key: cord-0006148-vqt6oiwz
authors: nan
title: Abstracts zum 125. Kongress der Deutschen Gesellschaft für Innere Medizin e.V.
date: 2019-04-18
journal: Internist (Berl)
DOI: 10.1007/s00108-019-0612-9
sha: 206859d05d2b141b6a846d81483773371c02fd7a
doc_id: 6148
cord_uid: vqt6oiwz

nan

zygote Mutationen im DES-Gen, welches für das Intermediärfilamentprotein Desmin kodiert. Material und Methoden: In zwei Familien mit einer dilatativen Kardiomyopathie (DCM) wurde jeweils eine neue DES-Genmutation mittels Next-Generation-Sequencing (NGS) identifiziert und weiter molekularbiologisch und zellbiologisch charakterisiert. Es erfolgte eine bioinformatische Bewertung der DES-Varianten und eine Klassifikation nach den Kriterien des American College of Genetic and Genomic Medicine (ACMG). Zur funktionellen Charakterisierung wurden DES-Mutationen generiert und in das pm-Ruby-N1-Desmin Plasmid inseriert und anschließend in H9c2-und SW-13-Zellen transfiziert. Zudem wurde verfügbares, explantiertes Myokard-Gewebe eines Mutationsträgers immunhistologisch untersucht. Ergebnisse: Die Sequenzierung zeigte zwei neue Mutationen im DES-Gen: p.Ile402Thr (c.1205T>C, Familie I) und p.Glu410Lys (c. 1228G>A, Familie II), die in großen Kontrollpopulationen (gnomAD, EVS) komplett abwesend sind und in allen Pathogenitäts-Vorhersageprogrammen kohärent als pathologisch bewertet wurden. Entsprechend der ACMG handelt es sich um ‚pathogenic variants' (class V). Eine Zweitmutation wurde nicht identifiziert. Klinisch zeigte der Indexpatient der Familie I eine milde DCM und eine Myopathie. In der großen Familie II hingegen zeigte sich eine schwere, familiäre DCM, eine arrhythmogene rechtsventrikuläre Kardiomyopathie (ARVC), diverse, zum Teil maligne Herzrhythmusstörungen und multiple plötzliche Herztode. In in-vitro-Versuchen zeigten beide Mutationen pathologische Desmin-Aggregate, wohingegen der Wildtyp reguläre Filamente ausbildete. Die Desmin-Aggregate wurden zudem in der explantierten Herzprobe aus Familie II nachgewiesen. Schlussfolgerung: Die Ergebnisse zeigen, dass Desminopathien eine variable, kardiale Expressivität haben können, die zum Teil schwer ausgeprägt sein kann. Die Bildung vermutlich toxischer Proteinaggregate untermauert die Pathogenitätsvorhersagen. Die frühzeitige Erkennung von DES-Mutationen hilft bei der genetische Beratung und Therapie betroffener Familien.

In der Therapie chronisch entzündlicher Darmerkrankungen ist Infliximab (IFX) neben weiteren Biologika ein wichtiger Bestandteil. Ein Problem ist die Entwicklung von Anti-Drug-Antibodies (ADA), welche die Pharmakokinetik und die Effektivität der eingesetzten Substanz negativ beeinflussen.

Hier werden Daten des Therapeutischen Drug Monitorings (TDM) eines Kollektives von 57 Patienten (n=47 Morbus Crohn; n=10 Colitis ulcerosa) retrospektiv ausgewertet, die Entwicklung von ADA im Therapieverlauf, der Einfluss der ADA auf die IFX-Drug-level und das Erzielen und Aufrechterhalten einer klinischen Remission untersucht.

Methode: Es erfolgt die Bestimmung des IFX trough-levels zeitgleich mit dem ADA -Spiegel vor der nächsten Infusion. Die Analyse erfolgt mittels kommerziell verfügbarer Testsysteme (IDKmonitor®infliximab drug level ELISA und total ADA Elisa). Eine Auswertung des ADA-Titers erfolgt in Korrelation mit dem IFX-Drug level, begleitender immunsuppressiver Therapie mit Azathioprin (AZA) und dem klinischen Ansprechen.

Ergebnisse und Schlussfolgerung: Bei n=57 Patienten wurden 686 Analysen durchgeführt. N=49 Patienten wurden mit IFX behandelt (n=15 IFX+AZA), Adalimumab erhielten 25%, Vedoluzimab 12%, Golimumab 4% und Ustekinumab 4% der Patienten. IFX-Drug-level lagen bei 6,30+/-5,68µg/ml, IFX-ADA > 10µg/ml waren bei n=17 (35%) Patienten (IFX 15/34 (44%); IFX+AZA 2/15 (13%) nachweisbar. Die ADA-Titer lagen bei 147,72+/-174,70µg/ml. Dies führte durchschnittlich nach 6, 9 Monaten bei 83% der Patienten zum Therapieabbruch. Niedrig-titrige IFX-ADA < 10µg/ml waren bei 27/49 (55%) (IFX 14/34 (41%);( IFX+AZA 13/15 (87%)) mit 3,76+/-1,99µg/ml messbar. Die Therapie wird bei 70% der Patienten seit 12,1 Monaten fortgesetzt.

Exemplarisch wird der Verlauf von Patienten mit niedrig-titrigen ADA unter einer Dosiseskalation gezeigt.

Somit zeigt sich, dass sehr häufig ADA in niedrigem Titer nachweisbar sind. Eine remissionerhaltende Therapie, ggf. unter einer Dosisanpassung, aber möglich ist.

Das TDM ist essentieller Bestandteil des Therapiemanagements einer Biologikatherapie bei CED. Besondere Bedeutung hat die ADA-Bestimmung. Wesentlich ist zukünftig, auch für neue Substanzen, die Differenzierung zwischen neutralisierenden und nichtneutralisierenden Antikörpern, sowie sensitivere Bestimmungsmöglichkeiten von niedrig-affinen und niedrig-titrigen Antikörpern. Dies unterstreicht die Bedeutung der Entwicklung neuer genauerer Messsysteme neben den konventionellen Elisa-Verfahren, zum Beispiel mittels Biosensoren. Somit wird eine individuell gesteuerte Dosis des Medikaments im Rahmen eines TDM ermöglicht. Clinical Decision Support Systeme (CDSS) werden als wichtige Waffe im Kampf gegen vermeidbare medizinische Fehler angesehen. Zudem können sie die Umsetzung von evidenzbasiertem Wissen in der Praxis beschleunigen. Im Zentrum effektiver CDSS stehen Künstliche Intelligenz (KI) und evidenzbasierte Medizin (EBM). In unserem Vortrag unterscheiden wir die verschiedenen Formen von KI und diskutieren sie im Hinblick auf ihre Eignung für den Einsatz in CDSS. Zudem zeigen wir, wie ein Expertensystem basierend auf deklarativer Künstlicher Intelligenz die Diagnostik und Therapie komplexer Erkrankungen wie Epilepsie, Kolonkarzinoms sowie der Stammzelltransplantation unterstützen kann.

Bei Clinical Decision Support geht es um den Einsatz von schwacher KI, d.h. ärztliche Entscheidungen sollen in Einzelbereichen unterstützt werden. Aus dem Bereich der Schwachen KI bieten sich insbesondere Wissensbasierte Systeme sowie Machine Learning zum Einsatz in CDSS an. Wissensbasierte Systeme modellieren eine Form rationaler Intelligenz für sogenannte Expertensysteme. Diese sind in der Lage, auf eine Frage des Anwenders auf Grundlage formalisierten Fachwissens und daraus gezogener logischer Schlüsse Antworten zu liefern. Machine-Learning ist für die CDSS nicht immer geeignet. Die heutigen "Big Data" über die klinische Versorgung repräsentieren weniger als 20 Prozent der evidenzbasierten Erkenntnisse. Zudem können Erhebungsverzerrungen erhebliche Auswirkungen haben. So sind Frauen, ethnischen Minderheiten und älteren Menschen in der Diagnostik und Therapie vieler Krankheiten unterrepräsentiert. Machine Learning auf Basis dieser Daten würde zu falschen Empfehlungen kommen.

Wir stellen daher ein Clinical Decision Support Framework vor, das einen deklarativen Ansatz der Wissensrepräsentation nutzt. Das Spezialwissen von evidenzbasierten Leitlinien und die Schlussfolgerungsfähigkeit klinischer Experten werden in der Programmiersprache PROforma formal nachgebildet, so dass sie von einem Computer interpretiert werden können. Der Lösungsweg wird nicht algorithmisch vorgegeben wird, sondern es werden nur mehr die Bedingungen definiert, die die Lösung des Problems erfüllen soll. Dies ermöglicht es zu überprüfen, wie Entscheidungen getroffen wurden oder warum bestimmte Optionen empfohlen wurden und andere nicht -es handelt sich also nicht um eine "Black-box" wie bei Machine Learning.

Wir zeigen die Ergebnisse der ersten klinischen Evaluationen des Clinical Decision Support Frameworks in drei Anwendungsfällen: 1) Unterstützung der Diagnostik & Therapie der Epilepsie am Universitätsklinikum in Tübingen, 2) Unterstützung des Tumorboards bei Patienten mit Kolonkarzinom und Ko-Morbidiäten am Johanniter-Krankenhaus in Bonn, 3 Methoden: Zielgruppe sind Patienten mit einer stationären Hauptoder Nebendiagnose, die mit CHI assoziiert ist. In der Evaluation werden unter 18-Jährige, stationär Pflegebedürftige, Patienten mit anderen schweren Erkrankungen, wie z. B. manifesten psychischen Erkrankungen, dialysepflichtiger Niereninsuffizienz oder Listung zur Herztransplantation ausgeschlossen. Im Intention-to-treat-Ansatz werden alle Patienten, die sich zwischen Januar 2014 und Juni 2017 in das Programm eingeschrieben haben berücksichtigt und für mindestens ein Jahr nachbeobachtet. Eine vergleichbare Kontrollgruppe wurde mittels Propensity Score-Matching aus den Routinedaten der AOK Nordost gebildet. Primäres Outcome ist das Überleben ein Jahr nach Programmaufnahme. Die Leistungsinanspruchnahme wird über Anzahl und Verweildauer der Krankenhausaufenthalte dargestellt.

Ergebnisse: Insgesamt haben sich im Beobachtungszeitraum vom 01.01. 2014-30.06.2018 n = 9.472 Patienten in das Betreuungsprogramm eingeschrieben, welche im Mittel 1,9 Jahre teilnahmen. Durchschnittlich lag das Alter der Patienten bei 73 Jahren, wobei Frauen (46 %) im Mittel 3,6 Jahre älter sind (p < 0,001). Die Patienten wiesen zu Teilnahmebeginn folgende NYHA-Stadien auf: I (5 %), II (30 %), III (31 %), IV (13 %). Bei 11 % wurde das Stadium nicht näher bezeichnet. Insgesamt versterben 6 % der Patienten innerhalb von 12 Monaten nach Teilnahmebeginn; die 24-Monats-Mortalität beträgt 9 %. In den ersten 12 Monaten waren die Patienten aufgrund einer Kreislauferkrankung durchschnittlich 1,3-mal im Krankenhaus. Bezogen auf die ersten 24 Monate steigt die Rate auf 2,3 an.

Diskussion: Die Evaluation des langjährigen telemedizinischen Betreuungsprogramms umfasst erstmalig einen Beobachtungszeitraum bis zu 4,5 Jahren sowie eine vergleichsweise sehr hohe Teilnehmerzahl. Sie basiert auf Real World Data, die nicht primär zur Bewertung von medizinischen Interventionen erhoben wurden. Die Sekundärdatenanalyse erfolgt aus der Perspektive der Versorgungsrealität. Die endgültigen Ergebnisse werden auf dem Kongress präsentiert.

The accuracy of TMB estimation by an in-house 327-gene panel was established in the TCGA HNSCC dataset. Interference of TMB with outcome after cCRTX was determined in a multicenter cohort of patients with locally advanced head and neck squamous cell carcinoma (HNSCC) uniformly treated with cCRTX. tNGS was successfully applied in 101 formalin-fixed, paraffin-embedded pretreatment tumor samples. In a subset of cases (n=40), tumor RNA was used for immune-related gene expression profiling by the nanoString platform. TMB was correlated with TP53 genotype, HPV status, immune expression signatures and survival parameters. Results were validated in the TCGA HNSCC cohort.

Results: A high accuracy of TMB estimation by the 327-gene panel was established. High TMB was significantly associated with an increased prevalence of TP53 mutations and immune gene expression patterns unrelated to T cell-inflamed gene expression profiles. Kaplan-Meier analysis revealed significantly reduced overall survival in the patient group with high TMB (hazard ratio for death: 1.79, 95% confidence interval: 1.02-3.14; P= 0.042) which remained significant after correcting for confounding factors in the multivariate model. The prognostic value of TMB was confirmed in the TCGA HNSCC cohort.

High TMB identifies HNSCC patients with poor outcome after cCRTX who might preferentially benefit from CRTX-ICI combinations.

Alexander Palant¹; Bettina Zippel-Schultz¹; Thom Hoedemakers²; Olga Golubnitschaja³; Hans-Peter Brunner -La Rocca⁴; Thomas M. Helms¹ ¹Deutsche Stiftung für chronisch Kranke, -, Berlin, Germany; ²Sananet Care BV, -, Sittard, Netherlands; ³Universitätsklinik Bonn, -, Bonn, Germany; ⁴Maastricht UMC+, Kardiologie, Maastricht, Netherlands

Bereits jetzt ist die Herzinsuffizienz (HI) eine der häufigsten chronischen Erkrankungen der inneren Medizin und ist durch eine hohe Morbidität und Mortalität gekennzeichnet [1] . In den westlichen Ländern sind etwa 2% der Bevölkerung von einer HI betroffen -Tendenz steigend [2] . Aufgrund des wachsenden Ungleichgewichts zwischen Behandlungsbedarf und Versorgungsangebot stellt die HI eine der großen Herausforderungen des Gesundheitssystems dar [3] .

Um in Zukunft eine optimale Versorgung der HI gewährleisten zu können, bedarf es alternativer Lösungen. Weitgehendes Selbstmanagement mit Hilfe von Anwendungen der Digitalen Medizin könnte ein Weg sein, diese Herausforderungen zu bewältigen [3] . Darüber hinaus schafft der Einsatz von künstlicher Intelligenz neue Möglichkeiten, die gesundheitliche Versorgung zu verbessern. Diese Maßnahmen können zu massiven Kosteneinsparungen im Gesundheitswesen führen.

Langfristiges Ziel des Projektes PASSION-HF (gefördert durch Interreg NWE, 2018 -2021 ist die Entwicklung einer virtuellen Ärztin "Abby", die Patienten mit chronischer HI im Alltag begleitet. Die Akzeptanz und Nutzung einer solchen Lösung hängt zu einem großen Teil von der Einstellung der Patienten gegenüber einem virtuellen Therapieunterstützungssystem und dem von ihnen erwarteten Nutzen ab. In dem Projekt werden daher im ersten Schritt die Anforderungen und Bedürfnisse der Patienten an ein solches System erhoben. Die Studie im Mixed-Methods-Design wird an vier Zentren aus Deutschland, den Niederlanden, Großbritannien und Irland durchgeführt. Semi-strukturierte Interviews werden durch einen standardisierten Fragebogen ergänzt. Befragt werden jeweils Patienten und deren, in Der Internist · Suppl 1 · 2019 | S11 die Versorgung eingebundenen, Angehörige. Folgende Fragen stehen im Fokus: Welchen Unterstützungsbedarf sehen Patienten mit HI (a) im alltäglichen Leben und (b) im aktuellen Versorgungsprozess der Erkrankung? Wie ist die generelle Einstellung der Patienten gegenüber digitalen Technologien? Welche Unterstützung wünschen sich die Patienten durch ein virtuelles Therapieunterstützungssystem? Welche Anforderungen muss ein solches System erfüllen? Was motiviert Patienten (a) sich therapieadhärent zu verhalten, (b) die digitale Lösung zu nutzen? Welche Unterschiede bestehen zwischen den Ländern bezüglich der Ergebnisse? Die Interviews werden mittels Inhaltsanalyse nach Mayring, die Fragebögen mittels deskriptiver Statistik ausgewertet.

Die im Frühjahr des nächsten Jahres vorliegenden ersten Ergebnisse der Studie geben einen Einblick in die Bedürfnisse, Anforderungen und Wünsche der Patienten und deren Angehörigen zu Design und Funktionen eines digitalen Therapieunterstützungssystems. Sie sind ein wichtiger Baustein im weiteren Entwicklungsprozess von PASSI-ON-HF und werden erstmalig auf dem Kongress der DGIM vorgestellt. [1] McMurray JJV, S.S., The burden of heart failure. European Heart Journal Supplements, 2002. 4: p. D50-D58. [2] Heider, D., et al., Health care costs in the elderly in Germany: an analysis applying Andersen's behavioral model of health care utilization. BMC Health Serv Res, 2014. 14: p. 71. [3] Brunner-La Rocca, HP., et al. Challenges in personalised management of chronic diseases -heart failure as prominent example to advance the care process. EPMA J, 2016. 7: p. 2

Tumaini Institut für Präventionsmanagement GmbH, eHealth, Dresden, Germany Fragestellung: Die Digitalisierung der Lebensbereiche verändert auch den Beratungsalltag in Therapie und Prävention. Unter dem Begriff eHealth entfaltet sich eine Vielzahl an Gesundheits-Apps, medi-zinischen Wearables und Internetportalen. Wie müssen Akteure des Gesundheitswesens daher weitergebildet werden, um diesen Herausforderungen adäquat begegnen zu können?

Methodik: Das TUMAINI-Institut entwickelt eine eHealth-Weiterbildung und ein Online-Netzwerk für Ak-teure im Gesundheitswesen. Zur Zielgruppe gehören vorrangig Gesundheitsakteure mit Patien-tenkontakt. Zur Bedarfserhebung wurde eine Online-Befragung (n=85) durchgeführt. Bereits bestehende curriculare Ansätze sowie wissenschaftliche Online-Netzwerke wurden systema-tisch recherchiert und ausgewertet. Die Pilotkurse der Weiterbildung wurden durch das Institut für Klinische Psychologie und Psychotherapie der TU Dresden mittels qualitativer und quantita-tiver Befragung der Teilnehmer evaluiert. Zudem wurden die Teilnehmer der Pilotkurse aktiv in die Ausgestaltung des Online-Netzwerkes eingebunden.

Ergebnisse: Die Erhebung zum Fortbildungsbedarf identifizierte Defizite der Zielgruppe im Umgang mit und in der Bewertung von eHealth-Anwendungen. Die Evaluation der beiden Pilotkurse zeigt einen deutlichen Wissenszuwachs der Teilnehmer (n=20) sowie eine positive Einschätzung der Kurs-inhalte hinsichtlich der Relevanz für den Arbeitsalltag. Parallel wird das Online-Netzwerk (eHealthWerk. de) bis Frühjahr 2019 vollumfänglich verfügbar sein und eine aktive eHealth-Community fördern sowie einen E-Learning-Bereich, aus der Weiterbildung bekannte, aktuell gehaltene Infomaterialen und aktuelle Blog-Beiträge bieten.

Schlussfolgerung: Die Ergebnisse der Evaluation bestätigen, dass es sich um einen vielversprechenden Ansatz in der Prävention lebensstilassoziierter Erkrankungen wie Diabetes mellitus handelt. In Zusam-menhang mit den umfangreichen Fortbildungsunterlagen und der parallelen Vernetzung der Teilnehmer im Online-Netzwerk "eHe-althWerk" wird die -vorwiegend digitale -Gesundheits-kompetenz der Teilnehmer nachhaltig gefördert. Die zukünftigen eHealth-Berater haben damit das Potential, eHealth-Anwendungen als zielgerichtete und individuelle Lösung zur Unterstüt-zung des Selbstmanagements der Patienten einzusetzen.

Evaluation of costs, utilization and mortality of a project for telemonitoring of patients with chronic heart failure Stefan Rabbe¹; Jonas Schreyögg¹; Rudolf Blankart²; Lutz Hager³; Martin Lehner⁴; Wolfgang-Michael Franz 5 ¹Universität Hamburg, Hamburg Center for Health Economics, Hamburg, Germany; ²Universität Bern, Kompetenzzentrum für Public Management, Bern, Switzerland; ³IKK Südwest, Geschäftsführer, Saarbrücken, Germany; ⁴SHL Telemedizin GmbH, CEO SHL-Telemedizin GmbH, München, Germany; 5 SHL Telemedizin GmbH, Medizinischer Direktor SHL-Telemendizin GmbH, München, Germany Background: The program "ZERTIVA" operated by SHL-Telmedizin aims at optimizing the therapy for high risk patients of the sickness fund IKK Südwest with chronic heart failure especially within the New York Heart Association (NYHA) classes II-IV. The patients were equipped with telemedical devices such as a body-scale, a blood pressure monitor or a 12 channel ECG system. With these devices information are collected in electronic medical records and analysed by a medical professional who contacts the patient after abnormal changes in the measurements aiming on early interventions to administer the episode. The 24/7 intervention program is supported by coaching modules related to co-morbidities. All patient related data were provided by IKK Südwest.

Methodology: For the evaluation the patient collective of the German sickness fund IKK Südwest was screened for eligibility for the program. Inclusion criteria are at least one inpatient stay due to heart failure or related conditions within the past 24 months before the start of the program as well as at least one outpatient diagnosis of heart failure or heart failure related diseases. Exclusion criteria are defined to eliminate patients with diagnoses such as cancer treatments, dialysis or mental illnesses.

After the first selection of all relevant patients for the study population patients are randomly assigned to either intervention or control group. To ensure pre-treatment balance on important characteristics between treatment-and control group different methods such as propensity score matching and propensity weighting are used. For these methods patient characteristics e.g., on costs, medications and comorbidities are used for the period of 24 months before the start of the intervention. Intervention groups were enrolled in 11 waves. The observation period was 24 months (Q3/2015-Q2/2017).

In a first analysis total health care costs consisting of inpatient and outpatient care, pharmaceutical as well as medical aids were analysed.

Following this outpatient contacts, length of hospital stays and the number of prescribed drugs related to heart failure will be analysed.

Further, mortality will be used as an outcome parameter.

Results: Preliminary results for the Gamma regression after propensity score matching on 714 patients in each group suggest a significant negative effect of the intervention of 0,1431 (p=0,005) for the total cost in the study, leading to an average decrease in cost of -2.187€ per patient. There were 998 hospitalizations accounted for in the intervention group vs. 1197 hospitalizations in the control group.

These effects appear to be driven by a decrease in inpatient costs, while costs in other areas such as outpatient care or drugs increased slightly.

Conclusion/Outlook: The preliminary results using propensity score matching suggest a sizable cost reduction for patients in the telemedical treatment group. Results on utilization and outcomes are still pending. Hep G2 Zellen induzieren. Nach Behandlung mit Sorafenib, Regorafenib und Cabozantinib zeigte sich eine Induktion von p63 und p73 und nur partiell eine Induktion von p53. Eine Spaltung von Caspase-3 sowie die Induktion proaptotischer Mitglieder der Bcl-2 Familie (Bax, Bak) konnten durch diese Targeted Therapies nicht induziert werden.

Schlussfolgerung: Neue HCC-Therapeutika können Zelltod in Hepatomzellen induzieren. Jedoch, auch wenn p53 von Sorafenib, Regorafenib und Cabozantinib hochreguliert wird, findet der Zelltod über einen apoptose-unabhängigen Mechanismus statt. Diese Ergebnisse erweitern nicht nur unsere Kenntnisse bezüglich der Wirkungsweise der HCC-Therapeutika, sondern deuten darüber hinaus darauf hin, dass die p53-Familie auch an der Regulation anderer apoptose-unabhängiger Zelltodarten beteiligt ist. Background and Aims: Development of primary liver cancer is a multi-stage process. Pre-neoplastic dysplastic lesions emerge on the basis of chronic liver damage and evolve into early hepatocellular carcinoma (eHCC) and, subsequently, progressed HCC (pHCC). Detailed molecular characterization and prediction of pre-neoplastic lesions at high risk for malignant transformation would significantly advance our diagnostic and therapeutic approaches. We here utilized integrative molecular analyses to characterize the sequential evolution of liver cancer and aimed to define key epigenetic drivers and biomarkers of HCC development and progression.

Methods: Methylation 450k-beadchip analyses were performed on cirrhotic liver (n=7), low-(n=4) and high-grade (n=9) dysplastic lesions, eHCC (n=5) and pHCC (n=3) from 8 HCC patients with chronic hepatitis B infection. Differentially methylated gene regions (DMGR) were identified in comparison to non-cirrhotic and non-infected liver (n=9). Potential epi-drivers and biomarkers were identified by integrative analyses of transcriptomic changes and validated in an independent cohort from the TCGA database.

The proportion of hypermethylated DMGR progressively increased from cirrhosis over dysplastic-to HCC and peaked in eHCC lesions. Early epigenetic alterations involved signaling pathways related to cell death, apoptosis and immune regulation, while late changes centered on cell survival, growth and migration. A common regulation of stem cell-associated pathways including Wnt/b-catenin signaling was revealed in dysplastic as well as eHCC potentially predisposing tumor progression. Moreover, we identified 101 genes with significant methylom changes in dysplastic and cancerous lesions with concomitant progressive gene expression alterations in cancer tissue. We further defined an epi-panel of early epigenetic marks in dysplastic lesions including selected CpG-sites with confirmed differential methylation in cancer tissue and consequential transcriptional alterations of the target genes using an independent cohort of 362 HCC and 49 surrounding liver samples. Unsupervised hierarchical clustering confirmed a robust classification in malignant and non-malignant lesions.

Our results confirm that epigenetic changes occur early during hepatocarcinogenesis. Epigenetic modifications, therefore, might be of high diagnostic/predictive utility for the identification of dysplastic lesions at risk for cancer progression. The identified (epi-) panel of oncogenic epigenetic marks might be useful to complement phenotypic classifications and facilitate selection of lesions amenable to early therapeutic interventions. Background: Distant metastasis is the leading cause of disease-related death among osteosarcoma patients. How cancer cells become metastatic and spread from the blood stream into secondary sites is still not fully understood. Studies in mice indicate that loss of the tumour suppressor Merlin (Moesin-Ezrin-Radixin-like protein) triggers highly metastatic osteosarcoma. Merlin is a multifunctional protein encoded by NF2 (neurofibromatosis type 2) gene. Analyses in cell culture suggest that Merlin establishes its tumour suppressor activity, at least in part, by forming an inhibitory complex with the cell surface protein "cluster of differentiation 44" (CD44). Consistently, numerous NF2 mutations in cancer patients are predicted to disturb the interaction of Merlin with CD44. We hypothesised that upon loss of Merlin, the complex with CD44 would not form releasing CD44 for putative tumour-or metastasis-promoting functions.

To evaluate the relevance of Merlin-CD44 interaction in vivo, we disrupted the Cd44 gene and tested the effect on spontaneous tumour growth and progression in mice carrying a mutation in one Nf2 allele. Subsequently, primary osteosarcoma cells were isolated from Nf2-mutant mice and Cd44 expression was manipulated using CRISPR-Cas9 and lentiviral constructs. These osteosarcoma cells with manipulated CD44 expression were subjected to in vitro and in vivo assays addressing cancer relevant processes. Moreover, we analysed expression profiles of Cd44 and Nf2 in a panel of 23 human osteosarcoma samples of primary and metastatic origin from publically available database.

Results: Compared to wild-type mice, heterozygous Nf2-mutant mice developed osteosarcomas, fibrosarcomas as well as hepatocellular carcinomas at increased frequencies. In contrast to Cd44-positive Nf2mutant mice, none of the Cd44-negative mice analysed developed hepatocellular carcinomas. Importantly, while the absence of Cd44 gene had no effect on the frequency of osteosarcoma generation, it strongly diminished osteosarcoma metastasis formation in the Nf2mutant mice. In vitro assays identified adhesion and transendothelial migration as the most prominent cellular phenotypes dependent on CD44. These properties correlated with an increased potential of Cd44-positive (compared to Cd44-negative) osteosarcoma cells to form lung metastases upon tail vein injection in vivo. The shortest standard isoform of CD44 was identified as sufficient to reconstitute the transendothelial migration and metastatic potential of Cd44-negative osteosarcoma cells. Analysis of publically available expression datasets revealed that increased expression of CD44 and downregulation of NF2 might also promote metastasis of human osteosarcoma.

Our results strongly suggest that in the absence of Merlin, CD44 plays a tumour and metastasis promoting role. Osteosarcoma cells may profit from the expression of CD44 in order to colonise distant sites. Methoden: Aszitesproben von Leberzirrhosepatienten wurden asserviert. Die Proteinmengen der potentiellen Biomarker Lactoferrin, C3a, IP-10, IL-6, IL-8 und IL-10 wurden mittels ELISA, der Gesamtproteingehalt mittels BCA-Test bestimmt.

Ergebnisse: 69 Aszitesproben von 41 Patienten 78% männlich, 22% weiblich; 58, 5% äthyltoxisch, 19, 5% kryptogen, 7, 4 ,9% viral, 2,4% autoimmun, 2,4% PBC, 2,4% nicht-alkoholische Steatohepatitis, 2,4% BuddChiari Syndrom) wurden untersucht. In 8 Proben (11,6%) lag eine gesicherte SBP-Diagnose vor. In 13 Proben (18,8%) lag die PMN-Zellzahl bei > 100 pro µl. Die Lactoferrinspiegel bei SBP (1006 ng/ml) waren gegenüber nicht-SBP-Proben (75 ng/ml) stark erhöht. Verlaufsproben ergaben, dass die Lactoferrinmenge bereits im SBP-Frühstadium ansteigt und mit dem Krankheitsverlauf bzw. der Therapieantwort korreliert. Die C3a-Spiegel warenim Vergleich zu nicht SBP-Proben (974 ng/ml) bei SBP (511 ng/ml) verringert und korrelierten ebenfalls mit dem Krankheitsverlauf. IP-10 sowie relevante Mengen von IL-6, IL-8 und IL-10 wurden in allen Proben nachgewiesen, zeigten jedoch keine Assoziation zum Frühstadium der SBP.

Schlussfolgerung: Lactoferrin und C3a sind molekulare Komponenten des Aszites, deren Menge mit dem Krankheitsverlauf bei SBP assoziiert werden können. Darüber hinaus sind inflammatorische Aktivitäten bei beginnender SBP bereits ab einer Zellzahl von über 100 Granulozyten pro µl nachweisbar. Die Vielzahl weiterer Entzündungsmediatoren und Zytokineunterstreicht die enorme inflammatorische Aktivität im Aszites bei Leberzirrhose, auf deren Basis neue Früherkennungssysteme zur SBP-Diagnose entwickelt werden können. Background: With a worldwide prevalence of 14 million patients, hepatocellular carcinoma (HCC) is the most common primary malignant neoplasia of the liver (85-90%) and displays the second highest tumor related mortality, often with poor prognosis upon diagnosis. The insulin like growth factor (IGF) system promotes growth and cell survival via IGF binding to the IGF receptor. Insulin like growth factor binding proteins (IGFBPs) control IGF availability by competitive binding of IGF, therefore limiting proliferative IGF effects. We previously identified IGFBP2 as a target gene of the p53 family, especially of p73, in HCC. These tumor suppressors reply to cellular stress signals by induction of senescence or apoptosis. However, physiologic functions of p53-family induced IGFBP2 in HCC are so far unknown. Thus, effects of IGFBP2 on HCC cell viability, proliferation and migration were evaluated and IGFBP2 induction by HCC-relevant therapeutics was studied.

Methods: IGF secretion and surface levels of IGF receptors were analyzed in the human HCC cell line Hep3B. Cells were cultured with recombinant IGFBP2 (100 -1000 ng/ml). Proliferation was measured by flow cytometry, cell viability was determined by MTS assay and cell migration was analyzed using a wound healing model. Activation of the IGF pathway was also determined by milliplex assay. Moreover, effects of HCC-relevant therapeutics on IGFBP2 and p73 were analyzed by Western blot, qPCR and ELISA.

Hep3B cells displayed an intact IGF system, indicated by IGF secretion and surface expression of insulin receptor and IGF receptor 1. Generally, in the presence of IGFBP2 cell viability of Hep3B cells increased in a time-dependent fashion, where most pronounced effects were observed using concentrations between 100 and 500 ng/ ml. Highest induction rates in proliferation were detected using IGF-BP2 levels between 100 and 250 ng/ml with a 13-and 18-fold increase at 48 h, decreasing thereafter. Concordantly, IGFBP2 doses between 100 and 500 ng/ml resulted in enhanced cell migration. Additionally, treatment with recombinant IGFBP2 resulted in decreased activation of the IGF pathway. Interestingly, treatment of Hep3B cells with bleomycin, doxorubicin and regorafenib caused an induction of both TP73 and IGFBP2.

Although being regarded as growth-limiting factor within the IGF-system, recombinant IGFBP2 exerted proliferative effects on HCC cells. Since an induction of IGF signaling was not observed, the exact mechanisms of action need further elucidation. Nonetheless, IGFBP2 was shown to be a p53 family target gene and was induced by HCC-relevant therapeutics together with the tumor suppressor p73. We therefore hypothesize, that p53-family-mediated mechanisms must exist which redirect IGFBP2-dependent signaling towards growth inhibition. Thus, detailed elucidation of signal transduction on the p73-IGFBP2-axis is indispensable to develop novel diagnostic and therapeutic options for HCC. Background and Aims: Hepatocellular carcinoma (HCC) is highly vascular tumor where activation of neo-angiogenic processes during disease progression is frequently associated with poor clinical outcome. Consequently, inhibition of neo-angiogenesis is an effective treatment strategy for advanced HCC. However, development of chemoresistance is observed in the majority of patients. Evidence suggests that cancer stem cells (CSCs) may contribute to the acquisition of resistance in many solid tumors, but their exact role in this process for HCC remains to be defined. Here, we evaluate the importance of CSCs in the development of resistance and relapse formation after exposure to different anti-angiogenic therapies in HCC and define concomitant adaptive molecular changes.

Method: Four HCC cell lines and two primary HCC isolates were exposed to sorafenib and sunitinib for a total of 14 days. The treatment effects on CSCs were estimated by sphere forming capacity in vitro and tumor-initiating potential in vivo, as well as the side-population (SP) approach. Expression of key oncogenic and CSC markers, such as EpCAM, CD133 and ABCG2 transporter, were assessed by qRT-PCR and flow cytometry. Furthermore, whole transcriptome analyses were performed across the cell lines.

Results: Both treatments effectively reduced oncogenic properties in all investigated HCC cells. However, sustained anti-proliferative effect after treatments was observed in only one cell line. In three other lines initial treatment effect was subsequently followed by rapid re-growth thereby mimicking the responses observed in patients. Interestingly, two cell lines showed differential response to applied drugs, showing anti-proliferative effects to sorafenib, while relapse formation occurred after sunitinib treatments. While anti-oncogenic effects in sensitive cell lines were associated with significant reduction in sphere forming and tumor-initiating capacity, CSC marker EpCAM as well as SP cells, resistant cell line showed transient increased in CSC properties. Acquired resistance to both drugs uniformly developed in cell lines suggesting that common molecular mechanisms might be operative. These adaptive molecular changes involved signaling pathways known to be associated to cell survival, proliferation and cell cycle regulation (RAS, AKT, MYC, P53), as well as angiogenesis (VEGFR, PDGFR). Furthermore, the resistant cell lines showed compensatory upregulation of key oncogenic molecules such as EGFR as well as multidrug resistance ABC transporters.

Our model recapitulates features of drug resistance observed in human HCC patients. Resistance to anti-angiogenic therapies might be fueled by transient expansion of CSCs. Therefore, specific targeting of CSCs as well as pro-oncogenic compensatory signaling pathways might be an effective therapeutic strategy to overcome resistance in HCC. P value 0.001. According to Stevenson et al. 15% of TB burden in India was attributed to diabetes. Diabetics is a major cause of conversion of latent to active TB, reactivation of old TB. MPV was not statistically significant to be used as a marker Conclusion: Large number of Diabetic population who are at risk of developing TB during travel to endemic countries. The cases of TB can be easily identified even at Primary Health Care Centre with just a peripheral smear from which NLR and PLR can be calculated and need not depend on costly investigation. This will reduce the financial burden of the travels. It will help in early identification of diseases among travellers and also to take necessary precaution before travel Key Words: NLR, PLR, Tuberculosis Objective: Epidemiological studies indicate that, the risk of venous thromboembolism increases by 2 to 3 folds during long-haul travels in potential risk group travellers. Management of Pulmonary Embolism is extremely difficult especially during air travel and the chances of mortality and morbidity is high. Pulmonary Embolism is preventable disease. The mortality can be highly reduced if identified at right time and precautionary measures are taken. There is no biomarker which can predict Pulmonary Embolism in quick and cost effective way. MPV and RDW are bio markers which can aid in early identification and effective management of Pulmonary Embolism.

We conducted a retrospective study by screening more than 2.5 lakh patients who presented to the hospital during 2013 to 2018 (6 Years) and identified 300 cases of Pulmonary Embolism. The patient's MPV and RDW values were analysed along with other details like demographic details and comorbid conditions. Statistical data analysis was done using SPSS Tool.

The result showed male predominance and the mean age of the study group was 54 years. Major Comorbid conditions were Dyslipidaemia and Diabetics. 53% of the study population were alcoholics and smokers. Mean Value analysis of the MPV and RDW values showed a very high statistical significance as biomarkers (with the 'p' value < 0.001). ROC analysis for specificity and sensitivity for MPV and RDW indicated high correlation with area under the curve coverage of 83% and 79% respectively. MPV value of 12 and RDW of 15 taken as cut off and increase in their value by 5% or more indicate the potential condition of Pulmonary Embolism.

Conclusion: MPV and RDW are novel and cost effective biomarkers. It is non-invasive, can easily be estimated from a complete blood count. Require no special lab setups or specialist to interpret the values and correlate with potential Pulmonary Embolism incidence. These biomarkers can be checked in the airport medical facility itself. The high risk cases can be identified and necessary precaution can be taken. This aids to bring down the instances of Pulmonary Embolism during air travel. Hintergrund: Chronische Bauchschmerzen sind eine häufige Ursache für medizinische Konsultationen und können mit anderen unspezifischen Symptomen assoziiert sein. Auch wenn keine organische Ursache bei der Routineuntersuchung offensichtlich ist, kann sich manchmal eine gründlichere Untersuchung wegen der zunehmenden Anzahl von Mastzellaktivierungserkrankungen und/oder GI-Allergie lohnen. Bei der früheren ÖGD wurde eine geringfügige unspezifische Gastritis gefunden und mit PPI ohne Verbesserung der Symptome behandelt.

Ein Symptomtagebuch zeigte einen Zusammenhang mit dem Verzehr von Käse und Schokolade, was möglicherweise auf eine Histaminintoleranz hindeutete. Eine Salicylat-Intoleranz wurde durch einen funktionellen Eicosanoid-Test diagnostiziert, der eine erhöhte Freisetzung der Leukotriene feststellte. Obwohl die Tryptase normal war, wurde ein erhöhter Serum-TNFα gefunden (27,7; normal < 8,1) sowie eine signifikant erhöhte Ausscheidung von Methylhistamin (17, 8 normal < 6, 5) , was auf eine hohe endogene Histaminproduktion hindeutete. Eine neue problemorientierte Endoskopie mit Immunhistochemie und endoskopischer Lavage zeigte noduläre hyperplastische Lymphfollikel im terminalen Ileum. Immunhistochemisch wurden bis zu 60 Gewebemastzellen/HPF (n < 30/HPF) mit normaler Morphologie nachgewiesen. Eine endoskopische Darmlavage am unteren GI-Trakt konnte keine lokale IgE-Sekretion nachweisen, so dass eine lokale Typ I GI-Allergie ausgeschlossen werden konnte. Die Histaminabbaufähigkeit des Gewebes war jedoch ex vivo verringert. Cholesterol crystal (CC) embolism may be an under-recognized cause of acute kidney injury (AKI), especially of catheter intervention-or major surgery-related AKI. Little is known about the pathophysiology of CC embolism because of lack of animal models. Injecting CC into the left renal artery of C57BL/6N mice caused a sudden drop in glomerular filtration rate (GFR) associated CC embolism and crystal clot formation leading to either partial CC or complete occlusion of numerous interlobar arcuate, and interlobular documented by histology and 3D reconstructions of vascular contrast micro-CT scans. 24h after CC injection partial obstruction was associated with ischemic necrosis of respective tubular S3 segments, while complete obstruction caused large territorial infarction. Such infarcts were surrounded by massive neutrophil infiltrates apparently also derived from vessels of the renal capsule (rim sign). Necroptosis is known to drive post-ischemic AKI, and lack of Mlkl had partially effect on infarct size and tubular injury but no effect on GFR loss. Obstructed artery quantification showed that Mlkl deficiency had no effect on crystal clot obstruction. Crystal clots stained positive for platelets, neutrophils, fibrin, and DNA. While neutrophil depletion only partially attenuated GFR loss and infarct size recombinant DNase I was fully protective as it reduced the number of complete vascular occlusion. In vitro studies revealed that CC induce membrane rupture and DNA release from endothelial cells and neutrophils and that CC-induced activation of platelets induces neutrophil extracellular traps formation. CC embolism was found in 446 of 92,000 diagnostic kidney biopsies (0.5%). Thus, CC embolism activates numerous cell types to release DNA, which is a central component of crystal clot formation, vascular occlusion, and kidney infarct-related AKI.

Uwe Zeymer¹; Stephan Hupfer²; Tobias Merkel² ¹Klinikum Ludwigshafen, Institut für Herzinfarktforschung, Ludwigshafen, Germany; ²Novartis Pharma GmbH, Cardio-Metabolic, Nürnberg, Germany Background: ARIADNE (Assessment of Real-life cAre Describing Eu-ropeaN heart failurE management) was designed as a prospective registry providing a thorough understanding of the demographic and clinical features of symptomatic patients with chronic heart failure with reduced ejection fraction (HFrEF) managed in the outpatient sector across Europe, and the way sacubitril/valsartan (S/V) is introduced by office-based cardiologists and specialised primary care physicians. Here, we present baseline data for the German subgroup.

Consecutive male or female patients (≥18 y) with symptomatic chronic HF (NYHA II-IV) and documented reduced LVEF were eligible for the study. The subgroup of patients recruited in Germany consisted of 4768 patients (main analysis set: 50.5 % Standard of Care (SoC) vs. 49.5 % S/V. For volatile clinical parameters (e.g. NYHA class, blood pressure and laboratory values), analysis was restricted to the S/V group who had been initiated no longer than 4 weeks ago (3452 patients, 68.3 % SoC vs. 31.7 % S/V).

Mean age at the time of inclusion into the study was statistically different between the two groups with patients receiving S/V being younger (S/V 67.8y ± 11.6 vs SoC 69.5y ±11.0; p < 0.0001). The study population divided into 76.2 % of male versus 23.8 % of female patients with no statistical difference between the different treatment groups (p= 0.2934). Mean LVEF at inclusion was lower in the S/V group compared to the SoC group (S/V 32.7 % ± 8.1 vs. SoC 36.3 % ± 8.5; p < 0.0001). Assessment of NYHA functional class showed a statistical significant enrichment in NYHA III (S/V 57.1 % vs. SoC 32 %) and NYHA IV (S/V 3.1 % vs. SoC 1.4 %) in the S/V group, whereas patients in the SoC group displayed enrichment in NYHA II (S/V 39.8 % vs. SoC 66.5 %). Analysis of the medical history revealed a higher burden of comorbidities in S/V as compared to SoC. Statistical significant differences were seen for example in the percentage of patients with atrial fibrillation (S/V 41.2 % vs. SoC 37.9 %; p= 0.0205), coronary heart disease (S/V 59.1 % vs. SoC 63.1 %; p= 0.0041), and renal disease due to hypertension (S/V 9.3 % vs. SoC 6.6 %; p= 0.0004).

Specification of heart failure treatment (in % of patients on current SoC HF treatment, S/V treatment started no longer than 4 weeks ago) showed a higher usage of MRAs (S/V 57.1 % vs. SoC 51.7 %; p= 0.0058) and loop diuretics (S/V 63.1 % vs. SoC 57.6 %; p= 0.0045) in the S/V group. Usage of calcium channel blockers (S/V 6.7 % vs. SoC 10.8 %; p=0.0004) was less frequent in the S/V group .

There was no statistical difference in the frequency of beta blockers, Ivabradine, Digitalis and diuretics other than loop diuretics.

The presented German subgroup data of ARIADNE offer insights into the prescription patterns in the German outpatient real-world setting. S/V use in Germany seems to be influenced by age, disease severity (e.g. NYHA class) and comorbidities.

Peripheral edema and headache associated with amlodipine treatment: a meta-analysis of randomized, placebo-controlled trials Davor Vukadinovic¹; Sean Scholz¹; Michael Böhm²; Felix Mahfoud² ¹Universitätsklinikum Homburg, Innere Medizin III -Kardiologie, Angiologie und internistische Intensivmedizin, Homburg, Germany; ²Universitätsklinikum des Saarlandes und Medizinische Fakultät der Universität des Saarlandes, Klinik für Innere Medizin III, Kardiologie, Angiologie und internistische Intensivmedizin, Homburg, Saar, Germany Background: Use of amlodipine for treatment of arterial hypertension (AH) and stabile angina pectoris (SAP) is sometimes limited by occurrence of peripheral edema and headache. We aimed to explore the true magnitude of this phenomenon by determining the rate and placebo-adjusted rate of these side effects (SE).

We performed a meta-analysis by including all randomized, placebo-controlled trials reporting edema and headache with amlodipine in patients with AH and SAP. Placebo-adjusted rate (%) was determined as follows: (SE amlodipine % -SE placebo %) / SE amlodipine %. Electronic databases PubMed, Web of Science, and Cochrane library were systematically searched for eligible trials published until July 2018. Diseases such as heart failure, severe renal or hepatic disease were not considered. Furthermore, in most of the trials, a wash-out period took place before the study medication was given.

Der Internist · Suppl 1 · 2019 | S21 Results: Data from 7,226 patients of 22 trials were analyzed. In most of the analyzed trials, duration of follow up was comparable, and lasted about 8 weeks. Rate of edema was higher on amlodipine compared with placebo (16.6 vs 6.2%, RR: 2.9, 95% CI: 2.5-3.36, p < 0.0001). The placebo-adjusted rate was 63%, indicating that 37% of edema cases were unrelated to amlodipine. Treatment with low/medium doses (2.5-5 mg) resulted in lower rates of edema (RR: 2.01, 95% CI: 1.41-2.88, p = 0.0001) compared with high dose (10 mg) (RR: 3.08, 95% CI 2.62-3.6, p < 0.0001, p for interaction = 0.03). Headache was reduced using amlodipine compared with placebo (7.9 vs 10.9%, RR: 0.77, 95% CI: 0.65-0.90, p = 0.002) and was driven by use of low/medium doses (RR: 0.52, 95% CI: 0.40-0.69, p < 0.00001 versus RR: 0.92, 95%-CI: 0.74-1.15, p = 0.45, for high doses, p for interaction = 0.002). Co-administration of renin-angiotensin-inhibitors to low/medium dose of amlodipine resulted in higher BP reductions with equivalent rates of edema in comparison with amlodipine monotherapy (p for interaction = 0.23).

Patients on amlodipine exhibit a dose-dependent 3-fold increased risk of peripheral edema compared with placebo. Of note, up to one third of edema cases on amlodipine might not be induced by amlodipine. Headache is reduced on amlodipine treatment, mainly driven by use of this drug at low/medium doses potentially related to better blood pressure control.

Verbessert eine positive Einstellung zur Chemotherapie die Prognose einer Krebserkrankung? Ergebnisse einer multizentrischen deutschen Therapiestudie bei nicht kleinzelligem Lungenkarzinom. 

Friederike Schumann¹; Tim Hollstein²; Elisabeth Steinhagen-Thiessen²; Ursula Kassner² ¹Charité -Universitätsmedizin Berlin, Lipidambulanz -Campus Virchow-Klinikum, Berlin, Germany; ²Charité Universitätsmedizin Berlin, Stoffwechselcentrum Lipidclinic, Berlin, Germany Aim: PCSK9-I reduce low-density lipoprotein cholesterol (LDL-C) and improve cardiovascular risk. The aim of this study is to provide new safety and effectivity data of PCSK9-I with focus on the FH genotype in a "real-world" cohort.

Methods: 781 patients receiving PCSK9-I following recommendations of the German Federal Joint Committee were recruited between 2016 and 2018 at the Outpatient Lipid Clinic of the Charité Berlin. Those patients with high or very high cardiovascular risk according to ESC guidelines did not reach their LDL-C goals under maximal tolerable lipid-lowering therapy or were statin-intolerant. Therefore they were treated with either Alirocumab (75 mg or 150 mg) or Evolocumab (140 mg) every other week. Blood tests were performed at baseline and after one month of PCSK9-I treatment. Patients were asked for side effects 2 weeks after the first injection with a standardized questionnaire. Out of these 781 patients 132 had a genetic test result available. Cases with a positive or likely positive genetic result for FH (group 1) where combined as well as those with a negative result or one with unknown significance (group 2).

The mean percent reduction of LDL-C after one month was 51.4% ± 17.3 of patients of group 1 (mean baseline LDL-C 201.3 mg/dl ± 76.5) compared to 53.8% ± 15.6 of patients of group 2 (mean baseline LDL-C was 184.4 mg/dl ± 67.6) and therefore not significantly different (p=0.426). There was no significant difference (p =0.728) in the choice of the PCSK9-I drug or dosage. Side effects were observed in 47.6% of the patients of group 1 compared to 40% of those of group 2 (p =0.397) but the difference in occurrence of side effects was not significant. There was a significant difference (p < 0.001) in both groups regarding the existing lipid-lowering therapy with statins as only 12% of the patients of group 2 were on high intensity statin therapy compared to 48.8% of the patients of group 1. In patients of group 1 without background statin therapy, the LDL-C lowering effect of PCSK9-I was significantly lower (p=0,001) compared to those with high intensity statin therapy (41% ± 13.3 vs. 58% ± 17.3).

Conclusion: PCSK9-I are safe and effective in a "real-world" cohort. Our study showed no significant difference in safety with respect of the genotype. The LDL-C reduction in both groups was comparable to large clinical trials. In group 1 was a more profound LDL-C lowering effect of PCSK9-I in patients on background statin therapy. We saw the same tendency in group 2 which gives the impression that it's worthwhile to put patients even on a low dose statin therapy to achieve a better efficacy of the PCSK9-I therapy. Anhand von Kaplan-Meier-Überlebenskurven wurde die prognostische Wertigkeit untersucht. Die Extraktion der gesamten RNA aus dem Serum erfolgte mittels miRNeasy Mini Kit. Die quantitative Analyse der miR-21 erfolgte mittels qPCR. Zur Normalisierung wurde die spiked-in cel-miR-39 verwendet.

Ergebnis: Die Analysen zeigten keine signifikanten Unterschiede im Überleben von Patienten mit hohen und niedrigen Serum-miR-21 Werten (p = 0,2697). Weiterhin fanden sich bei den Patienten ähnliche miR-21-Konzentrationen unabhängig vom Child-Pugh-Score (p = 0,7991), der BCLC-Klassifikation (p = 0,3947) oder der zu Grunde liegenden Ätiologie des HCC (p = 0,6331). Die Serum-miR-21 war unabhängig vom Alter (p = 0,2789), vom Geschlecht (p = 0,8263) und der Vortherapie der Patienten (p = 0,2244). Interessanterweise zeigte sich eine signifikant positive Korrelation zwischen Serum-miR-21 und ASAT (p = 0,0061), sowie ein Trend zwischen miR-21 und ALAT (p = 0,1053). Es bestand keine Korrelation mit AFP (p=0,3337). Zwischen Serum-miR-21 und Quick konnten wir eine Tendenz zu einer negativen Korrelation nachweisen (p = 0,0666). Weiterhin zeigte sich eine signifikant negative Korrelation zwischen miR-21 und Kreatinin (p = 0,0348) als Hinweis für eine Beeinflussung der Serum-miR-21 durch die Nierenfunktion.

In dieser europäischen Kohorte von Patienten mit HCC wies die Serum-miR-21 Konzentration keine prognostische Wertigkeit auf. Eine Abhängigkeit von Vortherapie, Ätiologie und Stadium des HCC fand sich nicht. Die Abhängigkeit der Serum-miR-21 Konzentration von Nierenfunktion und Leberschädigung hat eine wichtige translationale Bedeutung, welche in weiteren Studien berücksichtigt werden sollte.

Karen Nieber¹; Esther Raskopf²; O. Greinert³; G Zadoyan³; S. Schleicher³; Kija Sha-Hosseini³; Tankred Wegener⁴; Olaf Kelber⁵; J Singh³; R Mösges² ¹Universität Leipzig, Institut für Pharmazie, Leipzig, Germany;²ClinNovis GmbH, R&D, Köln, Germany; ³Universitätsklinikum Köln, Institut für Medizinische Statistik und Bioinformatik, Köln, Germany; ⁴Consulting HMP, R&D, Weinheim, Germany; ⁵Bayer Consumer Health Division, R&D, Darmstadt, Germany Data on patients with functional GI diseases from unselected patient cohorts can improve the understanding of patients' needs in daily practice. Therefore data on patients treated with a herbal medicinal product for this indication, STW 5, were selected from the PhytoVIS study, a non interventional study in 20,870 patients who had used a herbal products within the last 8 weeks before the survey. The aim was to describe the epidemiology, medical needs, and judgement of the perceived usefulness of the therapy expressed by this patient group.

The database contained 24,056 patient questionnaires, which had been documented in physicians' practices and pharmacies by respectively trained students of human medicine or pharmacy who acted as interviewers, in compliance to the ENCePP Code of Conduct [2] . Questionnaires related to STW 5 were evaluated regarding epidemiological data on gender, age and disease state as well as on the use of the medicine and its perception.

Of all datasets, 1515 could be retrieved containing STW5, including patients from pediatric and geriatric age groups most of them being females, with a broad range of functional GI symptoms. Usefulness was predominantly rated very good to good, also in the patients from pediatric age groups, with 71 patients. Tolerability in all age groups was predominantly very good, in accordance to the published data from more than 50,000 patients treated with this herbal medicine [3] .

PhytoVIS turned out to be a suitable tool to study the epidemiology of patients with functional GI diseases, under treatment with the herbal medicinal product STW 5, showing tolerability, safety and efficacy based on the rating of the patients. Through the high number of users included, special patient groups like children and elderly were also covered. As could be shown on this example, the database is accordingly an excellent source for medical information on patients using herbal medicinal products.

The study is supported by Kooperation Phytopharmaka GbR, Bonn, Germany Ergebnisse: Die Suche ergab 79 Ergebnisse zu FD bei Kindern, davon 27 zu pharmakologischen Behandlungsoptionen, von denen 2 pflanzliche Arzneimittel waren. Im Falle von IBS ergaben sich 321 Treffer, davon 90 bezüglich pharmakologischer Therapien, darunter 5 pflanzlichen Ursprungs. Bei diesen pflanzlichen Arzneimitteln handelte es sich um Flohsamen, Pfefferminzöl und STW 5 (Iberogast) sowie Kurkuma, Cannabis, Aloe vera und Ingwer, wobei sich nur bei Flohsamen, Pfefferminzöl und STW 5 die Angaben auf klinische Studien bei Kindern stützten (3, 2, 4, 5, 1) . Bei FD wurden Sanddorn und STW 5 als pflanzliche Therapieoptionen identifiziert, wobei zu beiden klinische Daten vorliegen (6) . Nur STW 5 zeigt für beide Krankheiten belegte Wirksamkeit bei Kindern. Die Suche nach weiteren Daten bezüglich der Evidenz von STW 5 zur Anwendung in dieser Altersgruppe ergab verschiedene retrospektive (7, 8) sowie prospektive (9, 10) Studien. Diese Anwendungsbeobachtungen beinhalteten insgesamt 44.315 Kinder und zeigten ein gutes Sicherheitsprofil mit nur wenigen leichten Nebenwirkungen in dieser Altersgruppe und eine nachvollziehbare Einschätzung des therapeutischen Nutzens.

Interesse in der Pädiatrie. Pflanzliche Arzneimittel bieten hier nebenwirkungsarme und wirksame Therapieoptionen und nehmen so eine wichtige Rolle in dieser Indikation ein. Bei sehr heterogenen Evidenzgraden der verschiedenen Präparate zeigt STW 5 die überzeugendste Wirksamkeit bei FD und IBS, während Flohsamenschalen und Pfefferminzöl bzw. Sanddorn nur bei IBS bzw. FD nachgewiesene Wirksamkeit bei Kindern aufwiesen.

[1] Malfertheiner, Dig Dis. 2017; 35 Suppl 1; 25-29, 2. Shulman et al., Clin Gastroenterol Hepatol. 2017 , 5:712-719, 3. Charrois et al., Pediatr Rev. 2006 , 7:49-51, 4. Grigoleit und Grigoleit, Phytomedicine 2005 , 8:601-6, 5. Fifi et al., Nutrients 2018 , 11 pii: E1715, 6. Hell et al. J Nucl Med. 2013 ,1:38-43, 7. Kelber Z Phytother, 2010 , 31:40, 8. Gundermann und Hänicke, Päd. 2004 , 10:408, 9. Vinson und Radke, Gatroenterol., 2011 , 140:102, 10. Nazarenko et al., Med. novosti 2008 

Esther Raskopf¹; Oliver Greinert²; Gregor Zadoyan²; Sabine Schleicher²; Kija Sha-Hosseini²; Tankred Wegener³; Olaf Kelber⁴; Karen Nieber⁵; Jaswinder Singh¹; Ralph Mösges¹ ¹ClinNovis GmbH, I&D, Köln, Germany; ²Universitätsklinikum Köln, Institut für medizinische Statistik und Bioinformatik, Köln, Germany; ³Consulting HMP, XY, Weinheim, Germany; ⁴Bayer Consumer Health Division, R&D, Darmstadt, Germany; ⁵Universität Leipzig, Institut für Pharmazie, Bonn, Germany Introduction: Pharmacoepidemiological research can be an important source of information on the use of medicinal products in the broad range of patients attending the practice of internists and general practitioners. This applies even more to the pediatric patient group and to herbal medicinal products, where clinical study data are rare. To address this gap, data from the PhytoVIS study, presumably the world's largest pharmacoepidemiological study on the use of herbal medicinal products [1] , were evaluated with the view on the pediatric population.

The PhytoVIS data set contains information on the epidemiology of the patients and the therapeutic indication, the efficacy and tolerability of the medicinal products used by them, which have been captured in doctor´s practices and pharmacies in compliance to the ENCePP Code of Conduct [2] . When screening it for pediatric data, information on indications, treatments, co-medication and tolerability was evaluated.

Overall, 2203 data sets from the pediatric population could be evaluated, thereof 297 for patients below 2 years, 505 from patients aged 2-5 years, 578 from age 6-11 years, and 823 from age 12-17 years. Of those, 67.7 % were treated because of common cold and fever, 13.6% due to digestive complaints, 4.9% because of skin diseases, 3.5% due to sleep disturbances and anxiety and 10.3% because of other complaints. A co-medication was documented in 25.0% of the patients. The efficacy of the therapy was rated very good in 48.8% of the patients, good to moderate in 36.3%, modest in 10.7% and missing in 4.1%. Tolerability was good in 93.6% and moderate in 5.5% of patients.

The data sheds light to a field of pharmacotherapy about which up to now not much was known, and give a picture of the use of herbal medicines in an unselected cohort of pediatric patients. The information gives a better understanding on the way these medicinal products are used in this age group and are also good background information for therapeutic decisions for these patients and their perception. Further age-and indication specific evaluations are desirable.

The study is supported by Kooperation Phytopharmaka GbR, Bonn, Germany 

Esther Raskopf¹; Oliver Greinert²; Gregor Zadoyan²; Sabine Schleicher²; Kija Sha-Hosseini²; Tankred Wegener³; Olaf Kelber⁴; Karen Nieber⁵; Jaswinder Singh²; Ralph Mösges² ¹ClinNovis GmbH, I&D, Köln, Germany;²Universitätsklinikum Köln, Institut für Medizinische Statistik und Bioinformatik, Köln, Germany; ³Consulting HMP, XY, Weinheim, Germany; ⁴Bayer Consumer Health Division, R&D, Darmstadt, Germany; ⁵Kooperation Phytopharmaka GbR, XY, Bonn, Germany Introduction: STW 42, a marshmallow-based cough medicine, is frequently used in the therapy of mucosal irritation with dry cough, a condition frequently occurring in the cold season, and as a merely local mode of action, in contrast to a number of other therapeutic options with more systemic effects and, accordingly, a higher potential of side effects. As a potential source of data on the epidemiology of patients using medicinal products, as well as for documenting their subjective rating of the efficacy and tolerability, the PhytoVIS study was accessed, a pharmacoepidemiological data base on the use of herbal medicinal products [1] , containing data from 20,870 users of herbal medicinal products, which have been captured in doctors' practices and pharmacies in compliance to the ENCePP Code of Conduct [2] .

The database was screened for users of STW 42 and information on indications, treatments, co-medication and tolerability was evaluated.

Data sets from 141 users of STW 42 syrup or lozenges could be retrieved, of which 43 were children. All patients, rated the treatment predominantly very good or good to moderate, with excellent tolerability.

Together with the data in more than thousand patients documented in earlier surveys, these data underline the usefulness and tolerability of marshmallow products, supporting the use of these medicines not only in adults, but also in the pediatric patients.

The study is supported by Kooperation Phytopharmaka GbR, Bonn, Germany Introduction: Herbal treatment options are increasingly used in functional gastroenterological disorders (FGID) like irritable bowel syndrome (IBS), while an understanding of their mechanisms of action is often lacking. According to recent national and international therapeutic guidelines (e.g, 1,2,3), STW 5, a combination product of nine herbal extracts, is an evidence-based treatment option in IBS. The question was, which mechanisms of action are involved in its therapeutic effect.

To warrant completeness, a systematic search according to the PRISMA statement was conducted in order to retrieve all data on STW 5 or its trade name (Iberogast), using PubMed, Toxlit and BIOSIS. Identification of data on the mechanisms of action was then done manually. In addition hand searching was done and text books were screened, to get a complete picture.

The search identified 468 publications. A considerable number of publications on spasmolytic as well as prokinetic activities could be identified, as well as on prosecretory effects. Also data showing that the product can counteract inflammatory changes as well as an intestinal hypersenstitivity and hyperpermeability were found. Even a beneficial effect on the microbiota was described. Accordingly, the product has a multitude of mechanisms of action.

In IBS, a number of therapeutic options with different mechanisms of action are used. A search for the mechanisms of action of a herbal treatment used in this indication (STW 5) revealed not just one, but a multitude of mechanisms of action. This confirms for this product, that its action in IBS can be classified as a multi-target action, and makes its therapeutic efficacy in this indication plausible. Introduction: The interest in safety assessments of herbal products is increasing, but not their quality, as limitations of available data are often not sufficiently taken into account. To address the issue, a classification of sources of bias and ways out is aimed to.

A systematic data base search for reviews in this field, combined with hand searching in text books, was conducted. Sources of bias were classified according to data types involved.

Depending from the data involved, different sources of bias were identified:

• Data on quality: Often the great differences of the composition of herbal products prepared from the same plant are neglected, so leading to flaws when tranferring data.

• Non-clinical data: Common pitfalls are the transfer of data from in vitro studies to the clinical setting, without taking into account the influence of ADME. Often also effects from sublethal high-dose settings are used without sufficiently taking into account dose dependency or, especially e.g. in carcinogenicity studies, methodological ambiguities [1] .

Der Internist · Suppl 1 · 2019 | S25

Referring to studies conducted with products of a different composition can lead to misleading attribution of efficacy to inefficient products and vice versa, lack of differentiation between negative studies and failed studies can lead to wrong conclusions on inefficacy, the evaluation of safety data is often flawed by neglecting background incidences, as e.g. in case of hepatotoxicity [2] by protopathic bias, and by the awareness and views of authors of case reports [3] .

A higher awareness of common pitfalls in the assessment of safety data on herbal products is needed, e.g. in case of hepatotoxic risks, if we want to avoid that methodological artefacts and misperceptions of the generalizability of data continue to influence our view of the safety of herbal products, both by neglecting risks, as, more abundant, by exaggerating non-existing risks.

[ Background: Multimorbid patients with polypharmacy are at risk for inappropriate prescribing and harmful medication overuse. A recently updated Cochrane review investigating complex and multi-faceted interventions to improve the appropriateness of polypharmacy in the elderly found the evidence for these interventions low to very low and inconclusive.1 There is a lack of evidence summaries on more simplified and pragmatic interventions to manage polypharmacy in multimorbid patients.

Objective: To identify from clinical trials interventions practicing physicians can employ to reduce drug overuse and inappropriate prescribing in polypharmacy and achieve meaningful endpoints in multimorbid patients.

A sensitive search protocol of original research articles indexed in MEDLINE from 2014 to 2018, including related primary sources. Reporting followed the PRISMA guidelines. We excluded non-interventional studies, trial protocols, feasibility studies, and trials in pediatric populations. We further excluded multi-professional interventions and studies addressing the roles of nurses and pharmacists. The authors screened articles, assessed risk of bias, and extracted data according to standardized conventions.

A total of 4323 citations were screened. 2892 studies were deemed irrelevant to the research subject, 1431 were assessed for eligibility. 43 studies met the inclusion criteria and were further assessed for methodologic quality, relevance and clinical applicability.

Select findings favoring the intervention included the use of the START/STOPP criteria and the FORTA list addressing drug over-and under-treatment in older hospitalized patients. Select findings with no effect on the primary outcome included a protocol for reduction of fall-risk-increasing drugs (FRID) in older fallers and an intervention targeting the number of medications and health-related quality of life by an intensification of the doctor-patient dialogue about treatment preferences and patient priorities.

The quality of evidence was very low due to imprecision, indirectness and serious risk of bias, occurring predominantly in the domains of selective outcome reporting, allocation concealment, and blinding Der Internist · Suppl 1 · 2019 | S27 which did not allow for valid effect estimates for prespecified critical outcomes.

Discussion: Despite the growing challenges of care for patients with polypharmacy and multimorbidity, evidence from clinical trials that address critical outcomes is limited. It is unclear whether the identified interventions that can be employed by individual physicians to reduce drug overuse and inappropriate prescribing in multimorbid patients, such as protocols for medication review, resulted in clinical improvements.

[ Background: It has been shown that handgrip strength is a strong predictor of cardiovascular and non-cardiovascular mortality and a moderately strong predictor of incident cardiovascular disease. Moreover, low grip strength was associated with higher case-fatality rates both as to cardiovascular or non-cardiovascular disease. It has been suggested that unmeasured factors, such as endothelial dysfunction as well as arterial stiffness might mediate the association between muscle strength and cardiovascular events.

We have measured pulse wave velocity (PWV) and handgrip strength (HGS), along with potential confounders both in the LipidCardio study, which is a cohort of 1,005 consecutive patients, recruited on the occasion of elective coronary angiography at the Charité-Universitätsmedizin Berlin during 2016-2018, and in the Berlin Aging Study 2 (BASE-II). In this analysis of merged baseline data from both studies we aimed to investigate if there is an independent association of handgrip strength and arterial stiffness, as assessed by pulse wave velocity (PWV). In multivariable regression analysis, stratified for sex, and adjusted for age, CAD, BMI, systolic blood pressure and current smoking there was reasonable evidence in support of an association between HGS and PWV in both men and women, respectively. There was no evidence of important effect modification by sex, and the association was evident in both original cohorts, LipidCardio and BASE-II. On average, per tertile decrease in HGS PWV increased by 0.12 m/s (95% confidence interval 0.08 to 0.18 m/s, p < 0.001). Similarly, odds for low handgrip strength (lowest tertile) were increased by 4.1 times (95% confidence interval 2.9 to 5.7) comparing participants with PWV > 11 vs. PWV ≤ 11 m/s.

There was reasonable evidence for an independent association of (low) HGS with (elevated) PWV. Increased arterial stiffness might be a factor contributing to and explaining part of the increased cardiovascular risk observed in individuals with lower handgrip strength. Rationale: Cardiovascular comorbidities are frequent in COPD and worsen the prognosis. Due to the overlap of symptoms, in particular dyspnea, the detection of concomitant left heart failure remains a challenge in COPD, but is required for adequate treatment. For therapy of systolic left heart failure, diuretics, beta-blockers and renin-angiotensin-aldosterone (RAAS) inhibitors are recommended. Neither the frequency of left heart failure in COPD, nor the frequency of sufficient treatment is well known. To elucidate this question, we evaluated echocardiographic criteria and heart failure medication in a large cohort of patients with stable COPD.

From the baseline data of the German COSYCONET cohort, those of patients with full and plausible lung function and echocardiographic data including left ventricular ejection fraction (LVEF) and end-diastolic diameter (LVEDD) were analyzed. Systolic left heart failure was assumed for LVEF ≤ 50% or LVEDD > 56 mm. Medication was assessed via a detailed questionnaire.

Overall, 1591 patients fulfilled the inclusion criteria (mean±SD age: 64.4±8.6 years; GOLD 0-4: n=230/126/614/498/123). Presence of arterial hypertension was reported in 54.1%. Systolic heart failure according to echocardiography was detected in 239 patients (15.0%). The magnitude of airway obstruction (FEV1, 55 vs 58%pred, p=0.039) was slightly more severe in the heart failure subgroup, whereas no difference was found for lung hyperinflation (ITGV, 141 vs 145%pred, p=0.148) when compared with the remaining cohort. Of note, the rate of diuretics use (including aldosterone antagonists) was not different between the groups (21.8 vs 17.2%, p=0.099), whereas a slightly increased rate of RAAS inhibitors (50.2 vs 42.0%, p=0.029), but a markedly increased rate of beta-blockers (31.8 vs 19.2%, p < 0.001) was found in the heart failure group compared to the remaining cohort.

Conclusion: Contrary to expectation, the overall rate of heart failure treatment in terms of diuretics was not significantly elevated in patients identified via LVEF reduction or LV dilatation. Although the prescription rate of beta-blockers (and marginally that of RAAS inhibitors) was higher in this subgroup, the total frequency remained low, in particular when taking into account other indications for these drugs, such as arterial hypertension with a reported prevalence of > 50%. Assuming the adequacy of echocardiographic criteria, these observations raise the suspicion that the presence of left heart failure is undetected and untreated in a significant proportion of patients with COPD, which bears the risk of worsening their prognosis. Background: Systolic (SBP) and diastolic blood pressure (DBP) as well as mean arterial pressure (MAP) are already known as important predictors respectively risk factors for cardiovascular mortality. Pulse pressure (PP) is considered as an easily available marker of vascular stiffness and the double product (DP; SBP x heart rate (HR)) as a marker of cardiac workload. Therefore we extended our analysis of outcome parameters by use of PP and DP.

We retrospectively analysed data from the Ludwigshafen Risk and Cardiovascular Health (LURIC) study.

Results: Long-term data from 3316 patients undergoing coronary angiography showed that by increasing SBP by 1mmHg the risk of both cardiovascular and overall mortality rose by 0.9%. However, there was no significant relationship between DBP and mortality. A higher PP of 1mmHg resulted in a higher cardiovascular mortality risk of 1.6% and an overall mortality risk of 1.7%. Increasing DP by 1 standard deviation was associated with a 26.1% higher risk of cardiovascular mortality and 25.7% higher risk of overall mortality.

We provide evidence that not only the classic standard blood pressure parameters SPB and MAP predict cardiovascular mortality, but also that PP and DP are powerful predictors of cardiovascular mortality risk in a cardiovascular risk population. Pharmacological approaches for treating atrial arrhythmias are limited. Recent genome wide association studies reported that the neuronal SCN10A Na-channel (NaV1.8) might play a role in atrial electrophysiology. This study investigated the role of NaV1.8 in the human atria and its in-volvement in cellular electrophysiology and arrhythmogenesis.

Atrial myocardium from 34 patients with sinus rhythm was investigated. By using quantitative real-time PCR, we could confirm that NaV1.8 mRNA is expressed in human atrial myocardium (n=8 patients) and found a ~3.0-fold higher mRNA expression compared to ventricular myocardium (n=10 patients). Western Blot experiments confirmed the protein expression of NaV1.8 in the human atrium, which was less compared to the predominant heart isoform NaV1.5 (NaV1.8: n=14 patients, NaV1.5: n=13). Co-immunofluorescence staining revealed that NaV1.8 is expressed in atrial cardiomyocytes and localized in both t-tubules and intercalated discs. To evaluate the electrophysiological role of NaV1.8 we performed patch clamp experiments using isolated human atrial cardiomyocytes. Specific inhibition of NaV1.8 by the inhibitors A-803467 or PF-01247324 had no effects on action potential amplitude, resting membrane potential and upstroke velocity of atrial action potentials, while the action potential duration was slightly but not significant shortened (n=11-14 cells from 5 patients each). However, we could demonstrate that NaV1.8 significantly contributes to the persistent "late" sodium current (INaL) and that inhibition of NaV1.8 by A-803467 (n=12 cells/ 4 patients) or PF-01247324 (n=10/4) significantly reduces INaL compared to control (n=15/6) in human atrial cardiomyocytes. Since INaL is linked to arrhythmia generation we studied the role of NaV1.8 in cellular arrhythmogenesis. Confocal line scans of human atrial cardiomyocytes loaded with the Ca indicator Fluo-4 showed that the proarrhythmic diastolic sarcoplasmic Ca leak could be significantly diminished by A-803467 (n=73/9) or PF-01247324 (n=88/11) compared to control (n=84/13). Moreover, the incidence of major diastolic sarcoplasmic Ca release events as proarrhythmic triggers like Ca waves was significantly reduced by ~68.8% after NaV1.8 inhibition (Control: n=116/13, A-803467: n=90/9, PF-01247324: n=104/11). Accordingly, specific inhibition NaV1.8 with both novel agents (n=11/4 each) potently reduced triggered activity (cellular afterdepolarizations and spontaneous action potentials) in patch clamp recordings of human atrial cardiomyocytes (Control: n=14/4).

This study demonstrates that NaV1.8 is expressed in the human atrium and contributes to INaL generation as well as cellular arrhythmogenesis. Importantly, selective inhibition of NaV1.8 with both novel inhibitors (PF-01247324 is orally bioavailable) reduces cellular arrhythmias. Thus, this study uncovers NaV1.8 as a new pharmacological approach for treating cellular arrhythmogenesis in the human atrium. Background: Sacubitril/valsartan (S/V) was approved to treat systolic heart failure (HFrEF) in Europe and US in 2015. In Germany, most HFrEF patients are managed by Primary Care Physicians (PCP). The prospective AURORA registry was therefore set up to characterize this cohort of PCP-treated HFrEF patients and to capture baseline factors associated with subsequent changes in HF therapy in a real-world setting.

Methods: A total of 220 Primary Care Physicians throughout Germany enrolled 1260 qualifying adult HFrEF patients between March 2016 and May 2018 in AURORA. Consenting patients treated with conventional HF therapy or with S/V therapy were to be followed up over 12 months to capture if the HF therapy was changed in the 28 days before or after the qualifying index visit. If PCPs deemed that no change in HF therapy was required, only index visit data was to be captured. Baseline data are presented here according to the treatment groups "conventional" HF therapy (CT) or S/V therapy (S/V) as per index visit. We used cell viability assays to determine the cell killing capabilities of i) viro-therapy, ii) starvation, and iii) the combination of these two. Virus growth curves were generated to assess the replication of MeV in starved and non-starved HT-29 cells.

c) Infection of starved cancer cells exhibited additional oncolytic potential of virotherapy plus starvation for most combinations.

Remarkably, long-term low serum/ standard glucose starvation potentiated the efficacy of MeV-mediated cell killing in HT-29 CRC cells, whereas it was decreased in normal colon cells CCD-18 Co and CCD-841 CoN. Interestingly, viral replication of MeV in HT-29 was decreased in long-term starved cells, but was increased after shortterm low glucose/ low serum starvation. d) In conclusion, starvation based virotherapy could enhance the oncolytic effect on CRC in future anti-cancer therapy while protecting normal tissues from side effects. ) . A meta-analysis was performed to assess the blood-pressure-lowering efficacy of catheter-based renal denervation in sham-controlled trials (RDN).

A total of 27 trials that enrolled 3,179 patients were included. The majority of studies (56%) were published during the last four years. Eight trials (28%) met all predefined primary efficacy endpoints. Invasive interventions achieved a large and moderate ES in 30% (3/10) each of the continuous endpoints, whereas the ES of a sham procedure was large in 10% (1/10) of the continuous endpoints. None of the sham procedures had a moderate ES. A deterioration of the continuous primary outcome was not documented following active treatment but one (10%) sham procedure.

A meta-analysis of sham-controlled trials investigating RDN in hypertension showed a more pronounced reduction in office (mean difference (MD) -5.72 mmHg, 95% confidence interval (CI) -8.29 to -3.15 mmHg), daytime (MD -4.06 mmHg, 95% CI -6.23 to -1.9 mmHg) and 24-hour ambulatory (MD -3.57 mmHg, 95% CI -5.23 to -1.91 mmHg) systolic blood pressure following RDN (n=582) when compared with sham (n=395).

Conclusion: ES of sham procedures were remarkable and underline the influence of non-specific mechanisms such as placebo on treatment effects. This meta-analysis adds to the growing body of evidence indicating the blood pressure-lowering efficacy of RDN. Introduction: Genetic causes should be considered in both syndromic and non-syndromic forms of cardiac diseases. Monogenic cardiac diseases have a prevalence of 1:20000 and represent a major socioeconomic burden. Identification of the underlying genetic defect remains challenging due to the vast heterogeneity and mostly unspecific clinical features. However, establishing a firm molecular diagnosis is important for risk stratification of affected individuals and their families. Information on genotype-phenotype correlations might guide monitoring for known accompanying clinical features. For instance it is known that patients with RBM20-associated cardiomyopathy bare a higher arrhythmia risk than patient with TTN-associated disease.

During the past two years we used exome-sequencing (enrichment Agilent Human Sure Select All exon kit v5/ v6/ v7, sequencing Illumina HiSeq 2500/ Novaseq 6000) to investigate 74 index patients with suspected genetic cardiomyopathies or primary cardiac arrhythmias. Using an in-house bioinformatics pipeline we prioritized rare variants in known disease-associated genes as well as in genes associated with clinical signs of differential diagnosis (including syndromic conditions).

In approximately 32% of cases (24 out of 74 patients) we established a firm molecular diagnosis. In about 19% of cases (14 out of 74 patients) we identified variants of unknown significance in known or putative disease-associated genes. Detection rate was 23.9% (20 out of 58 patients) in cardiomyopathy patients and 25% (4 out 16 patients) in patients with suspected primary arrhythmias. Highest detection rates were observed in NCM, LQTS, H(O)CM and ARVC patients with detection rates of 66% (2 out of 3 patients), 40% (4 out of 10 patients), 44% (8 out of 18 patients) and 44% ( 4 out of 9 patients) respectively.

Exome sequencing allows the identification of likely genetic cause of cardiac conditions in a substantial fraction of patients. The identification of the molecular bases of diseases allows risk stratification in patients and might guide treatment decisions (e.g. ICD-implantation). It also enables (predictive) genetic testing for relatives and thus an early identification of persons at risk for developing cardiac incidents. On the other hand it allows "discharge" of relatives from intensified cardiologic surveillance when a disease-causing mutation can be excluded. Thus genetic testing via exome sequencing is a crucial component of an interdisciplinary approach to the management of patients with primary cardiomyopathies and arrhythmias. Background: Atrial fibrillation (AF) is the most common cardiac arrhythmia. Similar autonomic in-nervation of the esophagus and left atrium with sympathovagal imbalance may contribute to the relation between non-valvular atrial fibrillation (AF) and gastroesophageal reflux disease (GERD).

The aim of our prospective study was to evaluate gastrointestinal symptoms in patients with AF undergoing pulmonary vein isolation (PVI). Furthermore, we investigated the effects of PVI on these symptoms during follow up.

Methods: Gastrointestinal symptoms were assessed by the standardized and validated PAGI SYM (Patient Assessment of Gastrointestinal Symptom Severity Index) questionnaire before scheduled PVI and six months after PVI. The PAGI SYM is intended to cover the main symptom groupings over a 2-week recall period for GERD, dyspepsia and gastroparesis.

In 82 patients with symptomatic AF before PVI (age 62±10 years, 73% male, BMI 29±5 kg/m2 38% EHRA III-IV, LVEF 55±9 %), 27% were suffering from GERD treated with a proton pump inhibitors (PPI). In terms of paroxysmal versus persistent AF, there was no significant difference regarding PPI medication (p=0.98). In the total population, the PAGI SYM median total score was 0.5 (0-3) corresponding to very mild gastrointestinal symptoms. In detail, 49% of patients showed no GI disorders, 43% mild GI symptoms and only 5% suffered from moderate gastrointestinal disorders. There were no patients with severe GI symptoms observed. Furthermore, there were no associations between intensity of GI symptoms, and gender, type of AF, left atrial size. There was a significant association between the PAGI SYM total score and the EHRA class: A higher EHRA score correlated with more UGI-Symptoms (r=0.249, p=0.027). No significant changes were observed within the PAGI-SYM-Score before and after PVI. (p=0.68)

Half of the patients undergoing PVI due to symptomatic AF showed no GI symptoms, the other half only mild disorders. A correlation between AF symptoms and GI symptoms were observed which may indicate an interaction between the heart and the gut in these patients. 

We evaluated the reliability, responsiveness and feasibility of logical memory, immediate verbal recall of a short story, compared to brief tests of attention as a bedside "Cognitive Vital Sign" in order to improve time to initialize treatment and therefore improve patient outcomes.

Out of 100 recruited patients, trained nursing staff performed twice-daily cognitive assessments on 84 clinically stable inpatients, 47 Males and 37 Females, in geriatric units in two hospitals over 3-5 consecutive days using logical memory and short tests of attention including months-of-the-year backwards, numbers counting forwards, numbers counting backwards and orientation to time and digit span. The majority of patients were aged 65 and above N=69.

Twelve patients were excluded due to being discharged less than three days after commencing the study. Four patients clinical condition worstened during the participation in the study and further measurements were not possible.

Logical memory was compared to these various short teests of attention. Ten different alternative logical memory stories were developed in order to reduce learning effect.

Scores were compared to those of an expert rater. Inter-rater reliability was excellent with correlation coefficients for logical memory increasing from r=0.87 on day one to r=0.97 by the fourt day (p < 0.0001).

Logical memory scores were statistically similar (p=0.99) with repeated testing and no learning effect could occur due to ten variations of the logical memory test.

Mean logical memory scores ranged from 0 to 30. The mean score was 10.7/30. The mean variations in scores was 3.4 points with standard deviation +-1.1 points, indicating that fluctuations of three points or greater from the individuals baseline were outside normal daily changes and therefore clinically significant.

Patients who had been listening to the news, had breakfast or recently checked the time in anticipation of cognitive testing scored better, which reflects real-life practice; a strength of the study.

All fourteen nurses taking part in the study reported that logical memory was feasible to score routinely and were willing to perform the logical memory along other vital signs in the future.

Logical memory is a reliable measure of cognition showing diurnal variation but no evident learning effects. Further study is required to define the properties of an ideal cognitive vital sign, although logical memory may satisfy these objectives. Purpose: The incretin hormones GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic peptide) are secreted from the gut following food intake leading to pancreatic insulin secretion and glucose lowering. GLP-1 agonism has recently been found to inhibit neointima formation after vascular injury in rodents (experimental model of in-stent restenosis) due to inhibition of vascular smooth muscle cell proliferation. In this study we analysed the effect of the other main incretin GIP on vascular remodeling.

Since vascular smooth muscle cells (VSMC) play a crucial role in pathological vascular remodeling processes like atherosclerosis or in-stent restenosis, we first asked whether GIP does affect VSMC proliferation under in vivo conditions. Using an adeno-associated viral vector system we overexpressed GIP and LacZ as control in C57BL/6J mice (n=7/group) before undergoing guide wire-induced endothelial denudation injury of the left femoral artery. Histological analyses were performed 4 weeks after vascular injury and revealed no difference in neointima formation and intima/media ratio between both groups, indicating that GIP has no direct effect on VSMC proliferation under in vivo conditions. Consistent with our in vivo findings GIP incubation showed no effect on mitogen-induced VSMC proliferation analyzed by BrdU incorporation 24h after PDGF-BB stimulation under in vitro conditions. In the next step we wondered whether GIP might affect inflammatory activation of VSMC. Indeed GIP treatment significantly diminished protein and mRNA expression of the cell adhesion molecule VCAM-1 by 50% (control 6.8 ± 0.9 vs. 3.5 ± 1.0 GIP fold change from basal; p < 0.05) in TNF-α treated VSMC. Furthermore, GIP decreased TNF-α-induced MMP-2 and MMP-9 expression in VSMC, suggesting a potential protective role of GIP in inflammation-induced vascular remodeling.

Unlike GLP-1 the other main incretin hormone GIP does not affect proliferation of VSMC in vitro or in vivo. However, GIP has direct anti-inflammatory effects in TNF-α treated VSMC by diminishing expression of cell adhesion molecules and extracellular-matrix-remodeling (ECM) markers. Further studies are needed to determine whether activation of the GIP-system might be protective in inflammation-driven vascular pathologies like atherosclerosis. Universitätsklinikum Heidelberg, Nephrologie, Heidelberg, Germany; 2 Universitätsklinikum Heidelberg, Anästhesiologie, Heidelberg, Germany; 3 Universitätsklinikum Heidelberg, Gastroenterology, Heidelberg, Germany

Background: Sepsis-induced acute kidney injury (AKI) is the dominating AKI etiology in critically ill patients and substantially associated with risk of death [1] . In the absence of kidney-specific therapeutic alternatives, renal replacement therapy (RRT) is often the final therapeutic option. However, whether and when to start RRT is an ongoing controversy [2] . A major issue that persists is to differentiate patients with progressive AKI and need for RRT from those with autonomous renal recovery [3, 4] . We investigated the diagnostic value of the soluble urokinase-type plasminogen activator receptor (suPAR) and the product of the two G1-cell cycle arrest and tubular injury biomarkers tissue inhibitor of metalloproteinase-2 and insulin-like growth factor-binding protein 7 ([TIMP-2]*[IGFBP7]) to predict future need for RRT

In a prospective, observational trial, 100 critically ill patients were enrolled immediately after the fulfillment of Sepsis-3 criteria. Su-PAR levels were measured once at inclusion, and urinary [TIMP-2]*[IG-FBP7] levels were measured over time. The primary clinical endpoint was the occurrence of need for RRT (predefined criteria) within 7 days. Area under the receiver-operating characteristic curves (AUC-ROC) and logistic regression models were calculated. Alle externen Untersuchungen (Bronchoskopie, Blutkulturen, Sonographie inkl. TEE, Urinstatus und -sediment, ANA, ANCA, C3, C4, anti-CCP, anti-GBM, Immunglobuline, Virologie, Bakteriologie und Mykologie (u.a. Influenza, Hanta, Hepatitis, Mycoplasmen, Leptospiren, Legionellen, Chlamydien, PJP, Aspergillen) verbleiben unauffällig.

In der erneuten diagnostischen Aufarbeitung 7 Tage später zeigt sich nun der Antikörper gegen Bestandteile der glomerulären Basalmembran deutlich erhöht (183 U/ml; n < 20 U/ml). Die erneute quantitative und qualitative Urinuntersuchung sowie die Nierenfunktion verbleiben unauffällig.

Wir stellten die Diagnose eines sekundären ausschließlich pulmonalen Goodpasture-Syndroms.

Eine Therapie mittels täglicher Plasmapherese, hochdosiertem Prednisolon (21.08.) und Cyclophophamid (28.08.) erfolgt. Ein Spannungs-Pneumothorax wird mittels Thoraxdrainage versorgt. Es erfolgt die komplikationslose dilatative Tracheotomie, die Sedierung wird beendet. Der Patient bleibt ECMO-abhängig und wird aus dem Bett mobilisiert.

Unter o.g. Therapie (10x Plasmapheresen) zeigt sich eine langsame, aber anhaltende klinische und laborchemische Besserung (anti-GBM < 20 U/ml). Die ECMO-Therapie kann nach 48 Tagen beendet werden. In den ambulanten Verlaufskontrollen (zuletzt 08/2018) zeigt sich auch nach stufenweiser Reduktion der immunsuppressiven Therapie über 6 Monate und deren Beendigung kein Anhalt für ein Rezidiv der Grunderkrankung.

In ähnlichen Fallberichten wird die Freilegung der Basalmembran durch ein inhalatives Trauma (u.a. Tabak, Kokain, Speed) als pathophysiologischer Auslöser für das sekundäre Goodpasture-Syndrom diskutiert [1 -5] .

Auch bei zuvor negativem anti-GBM sollte ein schweres akutes Lungenversagen nach Hämoptysen, inhalativer Noxenkonsum und Panbronchiolitis im HRCT, zur erneuten Bestimmung des anti-GBM-Wertes leiten, und die seltene Erkrankung eines sekundären, ausschließlich pulmonalen Goodpasture-Syndroms in Erwägung gezogen werden.

[ failure, coronary artery disease, chronic lung disease, intensive care, mechanical ventilation, and presence of central lines. For each control patient we evaluated the day during hospitalization on which the matched case had its onset of candidemia and then compared both groups concerning the post diagnosis length of stay. We estimated attributable mortality until day 30 post candidemia diagnosis. We performed Χ²-test for categorical and Students t-test for continuous variables, and defined a two-tailed p-value < 0.05 statistically significant.

Results: Cases and controls were 68% males. Median age was 62 and 63 years, and 25th and 75th percentile 55 and 74 years in both groups. Candidemia occurred a median 18 days post admission.

For cases and controls, median length of stay post diagnosis was 17 and 15.5 days (p=0.13), for those who died 12 and 19 days (p=0.21), and for survivors 24 and 13 days (p=0.006). Day 30 mortality rates were 38% and 11% for cases and controls (p=0.03), thus attributable mortality was 27%.

Conclusion: Attributable mortality of nosocomial candidemia is still substantial, but was lower in our study as compared to literature from before introduction of echinocandins. 

Hauke Tews

A 27-year-old patient with serotonin syndrome under Venlafaxine therapy A 27-year-old female, who was accompanied by her boyfriend, introduced herself to the emergency unit on the 10th of May 2018. Her boyfriend reported that she had sent him a farewell message via her smartphone. He also reported that he had found an empty tablet blister and an empty bottle of Ouzo.

The hospital admittance was based on a mixed intoxication. Clinical signs of a serotonin syndrome, like the flipping eye syndrome, tachycardia, akathisia and tremor were noticeable, suited to an intoxication with venlafaxine. A blood alcohol concentration of 2,32 per thousand was detected as well. During the first hours of therapy at the intensive care unit the patient was hemodynamically stable.

The next day the symptoms of the serotonin syndrome aggravated, leading to uncontrolled motoric movements with extreme hyperreflexia. A progressive cardiogenic shock with multiple organ failure (kidney, liver, heart), lactic acidosis and rhabdomyolysis developed. In spite of consumption of the conservative methods, a stabilization of the circulation could not be reached.

As ultima ratio, an assistance for the circulation via ECLS (A. and V. femoralis dextra) was initiated.

A few hours later, a massive bleeding out of the puncture of the arterial ECLS needle existed. In spite of the surgical intervention, it came to a hemorrhagic shock.

As a result, the needles for the ECLS were changed from the right inguinal side to the left inguinal side, and the vessels on the right side were sewed. In the course of time an acute kidney failure with anuria and metabolic acidosis developed, so that a hemodialysis was initiated. In the following hours, the dosis for the Catecholamin therapy increased rapidly. Using a volume replacement and an antibiotic therapy with Meropenem and Vancomycin by unknown focus, a haemodynamic stabilization could be reached.

After a few days we explanted the ECLS and documented a good systolic heart function. During the course of staying at the intensive care

Der Internist · Suppl 1 · 2019 | S45 unit, the patient developed a diuresis und by decreasing kidney retention parameters we finished hemodialysis.

In summary, we treated a 27-year-old patient with multiple symptoms of a serotonin syndrome with multiple organ failures by a mixed intoxication with Venlafaxin (at least 13,5 grams), Ibuprofen (6 grams) and alcohol in suicidal intention. The artificial respiration outlasted for 13 days. By the clinic of a cardiogenic shock, based on a toxic kardiomyopathie, a treatment via ECLS was realized from the 11th of May 2018 to the 17th of May 2018.

With regard to the ECLS therapy, an artificial respiration and an intermitting hemodialysis, several methods were indispensable for stabilising the patient.

Fortunately, the patient was discharged after 20 days of habitation at the intensive care unit. After approximately 20 days at the intensive care unit, we saw the clinical picture of a "restutio ad integrum". Background: Glucagon-like peptide 1 (GLP-1) is a gut incretin hormone, which induces post-prandial glucose-dependent insulin secretion. GLP-1 receptor agonists are used for the treatment of type 2 diabetes and have been found to improve cardiovascular outcomes in patients with diabetes at high cardiovascular risk. We recently found GLP-1 levels to be increased in patients with acute myocardial infarction. The aim of this study was to assess the predictive capacity of GLP-1 for cardiovascular outcome in patients with myocardial infarction.

Total GLP-1 levels, NT-proBNP concentrations and the Global Registry of Acute Coronary Events (GRACE) score were assessed at time of admission in 918 patients with myocardial infarction presenting with acute chest pain. Among these 597 patients presented with NSTEMI and 321 with STEMI. The primary composite outcome of the study was the first occurrence of all-cause death, nonfatal myocardial infarction, or nonfatal stroke with a median follow-up of 311 days. Background: Coronary artery disease (CAD) is associated with increased mortality in patients with chronic lung diseases. However, non-invasive diagnostic of CAD is limited, especially in patients with more advanced disease. Therefore, we aimed to assess the feasibility and accuracy of SPECT-myocardial perfusion imaging (MPI) stress testing with regadenoson in patients with end-stage lung disease (ELD) undergoing assessment of stable CAD.

Methods: In total, 102 consecutive patients with ELD were assessed retrospectively from 2012 to 2018. All patients underwent both SPECT-MPI and coronary angiography as part of a lung transplant evaluation.

The mean age was 58±6 years. Mean forced vital capacity and forced expiratory volume in 1 second were 50±16 and 36±20% predicted, respectively. 86% of patients required long-term oxygen therapy. Regadenoson-related symptoms requiring medical intervention were observed in 2 patients (2%) and 14 patients (14%) reported symptoms. In total, 8 patients (8%) had abnormal SPECT-MPI and revascularisation was performed in 6 patients (6%). Specificity and negative predictive value of SPECT-MPI were 95% and 98%, respectively and were not influenced by confounding factors.

Our findings suggest that SPECT-MPI stress testing with regadenoson is well tolerated and has a high value to rule out CAD in patients with ELD. Der Internist · Suppl 1 · 2019 | S47 Methods: We investigated the effect of LPS on the response to chemotherapy and radiotherapy in vitro using the human adenocarcinoma cell lines A549 and H1975. The cells were incubated with LPS (0.1, 1, 10 µM) and treated with cisplatin (various dosages) and/or ionizing radiation. The clonogenic survival was determined by colony formation assay. To analyze the relative levels of phosphorylation of different kinases in relation to exposure to LPS and ionizing radiation a human phospho-kinase array was performed. Furthermore cellular IL-8-synthesis after LPS-incubation, irradiation and inhibitor-treatment was quantified by ELISA.

Results: Neihter A549 cells nor H1975 cells showed a reduced response to cisplatin after incubation with LPS. The A549 cells exposed to 10 µM LPS showed a significant decreased response to radiotherapy. Further investigations showed that the relative phosphorylation levels of ERK1/2 were increased significantly after exposure to LPS. Moreover, inhibition of ERK1/2 resulted in a restoration of radiosensitivity of A549 cells even in the presence of LPS. After exposure to LPS the cellular synthesis of IL-8 was increased significantly, especially if cells were additionally treated with ionizing radiation, whereas the application of the ERK-inhibitor led to a reduction in levels of IL-8.

: LPS reduce radiosensitivity of A549. The effect of LPS on therapy resistance is mediated by ERK1/2 and possibly by IL-8. These findings could be of clinical importance, as NSCLC patients who suffer from infections could develop radiotherapy resistance and tumor progression. Interference with the ERK-pathway may be a promising option to restore radiosensitivity in NSCLC patients. Pulmonary hypertension (PH) is characterized by the thickening of the distal pulmonary arteries caused by medial hypertrophy, intimal proliferation and fibrosis. Low density lipoprotein receptor-related protein1 (LRP1) has the capacity to maintain vascular homeostasis by mediating the endocytosis of numerous ligands and by initiating and regulating signaling pathways.

Here, we demonstrate the increased LRP1 protein levels in the lungs of idiopathic pulmonary arterial hypertension (IPAH) patients, hypoxia-exposed mice, and monocrotaline (MCT)-treated rats. Platelet-derived growth factor (PDGF)-BB upregulated LRP1 expression in pulmonary artery smooth muscle cells (PASMC). This effect was reversed by PDGF-BB neutralizing antibody or the PDGF-BB receptor antagonist Imatinib. Depletion of LRP1 decreased proliferation of donor and IPAH PASMC in a β1-integrin-dependent manner. Furthermore, LRP1 silencing attenuated the protein expression of fibronectin and intercellular adhesion molecule 1 and increased the levels of alpha-smooth muscle actin (α-SMA) and myocardin in donor, but not in IPAH, PASMC. In addition, smooth muscle cell (SMC)-specific LRP1 knockout augmented α-SMA expression in pulmonary vessels and reduced SMC proliferation in 3D ex vivo murine lung tissue cultures.

In conclusion, our results indicate that LRP1 promotes dedifferentiation of PASMC from a contractile to a synthetic phenotype thus suggesting its contribution to vascular remodeling in PH. The diagnosis of depression, a frequent comorbidity of COPD, is often supported by questionnaires, such as the Patient Health Questionnaire 9 (PHQ-9). It is unknown to which extent its single questions are affected by the characteristics of COPD patients.

We addressed this question in 2255 GOLD grade 1-4 patients from the COSYCONET COPD cohort. The dependence on COPD severity was assessed using symptoms, exacerbation risk (GOLD A-D; mMRC), and frequent comorbidities as predictors of PHQ-9 results, while including age, gender, BMI and smoking habits as covariates.

Symptoms and exacerbation risk were associated in an additive manner, with mean elevations in the PHQ-9 sum score by 2.75 and 1.44 points, respectively. Asthma, sleep apnoea, gastrointestinal disorders, osteoporosis and arthritis were linked to increases by 0.8 to 1.3 points. Overall, the COPD characteristics contributed to the mean score by increases from 4.5 or 5.2 to 6.3 points, respectively, when either taking GOLD A as reference or the absence of comorbidities, independent of the diagnosis of mental disorder or intake of antidepressants. The presence of COPD led to an increase in the proportion of scores indicating depression from 12 to 22%. Single item analysis revealed homogenous effects regarding GOLD groups, but heterogeneous effects regarding other COPD characteristics.

These findings indicate specific effects of COPD severity, especially symptoms and exacerbation risk, on the PHQ-9 depression score, explain the high prevalence of depression in COPD. Alternatively, our findings raise the question of a bias from COPD severity on the PHQ-9, but also suggest COPD treatment effects on depression scores. Background: Chronic Obstructive Pulmonary Disease (COPD) is characterized by an irreversible airway obstruction. The course of the disease including morbidity and mortality is strongly associated with severe exacerbations.

The current international GOLD recommendations emphasize blood eosinophils as marker for responsiveness to inhaled corticosteroids (ICS). The recommended thresholds are < 100 cells/µl and > 300 cells/µl.

Retrospective analyses from randomized clinical trials as well as prospective clinical trial data indicate a favorable response to systemic corticosteroids in exacerbated COPD patients with blood eosinophils > 2 %, however data outside clinical trials are scarce.

We thus aimed to examine the outcome of severe COPD exacerbations measured as length of hospital stay (LOS) according to the blood eosinophil count in a real life setting.

In this preliminary analysis, we present retrospectively collected data from 374 patients who were admitted to the University Hospital Marburg between 01/2013 and 05/2015. All patients had been diagnosed with an acute exacerbation of COPD according to the ICD code (J44.0/J44.1). Patients were predominantly male (67.4 %), had a mean age of 74.2 ± 11.8 years and a mean FEV1 of 1.21 ± 0.6 l (46. 9 ± 19.8 % predicted) . This analysis was based on a subgroup of 262 patients in whom a full blood cell count was obtained at day of admission. These patients exhibited similar baseline characteristics (66.8 % male, 74.2 ± 11.7 years of age, FEV1 1.22 ± 0.65 l, 47.1 ± 19.7 % predicted) .

We compared the hospital length of stay as well as other markers of disease severity using various established thresholds for the eosinophil blood cell count (100 and 300 eosinophils/µl and 2%).

Patients with low eosinophils ( < 2 %, < 100 cells/µl) had a shorter median time in hospital (length of hospital stay -LOS) as compared to patients with high eosinophils. This was true for both relative (7 vs. 9 days; p < 0.05) and absolute values (7 vs. 8 vs. 10 days; p < 0.05). In contrast, the median CRP was higher in patients with low eosinophils as compared to the other groups ( < 2 %: 33 mg/dl vs. ≥ 2 %: 14.5 mg/dl; p < 0.005). There were no differences in age, Procalcitonin, or case mix index (CMI) between the low eosinophil groups and their respective control groups. Background and aims: The associated harm of tobacco smoking on the cardiovascular system is worldwide well known for cigarettes. But there are still only few studies about this effect for shisha smoking, which is becoming more prevalent globally, particularly among younger populations and believed to be "less harmful". The aim of this study is to investigate the relation of shisha smoking to some of cardiovascular risk parameters compared to cigarette smoking among adults in a general population.

A cross-sectional study based on Data from a cardiovascular risk factors survey conducted by University of Aleppo in cooperation with Syrian Centre for Tobacco Studies in 2006 in Aleppo city. A total of 806 participants were included, who provided demographic, beha-vioral, and smoking-related information, as well as measurements of weight, height, blood pressure, and heart rate. Fasting blood samples were obtained to analyze C-reactive protein, glucose, triglyceride, total cholesterol, LDL-and HDL-cholesterol. The correlation between smoking and the studied parameters was assessed using multivariate linear regression analyses adjusted for potential confounders (age, gender, BMI, physical activity).

Results: Daily shisha smoking was associated with an increased BMI (p = 0.009), whereas an opposite association was observed with daily cigarette smoking (p < 0.001). Daily cigarette smoking independently correlated with higher levels of LDL-cholesterol (p = 0.003) and CRP (p < 0.001), while shisha smoking correlated with higher levels of triglyceride (p = 0.012). Both shisha und cigarette smoking correlated with lower HDL-cholesterol levels (p = 0.012 and p = 0.004 respectively). Unlike cigarette smoking, daily shisha smoking was associated with increased heart rate (p < 0.001). Blood pressure tended to be increased among daily shisha smokers and to be decreased among daily cigarette smokers.

The results of this study show that shisha smoking is associated with cardiovascular biomarkers abnormalities, suggesting to be as harmful for cardiovascular health as Cigarette smoking.

known to be linked to a potential increased risk of HZ, were enrolled in these studies. The study population is a representative sample of the general adult population over the age of 50 years.

A post-hoc analysis of the pooled ZOE-50 and -70 (ZOE-50/70) trials (NCT01165177; NCT01165229) assessed VE and safety in adults ≥50 years old reporting at least 1 medical condition at enrollment. The medical conditions included in the analysis were present at enrollment in ≥500 participants in both the placebo and the RZV recipients of the ZOE-50 and -70. These medical conditions included those that have been recognized to be associated with an increased risk of HZ (asthma, depression, respiratory disorders, and renal disorders). Fatal/serious adverse events (SAEs) were recorded for at least 12 months after the 2nd vaccination, potential immune-mediated diseases (pIMDs) were recorded during the entire study period and were assessed with consideration of subjects' baseline medical conditions. To this end, gene expression profiling, FACS analysis and cytokine production measurement was performed on anti-CD3/anti-CD28 activated CD3+ T cells of healthy donors (N=3) cultured in the presence or absence of an unspecific adenosine receptor agonist 5'-(N-Ethylcarboxamido)adenosine (NECA).

While T-cell proliferation and IL-2 production were significantly down-regulated by NECA, IL-10 and IL-17A were increased. Inhibition of proliferation coincided with down-regulation of genes belonging to cell cycle progression. In Kegg pathway analysis, negatively enriched pathways mainly clustered in the categories metabolism and genetic information processing while positively enriched pathways mainly clustered in signal transduction and immune system. Analysis of master transcription factors for Th differentiation, i.e. TBET, GATA3, RORyt and FOXP3 as well as members of the STAT family and markers for Th9, Th22 and Tfh differentiation revealed no consistent up-or down-regulation in the presence of NECA. Changes in the adenosinergic system were confined to up-regulation of CD26 in the presence of NECA, which was confirmed by FACS.

Since concurrent adenosine signaling at the time of T-cell activation does not find its reflection in Th lineage commitment but rather in increased IL-17 production, changes in CD73, CD39 and CD26 in T-cells of AAV patients are unlikely directly involved in expansion of Th17 and impairment of Treg as a consequence of decreased extracellular adenosine concentrations. However, because adenosine profoundly inhibits T-cell activation, a relative shortage of extracellular adenosine may explain persistent T-cell activation in AAV patients. Results: A biallelic mutation of TP53 (mutation and deletion) was present in 25 pts (32%), further 19 (24%) had aTP53 mutation without deletion. A deletion without mutation was present in three pts (4%). All pts without cA were TP53 wildtype. We included 22 pts with tMDS, 14 of them with cA.

In five pts we found a sequence variant of PPM1D. All five pts had cA. Two variants have already been described as very rare SNPs. The other three have not been described before. Two of them are at the same position in exon 1, the third very close to the others. All of them are potential missense mutations. One of those three pts shows a TP53 mutation. None of them showed a deletion in 5q. The median number of aberrations in these three pts was 4 (range: 4-8).

As an inhibitor of TP53, and potential pathogenetic alternative to mutations of TP53 itself, we hypothesized that the gene encoding for Wip1, PPM1D, might be mutated in MDS pts with cA but without TP53 mutation, especially in tMDS. We could show that PP-M1D is mutated in pts with cA. In our cohort 7% of the pts with cA are affected. One of them had a tMDS. PPM1D mutations might contribute to the pathogenesis of cA as 2/3 potential mutations do not co-occur with a TP53 mutation. To further determine the influence on the prognosis we will test the PPM1D mutation status in a higher number of MDS pts. Respective analyses are on the way. Therapeutisch bekam die Patientin zum Ausgleich der Azidose Natriumhydrogencarbonat i.v. und später peroral, außerdem Kaliumbinder zur Behandlung der Hyperkaliämie und drei Erythozytenkonzentrate aufgrund der Anämie. Die schwere Hypercalcämie verbesserte sich deutlich nach einer forcierten Diurese und nach der Gabe von Denosumab. Zudem wurde die Hypertonie mit ACE-Hemmern eingestellt und es wurde eine Schmerztherapie nach WHO-Stufe 2 begonnen. Versuchsweise wurde außerdem eine regelmäßige EPO-Substitution eingeleitet, unter der es bis zum jetzigen Zeitpunkt zu keinen weiteren hämolytischen Krisen mehr gekommen ist, deren längerfristiger Nutzen jedoch noch abgewartet werden muss. Die Patientin konnte so nach wenigen Wochen mit annähernd normwertigen Laborwerten entlassen werden. 

Rim Dhaouadi

Case report: A 17-Year old Tunisian male, presented to the emergency with a right painful swollen scrotum and high fever (39°C) starting the day before the admission.No context of trauma was reported. Physical examination revealed a swollen erythematous right scrotum. Cremastic reflexes were present. He had no abdominal pain or other symptoms. Lab results showed leucocytosis , an elevated erythrocyte sedimentation rate and a mildly elevated C-reactive protein level. Cytobacteriological examination of urine was negative. Scrotal and abdominal ultrasonography showed epididymal and testicular enlargement and a thickened scrotal skin.Thus, testicular torsion was excluded and the diagnosis of unilateral epididymo-orchitis was considered. Recovery was spontaneous within four days. Five weeks later, the patient was admitted in internal medecine departement for similar symptoms enluding epigastric pain with no other digestive disorder. Lab results were normal except for a significantly elevated erythrocyte sedimentation rate. Abdominal-CT and upper endoscopy were normal. Specific serological tests for CMV, EBV, HIV, Hepatitis B and C as well as Widal and Wright serologies (patient originated from an endemic area) were performed and came back all negative. PPD skin test was negative too. Autoimmune anti-bodies (ANA) were not detectable. Additional history revealed that the patient had during the last eight months four similar attacks of abdominal pain with fever lasting no longer than two or three days, resolving spontaneously. Because of his mediterranean origin, Familial Mediterranean Fever was suspected. Colchicine therapy was initiated. A followup for 12 months showed that he had no similar episodes.

Discussion: Familial Mediterranean Fever (FMF) is a genetic disease caracterized by idiopathic, self-limited attacks of fever mostly associated with inflammation of serosae. The most commun presenting symptoms enclude fever, abdominal or chest pain, arthiritis, myalgia and erysipelas-like erythema. Acute scrotum was the presenting feature of FMF in rare reported cases in literature (1, 2) . With our patient, the first two episodes were not characteristic of the diagnosis, however, short attacks of fever, swelling, association with new symptoms and recurrence in a subject of Mediterranean origin (especially that other differential diagnosis of acute scrotum were ruled out by physical examination, laboratory and radiological test findings), strongly points toward the diagnosis of FMF. In that case, Colchicine was given with the purpose of controlling the disease and preventing its most fatal complication which is Amyloidosis (3).

Acute scrotum is a rare manifestation of FMF, but, with the absence of objective markers and the recognition of the symp-toms in individuals with Mediterranean origins, this disease should be considered and treated.

Novel insights into postprandial hypoglycemia after gastric bypass: Empagliflozin as well as Anakinra reduce symptomatic episodes by lowered insulin secretion Background: Postprandial hypoglycemia after bariatric surgery is characterized by a pronounced glycemic rise after carbohydrate ingestion and an exaggerated hyperinsulinemic response (1) . Recent studies have shown that IL-1β contributes to the postprandial stimulation of insulin (1) , and that bariatric surgery affects the gut flora and associated inflammatory response. Furthermore, inhibition of the SGLT2 may reduce excessive plasma glucose increase. Therefore, we investigated whether inhibition of IL-1β with the IL-1 receptor antagonist anakinra and/or inhibition of SGLT2 with empagliflozin reduces postprandial hypoglycemia after bariatric surgery.

In this placebo controlled, double-blind, randomized, cross-over proof-of-concept study 12 subjects with confirmed postprandial hypoglycemia after gastric bypass were included. Subjects received on each of the 3 study days either empagliflozin p. o. or anakinra s. c. along with the respective placebo or double placebos. Three hours after injection (anakinra or placebo) and two hours after ingestion of the oral study medication (empagliflozin or placebo) a mixed-meal-test was performed with assessment of hypoglycemia. Clinical assessments (Edinburgh hypoglycemia scale, mini mental status test, Sigstad score, Stanford sleepiness Scale) were performed aside measurement for glucose, insulin, c-peptide as well as inflammatory parameters.

Results: Empagliflozin reduced peak glycaemia at 30 (11.2 vs. 10.1 mmol/l), 60 (9.1 vs. 6.9 mmol/l) and 90 (4.5 vs. 3.5 mmol/l) minutes after ingestion of the mixed meal compared to placebo and was followed by a significant reduction of glucose-requiring hypoglycemic events (n = 2, 16.6 %) compared to placebo (n = 8, 61.5 %). In contrast, treatment with Anakinra did not result in significant changes of the glucose curve within the first 90 minutes, but was also followed by a significantly reduced rate of glucose-requiring hypoglycemic events (n = 2, 16.6 %) compared to placebo (n = 8, 61.5 %). Both treatment interventions showed significantly lowered insulin secretion compared to placebo.

Empagliflozin as well as Anakinra lowered glucose-requiring hypoglycemic episodes in patients after Roux-Y-gastric bypass by decreased insulin secretion. Therefore, empagliflozin may be a promising novel therapeutic option for patients with refractory postprandial hypoglycemia.

[ Purpose: Growth differentiation factor-15 (GDF15) is a member of the TGF-β cytokine superfamily that was shown to be elevated in patients with chronic kidney disease (CKD) and is associated with CKD progression. Encouraged by our observation that GDF15 is highly expressed in podocytes, we investigated the role of GDF15 in these cells using the puromycin aminonucleoside (PAN)-induced model of minimal change disease (MCD) both in-vivo and in vitro. We hypothesized that GDF15 may be an important factor of podocyte pathophysiology and study whether GDF15-mediated signaling affects the inflammatory responses as well as TGF-β signaling in podocytes.

Puromycin aminonucleoside (PAN)-induced model of minimal change disease (MCD).

Results: Biochemical renal function indicators including serum BUN, creatinine and urine protein showed no clear phenotype upon PAN injection. Our in vivo experiments show that gender influences the renal phenotype of GDF15-deficient animals. We observed decreased albuminuria in female mice 3 days after PAN injection. Expression of chemokines such as Cxcl1 or Ccl2 increased in the GDF15-deficient PAN-treated males but not in females, confirmed that anti-inflammatory function of GDF15 might be gender-specific. Surprisingly, levels of GDF15 did not differ between males and females. Moreover, number of glomerular macrophages, neutrophils and T cells did not show significant differences between wild-type and GDF15-deficient mice upon PAN injection. Cultured podocytes constitutively expressed significant levels of GDF15 mRNA and its expression was decreased by PAN and upon stimulation with LPS. In vitro, pre-incubation with recombinant GDF15 of podocytes did not confirmed our in vivo findings. Oxidative stress responses in podocytes and chemokine production associated with PAN-induced injury were not affected by GDF15 pretreatment.

We conclude that GDF15 could potentially regulate the chemokine release pattern and the effects of GDF15 might be gender-specific. We suggest that podocyte-derived GDF15 may play role in glomerular disorders, but perhaps only by paracrine-acting on non-podocyte glomerular cells. Introduction: Allogeneic hematopoietic stem cell transplantation (HSCT) is for many patients suffering from AML the only curative treatment option. One major complication is graft versus host disease (GvHD), caused by donor immune cells attacking healthy tissue.

Regulatory T cells (Treg) have been getting huge attention during the past years because of their important role in maintaining immune balance. Here we collected peripheral blood samples from 11 patients at different time points after HSCT to investigate immune-reconstitution of Treg as predictive marker for the development of GvHD.

We collected blood samples from 11 patients in the course of allogeneic HSCT prospectively once a week from d+7 up to d+200. All patients received conditioning regimen with Fludarabine and Melphalan, combined with Alemtuzumab for T cell depletion. 10 patients developed acute GVHD in the later course.

After isolation of PBMC`s we performed FACS multicolor staining of T cell and NK cells. Treg were identified as CD3+CD4+CD25++Foxp3+, NK cells were characterized as CD3negCD56+CD16+ and divided in NK cell subpopulation due to their expression of CD56dim or CD56high.

1. CD52neg T cells: All patients developing acute GVHD in the later course showed significant elevated levels of CD4+CD52neg T cells, especially CD52neg Treg at d+50.

Treg / CD8+ CD52+T cells: One patient not developing acute GVHD showed lots of CD52neg Treg but missed CD8+CD52+ effector T cells. We recently showed that CD8+CD52neg effector T cells are of impaired effector function. These data suggest that CD52neg Treg are only of relevance combined with functional CD8+CD52+ effector T cells in the development of aGVHD.

3. T cell marker: The patient without aGVHD showed elevated expression of Garp on Treg. Garp was significantly higher expressed on CD52+ Treg, indicating a better suppressive capacity of CD52+ Treg. This was detected throughout from d+50 until d+200. Tigit and ILT3 showed a heterogeneous expression profile without significant differences between the two groups.

We detected a higher ratio of CD65++/CD56dim NK-cell population in the patient without GVHD. We could also show that Tigit is mainly expressed on CD56dim NK cells.

Recently we presented Data on impaired suppressive capacity of CD52neg Treg and the association with acute GVHD retrospectively (Wölfinger EBMT 2018 , ASH 2017 . Here we provide prospective Data on patients after the use of Alemtuzumab in the context of HSCT: Our preliminary data suggest that the total amount of CD-52negTreg and the ratio of CD52neg Treg to CD8+CD52+Treg on d+50 after allogenic HSCT could predict aGvHD. This data may be a basis for immune monitoring of patients at d+50 to evaluate their risk for aG-VHD and could lead to the use of prophylactic Treg DLI in the context of Alemtuzumab mediated T cell depletion. In unserer Studie untersuchten wir die mononukleären Zellen des peripheren Bluts (PBMCs) von 76 Patienten nach allo-HSZT. Die Proben wurden uns durch die Knochenmarktransplantationseinheit der Universitätsmedizin Mainz zur Verfügung gestellt: 33 ohne GvHD, 31 mit cGvHD und 12 mit akuter GvHD (aGvHD). Die Patienten waren hauptsächlich an AML erkrankt, andere Erkrankungen umfassten MDS, ALL, CML, aplastische Anämie und CLL. Nach Ficoll-Dichte-Zentrifugation wurden die PBMCs mit Antikörpern gegen TIGIT, CD3, CD4 und CD8 gefärbt und mittels Durchflusszytometrie analysiert.

Beim Vergleich von Patienten mit cGvHD und keiner GvHD fanden wir ein signifikant niedrigeres TIGIT Level bei Patienten mit cGvHD (p=0.0081). Im Gegensatz dazu scheint die TIGIT Expression bei Patienten mit aGvHD höher zu sein als bei cGvHD, jedoch war dieser Unterschied nicht signifikant. Die Korrelation der TIGIT Expression und cGvHD wurde insbesondere für die männlichen Empfänger unabhängig vom Spendergeschlecht beobachtet. Des Weiteren untersuchten wir, ob sich die TIGIT Expression in der CD4+ und CD8+ Fraktion unterscheidet und fanden, dass die Expression bei den CD8+ T Zellen deutlich höher ist als bei den CD4+ T Zellen. Erstaunlicherweise war cGvHD ausschließlich mit der TIGIT Expression in der Untergruppe der CD8+ T Zellen assoziiert. Die Intensität des Konditionsregimens (myeloablativ; reduzierte Intensität) korrelierte nicht mit dem Level der TIGIT Expression.

Obwohl der Unterschied der TIGIT Expression und cGvHD hauptsächlich bei männlichen Patienten beobachtet wurde, ist die Auswertung einer größeren Patientenkohorte notwendig, um diese Daten zu validieren. Außerdem deutet die signifikante Korrelation im CD8+

of Rheumatoid Arthritis: Results of Two Randomized Phase IIa Trials

Pharmacokinetics, Pharmacodynamics, and Safety of AS-P015K (Peficitinib), a New Janus Kinase Inhibitor

Issues of Acute Kidney Injury Staging and Management in Sepsis and Critical Illness: A Narrative Review

Inflamm-Aging" und zunehmend auftretender Sarkopenie zeigen sich als Prädiktoren für kardiometabolische Erkrankungen, Multimorbidität, Gebrechlichkeit, und letztendlich erhöhtem Sterblichkeitsrisiko

Muskelaufbautraining erfordert hingegen grundsätzlich eine hohe Intensität, um über Stresshormone und auch proinflammatorische Zytokine einen trainingswirksamen Reiz zu bewirken und Muskelabbauprozessen entgegen zu wirken

MORTALITY AS AN ADVERSE OUTCOME OF SARCOPENIA. The journal of nutrition, health & aging

Inflammation and sarcopenia: A systematic review and meta-analysis

Exercise as an anti-inflammatory therapy for rheumatic diseases-myokine regulation

Role of Inactivity in Chronic Diseases: Evolutionary Insight and Pathophysiological Mechanisms

Physical Activity, Brain Plasticity, and Alzheimer's Disease. Archives of medical research

Physical exercise induces structural alterations in the hippocampal astrocytes: exploring the role of BDNF-TrkB signaling

Inflammaging: a new immune-metabolic viewpoint for age-related diseases

Role of Redox Signaling and Inflammation in Skeletal Muscle Adaptations to Training

Inflammation and Atherosclerosis

The vagus nerve and the inflammatory reflex--linking immunity and metabolism

Exercise-induced myokines and their role in chronic diseases

The Janus Head of Oxidative Stress in Metabolic Diseases and During Physical Exercise

Immune and Neuroprotective Effects of Physical Activity on the Brain in Depression

Physiologic and molecular bases of muscle hypertrophy and atrophy: impact of resistance exercise on human skeletal muscle (protein and exercise dose effects)

National Recommendations for Physical Activity and Physical Activity Promotion

Factors influencing heart rate variability

Effects of aerobic exercise on the circadian rhythm of heart rate and blood pressure

Sarcopenia and Predictors of Skeletal Muscle Mass in Elderly Men With and Without Obesity

Exercise for Cardiovascular Disease Prevention and Treatment. From Molecular to Clinical

Klinik Schönsicht Berchtesgaden, Rehabilitation für Kinder und Jugendliche, AHB, Kind-Mutter / Vater-Rehabilitation

Dagmar Mainz⁴; Gundula Zimper⁵

Michael Jansky¹ 0

Tobias Engelmann 11 ; Erika Graf⁸

Ficht-ner⁸

Louis Velthuis 12 ; Frank Lammer 13

⁴Berufsverband Niedergelassener Gastroenterologen (bng), Berufsverband Niedergelassener Gastroenterologen (bng)

A rare presentation of familial mediterranean Fever; acute scrotum and hydrocele amyloidosis

The acute scrotum in Arab children with familial Mediterranean fever

Colchicine for Familial Mediterranean Fever

Treatment of achalasia in the era of high-resolution manometry

Magnification endoscopy in esophageal squamous cell carcinoma:a review of the intrapapillary capillary loop classification

Uncommon recurrence of follicular lymphoma

Treatment results of tonsillar lymphoma: 10 years experience

Samira Reuß¹; Beate Hauptrock¹

Kompartiment auf die potentielle Rolle dieser Zellen im Auftreten der cGvHD hin

The surface protein TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells

TIGIT predominantly regulates the immune response via regulatory T cells

The Immunoreceptor TIGIT Regulates Antitumor and Antiviral CD8+ T Cell Effector Function

Cutane-ous nocardiosis: report of two cases and review of the litera-ture

Subcutaneous nodules attributed to nocardiosis in a renal transplant recipient on tacrolimus therapy

Disseminated Nocardia asteroids with pustules

Disseminated cutaneous Nocardiosis mimicking cellulitis and erythemanodosum

Disseminated Nocardia farcinica infection in a patient with systemic lupus erythematosus

Nocardia bra-in abscesses in a male patient with SLE: successful outcome despite delay in diagnosis

Nocardiosis in patients with systemic lupus erythematosus. The Singapore Lupus Study Group

Nocardiosis in a patient with primary anti-phospholipid syndrome

Early development of disseminated nocardiosis during immunosuppressive treatment for pemphigus vulga-ris

Subcutaneous nocardial abscesses in a patient with bullous pemphigoid during immunosuppressive therapy: re-port of a case and review of the Japanese literature

Disseminated Nocardia nova infection

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Problem: Adipositas nach WHO eines der größten Gesundheitsprobleme des 21. Jh..

Ziel war die Wirksamkeit der sportlichen Intervention in der Reha zu überprüfen, ob diese zu der gewünschten Gewichtsreduktion durch Verlust von Körperfett führt u. ob in einem Interventionszeitraum von 3 Wo. schon sign. Ergebnisse erzielt werden können.Methodik: 34 Kinder u. Jugendliche stationär in Reha multimodal behandelt, 20 w. u. 14 m., im Alter von 10 -17 Jahren, BMI 34,6kg/m2 (MW) ±6.9 (SD) bzw. 33,3kg/m2 (MW) ± 7,4 (SD).Einschlußkriterien: für mindestens 4 Wo. Patient, Diagnose Adipositas, ärztl. Sporterlaubnis, zwischen 10-18 Jahren. Ausschlusskriterien: Medikamente, die Flüssigkeitshaushalt beeinflussen, Infekt (akut während letzter 14 Tage), metallische Implantate (OP-induziert), Schwangerschaft, Herzschrittmacher, Defibrillator.Messungen mit 2 BIA-Geräten, MALTRON Körperfett-Analysegerät BF-906 u. BIA-Gerät "DENNER Systemtechnik" .Daten sowohl deskriptiv als auch inferenzstatistisch ausgewertet (Statistikprogramm IBM SPSS 21). zum 6min-Lauf, der Bestandteil der Leistungsdiagnose ist, ausgewertet. Dabei wurde die Anfangsleistung mit der Endlaufleistung verglichen, der BMI mit der Anfangs. Und Endlaufleistung korreliert, der Retest bezüglich der Reliabilität ausgewertet, die sportliche Aktivität des vorangegangenen Jahres mit der Anfangslaufleistung korreliert, sowie die Standardisierung des 6min-Laufs beschrieben.

Ergebnisse und Diskussion: Die Ergebnisse konnten eine Steigerung der Laufleistung mit einer durchschnittlichen Verbesserung von 81 m bei den Jungen bzw. 108 m bei den Mädchen belegen. Während eine hohe Korrelation zwischen Retest und Laufleistung festgestellt werden konnte, besteht nur eine geringe Korrelation zwischen BMI und Laufleistung sowie zwischen der sportlichen Aktivität im vorangegangenen Jahr und der Anfangslaufleistung. Bezüglich der Standardisierung des 6min-Laufs konnte ein hoher Durchführungsstandard festgestellt werden, während die Teststandards an sich vereinzelt Mängel aufwiesen.Konklusion: Für die Praxis kann geschlussfolgert werden, dass der 6min-Lauf durchaus ein Mittel zur Leistungsdiagnose darstellt. Dennoch ist zu berücksichtigen, dass er oftmals zur Analyse der aeroben Ausdauerleistung durchgeführt wird. Dies kann aber nur unter Berücksichtigung der Gütekriterien erfolgen, die neben der Standardisierung auch die Validität umfassen. Diese kann jedoch erst anhand eines weiteren Kriteriums, neben der Laufleistung, wie beispielsweise der Schwimmleistung, festgestellt werden und erfordert folglich zusätzliche Daten zur Auswertung. Background: Herpes zoster (HZ) and its related complications are associated with a significant burden of illness in older adults, which negatively impacts patients' physical functioning and quality-of-life (QoL). The recombinant zoster vaccine (RZV) shows high efficacy for the prevention of HZ in older adults and is associated with local and systemic reactions. Therefore, this study assessed the impact of RZV reactogenicity upon the physical functioning and QoL of participants.

Methods: 401 adults aged ≥50 years received a dose of RZV at 0 and 2 months in this open-label, single-arm, multicenter study (NCT02979639). Changes in mean SF-36 Physical Functioning score were assessed between pre-dose-1 vaccination and post-dose-1 vaccination for 7 days (primary endpoint). Decreased scores are associated with decreased physical functioning. QoL, reactogenicity and safety were also assessed. The current analysis was performed post-dose-1 vaccination of the 2-dose RZV schedule.

No clinically meaningful reductions in overall mean SF-36 Physical Functioning scores from pre-to post-RZV dose-1 were observed (mean +1.9 points) and no overall quality-adjusted-life-year loss was recorded post-dose-1. However, grade 3 reactogenicity occurred in 9.5% of participants, and was associated with a transient, clinically-important decrease in SF-36 Physical Functioning score (impacting activities such as walking, carrying groceries, climbing stairs) on Days 1-2 post-first-vaccination. The solicited local symptoms were pain (77.5%), redness (23.0%) and swelling (13.3%); the most frequent solicited systemic reactions were fatigue (33.5%), headache (28.3%) and myalgia (26.8%).

Overall, the physical functioning and QoL of older adults were not significantly affected by the first RZV dose. Grade 3 reactogenicity was associated with a small transient decrease in physical functioning 1-2 days post-dose-1 that resolved by Day 3 post-vaccination. Conclusions :This case of Nocardiosis had unusual cutaneous, pulmonary, brain and retinal findings that could have misguided the clinician, but the blood culture and Gram stain proved to be useful for rapid diagnosis and proper treatment. Nocardiosis has been increasingly recognized in SLE. Although still uncommon, it is an important opportunistic infection because it is curable and mortality is usually caused by delay in diagnosis and treatment. A high index of suspici-on, an aggressive approach to diagnosis, and early empirical therapy are essential principles of management. Nocardial infection, though rare in SLE has a good outcome. Involvement of brain, skin and lung together in a patient with background of immunosuppression should raise a suspicion of nocardial infection.