Publications by authors named "André Scherag"

167 Publications

Bridging animal and clinical research during SARS-CoV-2 pandemic: A new-old challenge.

EBioMedicine 2021 Apr 1;66:103291. Epub 2021 Apr 1.

Ludwig Boltzmann Institute for Experimental and Clinical Traumatology in the AUVA Research Center, Donaueschingenstrasse 13, 1200, Vienna, Austria. Electronic address:

Many milestones in medical history rest on animal modeling of human diseases. The SARS-CoV-2 pandemic has evoked a tremendous investigative effort primarily centered on clinical studies. However, several animal SARS-CoV-2/COVID-19 models have been developed and pre-clinical findings aimed at supporting clinical evidence rapidly emerge. In this review, we characterize the existing animal models exposing their relevance and limitations as well as outline their utility in COVID-19 drug and vaccine development. Concurrently, we summarize the status of clinical trial research and discuss the novel tactics utilized in the largest multi-center trials aiming to accelerate generation of reliable results that may subsequently shape COVID-19 clinical treatment practices. We also highlight areas of improvement for animal studies in order to elevate their translational utility. In pandemics, to optimize the use of strained resources in a short time-frame, optimizing and strengthening the synergy between the preclinical and clinical domains is pivotal.
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http://dx.doi.org/10.1016/j.ebiom.2021.103291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016444PMC
April 2021

Mid-German Sepsis Cohort (MSC): a prospective observational study of sepsis survivorship.

BMJ Open 2021 Mar 17;11(3):e043352. Epub 2021 Mar 17.

Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany

Purpose: The Mid-German Sepsis Cohort (MSC) aims to investigate mid-term and long-term functional disabilities in sepsis survivors from intensive care unit (ICU) discharge until 1 year after. Secondary, post-acute mortality and morbidity, health-related quality of life and healthcare utilisation will be investigated.

Participants: The MSC comprises adult (aged ≥18 years) patients who were treated for (severe) sepsis or septic shock on ICU. The participants were recruited between 15 April 2016 and 30 November 2018 from five German centres. Three thousand two hundred and ten patients with sepsis were identified, of which 1968 survived their ICU stay and were eligible for enrolment in the follow-up cohort. Informed consent for follow-up assessment was provided by 907 patients (46.1% of eligible patients).

Findings To Date: The recruitment of the participants for follow-up assessments and the baseline data collection is completed. Incidence of sepsis was 116.7 patients per 1000 ICU patients. In this cohort profile, we provide an overview of the demographics and the clinical characteristics of both the overall sepsis cohort and the ICU survivors who provided informed consent for follow-up assessment (907 out of 1968 ICU survivors (46.1%)).

Future Plans: The follow-ups are conducted 3, 6 and 12 months after ICU discharge. Another yearly follow-up up to 5 years after ICU discharge is pursued. Several cooperation and satellite projects were initiated. This prospective cohort offers a unique resource for research on long-term sequelae of sepsis survivors.

Trial Registration Number: German Clinical Trials Registry (DRKS00010050).
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http://dx.doi.org/10.1136/bmjopen-2020-043352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7978081PMC
March 2021

Prospective surveillance study in a 1,400-bed university hospital: COVID-19 exposure at home was the main risk factor for SARS-CoV-2 point seroprevalence among hospital staff.

Transbound Emerg Dis 2021 Feb 19. Epub 2021 Feb 19.

Institute for Infectious Diseases and Infection Control, Jena University Hospital/Friedrich-Schiller-University, Jena, Germany.

The Co-HCW study is a prospective cohort study among hospital staff, including healthcare workers (HCWs) and administration staff, at the Jena University Hospital (JUH), Germany. The objectives of this study were to assess SARS-CoV-2 IgG seroprevalence, individual exposure risk factors and compliance of HCWs to wear personal protective equipment (PPE). After the first nosocomial COVID-19 outbreak at JUH, mandatory masking was implemented on 20th March 2020. We evaluated point seroprevalence using two IgG detecting immunoassays and issued a questionnaire to assess COVID-19 exposure, clinical symptoms and compliance to wear PPE. Antibody retesting was offered to participants with a divergent result of both immunoassays 5-10 weeks after the first test. Between 19th May and 19th June 2020, we analysed 660 participants [out of 3,228; 20.4%]. Among them, 212 participants (32.1%) had received a previous COVID-19 test. Four of them (1.9%) reported a positive test result. After recruitment, 18 participants (2.7%) had SARS-CoV-2 antibodies in at least one immunoassay. Overall, 21 participants (3.2%) had any evidence of a past or current SARS-CoV-2 infection. Among them, 13 (61.9%) were not aware of direct COVID-19 exposure and 9 (42.9%) did not report any clinical symptoms. COVID-19 exposure at home (adjusted OR (aOR) with 95% CI: 47.82 (5.49, 416.62)) was associated with SARS-CoV-2 seroprevalence. We observed no evidence for an association between seroprevalence and exposure at work (aOR 0.48 (0.13, 1.70)) or with COVID-19 risk area according to the working place (aOR for intermediate-risk vs. high-risk: 1.97 (0.42, 9.22), aOR for low-risk versus high-risk: 2.10 (0.40, 11.06); p = .655). Reported compliance of HCWs to wear PPE differed (p < .001) between working in high-risk (98.3%) and in intermediate-risk areas (69.8%). In conclusion, compared to administration staff, we observed no additional risk to acquire SARS-CoV-2 infections by patient care, probably due to high compliance to wear PPE.
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http://dx.doi.org/10.1111/tbed.14041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014017PMC
February 2021

Long-Term Survival Following Sepsis.

Dtsch Arztebl Int 2020 11;117(46):775-782

Center for Sepsis Control and Care (CSCC), Jena University Hospital; Institute of General Practice and Family Medicine, Jena University Hospital; Institute of General Practice, Charité-Universitätsmedizin Berlin; Institute of General Practice and Family Medicine, Munich University Hospital, Ludwig-Maximilians-Universität München; Center for Clinical Studies, Jena University Hospital; Clinic for Anaesthesiology and Intensive Care Medicine, Jena University Hospital; Institute for Medical Informatics, Statistics and Epidemiology (IMISE), Leipzig University; Institute of General Practice and Family Medicine, Ruhr-University Bochum; Institute of Medical Statistics, Computer Science and Data Sciences, Jena University Hospital.

Background: There have not yet been any prospective registry studies in Germany with active investigation of the long-term survival of patients with sepsis.

Methods: The Jena Sepsis Registry (JSR) included all patients with a diagnosis of sepsis in the four intensive care units of Jena University Hospital from January 2011 to December 2015. Long-term survival 6-48 months after diagnosis was documented by asking the treating general practitioners. The survival times were studied with Kaplan-Meier estimators. Cox regressions were calculated to show associations between possible predictors and survival time.

Results: 1975 patients with sepsis or septic shock were included. The mean time of observation was 730 days. For 96.4% of the queries to the general practitioners, information on long-term survival was available. Mortality in the intensive care unit was 34% (95% confidence interval [32; 37]), and in-hospital mortality was 45% [42; 47]. The overall mortality six months after diagnosis was 59% [57; 62], the overall mortality 48 months after diagnosis was 74% [72; 78]. Predictors of shorter survival were age, nosocomial origin of sepsis, diabetes, cerebrovascular disease, duration of stay in the intensive care unit, and renal replacement therapy.

Conclusion: The nearly 75% mortality four years after diagnosis indicates that changes are needed both in the acute treatment of patients with sepsis and in their multi-sector long-term care. The applicability of these findings may be limited by their having been obtained in a single center.
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http://dx.doi.org/10.3238/arztebl.2020.0775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930463PMC
November 2020

Right Mini-Thoracotomy for Aortic Plus Mitral with or without Tricuspid Valve Surgery.

Thorac Cardiovasc Surg 2020 Dec 13. Epub 2020 Dec 13.

Department of Cardiothoracic Surgery, Jena University Hospital, Friedrich-Schiller-University Jena, Jena, Germany.

Objectives:  Minimally invasive surgery is increasingly performed for isolated aortic or mitral valve procedures. However, combined minimally invasive aortic and mitral valve surgery is rare. We report our initial experience performing multiple valve procedures through a right-sided mini-thoracotomy (RMT) compared with sternotomy.

Methods:  A total of 264 patients underwent aortic and mitral with or without tricuspid valve surgery through RMT ( = 25) or sternotomy ( = 239). Propensity score matching was used for outcome comparisons.

Results:  Of the 264 patients, 25 (age: 72 ± 10 years; 72% male) underwent double ( = 19) and triple valve surgery ( = 6) through RMT and 239 (age: 71 ± 11 years; 54% male) underwent double ( = 176) and triple valve surgery ( = 63) through sternotomy. Sternotomy patients had more co-morbidities and preoperative risk factors (EuroSCORE II 10.25 ± 10.89 vs. RMT 3.58. ± 4.98;  < 0.001). RMT procedures were uneventful without intraoperative complications or conversions to sternotomy. After propensity score matching, surgical procedures were comparable between groups with a higher valve repair rate in RMT. Despite longer cardiopulmonary bypass times in RMT, there was no evidence for differences in 30-day mortality (RMT:  = 2 vs. sternotomy:  = 2) and there were no significant differences in other outcomes. During 5-year follow-up, reoperation was required in sternotomy patients only ( = 2). Follow-up echocardiography showed durable results after valve surgery. RMT patients showed higher survival probability compared with sternotomy, although this difference was not significant (hazard ratio = 0.33; 95% confidence interval: 0.06-1.65;  = 0.18).

Conclusion:  Combined aortic plus mitral with or without tricuspid valve surgery can safely be performed through a RMT with a trend toward better mid-term outcomes.
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http://dx.doi.org/10.1055/s-0040-1721083DOI Listing
December 2020

Safety and efficacy of prednisone versus placebo in short-term prevention of episodic cluster headache: a multicentre, double-blind, randomised controlled trial.

Lancet Neurol 2021 01 24;20(1):29-37. Epub 2020 Nov 24.

Department of Neurology, University Hospital Essen, Germany.

Background: Prednisone is commonly used for initial short-term therapy of episodic cluster headaches before preventive medication such as verapamil becomes effective, but this strategy has not been tested in large randomised trials. We aimed to access the safety and efficacy of this treatment approach.

Methods: This study was a multicentre, randomised, double-blind, placebo-controlled trial done in ten specialised headache centres in Germany. Patients with episodic cluster headaches who were aged between 18 and 65 years and within a current pain episode for not more than 30 days, received 100 mg oral prednisone for 5 days followed by tapering of 20 mg every 3 days, or matching placebo (17 days total exposure). All patients received oral verapamil for long-term prevention, starting with 40 mg three times daily and increasing to 120 mg three times daily by day 19; patients then continued with verapamil 120 mg throughout the study. Randomisation was computer-generated at a 1:1 ratio by use of an interactive web-response system, with stratification according to age, sex, and participating site. Participants, investigators, and those assessing outcomes were unaware of treatment allocation. The primary endpoint was the mean number of attacks within the first week of treatment with prednisone compared with placebo. An attack was defined as a unilateral headache with moderate-to-severe intensity of at least five on a numerical rating scale. All efficacy and safety analyses were done in the modified intention-to-treat (mITT) population, which consisted of all patients who had been randomly assigned to a trial group and received at least one dose of prednisone or placebo. The study was stopped early due to slow recruitment and expired funding. The study was registered with EudraCT (2011-006204-13) and with the German Clinical Trials Register (DRKS00004716).

Findings: Between April 5, 2013, and Jan 11, 2018, 118 patients were enrolled in the study. Two patients dropped out immediately and 116 patients were randomly assigned (57 patients to prednisone and 59 patients to placebo); 109 patients were included in the mITT analysis (53 patients assigned to prednisone and 56 patients assigned to placebo). Participants in the prednisone group had a mean of 7·1 (SD 6·5) attacks within the first week compared with 9·5 (6·0) attacks in the placebo group (difference -2·4 attacks, 95% CI -4·8 to -0·03; p=0·002). Two serious adverse events occurred, both in the placebo group (inguinal hernia and severe deterioration of cluster headache). A total of 270 adverse events were observed: in the prednisone group, 37 (71%) of 52 patients reported 135 adverse events (most common were headache, palpitations, dizziness, and nausea) and in the placebo group, 39 (71%) of 55 patients had 135 adverse events (most common were nausea, dizziness, and headache).

Interpretation: Oral prednisone was an effective short-term preventive therapy in our population of patients with episodic cluster headache. Our findings support the use of prednisone as a first-line treatment in parallel to the up-titration of verapamil, although the efficacy of prednisone alongside other long-term prevention requires additional investigation.

Funding: German Federal Ministry for Education and Research.
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http://dx.doi.org/10.1016/S1474-4422(20)30363-XDOI Listing
January 2021

Antibody response using six different serological assays in a completely PCR-tested community after a coronavirus disease 2019 outbreak-the CoNAN study.

Clin Microbiol Infect 2021 Mar 20;27(3):470.e1-470.e9. Epub 2020 Nov 20.

Institute for Infectious Diseases and Infection Control, Jena University Hospital - Friedrich Schiller University, Jena, Germany.

Objectives: Due to a substantial proportion of asymptomatic and mild courses, many severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections remain unreported. Therefore, assessment of seroprevalence may detect the real burden of disease. We aimed to determine and characterize the rate of SARS-CoV-2 infections and the resulting seroprevalence in a defined population. The primary objective of the study was to assess SARS-CoV-2 antibody seroprevalence using six different IgG-detecting immunoassays. Secondary objectives of the study were: (a) to determine potential risk factors for symptomatic versus asymptomatic coronavirus disease 2019 courses, and (b) to investigate the rate of virus RNA-persistence.

Methods: CoNAN is a population-based cohort study performed in the community Neustadt am Rennsteig, Germany, which was quarantined from 22 March to 5 April after six SARS-CoV-2 cases were detected in the village's population. The SARS-CoV-2 outbreak comprised 51 cases and 3 deaths. The CoNAN study was performed from 13 May to 22 May 2020, 6 weeks after a SARS-CoV-2 outbreak.

Results: We enrolled a total of 626 participants (71% of the community population) for PCR and antibody testing in the study. All actual SARS-CoV-2 PCR tests were negative. Fifty-two out of 620 (8.4%) participants had antibodies against SARS-CoV-2 in at least two different assays. There were 38 participants with previously PCR-confirmed SARS-CoV-2 infection. Of those, only 19 (50%) displayed anti-SARS-CoV-2 antibodies. We also show that antibody-positive participants with symptoms compatible with a respiratory tract infection had significantly higher antibody levels then asymptomatic participants (EU-assay: median 2.9 versus 7.2 IgG-index, p 0.002; DS-assay: median 45.2 versus 143 AU/mL, p 0.002). Persisting viral replication was not detected.

Conclusions: Our data question the relevance and reliability of IgG antibody testing to detect past SARS-CoV-2 infections 6 weeks after an outbreak. We conclude that assessing immunity for SARS-CoV-2 infection should not rely on antibody tests alone.
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http://dx.doi.org/10.1016/j.cmi.2020.11.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677041PMC
March 2021

Validation of the qSOFA score compared to the CRB-65 score for risk prediction in community-acquired pneumonia.

Clin Microbiol Infect 2020 Oct 10. Epub 2020 Oct 10.

Division of Pulmonology, Medical Department I, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany. Electronic address:

Objective: The qSOFA (quick sepsis-related organ failure assessment) score shows similarities to the CRB-65 pneumonia score, but its prognostic accuracy in patients with community-acquired pneumonia (CAP) has not been extensively evaluated. Our aim was to validate the qSOFA (-65) score in a large cohort of CAP patients.

Methods: We conducted a retrospective population-based cohort study including all CAP cases hospitalized between 1st January 2014 and 31st December 2018 from the German nationwide mandatory quality assurance programme. We excluded cases transferred from another hospital, with mechanical ventilation present on admission, and without documented respiratory rate. Predefined outcomes were hospital mortality and need for mechanical ventilation.

Results: Among the 1,262,250 included cases, hospital mortality was 12.4% and the mechanical ventilation rate was 7.1%. All CRB and qSOFA criteria were associated with both outcomes, but the qSOFA had inferior sensitivity compared to the CRB-65 for mortality prediction. Including the age criterion ≥65 years, qSOFA-65 and CRB-65 performed similarly (AUC 0.69, 95%CI 0.69-0.69 versus 0.68, 95%CI 0.68-0.68). A qSOFA-65 of 0 was associated with fewer missed deaths (3328, 2.0%) compared to a CRB-65 of 0 (5480, 2.4%). The sensitivity of the suggested qSOFA cut-off of ≥2 for sepsis was low (mortality 25.8%, 95%CI 25.6-26.0%; mechanical ventilation 24.1%, 95%CI 23.8-24.4%). Results were similar when frail and palliative patients were excluded.

Conclusions: The qSOFA parameters show prognostic accuracy similar to the CRB parameters in CAP, but the sepsis cut-off of ≥2 lacked sensitivity. For sensitive mortality prediction, the age criterion ≥65 years should be added to the qSOFA.
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http://dx.doi.org/10.1016/j.cmi.2020.10.008DOI Listing
October 2020

Air Pollution and Progression of Atherosclerosis in Different Vessel Beds-Results from a Prospective Cohort Study in the Ruhr Area, Germany.

Environ Health Perspect 2020 10 5;128(10):107003. Epub 2020 Oct 5.

Institute of Occupational, Social and Environmental Medicine, Center for Health and Society, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.

Objectives: Due to inconsistent epidemiological evidence on health effects of air pollution on progression of atherosclerosis, we investigated several air pollutants and their effects on progression of atherosclerosis, using carotid intima media thickness (cIMT), coronary calcification (CAC), and thoracic aortic calcification (TAC).

Methods: We used baseline (2000-2003) and 5-y follow-up (2006-2008) data from the German Heinz Nixdorf Recall cohort study, including 4,814 middle-aged adults. Residence-based long-term air pollution exposure, including particulate matter (PM) with aerodynamic diameter (), (), and nitrogen dioxide () was assessed using chemistry transport and land use regression (LUR) models. cIMT was quantified as side-specific median IMT assessed from standardized ultrasound images. CAC and TAC were quantified by computed tomography using the Agatston score. Development (yes/no) and progression of atherosclerosis (change in cIMT and annual growth rate for CAC/TAC) were analyzed with logistic and linear regression models, adjusting for age, sex, lifestyle variables, socioeconomic status, and traffic noise.

Results: While no clear associations were observed in the full study sample (mean age 59.1 () y; 53% female), most air pollutants were marginally associated with progression of atherosclerosis in participants with no or low baseline atherosclerotic burden. Most consistently for CAC, e.g., a higher exposure to (LUR) yielded an estimated odds ratio of 1.19 [95% confidence interval (CI): 1.03, 1.39] for progression of CAC and an increased annual growth rate of 2% (95% CI: 1%, 4%).

Conclusion: Our study suggests that development and progression of subclinical atherosclerosis is associated with long-term air pollution in middle-aged participants with no or minor atherosclerotic burden at baseline, while overall no consistent associations are observed. https://doi.org/10.1289/EHP7077.
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http://dx.doi.org/10.1289/EHP7077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7535085PMC
October 2020

Effect of antiviral therapy on the outcomes of mechanically ventilated patients with herpes simplex virus detected in the respiratory tract: a systematic review and meta-analysis.

Crit Care 2020 09 29;24(1):584. Epub 2020 Sep 29.

Institute for Infectious Diseases and Infection Control, Jena University Hospital - Friedrich Schiller University Jena, Jena, Germany.

Background: Herpes simplex virus (HSV) is frequently detected in the respiratory tract of mechanically ventilated patients. The aim of this study was to assess current evidence to determine whether antiviral therapy is associated with better outcomes in these patients.

Methods: MEDLINE, ISI Web of Science, Cochrane Database and ClinicalTrials.gov were searched from inception to 25 May 2020. All clinical studies investigating the effects of antiviral therapy on the outcome of mechanically ventilated ICU patients in whom HSV was detected in the respiratory tract were eligible for inclusion, regardless of study design, publication status or language. Titles and abstracts were reviewed independently by two authors. If the articles seemed eligible, full-text articles were reviewed and data extracted. We performed a random-effects meta-analysis to estimate relative risks (RRs) with corresponding 95% confidence intervals (CIs). The primary endpoint was hospital all-cause mortality.

Results: Nine studies were included in the meta-analysis (one randomized controlled trial, eight cohort studies). Antiviral treatment was associated with lower hospital mortality (with antiviral treatment, 40.6% (189 out of 465 patients); without, 52.7% (193 out of 366 patients); RR 0.74 [0.64, 0.85]; eight studies, low quality of evidence). Furthermore, antiviral treatment was associated with lower 30-day mortality (RR 0.75 [0.59, 0.94]; three studies, very low quality of evidence). We did not observe evidence for differences in ICU mortality (RR 0.73 [0.51, 1.05]; three studies, very low quality of evidence).

Conclusions: This meta-analysis of the available data shows that antiviral therapy might result in lower hospital and 30-day all-cause mortality in mechanically ventilated ICU patients who are positive for HSV in the respiratory tract. However, this result must be interpreted with great caution due to the high risk of bias and limited number of patients. Large, well-designed randomized controlled clinical trials are urgently needed.

Trial Registration: The study was registered in advance on International Prospective Register of Systematic Reviews (CRD42020180053) .
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http://dx.doi.org/10.1186/s13054-020-03296-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7522924PMC
September 2020

[Period Prevalence of SARS-CoV-2 in an Unselected Sample of Pregnant Women in Jena, Thuringia].

Z Geburtshilfe Neonatol 2020 08 24;224(4):194-198. Epub 2020 Aug 24.

Klinik für Geburtsmedizin, Universitätsklinikum Jena, Jena.

Introduction: Following an exponential increase in SARS-CoV-2 infections, the city of Jena, Thuringia, was the first in Germany to introduce mandatory mouth and nose coverings. An estimation of the SARS-CoV-2 period prevalence was achieved by screening an unselected cohort of pregnant women. Of interest was the number of unreported cases.

Methods: Upon admission to hospital, patients were screened for SARS-CoV-2 by a specific real-time PCR and antibodies determined by a specific SARS-CoV-2 IgG in serum by ELISA. The SARS-CoV-2 period prevalence was estimated using the Clopper-Pearson exact method, the group comparison with Fischer's exact test.

Results: From 6 April to 13 May 2020, 234 pregnant women were admitted to the Department of Obstetrics. A total of 225 (96.2%) SARS-CoV-2 PCRs were carried out and all remained negative. Specific IgG antibodies were detected in one (0.6%) of 180 (76.9%) antibody tests performed. The interval estimate of the period prevalence thus results in a 95% confidence interval between 0-1.7%. For 96 households with children, the period prevalence is 0-3.8%, which does not differ from the 0-4.8% for 76 households without children (p=1.00).

Discussion: This is the first report on the SARS-CoV-2 period prevalence of an unselected sample of pregnant women in Germany. Antibody testing showed no evidence of the feared high number of unreported asymptomatic SARS-CoV-2 infections. The seroconversion rate was below 1% (0.6%).
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http://dx.doi.org/10.1055/a-1206-1033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7516362PMC
August 2020

Effect size estimates from umbrella designs: Handling patients with a positive test result for multiple biomarkers using random or pragmatic subtrial allocation.

PLoS One 2020 14;15(8):e0237441. Epub 2020 Aug 14.

Institute of Medical Statistics, Computer and Data Sciences, Jena University Hospital, Jena, Germany.

Umbrella trials have been suggested to increase trial conduct efficiency when investigating different biomarker-driven experimental therapies. An overarching platform is used for patient screening and subsequent subtrial allocation according to patients' biomarker status. Two subtrial allocation schemes for patients with a positive test result for multiple biomarkers are (i) the pragmatic allocation to the eligible subtrial with the currently fewest included patients and (ii) the random allocation to one of the eligible subtrials. Obviously, the subtrials compete for such patients which are consequently underrepresented in the subtrials. To address questions of the impact of an umbrella design in general as well as with respect to subtrial allocation and analysis method, we investigate an umbrella trial with two parallel group subtrials and discuss generalisations. First, we analytically quantify the impact of the umbrella design with random allocation on the number of patients needed to be screened, the biomarker status distribution and treatment effect estimates compared to the corresponding gold standard of an independent parallel group design. Using simulations and real data, we subsequently compare both allocation schemes and investigate weighted linear regression modelling as possible analysis method for the umbrella design. Our results show that umbrella designs are more efficient than the gold standard. However, depending on the biomarker status distribution in the disease population, an umbrella design can introduce differences in estimated treatment effects in the presence of an interaction between treatment and biomarker status. In principle, weighted linear regression together with the random allocation scheme can address this difference though it is difficult to assess if such an approach is applicable in practice. In any case, caution is required when using treatment effect estimates derived from umbrella designs for e.g. future trial planning or meta-analyses.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0237441PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428134PMC
October 2020

Generate-Boost: study protocol for a prospective, multicenter, randomized controlled, double-blinded phase II trial to evaluate efficacy and safety of bortezomib in patients with severe autoimmune encephalitis.

Trials 2020 Jul 8;21(1):625. Epub 2020 Jul 8.

Section of Translational Neuroimmunology, Hans Berger Department of Neurology, Jena University Hospital, Am Klinikum 1, 07747, Jena, Germany.

Background: Autoimmune encephalitis is a new spectrum of autoimmune disorders of the central nervous system (CNS), which are characterized by pathogenic autoantibodies against neuronal surface antigens. Clinical presentations range from acute to subacute encephalopathy with neurological and psychiatric symptoms, and life-threatening autonomic dysfunction in severe cases. There exist no approved therapies nor is data available from controlled clinical trials. Patients are usually treated with diverse combinations of immunotherapy. However, effect of immunotherapy on antibody-producing cells and thus on levels of pathogenic autoantibodies is insufficient. Therefore, therapeutic response is sometimes prolonged with necessity of long-time intensive care treatment and also irreversible deficits occur in severe cases. This trial will investigate the efficacy and safety of bortezomib, a proteasome inhibitor known to selectively deplete plasma cells, in patients with severe autoimmune encephalitis who have been treated with rituximab with insufficient response.

Methods: Generate-Boost is an investigator-initiated, multicenter, double-blinded, randomized controlled phase II trial which will be conducted in specialized neurological hospitals within the GENERATE (GErman NEtwork for Research on AuToimmune Encephalitis) network in Germany. Adult patients with severe autoimmune encephalitis (modified Rankin scale, mRS ≥ 3), autoantibodies against neuronal surface antigens, and pretreatment with rituximab are eligible for study participation. Fifty patients will be randomized 1:1 and undergo up to 3 cycles (each 21 days with 4 s. c. applications) of bortezomib or placebo. All patients will receive concomitant medication with dexamethasone, acyclovir and co-trimoxazole. The primary efficacy endpoint is the mRS score 17 weeks after first treatment application. Secondary endpoints are neurocognitive function, antibody titers, markers of neuronal cell damage, length of ICU/hospital stay, and mRS and Glasgow coma scale scores throughout the trial up to week 17. General and bortezomib-specific adverse events are monitored continuously.

Discussion: The expected outcome of the study is to obtain first reliable data on a hypothesis-driven therapeutic option in severe and difficult-to-treat autoimmune encephalitis. If treatment with bortezomib is beneficial in these cases, this will be the basis for implementation in the current guidelines.

Trial Registration: Clinicaltrials.gov , NCT03993262 . Registered June 20, 2019; German Clinical Trials Register, DRKS00017497.
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http://dx.doi.org/10.1186/s13063-020-04516-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346383PMC
July 2020

Effect of Antiviral Therapy on the Outcome of Mechanically Ventilated Patients With Herpes Simplex Virus Type 1 in BAL Fluid: A Retrospective Cohort Study.

Chest 2020 Nov 3;158(5):1867-1875. Epub 2020 Jul 3.

Institutes for Infectious Diseases and Infection Control, Jena University Hospital, Jena, Germany. Electronic address:

Background: Herpes simplex virus type 1 (HSV-1) is frequently detected in the BAL fluid of patients on mechanical ventilation.

Research Question: The aim of the study was to investigate whether antiviral therapy is associated with improved overall survival within 30 days.

Study Design And Methods: This was a retrospective cohort study in four ICUs between January 2011 and December 2017. All adult patients on mechanical ventilation with a respiratory tract infection with positive polymerase chain reaction testing for HSV-1 in the BAL were included. Patients already receiving antiviral agents on the day BAL was performed were excluded. We performed uni- and multivariable Cox and logistic regression modeling.

Results: Overall, 306 patients were included in the analysis. Among them, 177 patients (57.8%) received antiviral therapy (90.9% acyclovir, 6.2% ganciclovir, 2.9% both). The overall 30-day mortality rate was 42.4% (n = 75) in the antiviral treatment group and 50.4% (n = 65) in the control group. The adjusted hazard ratio (HR) for the primary outcome was 0.62 (95% CI, 0.44-0.87; P = .005), indicating better overall survival within 30 days for the antiviral-treated group than for the untreated group. This benefit was also present in the subgroup of patients without immunosuppression (n = 246; adjusted HR, 0.53; 95% CI, 0.36-0.78; P = .001). Overall, the median lengths of hospital stay (31 vs 24 days, P = .002) and ICU stay (24 vs 17 days, P < .001), and the duration of mechanical ventilation (18 vs 11 days, P < .001), were longer for patients with therapy. No evidence for the treatment-related deterioration of renal function was observed.

Interpretation: These data suggest that detection of HSV-1 in the BAL of patients on mechanical ventilation may be of clinical significance and that specific antiviral treatment may improve clinical outcomes. However, this needs to be proven in multicenter randomized controlled trials before implementation into the clinical routine.
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http://dx.doi.org/10.1016/j.chest.2020.06.056DOI Listing
November 2020

Identification of cardiovascular and molecular prognostic factors for the medium-term and long-term outcomes of sepsis (ICROS): protocol for a prospective monocentric cohort study.

BMJ Open 2020 06 23;10(6):e036527. Epub 2020 Jun 23.

Department of Anaesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany.

Introduction: Sepsis is one of the most prevalent life-threatening conditions in the intensive care unit. Patients suffer from impaired organ function, reduced physical functional capacity and decreased quality of life even after surviving sepsis. The identification of prognostic factors for the medium-term and long-term outcomes of this condition is necessary to develop personalised theragnostic approaches. Sepsis can cause cardiac impairment. The impact of this septic cardiomyopathy on patient's long-term outcome remains unclear. This study aims to evaluate cardiovascular risk factors, particularly the occurrence of septic cardiomyopathy, regarding their suitability as prognostic factors for the short-term and long-term outcomes of septic patients. Additionally, the study seeks to validate preclinical pathophysiological findings of septic cardiomyopathy in the clinical setting.

Methods And Analysis: In this prospective monocentric cohort study, patients will be clinically assessed during the acute and postacute phase of sepsis and two follow-ups after 6 and 12 months. To determine the effect of septic cardiomyopathy and concomitant cellular and molecular changes on patient mortality and morbidity, a comprehensive cardiovascular and molecular deep phenotyping of patients will be performed. This includes an echocardiographic and electrocardiographic assessment, and the evaluation of heart rate variability, body composition, mitochondrial oxygen metabolism, macrocirculation and microcirculation, and endothelial barrier function. These analyses are complemented by routine immunological, haematological and biochemical laboratory tests and analyses of the serum metabolome and lipidome, microbiome and epigenetic modifications of immune cells. The reversibility of patients' organ dysfunction, their quality of life and physical functional capacity will be investigated in the follow-ups. Patients with cardiomyopathy without infection and healthy subjects will serve as control groups.

Ethics And Dissemination: Approval was obtained from the Ethics Committee of the Friedrich Schiller University Jena (5276-09/17). The results will be published in peer-reviewed journals and presented at appropriate conferences.

Trial Registration Numbers: DRKS00013347; NCT03620409.
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http://dx.doi.org/10.1136/bmjopen-2019-036527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312455PMC
June 2020

Assessing efficacy of CytoSorb haemoadsorber for prevention of organ dysfunction in cardiac surgery patients with infective endocarditis: REMOVE-protocol for randomised controlled trial.

BMJ Open 2020 03 30;10(3):e031912. Epub 2020 Mar 30.

Department of Cardiothoracic Surgery, Jena University Hospital - Friedrich Schiller University of Jena, Jena, Thuringia, Germany

Introduction: Infective endocarditis (IE) is associated with high mortality and morbidity. Multiple organ failure is the main cause of death after surgery for IE. Cardiopulmonary bypass (CPB) can cause a systemic inflammatory response. In a pilot study (REMOVE-pilot (Revealing mechanisms and investigating efficacy of hemoad-sorption for prevention of vasodilatory shock in cardiac surgery patients with infective endocarditis - a multicentric randomized controlled group sequential trial)), we found that plasma profiles of cytokines during and after CPB were higher in patients with IE compared with patients with non-infectious valvular heart disease. Sequential Organ Failure Assessment (SOFA) scores on the first and second postoperative days and in-hospital mortality were also higher in IE patients. This protocol describes the design of the REMOVE trial on cytokine-adsorbing columns, for example, CytoSorb, for non-selective removal of cytokines. The aim of the REMOVE study is to demonstrate efficacy of CytoSorb on the prevention of multiorgan dysfunction in patients with IE undergoing cardiac surgery.

Methods And Analysis: The REMOVE study is an interventional randomised controlled multicenter trial with a group sequential (Pocock) design for assessing efficacy of CytoSorb in patients undergoing cardiac surgery for IE. The change in mean total SOFA (∆ SOFA) score between preoperative and postoperative care will be used as primary endpoint. Data on 30-day mortality, changes in cytokines levels, duration of mechanical ventilation, length of intensive care unit and hospital stay, and postoperative stroke will be collected as secondary endpoints. An interim analysis will be conducted after including 25 participating patients per study arm (with a focus on feasibility of the recruitment as well as differences in cytokines and cell-free DNA levels).

Ethics And Dissemination: The protocol was approved by the institutional review board and ethics committee of the University of Jena as well as by the corresponding ethics committee of each participating study centre. The results will be published in a renowned international medical journal, irrespective of the outcomes of the study.

Trial Registration Number: The ClinicalTrials.gov registry (NCT03266302).
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http://dx.doi.org/10.1136/bmjopen-2019-031912DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7170567PMC
March 2020

Outcome of Older Patients with Acute Neuropsychological Symptoms Not Fulfilling Criteria of Delirium.

J Am Geriatr Soc 2020 07 20;68(7):1469-1475. Epub 2020 Mar 20.

Hans-Berger-Department of Neurology, Jena University Hospital, Jena, Germany.

Objectives: Although delirium is often investigated, little is known about the outcomes of patients having acute neuropsychological changes at a single time point without fulfilling the criteria of full delirium. Our aim was to determine point prevalence, predictors, and long-term outcomes of delirium and acute neuropsychological changes in patients aged 60 years and older across different departments of a university hospital with general inpatient care.

Design: Prospective observational study.

Setting: University hospital excluding psychiatric wards.

Participants: At baseline, 669 patients were assessed, and follow-ups occurred at months 6, 12, 18, and 36.

Measurements: Measurements were obtained using the Confusion Assessment Method (CAM), comprehensive geriatric assessment, health-related quality of life, functional state (month 6), and mortality rates (months 6, 12, 18, and 36). Subjects were classified into (1) patients with delirium according to the CAM, (2) patients with only two positive CAM items (2-CAM state), and (3) patients without delirium.

Results: Delirium was present in 10.8% and the 2-CAM state in an additional 12.7% of patients. Highest prevalence of delirium was observed in medical and surgical intensive care units and neurosurgical wards. Cognitive restrictions, restricted mobility, electrolyte imbalance, the number of medications per day, any fixations, and the presence of a urinary catheter predicted the presence of delirium and 2-CAM-state. The mean Karnofsky Performance Score and EuroQol-5D were comparable between delirium and the 2-CAM state after 6 months. The 6-, 12-, 18-, and 36-month mortality rates of patients with delirium and the 2-CAM state were comparable. The nurses' evaluation of distinct patients showed high specificity (89%) but low sensitivity (53%) for the detection of delirium in wide-awake patients.

Conclusion: Patients with an acute change or fluctuation in mental status or inattention with one additional CAM symptom (ie, disorganized thinking or an altered level of consciousness) have a similar risk for a lower quality of life and death as patients with delirium. J Am Geriatr Soc 68:1469-1475, 2020.
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http://dx.doi.org/10.1111/jgs.16422DOI Listing
July 2020

Shared genetic risk between eating disorder- and substance-use-related phenotypes: Evidence from genome-wide association studies.

Authors:
Melissa A Munn-Chernoff Emma C Johnson Yi-Ling Chou Jonathan R I Coleman Laura M Thornton Raymond K Walters Zeynep Yilmaz Jessica H Baker Christopher Hübel Scott Gordon Sarah E Medland Hunna J Watson Héléna A Gaspar Julien Bryois Anke Hinney Virpi M Leppä Manuel Mattheisen Stephan Ripke Shuyang Yao Paola Giusti-Rodríguez Ken B Hanscombe Roger A H Adan Lars Alfredsson Tetsuya Ando Ole A Andreassen Wade H Berrettini Ilka Boehm Claudette Boni Vesna Boraska Perica Katharina Buehren Roland Burghardt Matteo Cassina Sven Cichon Maurizio Clementi Roger D Cone Philippe Courtet Scott Crow James J Crowley Unna N Danner Oliver S P Davis Martina de Zwaan George Dedoussis Daniela Degortes Janiece E DeSocio Danielle M Dick Dimitris Dikeos Christian Dina Monika Dmitrzak-Weglarz Elisa Docampo Laramie E Duncan Karin Egberts Stefan Ehrlich Geòrgia Escaramís Tõnu Esko Xavier Estivill Anne Farmer Angela Favaro Fernando Fernández-Aranda Manfred M Fichter Krista Fischer Manuel Föcker Lenka Foretova Andreas J Forstner Monica Forzan Christopher S Franklin Steven Gallinger Ina Giegling Johanna Giuranna Fragiskos Gonidakis Philip Gorwood Monica Gratacos Mayora Sébastien Guillaume Yiran Guo Hakon Hakonarson Konstantinos Hatzikotoulas Joanna Hauser Johannes Hebebrand Sietske G Helder Stefan Herms Beate Herpertz-Dahlmann Wolfgang Herzog Laura M Huckins James I Hudson Hartmut Imgart Hidetoshi Inoko Vladimir Janout Susana Jiménez-Murcia Antonio Julià Gursharan Kalsi Deborah Kaminská Leila Karhunen Andreas Karwautz Martien J H Kas James L Kennedy Anna Keski-Rahkonen Kirsty Kiezebrink Youl-Ri Kim Kelly L Klump Gun Peggy S Knudsen Maria C La Via Stephanie Le Hellard Robert D Levitan Dong Li Lisa Lilenfeld Bochao Danae Lin Jolanta Lissowska Jurjen Luykx Pierre J Magistretti Mario Maj Katrin Mannik Sara Marsal Christian R Marshall Morten Mattingsdal Sara McDevitt Peter McGuffin Andres Metspalu Ingrid Meulenbelt Nadia Micali Karen Mitchell Alessio Maria Monteleone Palmiero Monteleone Benedetta Nacmias Marie Navratilova Ioanna Ntalla Julie K O'Toole Roel A Ophoff Leonid Padyukov Aarno Palotie Jacques Pantel Hana Papezova Dalila Pinto Raquel Rabionet Anu Raevuori Nicolas Ramoz Ted Reichborn-Kjennerud Valdo Ricca Samuli Ripatti Franziska Ritschel Marion Roberts Alessandro Rotondo Dan Rujescu Filip Rybakowski Paolo Santonastaso André Scherag Stephen W Scherer Ulrike Schmidt Nicholas J Schork Alexandra Schosser Jochen Seitz Lenka Slachtova P Eline Slagboom Margarita C T Slof-Op't Landt Agnieszka Slopien Sandro Sorbi Beata Świątkowska Jin P Szatkiewicz Ioanna Tachmazidou Elena Tenconi Alfonso Tortorella Federica Tozzi Janet Treasure Artemis Tsitsika Marta Tyszkiewicz-Nwafor Konstantinos Tziouvas Annemarie A van Elburg Eric F van Furth Gudrun Wagner Esther Walton Elisabeth Widen Eleftheria Zeggini Stephanie Zerwas Stephan Zipfel Andrew W Bergen Joseph M Boden Harry Brandt Steven Crawford Katherine A Halmi L John Horwood Craig Johnson Allan S Kaplan Walter H Kaye James Mitchell Catherine M Olsen John F Pearson Nancy L Pedersen Michael Strober Thomas Werge David C Whiteman D Blake Woodside Jakob Grove Anjali K Henders Janne T Larsen Richard Parker Liselotte V Petersen Jennifer Jordan Martin A Kennedy Andreas Birgegård Paul Lichtenstein Claes Norring Mikael Landén Preben Bo Mortensen Renato Polimanti Jeanette N McClintick Amy E Adkins Fazil Aliev Silviu-Alin Bacanu Anthony Batzler Sarah Bertelsen Joanna M Biernacka Tim B Bigdeli Li-Shiun Chen Toni-Kim Clarke Franziska Degenhardt Anna R Docherty Alexis C Edwards Jerome C Foo Louis Fox Josef Frank Laura M Hack Annette M Hartmann Sarah M Hartz Stefanie Heilmann-Heimbach Colin Hodgkinson Per Hoffmann Jouke-Jan Hottenga Bettina Konte Jari Lahti Marius Lahti-Pulkkinen Dongbing Lai Lannie Ligthart Anu Loukola Brion S Maher Hamdi Mbarek Andrew M McIntosh Matthew B McQueen Jacquelyn L Meyers Yuri Milaneschi Teemu Palviainen Roseann E Peterson Euijung Ryu Nancy L Saccone Jessica E Salvatore Sandra Sanchez-Roige Melanie Schwandt Richard Sherva Fabian Streit Jana Strohmaier Nathaniel Thomas Jen-Chyong Wang Bradley T Webb Robbee Wedow Leah Wetherill Amanda G Wills Hang Zhou Jason D Boardman Danfeng Chen Doo-Sup Choi William E Copeland Robert C Culverhouse Norbert Dahmen Louisa Degenhardt Benjamin W Domingue Mark A Frye Wolfgang Gäebel Caroline Hayward Marcus Ising Margaret Keyes Falk Kiefer Gabriele Koller John Kramer Samuel Kuperman Susanne Lucae Michael T Lynskey Wolfgang Maier Karl Mann Satu Männistö Bertram Müller-Myhsok Alison D Murray John I Nurnberger Ulrich Preuss Katri Räikkönen Maureen D Reynolds Monika Ridinger Norbert Scherbaum Marc A Schuckit Michael Soyka Jens Treutlein Stephanie H Witt Norbert Wodarz Peter Zill Daniel E Adkins Dorret I Boomsma Laura J Bierut Sandra A Brown Kathleen K Bucholz E Jane Costello Harriet de Wit Nancy Diazgranados Johan G Eriksson Lindsay A Farrer Tatiana M Foroud Nathan A Gillespie Alison M Goate David Goldman Richard A Grucza Dana B Hancock Kathleen Mullan Harris Victor Hesselbrock John K Hewitt Christian J Hopfer William G Iacono Eric O Johnson Victor M Karpyak Kenneth S Kendler Henry R Kranzler Kenneth Krauter Penelope A Lind Matt McGue James MacKillop Pamela A F Madden Hermine H Maes Patrik K E Magnusson Elliot C Nelson Markus M Nöthen Abraham A Palmer Brenda W J H Penninx Bernice Porjesz John P Rice Marcella Rietschel Brien P Riley Richard J Rose Pei-Hong Shen Judy Silberg Michael C Stallings Ralph E Tarter Michael M Vanyukov Scott Vrieze Tamara L Wall John B Whitfield Hongyu Zhao Benjamin M Neale Tracey D Wade Andrew C Heath Grant W Montgomery Nicholas G Martin Patrick F Sullivan Jaakko Kaprio Gerome Breen Joel Gelernter Howard J Edenberg Cynthia M Bulik Arpana Agrawal

Addict Biol 2021 01 16;26(1):e12880. Epub 2020 Feb 16.

Department of Psychiatry, Washington University School of Medicine, Saint Louis, Missouri, USA.

Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [r ], twin-based = 0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from ~2400 to ~537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder- and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (r = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN (r = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating (r = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating (r = -0.19 to -0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for major depressive disorder loci. The patterns of association between eating disorder- and substance-use-related phenotypes highlights the potentially complex and substance-specific relationships among these behaviors.
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http://dx.doi.org/10.1111/adb.12880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429266PMC
January 2021

Hospital-wide ELectronic medical record evaluated computerised decision support system to improve outcomes of Patients with staphylococcal bloodstream infection (HELP): study protocol for a multicentre stepped-wedge cluster randomised trial.

BMJ Open 2020 02 10;10(2):e033391. Epub 2020 Feb 10.

Institute of Medical Statistics, Computer and Data Sciences, Jena University Hospital, Jena, Thüringen, Germany

Introduction: are the most commonly identified pathogens in bloodstream infections. Identification of in blood culture (SAB) requires a prompt and adequate clinical management. The detection of coagulase-negative staphylococci (CoNS), however, corresponds to contamination in about 75% of the cases. Nevertheless, antibiotic therapy is often initiated, which contributes to the risk of drug-related side effects. We developed a computerised clinical decision support system (HELP-CDSS) that assists physicians with an appropriate management of patients with bacteraemia. The CDSS is evaluated using data of the (DIC) established at each clinic. DICs transform heterogeneous primary clinical data into an interoperable format, and the HELP-CDSS displays information according to current best evidence in bacteraemia treatment. The overall aim of the HELP-CDSS is a safe but more efficient allocation of infectious diseases specialists and an improved adherence to established guidelines in the treatment of SAB.

Methods And Analysis: The study is conducted at five German university hospitals and is designed as a stepped-wedge cluster randomised trial. Over the duration of 18 months, 135 wards will change from a control period to the intervention period in a randomised stepwise sequence. The coprimary outcomes are hospital mortality for all patients to establish safety, the 90-day disease reoccurrence-free survival for patients with SAB and the cumulative vancomycin use for patients with CoNS bacteraemia. We will use a closed, hierarchical testing procedure and generalised linear mixed modelling to test for non-inferiority of the CDSS regarding hospital mortality and 90-day disease reoccurrence-free survival and for superiority of the HELP-CDSS regarding cumulative vancomycin use.

Ethics And Dissemination: The study is approved by the ethics committee of Jena University Hospital and will start at each centre after local approval. Results will be published in a peer-reviewed journal and presented at scientific conferences.

Trial Registration Number: DRKS00014320.
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http://dx.doi.org/10.1136/bmjopen-2019-033391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7044885PMC
February 2020

Sepsis-associated acute respiratory distress syndrome in individuals of European ancestry: a genome-wide association study.

Lancet Respir Med 2020 03 23;8(3):258-266. Epub 2020 Jan 23.

Research Unit, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain; Genomics Division, Instituto Tecnológico y de Energías Renovables, Santa Cruz de Tenerife, Spain; CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain; Instituto de Tecnologías Biomédicas, Universidad de La Laguna, Santa Cruz de Tenerife, Spain. Electronic address:

Background: Acute respiratory distress syndrome (ARDS) is a lung inflammatory process caused mainly by sepsis. Most previous studies that identified genetic risks for ARDS focused on candidates with biological relevance. We aimed to identify novel genetic variants associated with ARDS susceptibility and to provide complementary functional evidence of their effect in gene regulation.

Methods: We did a case-control genome-wide association study (GWAS) of 1935 European individuals, using patients with sepsis-associated ARDS as cases and patients with sepsis without ARDS as controls. The discovery stage included 672 patients admitted into a network of Spanish intensive care units between January, 2002, and January, 2017. The replication stage comprised 1345 individuals from two independent datasets from the MESSI cohort study (Sep 22, 2008-Nov 30, 2017; USA) and the VISEP (April 1, 2003-June 30, 2005) and MAXSEP (Oct 1, 2007-March 31, 2010) trials of the SepNet study (Germany). Results from discovery and replication stages were meta-analysed to identify association signals. We then used RNA sequencing data from lung biopsies, in-silico analyses, and luciferase reporter assays to assess the functionallity of associated variants.

Findings: We identified a novel genome-wide significant association with sepsis-associated ARDS susceptibility (rs9508032, odds ratio [OR] 0·61, 95% CI 0·41-0·91, p=5·18 × 10) located within the Fms-related tyrosine kinase 1 (FLT1) gene, which encodes vascular endothelial growth factor receptor 1 (VEGFR-1). The region containing the sentinel variant and its best proxies acted as a silencer for the FLT1 promoter, and alleles with protective effects in ARDS further reduced promoter activity (p=0·0047). A literature mining of all previously described ARDS genes validated the association of vascular endothelial growth factor A (VEGFA; OR 0·55, 95% CI 0·41-0·73; p=4·69 × 10).

Interpretation: A common variant within the FLT1 gene is associated with sepsis-associated ARDS. Our findings support a role for the vascular endothelial growth factor signalling pathway in ARDS pathogenesis and identify VEGFR-1 as a potential therapeutic target.

Funding: Instituto de Salud Carlos III, European Regional Development Funds, Instituto Tecnológico y de Energías Renovables.
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http://dx.doi.org/10.1016/S2213-2600(19)30368-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772505PMC
March 2020

Treatment with etanercept and low monocyte concentration contribute to the risk of invasive aspergillosis in patients post allogeneic stem cell transplantation.

Sci Rep 2019 11 21;9(1):17231. Epub 2019 Nov 21.

University Hospital Würzburg, Medical Hospital II, WÜ4i, Würzburg, Germany.

Invasive aspergillosis (IA) is a life-threatening complication among allogeneic hematopoietic stem cell transplant (alloSCT) recipients. Despite well known risk factors and different available assays, diagnosis of invasive aspergillosis remains challenging. 103 clinical variables from patients with hematological malignancies and subsequent alloSCT were collected. Associations between collected variables and patients with (n = 36) and without IA (n = 36) were investigated by applying univariate and multivariable logistic regression. The predictive power of the final model was tested in an independent patient cohort (23 IA cases and 25 control patients). Findings were investigated further by in vitro studies, which analysed the effect of etanercept on A. fumigatus-stimulated macrophages at the gene expression and cytokine secretion. Additionally, the release of C-X-C motif chemokine ligand 10 (CXCL10) in patient sera was studied. Low monocyte concentration (p = 4.8 × 10), severe GvHD of the gut (grade 2-4) (p = 1.08 × 10) and etanercept treatment of GvHD (p = 3.5 × 10) were significantly associated with IA. Our studies showed that etanercept lowers CXCL10 concentrations in vitro and ex vivo and down-regulates genes involved in immune responses and TNF-alpha signaling. Our study offers clinicians new information regarding risk factors for IA including low monocyte counts and administration of etanercept. After necessary validation, such information may be used for decision making regarding antifungal prophylaxis or closely monitoring patients at risk.
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http://dx.doi.org/10.1038/s41598-019-53504-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6872713PMC
November 2019

Current gaps in sepsis immunology: new opportunities for translational research.

Lancet Infect Dis 2019 12 17;19(12):e422-e436. Epub 2019 Oct 17.

Hospital Universitario Río Hortega, Valladolid, Spain; Group for Biomedical Research in Sepsis, Instituto de Investigación Biomédica de Salamanca, Salamanca, Spain; Centro de Investigación Biomedica En Red-Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain. Electronic address:

Increasing evidence supports a central role of the immune system in sepsis, but the current view of how sepsis affects immunity, and vice versa, is still rudimentary. The European Group on Immunology of Sepsis has identified major gaps that should be addressed with high priority, such as understanding how immunological alterations predispose to sepsis, key aspects of the immunopathological events during sepsis, and the long-term consequences of sepsis on patient's immunity. We discuss major unmet topics in those three categories, including the role of key immune cells, the cause of lymphopenia, organ-specific immunology, the dynamics of sepsis-associated immunological alterations, the role of the microbiome, the standardisation of immunological tests, the development of better animal models, and the opportunities offered by immunotherapy. Addressing these gaps should help us to better understand sepsis physiopathology, offering translational opportunities to improve its prevention, diagnosis, and care.
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http://dx.doi.org/10.1016/S1473-3099(19)30567-5DOI Listing
December 2019

Quality Assessment of the Preanalytical Workflow in Liquid Biobanking: Taurine as a Serum-Specific Quality Indicator for Preanalytical Process Variations.

Biopreserv Biobank 2019 Oct 24;17(5):458-467. Epub 2019 Jul 24.

Institute of Clinical Chemistry and Laboratory Diagnostics and Integrated Biobank Jena (IBBJ), Jena University Hospital, Jena, Germany.

The scientific impact of translational biomedical research largely depends on the availability of high-quality biomaterials. However, evidence-based and robust quality indicators (QIs) covering the most relevant preanalytical variations are still lacking. The aim of this study was to identify and validate a QI suitable for assessing time-to-centrifugation (TTC) delays in human liquid biospecimens originating from both healthy and diseased individuals. Serum and plasma samples with varying TTCs were analyzed by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) in a pilot cohort of healthy individuals to identify a suitable QI candidate. Taurine (TAU), as a TTC QI candidate, was validated in healthy individuals and patients with rheumatologic and cardiologic diseases, considering the (1) preanalytical handling temperature, (2) platelet count, and (3) postcentrifugation delay. For discrimination of high TTC (TTC >60 minutes) from low TTC serum specimens, a probability calculation tool was developed (Triple-T-cutoff-model). TTC-dependent changes in healthy individuals were observed for amino acids, particularly TAU. Validation of the TAU levels in an independent cohort of healthy individuals revealed a time-dependent increase in serum, but not in plasma, for a TTC delay of 30-240 minutes. TAU increases were dependent on the handling temperature and platelet count and volume. By contrast, no changes in TAU concentrations were observed for additional postcentrifugation delays. Validation of TAU and the Triple-T-cutoff-model, in rheumatologic/cardiologic patient collectives, allowed the discrimination of samples with TTC ≤60 min/>60 min with estimated AUROC (area under the receiver operating characteristic curve) values of 89% [78%-100%]/86% [71%-100%] and 91% [79%-100%]/84% [68%-100%], respectively. Considering the preanalytical handling temperature and platelet count and volume, TAU and the Triple-T-cutoff-model represent reliable QIs for TTC >60 minutes in serum samples from healthy individuals and selected rheumatologic/cardiologic patients. However, further studies in larger patient collectives with various diseases are needed to assess the robustness and potential of the QIs presented in this article as biobanking quality assurance/quality control tools to support high-quality biomedical research.
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http://dx.doi.org/10.1089/bio.2019.0004DOI Listing
October 2019

Genome-wide association study identifies eight risk loci and implicates metabo-psychiatric origins for anorexia nervosa.

Authors:
Hunna J Watson Zeynep Yilmaz Laura M Thornton Christopher Hübel Jonathan R I Coleman Héléna A Gaspar Julien Bryois Anke Hinney Virpi M Leppä Manuel Mattheisen Sarah E Medland Stephan Ripke Shuyang Yao Paola Giusti-Rodríguez Ken B Hanscombe Kirstin L Purves Roger A H Adan Lars Alfredsson Tetsuya Ando Ole A Andreassen Jessica H Baker Wade H Berrettini Ilka Boehm Claudette Boni Vesna Boraska Perica Katharina Buehren Roland Burghardt Matteo Cassina Sven Cichon Maurizio Clementi Roger D Cone Philippe Courtet Scott Crow James J Crowley Unna N Danner Oliver S P Davis Martina de Zwaan George Dedoussis Daniela Degortes Janiece E DeSocio Danielle M Dick Dimitris Dikeos Christian Dina Monika Dmitrzak-Weglarz Elisa Docampo Laramie E Duncan Karin Egberts Stefan Ehrlich Geòrgia Escaramís Tõnu Esko Xavier Estivill Anne Farmer Angela Favaro Fernando Fernández-Aranda Manfred M Fichter Krista Fischer Manuel Föcker Lenka Foretova Andreas J Forstner Monica Forzan Christopher S Franklin Steven Gallinger Ina Giegling Johanna Giuranna Fragiskos Gonidakis Philip Gorwood Monica Gratacos Mayora Sébastien Guillaume Yiran Guo Hakon Hakonarson Konstantinos Hatzikotoulas Joanna Hauser Johannes Hebebrand Sietske G Helder Stefan Herms Beate Herpertz-Dahlmann Wolfgang Herzog Laura M Huckins James I Hudson Hartmut Imgart Hidetoshi Inoko Vladimir Janout Susana Jiménez-Murcia Antonio Julià Gursharan Kalsi Deborah Kaminská Jaakko Kaprio Leila Karhunen Andreas Karwautz Martien J H Kas James L Kennedy Anna Keski-Rahkonen Kirsty Kiezebrink Youl-Ri Kim Lars Klareskog Kelly L Klump Gun Peggy S Knudsen Maria C La Via Stephanie Le Hellard Robert D Levitan Dong Li Lisa Lilenfeld Bochao Danae Lin Jolanta Lissowska Jurjen Luykx Pierre J Magistretti Mario Maj Katrin Mannik Sara Marsal Christian R Marshall Morten Mattingsdal Sara McDevitt Peter McGuffin Andres Metspalu Ingrid Meulenbelt Nadia Micali Karen Mitchell Alessio Maria Monteleone Palmiero Monteleone Melissa A Munn-Chernoff Benedetta Nacmias Marie Navratilova Ioanna Ntalla Julie K O'Toole Roel A Ophoff Leonid Padyukov Aarno Palotie Jacques Pantel Hana Papezova Dalila Pinto Raquel Rabionet Anu Raevuori Nicolas Ramoz Ted Reichborn-Kjennerud Valdo Ricca Samuli Ripatti Franziska Ritschel Marion Roberts Alessandro Rotondo Dan Rujescu Filip Rybakowski Paolo Santonastaso André Scherag Stephen W Scherer Ulrike Schmidt Nicholas J Schork Alexandra Schosser Jochen Seitz Lenka Slachtova P Eline Slagboom Margarita C T Slof-Op 't Landt Agnieszka Slopien Sandro Sorbi Beata Świątkowska Jin P Szatkiewicz Ioanna Tachmazidou Elena Tenconi Alfonso Tortorella Federica Tozzi Janet Treasure Artemis Tsitsika Marta Tyszkiewicz-Nwafor Konstantinos Tziouvas Annemarie A van Elburg Eric F van Furth Gudrun Wagner Esther Walton Elisabeth Widen Eleftheria Zeggini Stephanie Zerwas Stephan Zipfel Andrew W Bergen Joseph M Boden Harry Brandt Steven Crawford Katherine A Halmi L John Horwood Craig Johnson Allan S Kaplan Walter H Kaye James E Mitchell Catherine M Olsen John F Pearson Nancy L Pedersen Michael Strober Thomas Werge David C Whiteman D Blake Woodside Garret D Stuber Scott Gordon Jakob Grove Anjali K Henders Anders Juréus Katherine M Kirk Janne T Larsen Richard Parker Liselotte Petersen Jennifer Jordan Martin Kennedy Grant W Montgomery Tracey D Wade Andreas Birgegård Paul Lichtenstein Claes Norring Mikael Landén Nicholas G Martin Preben Bo Mortensen Patrick F Sullivan Gerome Breen Cynthia M Bulik

Nat Genet 2019 08 15;51(8):1207-1214. Epub 2019 Jul 15.

Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Characterized primarily by a low body-mass index, anorexia nervosa is a complex and serious illness, affecting 0.9-4% of women and 0.3% of men, with twin-based heritability estimates of 50-60%. Mortality rates are higher than those in other psychiatric disorders, and outcomes are unacceptably poor. Here we combine data from the Anorexia Nervosa Genetics Initiative (ANGI) and the Eating Disorders Working Group of the Psychiatric Genomics Consortium (PGC-ED) and conduct a genome-wide association study of 16,992 cases of anorexia nervosa and 55,525 controls, identifying eight significant loci. The genetic architecture of anorexia nervosa mirrors its clinical presentation, showing significant genetic correlations with psychiatric disorders, physical activity, and metabolic (including glycemic), lipid and anthropometric traits, independent of the effects of common variants associated with body-mass index. These results further encourage a reconceptualization of anorexia nervosa as a metabo-psychiatric disorder. Elucidating the metabolic component is a critical direction for future research, and paying attention to both psychiatric and metabolic components may be key to improving outcomes.
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http://dx.doi.org/10.1038/s41588-019-0439-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779477PMC
August 2019

Comment on 'Naked mole-rat mortality rates defy Gompertzian laws by not increasing with age'.

Elife 2019 07 9;8. Epub 2019 Jul 9.

Leibniz Institute on Aging - Fritz Lipmann Institute, Jena, Germany.

Ruby et al. recently analyzed historical lifespan data on more than 3200 naked mole-rats, collected over a total observation period of about 38 years (Ruby et al., 2018). They report that mortality hazards do not seem to increase across the full range of their so-far-observed lifespan, and conclude that this defiance of Gompertz's law 'uniquely identifies the naked mole-rat as a non-aging mammal'. Here, we explain why we believe this conclusion is premature.
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http://dx.doi.org/10.7554/eLife.45415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6615855PMC
July 2019

Comparative validation of three screening instruments for posttraumatic stress disorder after intensive care.

J Crit Care 2019 10 18;53:149-154. Epub 2019 Jun 18.

Jena University Hospital, Friedrich Schiller-University Jena, Center for Sepsis Control and Care, Jena, Germany; Jena University Hospital, Friedrich Schiller-University Jena, Institute of Medical Statistics, Computer and Data Sciences, Jena, Germany.

Purpose: Aim of the present study was to compare the validity of three screening instruments to assess symptoms of posttraumatic stress disorder (PTSD) after intensive care of sepsis.

Material And Methods: Participants were recruited within a large multicenter patient cohort study on long-term sequelae of sepsis. Adult patients (n = 83) on average four months after intensive care of (severe) sepsis or septic shock were included (median age 64 years, 60% male). PTSD symptom severity was assessed by three different self-report measures: two versions of the Posttraumatic Stress Scale (PTSS-10; PTSS-14), and the Posttraumatic Stress Disorder Checklist for DSM-5 (PCL-5). A clinical PTSD diagnosis was derived by using the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5).

Results: Ten patients (12%) were diagnosed with PTSD. PTSS-10, PTSS-14, and PCL-5 revealed good reliability and concurrent validity. PTSS-14 showed the best accuracy in screening patients at risk for PTSD after intensive care with 80% sensitivity and 92% specificity at the recommended cutoff of 40.

Conclusions: Compared to PTSS-10 and PCL-5, PTSS-14 appeared more appropriate for post-ICU PTSD screening when validated against a DSM-5 diagnostic interview.
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http://dx.doi.org/10.1016/j.jcrc.2019.06.016DOI Listing
October 2019

Estimating extra length of stay due to healthcare-associated infections before and after implementation of a hospital-wide infection control program.

PLoS One 2019 17;14(5):e0217159. Epub 2019 May 17.

Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany.

Introduction: Healthcare-associated infections (HAIs) are a major health concern and have substantial effects on morbidity and mortality and increase healthcare costs. We investigated the effect of a hospital-wide program for the prevention of HAIs on additional length of stay (LOS).

Methods: We analyzed data from a prospective, single-center, quasi-experimental study with two surveillance periods before and after implementation of an infection prevention intervention program. HAI diagnosis was made according to surveillance definition criteria established by the US Centers for Disease Control and Prevention. A multistate model was used to estimate additional LOS for patients with HAI in both surveillance periods.

Results: During the first and second periods, 1,568 and 2,336 HAIs were identified among 26,943 and 35,211 patients, respectively. For HAI patients exclusively treated in a general ward, additional LOS was 8.4 (95% confidence interval, CI: 6.8-10.0) days in the first period and 9.6 (95% CI: 8.3-11.0) days in the second period (p = 0.26). For HAI patients treated in both an intensive care unit (ICU) and a general ward, additional LOS was 8.1 (95% CI: 6.3-9.9) days in the first period to 7.3 (95% CI: 6.1-8.5) days in the second period (p = 0.47).

Conclusions: Healthcare-associated infections prolong LOS. A hospital-wide infection control program did not alter the prolongation of LOS.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0217159PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6524816PMC
January 2020

[Current challenges in the assessment of ethical proposals-aspects of digitalization and personalization in the healthcare system].

Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2019 Jun;62(6):758-764

Bundesinstitut für Impfstoffe und biomedizinische Arzneimittel, Paul-Ehrlich-Institut, Langen, Deutschland.

The global aim of medical ethics committees is to judge the scientific quality and the integrity of the content of medical research projects (studies), thereby assessing the benefit-risk profile. Apart from judging content-related aspects and the legal correctness, the study design and the analysis strategy must also be assessed from a biostatistical point of view. This very sophisticated task is further complicated by the fact that medical research constantly faces new challenges.Within this work, current developments in medical research that directly impact the assessability of ethical proposals will be identified and discussed. The aim is to sensitize researchers to the opportunities and challenges of new developments.The work focusses on the topics of digitalization in the healthcare system and individualized medicine. The authors illustrate some problems resulting from these developments that affect the ethical justification of medical research projects. Problems related to medical as well as biostatistical aspects are presented and their direct implications on the legal justification and ethical and moral conceptual integrity are highlighted.New developments in medical research such as digitalization and individualized medicine offer new perspectives for optimized therapies. These promising developments must be further advanced. A critical view on the so far only poorly investigated consequences of embedding new data sources and study designs must urgently accompany this process. Transparency and clarity in formulating ethical proposals is thereby of utmost importance.
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http://dx.doi.org/10.1007/s00103-019-02955-5DOI Listing
June 2019

[Scientific and ethical evaluation of projects in data-driven medicine].

Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2019 Jun;62(6):765-772

Institut für Medizinische Informationsverarbeitung, Biometrie und Epidemiologie, Lehrstuhl Medizinische Biometrie und Bioinformatik, LMU München, Marchioninistraße 15, 81377, München, Deutschland.

The generation and usage of extensive data from medical care aims at answering crucial medical research questions. Buzzwords in this area are learning health system, data-driven medicine and big data. In addition to classical biostatistical methods, machine learning approaches are frequently applied for analysis.In the evaluation of projects from data-driven medicine by research ethics committees, the question arises of how to assess the benefit-risk ratio and the scientific and social value. Which knowledge is required for that purpose? How can research ethics committees prepare for these challenges? Scientific approaches from the area of observational studies and the consideration of agreed-upon ethical aspects (consent, validity, justice, benefit-risk ratio and transparency) can help to answer the above-mentioned questions. One has to bear in mind that data-driven medicine is no paradigm shift that in principle challenges the established scientific and ethical evaluation procedures. Nevertheless, the evaluation of projects from data-driven medicine requires enhanced specialisation and comprehensive methodical expertise from the areas of machine learning and observational studies.Empirical research of the progression and governance of data-driven medicine will support the development and continual adaptation of effective strategies for evaluation by research ethics committees. Training and networking of experts will enable us to meet the challenges of data-driven medicine.
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http://dx.doi.org/10.1007/s00103-019-02958-2DOI Listing
June 2019

[The role of biostatistics in institutional review boards].

Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2019 Jun;62(6):751-757

Institut für medizinische Informationsverarbeitung, Biometrie und Epidemiologie, LMU München, München, Deutschland.

Research in humans is associated with risks. These risks are only justifiable if an independent institutional review board (IRB) has evaluated the planned research in terms of scientific integrity. Only scientifically sound research can be considered ethical. A biostatistician should be a member of the IRB to assure adequate evaluation of fundamental topics like design, sample size estimation, and statistical analysis of the study.This paper presents core biostatistical concepts following the current guidelines of the International Council of Harmonization (ICH E6 and ICH E9). We discuss important pitfalls based on examples from published clinical trials. Furthermore, we discuss new concepts like estimands and their relevance for biostatisticians working in IRBs. Finally, we discuss the role of biostatisticians in IRBs and present thoughts on the way they should be trained.
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http://dx.doi.org/10.1007/s00103-019-02951-9DOI Listing
June 2019