria of snn and the last one had a sensory neuropathy in the lower limb with abnormal sensory action potentials in the four limbs suggesting snn without reaching the requested criteria. one patient developed uveitis which is a new symptom with anti-fgfr ab. an unclassified dysimmune context was present at the initial work up in patients and one patient developed sjögren syndrome with follow-up. as a whole the clinical pattern of these patients is consistent with that of the initially published series. the lower prevalence of positive sera may be due to more stringent criteria used for elisa but needs to be confirmed on the complete prospective series. peripheral neuropathy research registry (pnrr) neurological assessment was scored using the total neuropathy score clinical version (tnsc), comprising pinprick and vibration sensibility, deep tendon reflexes, strength and patient symptom report. compound sensory action potential (csap) amplitudes were recorded antidromically at the lateral malleolus, stimulating the sural nerve at the mid-calf. of the total sample, % reported lower limb neuropathy, with % of patients reporting 'quite a bit' or 'very much' severity of tingling and numbness in their feet. the average sural csap amplitude was . ± . v and % of patients had sural amplitudes below the lower limit of normal for age. the total tnsc score correlated with the pro fact-gog ntx score (r = −. , p<. ) and sural amplitude (r = −. , p <. ). vibration sensibility correlated with the overall fact-gog ntx score (r =−. , p <. ), and sural amplitude (r = −. , p <. ). sural amplitude correlated with patient reported severity of numbness and tingling in the lower limbs (r =−. , p <. ) but not with the overall fact-gog ntx score. patient reports of neuropathic symptoms in the lower limb correlate with both objective neurophysiological and clinical measures of neuropathy severity. identifying links between objective neurophysiological markers and patient reported outcomes are critical to assess the impact of clinical interventions. tomaselli pj , gouvea sp , nyshyama kfs , nicolau n jr , lourenço cm , marques w jr , . division of neuromuscular diseases, department of neurosciences and behaviour sciences, clinical hospital of ribeirão preto, university of são paulo, ribeirão preto, brazil; neurogenetics, department of neurosciences and behaviour sciences, university of são paulo, ribeirão preto, brazil. mutations in the gab junction beta -protein gene (gjb ) are the second most frequent cause of charcot-marie-tooth disease (cmt), accounting for approximately % of cmt cases worldwide. the gjb codes for connexin protein (cx ). in the peripheral nervous system, the cx is expressed in the schwann cells and allows intercellular traffic of ions and small molecules between opposed cells. we analysed retrospectively detailed clinical and neurophysiological data of five families carrying novel gjb mutation submitted for testing at our neurogenetics laboratory. mutations were identified by bidirectional sanger sequence analysis of gjb coding region. we identified a total of subjects from five different kindreds with novel mutations (p.a v, p.l w, p.l q, p.f s, p.r l). these five novel mutations segregate with phenotype, are located in highly conserved amino acids among gjb and other gab junction protein sequences and among different species, are not present in any public database (exac, dbsnp and genome database), and were not found in normal brazilian controls. in silico analysis, predict these variants to be pathogenic, there was no male-to-male transmission; males were more severely affected than females. four out seven female have subclinical neuropathy and were only identified after clinical and electrophysiological evaluation. the conduction velocities were in the intermediated range in the males patients and higher in the females included in this study. we describe five new pathogenic mutations causing cmtx in a brazilian population and expand the number of causative mutations in the gjb gene. funded pure neural leprosy (pnl) is a slowly progressive, predominantly sensory patchy neuropathy presenting with positive and/or negative sensory symptoms, which are usually followed over time by distal asymmetrical weakness. despite rare, monomelic involvement in leprosy has already been reported. we sought to describe the clinical and electrophysiological patterns of an unusual leprosy neuropathy presentation. clinical data were retrospectively collected from nine patients who had monomelic involvement and were referred for further investigation to the emg lab. seven out nine patients were male. four patients had a brachial plexus like presentation and five have a lumbosacral plexus like presentation. the initial complaint was hypoesthesia in four patients, tingling in two patients and hypoesthesia with tingling in two patients. severe pain was observed in just one patient. all individuals from the group of patients with lumbosacral plexus-like presentation and three with brachial plexus-like presentation had no sensory nerve action potentials (snaps) for all nerves tested in the affected limb with or without motor involvement. one patient with brachial plexus-like presentation had focal slowing of conduction velocity with temporal dispersion of both median and ulnar nerves in the affected limb. one patient with plexus-like presentation had snaps with low amplitude of all nerves in the affect limb. the diagnosis of leprosy was confirmed by nerve biopsy findings, anti-pgl antibody, and positive response to specific treatment. nerve biopsy was performed in four patients, and the bacillus was found in two. the anti-pgl antibody was positive in four patients. plexus mri was performed in two patients and was normal. we found the distribution of motor and sensory symptoms were restricted to on limb in this group of patients. as a typically patchy disorder pnl may affect any nerve, although the reason why damage are restrict to only one limb has to be elucidated. the description of these cases increases the clinical spectrum of leprosy neuropathy. this possibility should be considered in the differential diagnosis of patients with plexopathy from endemic areas after excluding other causes. funded ataxia with oculomotor apraxia type (aoa ) is a very complex disorder characterized by an early-onset progressive cerebellar ataxia with cerebellar atrophy and peripheral neuropathy and it is caused by recessive mutations in the aprataxin gene (aptx ). when the neuropathy is present, it has been described in % of cases as primarily axonal. we describe a case of aoa due compound heterozygous mutations in aptx associated with demyelinating neuropathy. the patient was born from healthy and non-consanguineous parents and presented in the first decade with progressive cerebellar ataxia, multidirectional ophtalmoparesia, oculomotor apraxia, choreiform movements of limbs and peripheral neuropathy. he had normal cognition and stopped walking at age of . blood tests were unremarkable with normal levels of leucocytes, serum proteins, immunoglobulin, cholesterol, vitamin e, and alfa-feto protein. brain mri showed severe cerebellar atrophy. the motor conduction velocity in the upper limbs was slow with preserved amplitudes. the distal latencies and the minimal f wave latencies were prolonged. there was no evidence for superimposed acquired demyelinating neuropathy. direct sequencing of the aptx gene revealed two variants, c. - a>g, p? and c. g>a; p.w x. the first variant is novel and affects a highly conserved acceptor splice site of exon . the other variant is the most common portuguese variant, the nonsense mutation w x is located in exon . parental dna was tested and confirmed the variants were in different alleles. the presence of a demyelinating neuropathy in aoa suggests that phenotypic variability in this condition may be larger than previously considered. at the same time, it increases the differential diagnosis of inherited conditions with cerebellar ataxia and demyelinating neuropathy. finally, this finding opens the functional effects of the aptx gene. funded by: cnpq, fapesp, faepa, pronas (ministry of health). topa a , spina e , iodice r , tozza s , ruggiero l , dubbioso r , esposito m , santoro l , manganelli f . university of naples "federico ii", naples, italy. we report our -year experience of subcutaneous immunoglobulin (scig) in a cohort of patients with chronic inflammatory demyelinating polyneuropathy (cidp) from a tertiary care neuromuscular center. we analyzed data from cidp patients ( males and females, mean age: ± . years; mean age at onset: . ± . years; disease duration: . ± . years) treated with scig and with a follow-up period of months. all patients were previously responders to intravenous immunoglobulin (ivig). eight patients had a typical cidp and five patients had an atypical variant of cidp. five patients switched to weekly maintenance scig therapy (continuous regimen) because of short-lasting response to ivig therapy. eight patients with a longer lasting response to ivig received scig with a pulsed regimen similar to that used for ivig (from to cycles per year); seven of them because of difficulty in hospitalization and one for allergic reaction to ivig. changes in clinical status were assessed over the period of follow-up by using clinical evaluation of muscle strength, modified rankin scale, overall neuropathy scale and inflammatory neuropathy cause and treatmentsum score. in patients we evaluated also six minute walking test, hole-peg-test and meter walking test. all the five patients treated with a continuous regimen of scig remained clinically stable throughout the follow-up period. among the patients receiving pulsed scig treatment, out of ( %) responded to scig similarly to ivig, while three patients ( . %) worsened and needed to be treated again with ivig and the other one ( . %) stopped any therapy. subcutaneously administered immunoglobulin were well tolerated and no patients complained of adverse events. in conclusion, our findings confirm that continuous scig therapy is efficacious in maintaining clinical stability in patients with short-lasting response to ivig. moreover, our data suggest that pulsed therapy with scig may represent an alternative therapeutic option for the treatment of a subset of cidp patients. touvier t , ferri c , mastrangelo r , glimcher l , , wrabetz l , , , d'antonio m . myelin biology unit, division of genetics and cell biology, san raffaele scientific institute, dibit, milan, italy; department of cancer immunology and virology, dana-farber cancer institute, boston, usa; department of medicine, harvard medical school, boston, usa; hunter james kelly research institute, university at buffalo, buffalo, usa; department of biochemistry, university at buffalo, buffalo, usa; neurology, jacobs school of medicine and biomedical sciences, university at buffalo, buffalo, usa. mpz glycoprotein is an abundant product of terminal differentiation in myelinating schwann cells. the mutant mpzs del causes charcot-marie-tooth (cmt) b disease in humans and a similar demyelinating neuropathy in transgenic mice. mpzs del protein is retained in the endoplasmic reticulum (er) of schwann cells and induces an unfolded protein response (upr) characterized by activation of perk, atf and ire /xbp pathways. we have previously reported that activation of chop and gadd , two downstream mediators of perk, is pathogenetic in mpzs del mice (pennuto, ; d' antonio, ) but the role of the other upr branches remains to be investigated. in this study, we investigated the role of the er stress sensor enzyme ire and of xbp -a transcription factor specifically activated by ire -in mpzs del pathogenesis. we generated a new mouse model with schwann cells-specific ablation of xbp and in parallel we exploited mpzs del dorsal root ganglia (drg) explant cultures in which xbp signaling is modulated by gain/loss of function approaches. we observed that absence of xbp dramatically worsens hypomyelination and electrophysiological/locomotor parameters in young and adult mpzs del neuropathic animals. interestingly we observed that perk, atf and ire -mediated ridd signalings are upregulated in neuropathic animals lacking xbp . this suggests that activation of xbp targets have an essential role in limiting mpzs del toxicity, which cannot be compensated by other stress responses. moreover, we demonstrated in mpzs del drg cultures that inhibition of xbp splicing by u c (cross, ) decreases myelination whereas activation of xbp splicing by quercetin (wiseman, ) slightly ameliorates myelination. altogether, these data demonstrate that xbp pathway has a critical adaptive role in mpzs del neuropathy and suggest that activation of this pathway may be beneficial for cmt b and perhaps for a broad range of neuropathies characterized by upr activation. tozza s , bruzzese d , iodice r , esposito m , dubbioso r , ruggiero l , topa a , spina e , santoro l , manganelli f . department of neuroscience, reproductive sciences and odontostomatology, university of naples "federico ii", naples, italy; department of public health, university federico ii of naples, naples, italy. in cmt a patients, the clinical impairment progressively increases over time and correlates with the axonal loss. evidence has suggested that the decline of physical performance in cmt a patients may reflect a process of normal ageing. the aim of our study was to describe, by a case-control cross-sectional design, the progression of physical impairment with ageing in cmt a patients. we enrolled cmt a patients ( m; range - years) and sex-and age-matched healthy controls. to assess physical performance, all patients and controls underwent -meter walk test ( mwt), -minute walk test ( mwt) and -hole peg test ( hpt) of their dominant (d) and non-dominant (nd) sides. moreover, to assess clinical disability, impairment and quality of life in the cmt a group we used the charcot-marie-tooth neuropathy score (cmtns), the mrc sum score and the short form- (sf- ) questionnaire. the linear regression model was used to evaluate the changes over time of clinical measures in patients and controls. the chow test was used to determine whether the ageing had a different impact on clinical measures for the two groups. physical performance worsened with ageing in both patients and controls, but with a greater slope for cmt a patients [difference in slopes: mwt, . (c.i. . to . ), p< . ; mwt, − . (c.i. - . to − . ), p< . ; hpt-d, . (c.i. . to . ), p< . ; hpt-nd, . (c.i. . to . ), p< . ]. the rate of deterioration of physical performance was not different between patients and controls until the th year of age. after the th year of age the rate of deterioration became greater in cmt a group [difference in slopes: mwt, . (c.i. . to . ), p< . ; mwt, − . (c.i. - . to − . ), p< . ; hpt-d, . (c.i. . to . ), p< . ; hpt-nd, . (c.i. . to . ), p< . ]. moreover, in cmt a patients also cmtns, mrc sum score and sf- worsened with ageing and with a greater rate of deterioration after the th year of age. our study demonstrates that clinical decline in cmt a patients goes parallel to the normal ageing process until the th year of age, whereupon the clinical deterioration accelerates. tsouni p , devic p , moura b , planque e , bédat-millet al , devaux j , steck aj , delmont e , hottinger af , kuntzer t . dcn, chuv, lausanne, switzerland; centre de référence maladies neuromusculaires, hospices civils de lyon, lyon, france; cabinet médical, epinal, france; département de neurologie, chu de rouen, rouen, france; cnrs, crn m-umr , université aix-marseille, marseille, france; centre de référence maladies neuromusculaires et sla, hôpital la timone, marseille, france. new therapeutic options in immuno-oncology have allowed significant progress in the management of melanomas. treatment usually consists of a combination of two monoclonal antibodies targeting cytotoxic lymphocyte-associated protein and programmed cell death- . as a result, the immunologic barrier protecting tumor cells is overcome allowing an antitumor response. we report cancer patients with immune checkpoint inhibitor-induced neuropathies as a complication of this immunomodulating oncologic treatment. case reports: our index patient developed severe myalgia days after introduction of ipilimumab-nivolumab followed by painful paresthesias of the face and extremities day after the nd cycle of treatment. generalized areflexic quadriparesis (mrc ) with gowers'sign and distal loss of vibratory sensation were found. a -day course of ivig plus corticosteroids (cs) had no effect. three monthly ivig courses were necessary to improve the deficits at months. a survey of sfnp members revealed other patients with similar acute courses but with phenotypes varying from sensorimotor deficits with areflexia and myalgia to purely sensory ataxic forms following immunomodulating treatment. work-up including anti-nodal antibodies were negative in patients. from the other , had abnormal csf and had necrotizing myopathy. detailed repeat ncs demonstrated signs of nerve hyperexcitability and of demyelination or conduction blocks. evolution was slowly favorable following ivig and cs. discussion: our report underscores that atypical acute generalized demyelinating neuropathies are induced by these novel treatments. they may be associated with severe myalgia or other systemic toxic effects. discontinuation of the oncologic treatment depends on severity of symptoms. outcome was slowly favorable following ivig or cs, albeit slower than in the case of primary inflammatory neuropathies, probably given the long half-life of the monoclonal antibodies. gap junctions (gjs) are membrane channels found in most tissues connecting adjacent cells or different cell compartments as in schwann cells. they are involved in electrical connectivity and metabolic homeostasis allowing the passage of small molecules such as ions, second messengers, nucleotides and peptides. an important functional role of peripheral nerve connexins is suggested by their involvement in x-linked inherited neuropathy as well as in acquired neuropathy caused by oxaliplatin. although gjs play a role in electrical connectivity their specific role in the formation of the sciatic nerve compound action potential (cap) remains unclear. the aim of this study was to investigate the role of peripheral nerve connexins in the electrical responses of the mouse sciatic nerve under normal and stress conditions. for this purpose we used sciatic nerves of three different mouse models, the cx knockout (ko), cx ko and the cx /cx double knockout (dko) mice. using our ex vivo model for extracellular recordings we exposed sciatic nerves from different genotypes to three different gj blockers: octanol, -beta-glycyrrhetinic acid (gra) and octanoic acid (oa) and recorded the cap. amplitude and duration of the cap were used as an indication for the effects of the different blockers on the cap formation. all gj blockers caused a gradual decrease of the cap without any changes in the duration of the cap in all genotypes, suggesting progressive disturbance of axonal membrane excitability in the absence of one or two gj proteins. comparison of the three genotypes showed that cx may play a dominant role in the maintenance of the cap formation since nerves from cx ko mice proved to be more sensitive to the gj blockers compared to the cx ko nerves showing a faster decline of the cap amplitude. moreover the effect of gj blockers was similar in cx ko and dko nerves. finally, the effect of gj blockers on the dko nerves implies the presence of another gj protein. in conclusion, our results confirm the direct functional involvement of cx gj channels and cx hemichannels in the cap formation and indicate the existence of at least one more connexin in peripheral nerve. ca( +)-dependent anti-ganglioside antibody in seronegative guillain-barrÉ syndrome uchibori a , gyohda a , chiba a . kyorin university, tokyo, japan. we have reported ca + -dependent igg anti-ganglioside gq b antibodies in gq b-seronegative patients with fisher syndrome and its related disorders (fs-rd). in patients with fs-rd who were gq b-seronegative in conventional assays using phosphate-buffered saline without ca + , % turned seropositive for gq b-related antigens in assays using ca + -added tris-buffered saline. objective: we investigated whether ca + -dependent anti-ganglioside antibodies was present also in ganglioside-seronegative patients with other clinical disease types of guillain-barré syndrome (gbs) other than fs-rd. methods: the subjects were the following: patients with final clinical diagnosis as gbs (acute motor axonal neuropathy [aman], n = , and acute inflammatory demyelinating polyradiculoneuropathy [aidp], n = ), and patients with final clinical diagnosis as sensory ataxic neuropathy (san), n = . all subjects were ganglioside-seronegative in the conventional assays. we assayed serum igg antibodies against various gangliosides (including asialo-gm ) in elisa using tris-buffered saline as a basal buffer in both ca + -added and -non-added conditions. increase of the optical density (od) more than . in ca + -added condition compared with ca + -non-added one was taken significant, i.e. positive for ca + -dependent antibody. results: ca + -dependent antibody was negative in all aman and san patients. in aidp, the antibody titers (ods) against gainac-gd a were significantly increased in patients, and those against asialo-gm were increased in other patients in ca + -added condition. however, the titiers of those ca + -dependent antibodies were all at low level. conclusions: in clinical disease types of gbs other than fs-rd, ca + -dependent igg antibodies against ganglioside were detected in a few patients with aidp, but the positive rate and the antibody titers were low compared with case of gq b-seronegative fs-rd. ca + -dependent antibodies against ganglioside are considered to be more specific for gq b. the aim of the study was to investigate the relationship between median sensory conduction of median nerve and ulnar nerve in patients diagnosed with carpal tunnel syndrome. two hundred and eighty-six hands with carpal tunnel syndrome and hands in control group were investigated. patients were staged clinically and electrophysiologically. diagnosis of carpal tunnel syndrome was made according to the presence of paresthesia, pain in the innervation area of the median nerve, weakness and atrophy in the median nerve innervated muscles, positive phalen and tinel tests. median motor and sensorial nerve conduction study, including first, second, third finger and palm, and ulnar motor and sensorial nerve conduction of fifth finger studies were performed to all patients and control group. the ratio of distal latency and velocity of nerve conduction of first, second, third and palmar branches to fifth finger was calculated. distal latency of first, second, third finger and palm of patients with cts are longer and velocity is more slowly than controls. in addition to these findings, the velocity of fifth finger is also slower and distal latency of this one is longer than healthy subjects. the most sensitive method of classifying the carpal tunnel syndrome as normal, mild and moderate is the ratio of distal latency and velocity of second finger (p< . ). carpal tunnel syndrome is the most common encountered neuropathy. in nerve conduction studies can be used the ratio of distal latency and velocity of second finger as determine the degree of carpal tunnel syndrome. the most surprising finding of this report is the nerve conduction studies of fifth finger. the subclinical susceptibility of fifth finger can be explained by overusing of wrist. ursino g , gemelli c , grandis m , reni l , bellone e , geroldi a , gotta f , mandich p , ferrara m , schenone a dinogmi university of genoa, genoa, italy; irccs-aou san martino hospital genoa, genoa, italy. charcot-marie-tooth (cmt) neuropathy represents a clinically and genetically heterogeneous group of hereditary peripheral neuropathies characterized by chronic motor and sensory impairment. to date mutations in up to genes may cause cmt. the aim of this study is to describe our large population of cmt patients, and, within this, highlight specific phenotypes. the cmt clinic in genova, started in . during the years, patients underwent complete neurological, rehabilitative, neurophysiological examinations and genetic testing. the patients were routinely tested for common genes (as pmp , gjb , mpz, mfn ), while in specific cases we followed the candidate gene approach testing single genes based on the genotype-phenotype correlation. however, the ngs techniques were used when routine genetic testing was negative and a clear genotype-phenotype correlation could not be identified. cases are present to date in our database of cmt patients. in ( . %) patients, in spite of a clinical diagnosis of cmt, a genetic diagnosis is still lacking; ( . %) patients had alternative diagnosis (i.e hereditary spastic paraparesis etc.). instead, in patients ( . %) a defined genetic diagnosis was reached, of them being females ( . %) and males ( . %). among these, except for the more common cmt a, hnpp and cmt x phenotypes, we frequently observed patients affected by cmt b and cmt f. according to most literature data, we observed ( . %) patients with cmt b and patients ( . %) affected by cmt f. at the first visit, the cmt b phenotype was clearly length-dependent: . % patients showed impairment of the lower limbs and saving of the upper limbs; in terms of severity of the neuropathy, the mean cmtns was . and the mean age was . years. similarly, % of patients affected by cmt f, present with the same phenotype; the mean cmtns at the first visit was . and the mean age was . years. in conclusion, based on the experience of the genova cmt clinic, we describe a large population of cmt patients and a specific phenotype in cmt b and f patients, characterized by involvement of the lower limbs and selective sparing of the upper ones, which may help in addressing the diagnostic algorithm. non-freezing cold injury (nfci) develops following sustained exposure to cold temperatures, resulting in tissue cooling but not freezing. this can result in persistent sensory disturbance of the hands and feet including numbness, paraesthesia and chronic pain. both vascular and neurological aetiologies of this pain have been suggested but remain unproven. we prospectively approached patients referred for clinical assessment of chronic pain following non-freezing cold injury between february and november . of patients approached consented to undergo detailed neurological evaluations including: questionnaires to detail pain location and characteristics, structured neurological examination, quantitative sensory testing, nerve conduction studies and skin biopsy for intra-epidermal fibre assessment. of the study participants all had experienced nfci whilst serving in the united kingdom armed services and the majority were of african descent ( . %) and male ( . %). many patients reported multiple exposures to cold. the median time between initial injury and referral was . years. pain was principally localised to the hands and the feet, neuropathic in nature and in all study participants associated with cold hypersensitivity. clinical examination and quantitative sensory testing were consistent with a sensory neuropathy. in all cases large fibre nerve conduction studies were normal. the intra-epidermal nerve fibre density, however, was markedly reduced; ⋅ % of subjects having a count at or below the ⋅ centile of published normative controls. using the neuropathic pain special interest group (neupsig) of the international association for the study of pain (iasp) grading for neuropathic pain % had probable and ⋅ % definite neuropathic pain. chronic non-freezing cold injury is a disabling neuropathic pain disorder due to a sensory neuropathy. why some individuals develop an acute painful sensory neuropathy on sustained cold exposure is not yet known but individuals of african descent appear vulnerable. screening tools, such as the dn questionnaire, and treatment algorithms for neuropathic pain should now be used in the management of these patients. funded by the wellcome trust and the uk ministry of defence guillain-barré syndrome (gbs) is highly heterogeneous regarding clinical presentation, course, electrophysiological subtype and outcome. in part this variety is associated with differences between geographical regions, although this had not been investigated in a single comparative study. one aim of igos is to define the influence of the geographical origin on the heterogeneity of gbs. in igos all gbs patients within weeks of onset can participate, independent of age, variant, severity and treatment. in february , patients were included from countries. the first inclusions in igos were used in this analysis. seventy-five patients ( %) were excluded because of alternative diagnoses (n= , including a-cidp), protocol violations (n= ) or missing data (n= ). of the remaining patients, % were males and % female with a median age of years (iqr - ). at entry % presented with tetraparesis and % with paraparesis. during follow-up % needed mechanical ventilation and % died. of all gbs patients % received treatment ( % ivig, % pe). the remaining % received supportive care only (mild gbs or low social-economic status). antecedent events were reported in % of patients, including upper respiratory tract infection ( %) and gastro-enteritis ( %) as the most frequent events. the pure motor form was the predominant subtype in patients from bangladesh ( %). in europe/americas and asia (without bangladesh) the predominant subtype was the sensorimotor form ( % in europe/americas and % in asia). in asia (without bangladesh) there was a relatively larger proportion of patients with mfs/mfs-overlap syndrome ( %) than in other regions ( - %, p< . ). the proportion of patients able to walk unaided at months after follow-up was % in europe/americas, % in bangladesh and % in asia (without bangladesh). kaplan-meier analysis comparing electrophysiological subtypes of gbs (as reported by neurologist) showed that patients with inexcitable nerves or axonal neuropathy needed more time to regain the ability to walk unaided than the patients with demyelinating or equivocal result (log-rank test, p < . ). these findings demonstrate the extensive geographical differences in gbs. future igos studies will investigate the role of genetic and environmental factors that additionally could explain these differences. van den bergh pyk , attarian s , grapperon am , nicolas g , cassereau j , rajabally ya , delmont e , woodard jl , piéret f and the university of louvain gbs electrodiagnosis study group * . corticosteroids are considered as one of the first line treatments for chronic inflammatory demyelinating polyneuropathy (cidp). different types of corticosteroids are used and there are no comparative studies assessing the improvement rates, remission rates, tolerability and the side effect profiles of these treatment regimens. in addition, there are currently no reliable predictors of favorable treatment response to steroids, which would greatly ease the choice of first line treatment. in this retrospective study we will compare efficacy, tolerability and safety of three different corticosteroid regimens used as first line treatment in three large cidp centers in netherlands, serbia and italy. treatment naïve cidp patients who received either pulsed dexamethasone, pulsed methylprednisolone or daily prednisone will be included in the study. data will be extracted from patient charts. the primary outcome is the percentage of treatment responders at months after start of first treatment, in which treatment response is defined as subjects who improved after treatment and are either without treatment after six months or are still being treated with the first chosen therapy. secondary endpoints include the remission rates and in case of a relapse, the mean duration of remission to relapse; the discontinuation rate within months of treatment due to inefficacy, adverse events or intolerance; and the frequency of adverse events and serious adverse events (sae) during treatment or within month after stopping treatment. furthermore, we will explore the value of previously reported potential predictors of treatment response. results will be presented at the peripheral nerve society meeting . van lieverloo g , , musters a , adrichem m , esveldt r , doorenspleet m , klarenbeek p , van schaik i , de vries n , eftimov f . academic medical center, department of neurology, amsterdam, the netherlands; academic medical center/university of amsterdam, department of clinical rheumatology and immunology, amsterdam, the netherlands. following reports that pathogenic antibodies are present in a minority of patients with chronic demyelinating inflammatory neuropathy (cidp), we studied whether oligoclonal expansions of b-cell clones are present in patients with cidp. recently, we developed a new method for b-cell receptor (bcr) repertoire landscaping based on high throughput sequencing (hts) of rna extracted from blood. bcr repertoire was analyzed in patients with cidp: patients with active disease and starting treatment (group ), patients with stable disease using intravenous immunoglobulin (ivig) treatment in which treatment withdrawal was attempted (group ), and patients in remission (i.e. no treatment in the last months, group ). clinical parameters and sampling was performed at baseline (group , and ), at months after start of treatment (group ), at months or earlier in case of relapse in group and at baseline only in group . most cidp patients had highly expanded bcr clones, regardless of disease activity and response to treatment. however, in group , the most expanded b-cell clones at baseline showed no overlap with the expanded bcr clones after improvement. based on these preliminary data expanded bcr clones are observed in the peripheral blood of most cidp patients, regardless of disease activity (active, stable disease or remission/cure). functional characterization of these expanded clones remains to be performed. van rijs w , fokkink wjr , tio-gillen ap , brem md , jacobs bc , huizinga r . erasmus mc, university medical centre, rotterdam, the netherlands. myeloid cells, including monocytes, macrophages and dendritic cells, are critically involved in the induction of adaptive immune responses, clearance of pathogens and in the initiation of tissue repair. in the guillain-barré syndrome (gbs), macrophages are present in the peripheral nerve, where they phagocytose (damaged) myelin and axons. dendritic cells (dc) are increased in the cerebrospinal fluid of patients with gbs. however, the composition and phenotype of monocytes and dc subsets in the peripheral blood is unclear and it is unknown if these cells can be used as biomarker to monitor disease activity or response to treatment. here we investigated the frequency and phenotype of six myeloid subsets in the peripheral blood mononuclear cells (pbmc) using advanced -color flow cytometry. pbmc were isolated from patients with gbs, before and after immunomodulatory treatment, and age and gender-matched, healthy controls. the frequency of total monocytes, determined as percentage of cd + cells, was increased in gbs patients compared to controls (p< . ). the monocyte population was skewed towards more intermediate (cd +cd +; p< . ) and less non-classical (cd -cd +; p< . ) monocytes. classical (cd +cd -) and intermediate monocytes as well as cd c+ dc expressed significantly higher levels of cd compared to healthy controls. in contrast, the expression of cd and siglec- was significantly higher in the non-classical monocytes of gbs patients compared to controls. no differences were observed in the expression of cd , cd , cd and siglec- . immunomodulatory treatment strongly reduced the frequency of non-classical monocytes and all dc populations in cd + pbmc. the expression of cd , cd c and hla-dr was reduced in classical monocytes after treatment. in addition, siglec- expression was reduced in several monocyte and dc populations after treatment. in summary, our data identify significant changes in the monocyte compartment in gbs. the decrease in non-classical monocytes may suggest that these cells have migrated to peripheral tissues, promoting the differentiation of classical monocytes into intermediate monocytes. further analysis should reveal whether these changes are related to preceding infections, disease severity and response to treatment. in mme. the two mutations were absent from control databases (e.g. exac), affected highly conserved aminoacids and were predicted to have deleterious effects by in silico analysis. unfortunately, both parents were deceased and we were therefore unable to prove that the two mutations reside on separate alleles. mme encodes the metalloprotease neprilysin whose role in peripheral nervous system is still unclear. higuchi and colleagues have described japanese cmt families with late-onset sensory-motor axonal neuropathy and recessive loss-of-function mutations in mme. we report two novel missense mutations in mme in a case of late-onset cmt . we hypothesize an autosomal-recessive mode of inheritance as most likely given the clinical phenotype and the absence of a family history. anti-contactin- (cntn ) antibodies were recently identified in a subgroup of patients with chronic inflammatory demyelinating polyneuropathy (cidp) showing acute/subacute onset of severe sensory-motor neuropathy and poor response to intravenous immunoglobulin (ivig) and corticosteroids. these antibodies belong to the igg isotype and interact with cntn -neurofascin (nf ) complex at paranodes leading to loss of nodal integrity. a -year-old man presented with acute onset of distal weakness in the lower limbs, four limbs paraesthesias and sensory ataxia. at clinical examination ankle swelling was also observed. nerve conduction study showed a demyelinating polyneuropathy and cerebrospinal-fluid examination revealed cyto-albuminologic dissociation. sural nerve biopsy disclosed diffuse loss of myelinated fibres. at routine blood test serum albumin was reduced and proteinuria was gr/ hours, thus leading to the diagnosis of nephrotic syndrome. kidney biopsy showed changes consistent with membranous glomerulonephritis, together with sub-epithelial deposits of immune complexes and complement deposition. treatment with ivig and corticosteroids did not improve neurological status, while membranous glomerulonephritis showed moderate response to ivig. a six-month course of cyclophosphamide was started leading to normalization of renal function and muscle strength and partial improvement of sensory ataxia. the patient did not require any further treatment and after years his condition remains stable. cntn antibodies were tested on a recently collected patient's serum and resulted positive on both elisa and cell-based assay. the patient here reported showed the typical clinical features of anti cntn -associated cidp including older age, acute onset, severe motor impairment and sensory ataxia. the contemporary occurrence of membranous glomerulonephritis was reported in only one other case. contactin- is expressed at low levels in the kidney and a direct damage of anti-cntn antibodies could be hypothesized. alternatively, renal damage might have been secondary to unspecific immune complexes deposition. a good response to anti-cd rituximab was recently reported in patients with cidp associated with anti-cntn and anti-nf antibodies. notwithstanding this single-case observation, our report suggests that also cyclophosphamide may be considered an effective therapy in anti-cntn antibodies-associated cidp and membranous glomerulonephritis, leading to persistent clinical remission. velasco r , , besora s , santos c , sala r , izquierdo c , simó m , gil-gil m , , jiménez l , pardo b , calvo m , palmero r , clapés v , bruna j duloxetine is the only agent demonstrated effective in treating pain related with chemotherapy-induced peripheral neuropathy (cipn). patients with symptomatic cipn treated with duloxetine were retrospectively collected in a single-institution. aim of the study was to evaluate the drug's efficacy and rate of compliance. only patients with cipn with distressing positive symptoms (pain, numbness and/or paresthesia), and non-progressive disease were included. cipn was graded employing the total neuropathy score (tns © ) and national cancer institute-common toxicity criteria. response to duloxetine was assessed with patient global impression of change (pigc) scale ( : no benefit; : excellent response). consecutive first one-hundred cipn patients treated with duloxetine were analyzed. median age was ( - ). , , and received platinum, taxane, bortezomib and vincristine-based regimen, respectively. median tnsc © was ( - ). severity of neuropathy was grade ( %), grade ( %), and grade ( %). sixteen patients were on treatment with other analgesic agents. median time from finishing chemotherapy to duloxetine initiation was months [ - ]. median pigc score was [ - ]. among responders, . % and . % scored low ( - ) and high ( - ) benefit, respectively. fifty-seven ( %) patients discontinued early duloxetine due to intolerable side effects (n= ) the goal of this study was to determine whether predicted fork stalling and template switching (fostes) during mitosis deletes exon in peripheral myelin protein kd (pmp ) and causes a gain-of-function mutation associated with peripheral neuropathy in a family with charcot marie tooth disease type e. two siblings previously reported to have genomic re-arrangements predicted to involve exon of pmp were evaluated clinically and by electrophysiology. skin biopsies from the proband were studied by rt-pcr to determine the effects of the exon re-arrangements on exon mrna expression in myelinating schwann cells. transient transfection studies with wild type and mutant pmp were performed in cos and rt cells to determine the fate of the resultant mutant protein. both affected siblings had a length-dependent demyelinating neuropathy with severely slow nerve conduction velocities (< m/sec). rt-pcr studies of schwann cell rna from one of the siblings demonstrated a complete in frame deletion of pmp exon (pmp delta ). transfection studies demonstrated that pmp delta protein is retained within the endoplasmic reticulum and not transported to the plasma membrane. our results confirm that that fostes mediated genomic rearrangement produced a deletion of exon of pmp , resulting in expression of both pmp mrna and protein lacking this sequence. in addition, we provide direct experimental evidence for endoplasmic reticulum retention of the mutant protein suggesting a gain-of-function mutational mechanism consistent with the observed cmt e in this family. pmp delta is another example of a mutated myelin protein that is misfolded and thus likely to contribute to the pathogenesis of the neuropathy. in poems and cidp, distal limb nerve conduction studies are limited in identifying demyelination and detecting treatment effects in severely affected patients. blink reflex r latency may help to not only identify demyelination but also provide a meaningful treatment outcome measure especially in severely affected patients. poems and cidp patients having undergone routine nerve conductions and blink reflex testing were identified. correlation between r latency, limb nerve conduction studies and neuropathy impairment scores (nis) was calculated with treatment. blink reflexes were performed in patients ( poems, cidp; nis range: - points). overall, r latency prolongation occurred in . % of patients ( . % poems, . % cidp). patients with r prolongation (> ms) had more severely affected nerve conductions in both poems (ulnar cmap . mv vs . mv, p= . ) and cidp (ulnar cmap . mv vs . mv, p< . ). r latency correlated with nis severity in poems better than cidp (r = . vs . , p=< . vs. . ). follow-up nis and r latency evaluations after treatment were available in patients ( poems, cidp). the r latency changes were concordant with the nis changes in % of poems and % of cidp patients. in severely affected patients [ulnar cmap amplitude ≤ . mv ( . %: / )] except for one, all had prolonged r (> ms), allowing for treatment follow up and initial diagnosis. blink reflex r latencies are valuable in defining demyelination in severely affected poems and cidp patients, but also provide a sensitive, early treatment outcome measure among those same severely affected patients. watson dj , martinez c , wallenhorst c , hubsch a , shebl a , simon tl . csl behring llc, king of prussia, usa; institute for epidemiology, statistics and informatics gmbh, frankfurt, germany; csl behring ag, bern, switzerland; csl behring gmbh, marburg, germany. chronic inflammatory demyelinating polyneuropathy (cidp) rarely occurs in children. clinical trials in pediatric patients have not been performed and there are little data on therapy with intravenous immunoglobulin (ivig). we performed an observational trial to investigate the risk of adverse events of special interest (aesi) with ivig, i.e. hemolytic anemia, aseptic meningitis, acute renal failure, thromboembolic events and anaphylactic reactions. the study cohort was derived from the us premier perspective database and consisted of patients < years with a diagnosis of cidp (icd- cm diagnosis code . ) treated with the ivig privigen ® (csl behring, bern switzerland) between jan and dec . we identified pediatric cidp patients: preschool children (age - years at first treatment for cidp), children ( - years) and adolescents ( - years); females and males; white, one black and two allocated to "other race". six patients had a history of other ivig use for guillain-barré syndrome, one patient for myasthenia gravis and one for immunodeficiency before the diagnosis of cidp. the mean privigen ® dose calculated from the cumulative quantity of privigen ® per treatment episode and the corresponding age-and gender specific median of the us population body weight estimate was . g/kg body weight. the number of recorded treatment episodes per patient ranged from to . using an at-risk period of days for hemolytic anemia, and days for other aesi after each privigen ® administration, no aesi were observed in the patients with cidp with a total of person-days at-risk for ha and person-days at-risk for other aesi. this observational study shows that ivig (privigen ® ) is used for treatment of cidp in pediatric patients with or without concomitant conditions and revealed no particular safety issues in this patient group. hsn- is a peripheral neuropathy most frequently caused by missense mutations in the sptlc or sptlc genes, which code for two subunits of the enzyme serine palmitoyltransferase (spt). spt catalyzes the first and rate limiting step of de novo sphingolipid synthesis. it has been shown that mutations in spt cause a change in enzyme substrate specificity which results in the production of two atypical sphinganines, deoxysphinganine (dsp) and deoxymethylsphinganine (dmsp), rather than the normal enzyme product, sphinganine (sp). levels of deoxysphingolipids are elevated in the blood of hsn- patients and this has been shown to cause the peripheral nerve damage characteristic of the disease, which affects both sensory as well as motor axons. however, the underlying pathomechanism of how deoxysphingolipids damage neurons remains elusive. here, dsp and dmsp-mediated neurotoxicity was examined in primary mouse motor and sensory neurons, by assessing cell survival and neurite outgrowth following exposure to different concentrations of sp, dsp or dmsp. the abnormal enzyme products were found to have a rapid and dose-dependent neurotoxic effect in primary neurons. we also explored the potential mechanisms that underlie deoxysphingolipid neurotoxicity, by characterizing mitochondrial function and changes in calcium handling. we found that mitochondrial dysfunction and calcium handling deficits may be key mediators of abnormal sphingolipid neurotoxicity, in both motor and sensory cell models. specifically, we revealed mitochondrial abnormalities, signs of endoplasmic reticulum stress and dysfunction of store-operated calcium channels. we propose that early deficits in mitochondria and calcium handling may underlie deoxysphingolipid neurotoxicity and thus present potential therapeutic targets for hsn- . months. one patient was excluded because the decrease in hba c was not contemporaneous with weight loss. the mean and median decrease in bmi per month was . and . respectively. the mean and median interval between surgery and decrease in hba c was . and . days respectively. records of these patients were scrutinized and classified as: 'probable tind': acute painful neuropathy and acute dysautonomia with temporal relationship to the decrease in hba c; 'possible tind': acute painful neuropathy or acute dysautonomia or temporal relationship to decrease in hba c is uncertain; 'unlikely tind': when an alternative explanation exists for symptoms. only one patient was classified as 'possible tind': a -year-old woman who developed neuropathic pain in both lower limbs month after a rapid hba c decline of . % and about months after bariatric surgery. she had no documented autonomic symptoms. our study is limited by small cohort size, retrospective design and reliance on hospital records. nonetheless, it demonstrates that besides nutritional neuropathies, tind should also be considered in dm patients who develop peripheral neuropathy after bariatric surgery. in another study, we found tind is uncommon in a general cohort of diabetic patients. the occurrence of 'possible tind' in only dm patients corroborates earlier data that weight loss may act in tandem to increase the risk of tind. woolums bm , tabuchi m , sung h , sullivan jm , mamah c , yang m , blum id , wu mn , sumner cj , lloyd te . johns hopkins university, baltimore, usa. dominant missense mutations in the gene encoding the cation channel transient receptor vanilloid, family member (trpv ) cause inherited neuropathies including charcot-marie-tooth disease c (cmt c). in vitro, mutations in trpv that cause cmt c cause a gain of trpv channel function and increased intracellular calcium which subsequently leads to cellular toxicity. however, the mechanisms by which cmt c mutations in trpv lead to neuronal dysfunction in vivo remain poorly understood. we generated transgenic drosophila that express either wild-type or a cmt c causing trpv mutant (trpv r c ) to assess the effect of trpv r c on neuron function in vivo. selective expression of trpv r c in drosophila ccap neurons (n ccap ) results in a failure of drosophila wing expansion that is blocked by genetically inactivating the channel pore, demonstrating the requirement of channel function in mediating this phenotype. perforated patch clamp analysis of n ccap reveals that trpv r c causes a calcium-dependent increase in n ccap neuronal excitability. this hyperexcitability is restored to control levels by application of a trpv selective antagonist. high level expression of trpv r c causes synaptic and dendritic degeneration, both of which are rescued genetically by inactivating the channel pore or pharmacologically by feeding larvae a trpv selective antagonist. we conducted a genetic screen in n ccap and found that camkii knockdown potently suppresses the trpv r c mediated wing expansion phenotype and selectively rescues degeneration of synapses but not dendrites. we also find that trpv r c , but not controls, disrupts mitochondrial transport in axons by increasing the number of stationary mitochondria. our data demonstrate that trpv r c elevates neuronal intracellular calcium which disrupts mitochondrial transport and mediates neurodegeneration through compartment-specific calcium-mediated signaling pathways, and supports the further investigation of trpv antagonists as potential therapeutics for the treatment of cmt c. mood disorders, including anxiety and depression, are commonly observed among chronic pain patients with prevalence estimates ranging from to %. comorbidity between mood and chronic pain disorders has been linked to altered limbic regulation of the hypothalamic-pituitary-adrenal (hpa) axis. stress activates the hpa axis and can initiate and/or exacerbate symptoms related to both chronic pain and mood disorders. previous studies from our laboratory have investigated the influence of early life stress on mechanical pain hypersensitivity, visceral hypersensitivity and behavioral evidence of mood disorder later in life. here, we are testing the hypothesis that chronic stress exposure in adulthood can increase somatic and visceral sensitivity and anhedonic behaviors in a mouse strain with a genetic predisposition to anxiety. adult, female a/j mice were exposed to repeated foot shock stress for continuous days and tested for alterations in mechanical sensitivity, sucrose preference, visceromotor response (vmr) during urinary bladder distension, and serum corticosterone levels. mice that underwent shock stress had a significantly decreased mechanical withdrawal threshold in the hind paw compared to their baseline and sham group measurements. sucrose preference was measured prior to shock exposure and throughout the shock paradigm as an indicator of anhedonic behavior. mice that underwent shock stress displayed a trend toward decreased sucrose preference, indicating anhedonia, in comparison to mice in the sham group that did not display anhedonia. mice that underwent shock stress displayed significant increases in vmr during bladder distension compared to sham mice. finally, serum corticosterone levels were significantly higher in the mice that underwent shock stress compared to sham mice, indicating a stress-induced increase in hpa axis output. together these data suggest that chronic stress exposure can induce mechanical allodynia, visceral hypersensitivity, and depression-like behaviors in an anxiety-prone mouse strain. future studies will incorporate gene expression in the hypothalamus, amygdala, and hippocampus, as well as investigation of possible downstream peripheral neuroimmune modulation and neuronal morphology changes. guillain-barré syndrome (gbs) is an acute monophasic immune-mediated neuropathy. as prognostic markers of gbs, modified erasmus gbs outcome score (megos), erasmus gbs respiratory insufficiency score (egris), and Δigg have been reported. however, the proportions of subtypes of gbs are known to be different between the western countries and japan, it remains to be elucidated whether those markers can also be applied to gbs in japan or not. we here investigated retrospectively gbs patients and determined the megos and the egris of those cases. among them, Δigg could be obtained in cases. we evaluated the prognosis using gbs outcome score (functional grade: fg) at months; we called good prognosis when fg at months was less than and poor prognosis when that was or more. as a result, in cases with higher score than at megos on admission cases ( %) had poor prognosis and in cases with higher score than at megos at day of admission cases had poor prognosis. in cases with higher score than on egris cases ( %) needed the mechanical ventilator. patients with good prognosis had higher Δigg(average: mg/dl) than patients with poor prognosis(average: mg/dl). we calculated the cut-off value of Δigg in patients, which was mg/dl. patients with higher Δigg than mg/dl could significantly walk independently at six months (p< . ). patients ( %) had poor prognosis in patients with lower Δigg than mg/dl. ( %) of patients were treated with the single cycle of intravenous immunoglobulin (ivig). other patients ( %) were treated with the combined therapies, such as intra venous methylprednisolone and/or plasmapheresis or the second cycle of ivig in addition to ivig. although there was no difference in prognosis between patients with the single cycle of intravenous immunoglobulin (ivig) and patients with the combined therapies, in the patients who had fg> and megos > on admission, the combined therapies made better prognosis than the single course of ivig (p< . ). we found that megos, egris and Δigg were also available in japan. the efficacy of the combined therapies in severe gbs patients should be investigated in the future large scale prospective studies. yiu em , , , burns j , , , menezes mp , , ryan mm , , and for the paediatric cmt best practice guidelines consortium. royal children's hospital melbourne, melbourne, victoria, australia; murdoch childrens research institute, melbourne, victoria, australia; university of melbourne, melbourne, victoria, australia; university of sydney, new south wales, australia; sydney children's hospitals network (randwick and westmead), new south wales, australia. charcot-marie-tooth disease (cmt) often presents during childhood. common symptoms include weakness, limb pain and cramps, foot deformity, and balance impairment. guidelines for the optimal management of common problems experienced by children with cmt do not currently exist. development of these guidelines will provide an evidence base for the management and monitoring of children with cmt. a series of systematic literature reviews utilising the grade (grades of recommendation, assessment, development, and evaluation) approach were conducted to answer pre-specified key clinical questions related to the management of paediatric cmt. these included treatment recommendations for symptoms such as weakness, pain, balance impairment, joint deformity, and impaired upper limb function, and anticipatory monitoring for associated complications such as hip dysplasia. this yielded minimal to no evidence for the pre-specified clinical questions, and evidence-based management recommendations could not be made. consensus-based statements will therefore be formulated via a three-round delphi process, to be conducted in . the delphi panel will consist of local and international medical and allied health professionals who have experience in the management of children with cmt. efficacy of pxt in the treatment of adult patients cmt a (n= ) was shown in a multicenter, randomized, double-blind, placebo-controlled phase ii study (attarian et al. ) . pxt taken x/day, orally, for consecutive months was well tolerated and safe. significant improvement of disability was observed for the highest tested dose, thought indicative for an early, meaningful change in disease course (meta-analysis by mandel et al., ) . this formed the rationale to initiate a multicenter, randomized, double-blind, placebo-controlled pivotal phase iii study (clin-icaltrials.gov: nct ) of pxt in mildly to moderately affected cmt a patients in december . the primary objective is to assess the efficacy of doses of pxt compared to placebo on disability as measured by the mean change from baseline overall neurology limitations scale (onls) score at month and . furthermore, efficacy on the proportion of responders (i.e. improvement of onls), impairment (cmtns-v ), functional tests ( -mwt, qmt, -hpt), electrophysiological parameters (cmap, snap and ncv) and quality of life (eq- d, vas) are secondary endpoints. pursuant this study, patients will be eligible for a -month extension study, in which pxt assigned patients will continue with the previously assigned dose, whereas placebo patients will be randomized to one of the two pxt doses. the study is conducted in investigational sites in countries (eu, canada and us). in december patient randomization was completed (n= ). the screen failure rate was %, as expected ( patients were screened). the independent dsmb recommended to continue the study as planned following a safety analysis on the first patients treated for > months. preliminary baseline characteristics are based on patients (data not cleaned). the study population had a mean age of . ± . years (range - ; male . %) of which . % had a confirmed genetic diagnosis of cmt a. the mean cmtns-v was . ± . and the mean motor nerve conduction of the ulnar nerve was . ± . m/s. ten patients withdrew from the study, due to adverse events unrelated to study treatment. the last patient completing the study is expected in march . zhang g , ghosh p , lin j , ghauri a , sheikh ka . department of neurology, university of texas health science center at houston, houston, tx, usa. assessment of epidermal nerve fiber density and its structure integrity is critical for the diagnosis and evaluating the effectiveness of potential therapies in small fiber neuropathies. currently, skin biopsies, at multiple sites, are most commonly used to assess these diseases. these studies are expensive and time consuming due to cumbersome processing and quantification techniques and serial biopsies over time are often not feasible due to costs and patient acceptance. moreover, vast majority of normative data for skin biopsies in humans are available only for few distal sites and a significant proportion of patients with small fiber neuropathies have focal or regional symptoms not involving the commonly biopsied sites in the leg. live imaging could overcome these limitations and provide a noninvasive real time assessment of epidermal nerve fibers all over the body. we previously found that anti-ganglioside antibody (aga) is an effective neuronal delivery vector for transport of various cargos, such as fluorescent dyes, to peripheral nerves. in the current proof of concept study, we examined whether non-invasive multiphoton microscopy can be used to probe/image the epidermal nerve fibers in living animals after systemic and/or local delivery of fluorescently conjugated aga. we found that the individual nerve endings in skin and cornea are distinctly labeled, and visualized under two-photon microscope. the epidermal nerve fiber labelling by fluorescent-tagged aga was further validated using transgenic mice selectively expressing yellow fluorescent protein in their nervous system. in-vivo multiphoton imaging provide a tool with potential for dynamic longitudinal evaluation of small fiber neuropathies, including nerve degeneration and regeneration, without tissue removal. thus, the use of multiphoton microscopy in conjunction with fluorescently labeled aga as neuronal vector can have many research and clinical applications, such as labeling and live visualization of epidermal nerve fibers to assess small sensory nerve fibers in health and disease. zhou y , tavori h , lee s , al salihi m , fazio s , notterpek l . mcknight brain institute, university of florida, gainesville, florida, usa; knight cardiovascular institute, oregon health and science university, portland, oregon, usa. the majority of hereditary neuropathies are due to abnormalities in peripheral myelin protein (pmp ), whose genetic variants include increased expression (gene duplication), haploinsufficiency (gene deletion), or point mutations. phenotypic heterogeneity in clinical presentation is common among hereditary neuropathy patients even within the same family, the cause of which has not been determined. to investigate the role of pmp in the pathogenesis of the neuropathies we have generated and characterized pmp null (pmp −/− ) mice (amici et al., ) whose peripheral nerves show alterations in lipid metabolism (lee et al., ) . to examine the molecular changes underlying these abnormalities we determined the expression of cholesterol synthesis (srebp pathway), and cholesterol uptake, transport and efflux genes (lxr pathway). in affected nerves, we found the cholesterol synthesis pathway inhibited, while the lxr pathway, and particularly apoe and abca , upregulated at the mrna and protein levels. since pmp is expressed at low levels in the liver, the central organ for the regulation of cholesterol in the body, we studied liver tissue form pmp −/− mice. liver from pmp −/− mice showed significant hepatomegaly, clear features of microvesicular steatosis, as well as marked increase in lxr pathway genes and proteins (abca and apoe), as compared to wt. ultrastructural studies identified lipid droplets and significantly enlarged mitochondria in the liver of male pmp −/− mice, which is not due to mitochondria fusion, as the levels of mfn and remained similar to wt. as disturbed hepatic cholesterol homeostasis induces the activation of kupffer and stellate cells, we determined the extent of inflammation in nerve and liver tissues from pmp −/− mice with leukocyte (cd b) and macrophage markers (cd ). in nerve sections, we detected an increase in the number of cd b+ cells, which was confirmed by western blots. in the liver of pmp −/− mice we found a significant increase in cd -reactive kupffer cells and elevated levels of tnf-alpha. the severe dysregulation of cholesterol metabolism in nerve and liver, including neuroand hepatic inflammation in the absence of pmp − suggest that dysregulated cholesterol metabolism and inflammation may act as a disease modifier in pmp -dependent neuropathies. our aim was to ascertain frequency of and risk factors for tee, arterial (ate) and venous thromboembolic events (vte) in neuromuscular patients receiving regular ivig. we performed a retrospective case-note review of inflammatory neuropathy patients receiving regular ivig treatment. we collected the following data over a month study period this analysis suggests tee incidence is higher in ivig treated patients than comparable population-based rates. examination of tee occurrence in age and vascular risk factor matched ivig-treated and ivig-naïve individuals is required to appreciate the excess risk associated with ivig treatment. référence des maladies neuromusculaires et la sla, hôpital de la timone ha) and whether temporal dispersion (td) parameters are helpful. fifty-eight patients diagnosed according to asbury and cornblath ( ) were prospectively included between january and september . edx and were performed - (mean= ) and - days (mean= ) after disease onset, respectively. there were no differences in classification consistency between ho and ha at edx (p= . ) and edx (p= . ), but more patients were classified as aman when comparing ra with ho and ha at edx (p< . ). at edx , ra classified more patients as equivocal with ho (p< . ) and as aman with ha (p< . ) ) or edx (ho, fe p= ; ra, fe p= . ; ra with td, fe p= . ). gm , gd a, gd b and gq b igg antibodies were tested (willison at edx , only ho showed maybe more antibodies with aman compared to aidp (fe p= . , phi=− . ) and with aman compared to equivocal cases since correlation with factors associated with axonal gbs, in casu rcf and antibodies, is far from exclusive, the usefulness of edx subtype classification using specific criteria sets, remains doubtful. the frequency of rcf indicates that nodal/paranodal alterations may represent the main pathophysiology in more gbs patients than currently thought ruiz m , lessi f , cacciavillani m , riva m , salvalaggio a , campagnolo m , briani c . neurology, department of neuroscience, university of padua, padua, italy; hematology and clinical immunology unit, department of medicine, university of padua, padua, italy; cemes, data medica group, padua, italy.arsenic trioxide (ato) is highly effective in treatment of acute promyelocytic leukemia (apl). it is licensed in italy for treatment of relapsed-refractory apl and for first line chemotherapy in low risk patients. ato most frequent side effects are well described, but less is known on ato induced. we describe apl patients who were treated with all-trans retinoic acid (atra)/ato as first line therapy. the characteristics of ato induced neuropathy was prospectically analyzed by neurological evaluation using both the total neuropathy score, clinical version (tnsc) (a validated scale for chemotherapy induced peripheral neuropathy) and neurophysiological assessment. patients have been evaluated at baseline, at the end of the induction phase, at the end of ato/atra treatment and year after discontinuation of treatment. baseline neurophysiology was performed at the end of induction phase. both patients were men, respectively and -yr-old. none of the patients had previous history of neuropathy. baseline tnsc was (no clinical signs of neuropathy) in both patients. neurophysiological evaluation performed after the end of induction cycle did not reveal signs of peripheral neuropathy in both patients. patient received mg of ato during induction, total , mg. patient received mg of ato during induction, total , . both patients developed leg numbness during consolidation cycles and patient also hand numbness. tnsc at the end of therapy was in patient and in patient . neurophysiology at the end of therapy detected signs of sensitive axonal neuropathy in both patients. they received full doses of ato consolidation ( . mg/kg/day for days/week, on alternate months for total months and tretinoin weeks on weeks off). during the first year of follow-up both tnsc and neurophysiology year after the end of consolidation cycle were consistent with full recovery. our patients developed sensory axonal neuropathy during ato therapy, that clinically manifested during consolidation cycles and improved up to complete recovery during follow-up. published case reports show that outcomes may not be as good as in our patients. a multicenter prospective study evaluating the characteristics of ato-induced neuropathy in apl is ongoing. ruiz m , campagnolo m , salvalaggio a , cacciavillani m , taioli f , fabrizi gm , briani c . department of neuroscience, neurology unit, university of padua, padua, italy; data medica group, emg unit, cemes, padua, italy;mutations in the mitochondrial copper-binding protein sco , cytochrome c oxidase assembly protein, have been reported in several cases of fatal infantile cardioencephalomyopathy with cox deficiency. we identified compound heterozygous variants in sco in two unrelated patients with isolated length dependent axonal sensorimotor polyneuropathy of variable clinical severity (axonal autosomal recessive charcot-marie-tooth disease type , cmt ) by whole exome sequencing. although peripheral neuropathy has been described as a secondary feature in a few cases of fatal infantile cardioencephalomyopathy, the disease onset, clinical phenotype and survival in our patients differ significantly from the previously described cases. our patients developed predominantly motor neuropathy; moreover, they are still alive and they have not developed cardiomyopathy, which is the main phenotype and cause of death at early infancy in reported patients. both of our patients harbor mutations adjacent or near the conserved copper-binding motif (cxxxc), including the common reported pathogenic variant e k and the novel change d g. in addition, each patient carries a second mutation located in the same loop region of the protein, p t and r q. western blots from fibroblasts from these cmt patients showed reduced levels of cox , a subunit of complex iv, indicating cox deficiency. our findings demonstrate that cmt can be the predominant phenotype associated with sco mutations, pointing to a broader phenotypic heterogeneity. the mechanism linking mitochondrial respiratory chain dysfunction to isolated axonal loss of variable severity remains to be elucidated. the muscarinic acetylcholine (ach) type receptor (m r) is a metabotropic g protein-coupled receptor expressed by adult sensory neurons. cholinergic signaling through muscarinic receptors can modulate axonal plasticity in invertebrates and lower vertebrates. we have recently shown that selective (pirenzepine) and specific (muscarinic toxin : mt ) m r antagonists elevate neurite outgrowth and protect from small and large fiber neuropathy in adult sensory neurons in various animal models (calcutt, et al., ) . furthermore, we demonstrated that excessive cholinergic signaling due to m r overexpression caused a significant reduction in neurite outgrowth (calcutt, et al., ) . the mechanism of m r-antagonist driven neurite outgrowth remains poorly understood, however, we have proposed that ach constrains axonal outgrowth via m r activation. cholinergic signaling is mediated via recruitment of trimeric g proteins, of which g alpha- and g alpha- regulate cytoskeleton dynamics by control of tubulin polymerization. activated gtp-bound g-alpha proteins destabilize microtubules by increasing the intrinsic gtpase activity of tubulin. we have therefore tested the hypothesis that cholinergic signaling regulates neurite outgrowth via modulation of g protein mobilization and the dynamics of the tubulin cytoskeleton. we found that over-expression of m r in adult sensory neurons induced dissolution of the tubulin cytoskeleton in distal neurites. g alpha- expression in adult sensory neurons was significantly higher (p< . , -fold) than g alpha- . subsequent knockdown the peripheral neuropathy research registry (pnrr) is a multicenter collaborative research project sponsored by the foundation for peripheral neuropathy to advance the science in distal symmetrical polyneuropathies (dsp). the registry was designed to prospectively characterize clinical phenotype and natural history of patients with dsp and obtain biofluids to identify new causes and genetic modifiers of dsp with careful genotype/phenotype correlations, and to develop biomarkers. the enrollment in the registry is still ongoing but an interim analysis was carried at the end of december . eligible study participants were years or older with a diagnosis of idiopathic, diabetic, chemotherapy-or hiv-induced peripheral neuropathy. they were examined by a physician at one of the six consortium members (johns hopkins university school of medicine, icahn school of medicine at mount sinai medical center, beth israel deaconess medical center, northwestern university medical center, university of utah medical center and kansas university medical center). the collected data set included ( ) a detailed questionnaire, discussing their symptoms, medical history and family history, ( ) a standardized neurological examination form, ( ) electrodiagnostic evaluation and ( ) diagnostic laboratory testing. blood samples (whole blood, plasma and serum) were collected for future biomarker and genotyping evaluations. at the end of , complete data sets and blood samples were collected from patients. % had diabetic pn, % had hiv-associated pn, % had chemotherapy induced pn and % were diagnosed with idiopathic pn. detailed analysis of clinical presentation, examination findings and diagnostic investigations will be discussed at the presentation. standardized phenotyping with linked bio-specimen banking will help establish the minimum data set required for neuropathy diagnosis and support genotype-phenotype correlations with next generation sequencing technologies and development of novel biomarkers. pnrr data will improve our understanding of disease mechanisms paving the way for new therapeutic discoveries in painful and non-painful neuropathies. chemotherapy-induced peripheral neuropathy (cipn) is a major side effect of treatment, typically presenting as a sensory neuropathy. symptoms include pain, paraesthesia, and numbness in the extremities, resulting in functional impairment. increasingly, patient reported outcomes (pros) are utilized to accurately examine the impact of cipn symptoms on patient function. however, the links between objective neurological assessment and pro measures remain ill defined. this study aimed to identify links between neurophysiological measures and pros in patients treated with neurotoxic chemotherapy. assessments were conducted in patients (f= , mean age . ± . years) who had completed neurotoxic chemotherapy on average . ± months previously (platinum-based n= , taxane-based n= or taxane/platinum combination therapy n= ). patients reported the presence and severity of neuropathic symptoms via the fact-gog ntx , a validated patient questionnaire. clinical the most important neurological side effect of a large number of anti-cancer drugs is a painful peripheral neuropathy. mainly chemotherapeutics that interfere with microtubules, including the plant derived vinca-alkaloids such as vincristine, are well known to cause chemotherapy-induced peripheral neuropathies (cipn). to date, few treatments are available and focus on symptom alleviation and pain reduction rather than on preventing the neuropathy all together. for the first time, we highlight the potential of specific histone deacetylase (hdac ) inhibitors as a preventive therapy for cipn, using novel rodent models for vincristine-induced peripheral neuropathies (vipn), characterized by a sensory axonopathy. one reason so few therapies are available, is because the exact pathophysiological mechanisms are poorly understood. mounting evidence proposes axonal transport, a pathway frequently disturbed in neurological disorders, as a major player in the pathophysiology of vipn. proper axonal transport requires dynamic microtubules which are highly modulated by post-translational modifications. since vincristine interferes with the polymerization of microtubules, we reason disturbances in microtubule dynamics, and by extension axonal transport, could contribute to vipn. we illustrate that increasing acetylation of -tubulin after hdac -inhibition, can restore vincristine-induced defects in axonal transport in cultured dorsal root ganglion neurons. also in vivo, -tubulin acetylation was restored in the saphenous nerve and dorsal root ganglia, two sensory tissues that are affected by vincristine. ultimately, this correlates to a reduced severity of the neurological symptoms, both on the electrophysiological and on the behavioral level. moreover, we discovered that hdac -inhibition was not only protective against neurotoxicity, but also reduced tumor progression in a mouse model for acute lymphoblastic leukemia. taken together, our results show that hdac -inhibition is an ideal strategy to prevent vipn with beneficial effects both on the neurotoxicity as well as on tumor growth.approximately two-thirds of cidp subjects need long-term corticosteroids or intravenous immunoglobulins (ivig), with ivig being slightly preferred based on safety profiles. subcutaneous ig (scig) is an alternative option for ig delivery but has not previously been investigated in a large-scale clinical trial in cidp.we performed a randomized, double-blind trial in cidp investigating . and . g/kg weekly doses of scig igpro (hizentra ® , csl behring) versus placebo in subjects for maintenance treatment. ivig-dependent adults with definite or probable cidp according to efns/pns criteria were eligible. the primary outcome was the percentage of subjects with a cidp relapse ( -point deterioration on adjusted incat disability score) or who were withdrawn for any other reason during the -week scig-treatment period. multiple secondary endpoints were assessed. superiority of at least one igpro dose over placebo was tested one-sided using the cochran-armitage trend test for the primary outcome and the jonckheere-terpstra tests for secondary outcomes.the primary outcome occurred in % of high-dose scig, % of low-dose scig, and % of placebo subjects (p < . ); cidp relapse occurred in % of high-dose scig, % of low-dose scig and % of placebo subjects (p < . ), respectively. both scig doses were superior to placebo (low-dose vs placebo p = . ; high dose vs placebo p < . ). median incat score, mrc sum score, and grip strength remained stable in scig subjects. high-dose scig prevented the r-ods decline seen with low-dose scig and placebo (p < . ). all placebo subjects deteriorated on measures of strength and disability.causally related adverse events occurred in ( %) subjects ( % placebo, % low dose, and % high dose).scig igpro was efficacious and safe as maintenance treatment. mutations in metalloendopeptidase (mme) gene have been associated with autosomal-recessive late-onset charcot-marie-tooth type- (cmt ). to date, all patients have had at least one truncating mutation, either in homozygosity or in trans with a missense mutation. more recently, loss-of-function and missense heterozygous mutations were also identified in autosomal-dominant cmt. we report the case of a previously healthy caucasian woman, born to healthy unrelated parents, who presented at the age of thirty-nine with numbness and cold sensation in the lower limbs. subsequently she developed progressive gait disturbance and impaired hand dexterity. her homozygous twin presented at the same age with similar symptoms. the family history was otherwise uneventful, in particular neither neuropathy nor dementia were described. neurological examination at the age of fifty-three revealed a steppage gait, distal upper and lower limb atrophy and weakness, distal sensory loss and bilateral pes cavus. deep tendon reflexes were normal in the upper limbs and absent in the lower limbs. nerve conduction studies revealed an axonal sensory and motor neuropathy. a sural nerve biopsy revealed a reduction in myelinated nerve fibers and active axonal degeneration. targeted sanger sequencing of mpz , gjb , gdap , nefl, fkrp, bscl , hspb and mfn were negative. sureselect focused exome sequencing was therefore performed and identified two missense heterozygous mutations [c. g>a,p.c y;c. t>c,p.y h] or lack of efficacy (n= ). most frequently reported adverse events were cognitive ( %), gastrointestinal ( %) and genitourinary ( %). discontinuation due to perception of lack of efficacy was more frequently reported by men ( % vs % p= . ). women presented higher punctuations on pigc scale compared with men ( . ± . vs . ± . , p= . ). pigc scores were significantly higher in patients receiving taxane ( . ± . ) than platinum ( . ± . ) agents (p= . ). no significant differences according severity of neuropathy neither type of chemotherapy were observed in drop-out and retention rates. patients with long-lasting cipn (> months) reported lower pigc scores ( . ± . vs . ± . , p= . ) and higher frequency of suspension due to adverse events ( % vs %, p= . ) and less rate of continuation of duloxetine ( % vs %, p= . ). more than one-third of patients with disturbing cipn discontinued duloxetine prematurely due to intolerable side-effects. low tolerability, male gender and long-lasting cipn may limit duloxetine usefulness in the treatment of symptomatic cipn. verboon c , jacobs bc , and the igos consortium. department of neurology, erasmus medical centre, rotterdam, the netherlands; department of immunology, erasmus medical centre, rotterdam, the netherlands.the efficacy of intravenous immunoglobulin (ivig) in guillain-barré syndrome (gbs) has only been demonstrated in severely affected patients who are unable to walk independently. although there is no proof that ivig is effective in milder forms of gbs, some neurologists are treating these patients with ivig considering that even milder forms of gbs may result in poor recovery, residual deficits, fatigue or pain.we determined the effectiveness of a single course of ivig ( g/kg in - days) in relatively mild forms of gbs in the ongoing observational international gbs outcome study (igos). the gbs disability score, mrc sum score and patient reported outcome measures (prom) were compared at and weeks. ordinal logistic regression analysis was used to determine the effect of ivig on the gbs disability score, adjusted for previously identified prognostic factors.data were analyzed from the first patients enrolled in igos by december , including patients with mild gbs at entry, of which patients ( %) were treated with supportive care, while patients ( %) received ivig (start ivig after onset of symptoms in days, median , iqr - ). at baseline, patients in the ivig treated group compared to the untreated group less frequently had pure motor gbs ( % versus %, p< . ) and axonal damage or unresponsive nerves ( % versus %, p= . ), but a worse gbs disability scores at nadir (p= . ). the adjusted common odds ratio for a better gbs disability score at weeks was . ( % ci . - . ). at weeks, the median mrc sum scores and prom were not significantly different between treated and untreated patients. however, more patients in the ivig group showed complete recovery of muscle strength at weeks than patients in the control group ( % versus %) (p= . ) and more frequently showed full neurological recovery on the gbs disability scale ( % versus %, p= . ). additional results will be presented at the conference.based on the results of this interim analysis in observational data, we conclude that patients with a relatively mild form of gbs may benefit from a single course of ivig. despite treatment with intravenous immunoglobulin (ivig), many patients with guillain-barré syndrome (gbs) recover insufficiently. we primarily aimed to determine whether a second ivig course ( g/kg in - days) in patients with a poor prognosis improves outcome on the gbs disability scale after weeks. we included patients from the prospective, observational international gbs outcome study (igos) treated with ivig and who had a poor prognosis on the modified erasmus gbs outcome score (megos). of patients enrolled in igos, patients were eligible; patients ( %) were treated with one ivig course (control group); patients ( %) received an 'early' second ivig course ( - weeks after start first course) and patients ( %) a 'late' second ivig course (within - weeks). one week after study entry, patients receiving an 'early' or 'late' second ivig course had significantly worse gbs disability scores and mrc sum scores than controls, implying the need for adjustment of baseline characteristics. the adjusted common odds ratio for a better gbs disability score at weeks was . ( % ci . - . ) for the 'early' group, and . ( % ci . - . ) for the 'late' group, suggesting worse outcomes with a second course of ivig compared to controls. at months, patients ( %) in the 'early' second ivig group, patients ( %) in the control group and only ( %) in the 'late' second ivig group were able to walk unaided (p= . ). the adjusted common odds ratio for a better gbs disability score at weeks was . ( % ci . - . ) for the 'early' second ivig group and only . ( % ci . - . ) for the 'late' second ivig group. in gbs patients with a poor prognosis, we did not find a beneficial effect of a second course of ivig after weeks follow-up. our results suggest that an 'early' administered second ivig course might improve outcome at weeks. given the limitations of this observational study, a randomized controlled trial with a larger number of gbs patients with a poor prognosis being treated early in the disease course is needed to confirm or refute these results. vidal c , bhatt n , agudelo c , mahapatra a , saporta ma . department of neurology, university of miami miller school of medicine, miami, usa.multifocal motor neuropathy (mmn) is an inflammatory demyelinating chronic neuropathy characterized by progressive asymmetric weakness in the distribution of two or more peripheral nerves, without objective sensory loss or upper motor neuron signs. the cardinal neurophysiological finding is conduction block outside the usual sites of nerve compression. supportive clinical criteria include high titers of anti-gm antibodies, good response to ivig, increased cerebrospinal fluid (csf) protein (< g/dl) and magnetic resonance imaging (mri) with diffuse swelling of the brachial plexus. we report a case of a year old woman with a two month history of progressive muscular weakness which began in the right upper extremity, described as difficulty in gripping objects, writing and typing on the computer, followed by progressive lower extremity weakness with difficulty rising from a chair and left foot drop. she also complained of pain in her right trapezius and scapular area. she denied any tingling or numbness. on neurological examination there was right scapular winging and asymmetric weakness predominantly involving the right upper and left lower extremities. reflexes were absent throughout. lumbar puncture revealed albuminocytological dissociation (wbc and protein . g/dl). ncs revealed slow conduction velocities for both ulnar and median nerves and a median nerve conduction block at the forearm segment. sensory nerve action potentials were normal for all tested nerves. needle emg revealed acute denervation of right periscapular muscles. brachial plexus mri showed symmetric bilateral thickening from trunks to peripheral nerves. anti-gm igg/igm were negative. two days after lumbar puncture and the beginning of ivig, patient presented binocular diplopia on extreme left lateral gaze. brain mri with and without contrast showed no intracranial pathologies. after five days of ivig, patient was discharged with significant clinical improvement and recovery of the right scapular winging. diplopia improved a week after discharge. we report an atypical multifocal motor neuropathy case. although this patient fulfills all clinical criteria for mmn, we report some features usually not found in mmn such as scapular winging and a mild and transient left vi nerve palsy. mmn should be included in the differential diagnosis of scapular winging. vlckova e , , raputova j , , srotova i , , sommer c , Üçeyler n , birklein f , rebhorn c , rittner hl , kovalova e , , nekvapilova e , , belobradkova j , olsovsky j , weber p , dusek l , jarkovsky j , bednarik j , . despite many studies addressing biomarkers for pain in diabetic polyneuropathy (dpn), little is known about why it affects only a certain proportion of dpn patients. the somatosensory system plays a key role in the pathophysiology of neuropathic pain (neup) and subgroups with different sensory profiles might respond differently to pain treatment. we aimed to characterize sensory phenotypes of patients with painful and painless diabetic neuropathy and to assess demographic, clinical, metabolic, electrophysiological and psychological parameters related to the presence of neup in a large cohort of well-defined dpn subjects.this observational cross-sectional multi-centre cohort study (performed as part of the ncrnapain eu consortium) of subjects with dpn (non-painful, ndpn, n= ; painful, pdpn n= ) associated with diabetes mellitus of type and (median age years, range - years; women) comprised detailed history taking, neurological examination, laboratory tests, quantitative sensory testing, nerve conduction studies, neuropathy severity scores, and neuropsychological questionnaires. all parameters were analysed with regard to the presence and severity of neup. the presence and severity of neup were positively correlated with severity of neuropathy and thermal hyposensitivity (p< . ). a minority of pdpn patients ( . %) had a sensory profile indicating thermal hypersensitivity; this was associated with less severe neuropathy and better response to pain therapy. the presence of neup was also associated with female gender (p< . ) and with higher cognitive appraisal of pain as assessed by the pain catastrophizing scale (p< . ), while parameters related to diabetes (duration, hba c, microangiopathy) showed no influence on neup presence and severity. this study confirms the necessity of comprehensive dpn phenotyping and underlines the importance of the severity of neuropathy that should be taken into account in the stratification of patients with pdpn for analgesic treatment and drug trials.people with charcot marie tooth disease (cmt) experience slowly progressive muscle weakness, sensory loss and musculoskeletal changes over time. this leads to disability and risk of comorbidities due to inactivity. exercise is important to maintain general health but may also help to improve symptoms of cmt. we conducted a randomised controlled crossover trial of aerobic exercise to ascertain the effect of training on fitness levels, muscle strength, function and general well-being. in addition, we monitored the safety of training and feasibility of participation in this type of exercise in local community gyms. motivation, confidence and barriers to exercise were explored using qualitative interviews. the recruitment target was people. in total people with cmt a were approached to participate and were unable to commit to the trial or did not meet the study criteria on initial screening. thirty-one people underwent more detailed screening but three failed to meet the study criteria, five people withdrew before starting and three withdrew part way through the study. the data for the people who started the study were analysed using a random effects model. there was a % participation level in the training and it was well tolerated with no increases in pain or blood serum creatine kinase. an increase in vo peak (ml/min/kg) was observed in the cmt group with (pre training: n= , . ± . , % ci . to . ; post training: n= , . ± . , % ci . to . ; pre control: n= , . ± . % ci . to . ; post control: n= , . ± . , % ci . to . ) . there was wide between subject variation leading to a small overall effect size with cohen d of . ( % ci:- . to . ). a tentative regression model showed no effect of group or time point. there were no major changes in other measures of impairment, function or patient reported outcome measures. this pilot study showed that a community based model of training had a small effect on cardiopulmonary fitness, and was well tolerated with good participation. ankle-foot orthoses (afo) are commonly prescribed for children with charcot-marie-tooth disease (cmt) to manage foot drop, however the type and severity of functional impairment results in gait deviations that might require alternate orthotic designs. the aim of this study was to identify d gait patterns of children with cmt based on severity of functional weakness (based on heel walk, toe walk and foot drop items during gait using the cmt pediatric scale) to inform a design pipeline for d printed orthoses. d gait data were captured with an -camera vicon nexus motion capture system using the lower body plug-in-gait model in children with cmt ( male; ± . yrs, ± . cm, ± . kg), of various cmt types: cmt a, cmt e, cmt f, cmt a, cmt c, cmtx , cmtx and compared to typically developing children ( male; . ± . yrs, ± . cm, ± . kg). data were subdivided into three groups denoting increasing severity of dorsiflexion and plantarflexion weakness: no difficulty heel or toe walking (cmt nd ), difficulty heel walking (cmt dh ), difficulty toe and heel walking (cmt dth ). the cmt nd group showed a near-normal gait pattern. the only significant differences noted at the ankle were reduced peak dorsiflexion in stance (p< . ), indicating that an orthotic intervention may not be required. in addition to reduced peak dorsiflexion, the cmt dh group demonstrated significantly reduced dorsiflexion in swing (foot-drop) and a reduced dorsiflexor moment in loading response (p< . ). this suggest, the cmt dh group would require a flexible afo to allow activation of the plantarflexors during push-off, prevent foot-drop and restore a heel rocker in loading response. in contrast, the cmt dth group presented with significantly delayed and increased peak dorsiflexion in stance and reduced plantarflexion and power at push-off (p< . ). they also had significantly increased mean knee extensor moment (p< . ) revealing early signs of 'crouch gait'. therefore, the cmt dth group would require a rigid afo to limit the amount of dorsiflexion and assist movement of the ground reaction force anterior to the knee during stance. three distinct gait patterns at the ankle were identified in children with cmt, indicating patient-specific orthotic design pathways to target specific functional impairment. wojciechowski e , , chang a , cheng t , , little d , , menezes mp , , hogan s , burns j , . university of sydney, new south wales, australia; sydney children's hospitals network (randwick and westmead), new south wales, australia.children with cmt are often prescribed ankle-foot orthoses (afo) to manage lower limb impairment such as foot drop and foot deformities. they are handmade by plaster cast followed by thermoplastic moulding. this traditional approach provides limited design options, can be costly, with long outpatient wait times. d printing, also known as additive manufacturing, has the potential to transform the way orthoses are prescribed, designed and manufactured. the aim of this review was to evaluate the evidence of d printing afos compared to traditional manufacturing methods, for children with cmt. there are currently no studies evaluating the application of d printing afos for children with cmt. however, a small, but emerging evidence base exists for d printed afo's in adults from studies including healthy participants and populations with rheumatoid arthritis, post-polio syndrome, foot drop and ankle weakness secondary to injury. samples sizes ranged from - participants for studies related to in-shoe orthoses and from - for studies related to afos. the methods of d printing included sterolithography, selective laser sintering and fused deposition modelling using materials such as nylon , nylon , polylactide, polycarbonate and abs. d printed afos were comparable to traditional manufactured orthoses in terms of patient-perceived comfort, temporal-spatial parameters, plantar pressure measurements and d gait analysis. however, the effects of long-term usage and durability of d printed afos has not been investigated. d printing orthoses have potential advantages including increased design possibilities, improved productivity, higher compliance, and reduced labour needs. disadvantages include redesigning clinical pathways, limited evidence base for clinical effectiveness, limited biocompatible materials, occupational safety considerations and a high level of expertise required for software operation and fabrication of devices. further research is required to determine the feasibility of d printed afos for children with cmt, and the most appropriate and effective printing pathway, materials to improve health outcomes of affected patients. wong shj , koh sj , lee bjh , chng ysk , pawa c , subramaniam t , cheng ksa , umapathi t . lee kong chian school of medicine, nanyang technological university, singapore; national neuroscience institute, singapore; yong loo lin school of medicine, national university singapore, singapore; khoo teck puat hospital, singapore.treatment-induced neuropathy of diabetes mellitus (dm) (tind) is a complication of rapid glycaemic control. individuals present with neuropathic pain and autonomic dysfunction within weeks of improvement in glucose control. the use of both insulin and oral hypoglycaemic agents has been associated with tind. its severity is determined by the rate and quantum of hba c decline. other predisposing factors include anorexia and weight loss. we studied the incidence of tind in dm patients who have undergone massive weight loss and hba c decline after bariatric surgery. we screened electronic records of patients ( dm, non-dm) who underwent bariatric surgery between and . dm patients fulfilled the tind hba c criteria of a decrease of ≥ % over months or ≥ % over