Validating genetic variants in innate immunity linked to infectious events in acute myeloid leukemia post-induction chemotherapy.

Infectious events, such as sepsis and invasive fungal disease (IFD), pose significant risks in patients with acute myeloid leukemia (AML). Previous studies, including our own, have suggested a potential role of single nucleotide polymorphisms (SNPs) within the innate immune system in influencing individual infection susceptibility. However, many of these associations lack validation in independent cohorts. This study sought to validate the impact of 11 candidate SNPs across 6 genes (TLR2, TLR4, Dectin-1, DC-SIGN, PTX3, L-Ficolin) in an independent cohort of patients. Two cohorts with newly diagnosed AML patients receiving intensive induction chemotherapy were analyzed: a stratification cohort comprising 186 patients and a validation cohort consisting of 138 patients. Multiple SNPs in each cohort were found to be associated to infectious complications, notably the DC-SIGN SNP rs4804800 demonstrated a significant association with sepsis in both cohorts. SNPs within the PTX3 and Dectin-1 genes were linked to IFD development in one cohort each. This study represents the first validation study of candidate genes associated with infectious events in AML patients after intensive induction chemotherapy. Identifying genetic predispositions to infections could significantly impact the management of antimicrobial prophylaxis and treatment in AML patients.

[INTERPOLAR-prospective, interventional studies as part of the Medical Informatics Initiative to improve medication therapy safety in healthcare]. / INTERPOLAR ­ prospektive, interventionelle Studien im Rahmen der Medizininformatik-Initiative zur Verbesserung der Arzneimitteltherapiesicherheit in der Krankenversorgung.

Medication analyses by ward pharmacists are an important measure of drug therapy safety (DTS). Medication-related problems (MRPs) are identified and resolved with the attending clinicians. However, staff resources for extended medication analyses and complete documentation are often limited. Until now, data required for the identification of risk patients and for an extended medication analysis often had to be collected from various parts of the institution's internal electronic medical record (EMR). This error-prone and time-consuming process is to be improved in the INTERPOLAR (INTERventional POLypharmacy-Drug interActions-Risks) project using an IT tool provided by the data integration centers (DIC).INTERPOLAR is a use case of the Medical Informatics Initiative (MII) that focuses on the topic of DTS. The planning phase took place in 2023, with routine implementation planned from 2024. DTS-relevant data from the EMR is to be presented and the documentation of MRPs in routine care is to be facilitated. The prospective multicenter, cluster-randomized INTERPOLAR­1 study serves to evaluate the benefits of IT support in routine care. The aim is to show that more MRPs can be detected and resolved with the help of IT support. For this purpose, six normal wards will be selected at each of eight university hospitals, so that 48 clusters (with a total of at least 70,000 cases) are available for randomization.

[Automated surveillance and risk prediction with the aim of risk-stratified infection control and prevention (RISK PRINCIPE)]. / Automatisierte Surveillance und Risikovorhersage mit dem Ziel einer risikostratifizierten Infektionskontrolle und -prävention (RISK Prediction for Risk-stratified Infection Control and Prevention).

Healthcare-associated infections (HCAIs) represent an enormous burden for patients, healthcare workers, relatives and society worldwide, including Germany. The central tasks of infection prevention are recording and evaluating infections with the aim of identifying prevention potential and risk factors, taking appropriate measures and finally evaluating them. From an infection prevention perspective, it would be of great value if (i) the recording of infection cases was automated and (ii) if it were possible to identify particularly vulnerable patients and patient groups in advance, who would benefit from specific and/or additional interventions.To achieve this risk-adapted, individualized infection prevention, the RISK PRINCIPE research project develops algorithms and computer-based applications based on standardised, large datasets and incorporates expertise in the field of infection prevention.The project has two objectives: a) to develop and validate a semi-automated surveillance system for hospital-acquired bloodstream infections, prototypically for HCAI, and b) to use comprehensive patient data from different sources to create an individual or group-specific infection risk profile.RISK PRINCIPE is based on bringing together the expertise of medical informatics and infection medicine with a focus on hygiene and draws on information and experience from two consortia (HiGHmed and SMITH) of the German Medical Informatics Initiative (MII), which have been working on use cases in infection medicine for more than five years.

Cytokine Hemoadsorption During Cardiac Surgery Versus Standard Surgical Care for Infective Endocarditis (REMOVE): Results From a Multicenter Randomized Controlled Trial.

BACKGROUND: Cardiac surgery often represents the only treatment option in patients with infective endocarditis (IE). However, IE surgery may lead to a sudden release of inflammatory mediators, which is associated with postoperative organ dysfunction. We investigated the effect of hemoadsorption during IE surgery on postoperative organ dysfunction. METHODS: This multicenter, randomized, nonblinded, controlled trial assigned patients undergoing cardiac surgery for IE to hemoadsorption (integration of CytoSorb to cardiopulmonary bypass) or control. The primary outcome (change in sequential organ failure assessment score [ΔSOFA]) was defined as the difference between the mean total postoperative SOFA score, calculated maximally to the 9th postoperative day, and the basal SOFA score. The analysis was by modified intention to treat. A predefined intergroup comparison was performed using a linear mixed model for ΔSOFA including surgeon and baseline SOFA score as fixed effect covariates and with the surgical center as random effect. The SOFA score assesses dysfunction in 6 organ systems, each scored from 0 to 4. Higher scores indicate worsening dysfunction. Secondary outcomes were 30-day mortality, duration of mechanical ventilation, and vasopressor and renal replacement therapy. Cytokines were measured in the first 50 patients. RESULTS: Between January 17, 2018, and January 31, 2020, a total of 288 patients were randomly assigned to hemoadsorption (n=142) or control (n=146). Four patients in the hemoadsorption and 2 in the control group were excluded because they did not undergo surgery. The primary outcome, ΔSOFA, did not differ between the hemoadsorption and the control group (1.79±3.75 and 1.93±3.53, respectively; 95% CI, -1.30 to 0.83; P=0.6766). Mortality at 30 days (21% hemoadsorption versus 22% control; P=0.782), duration of mechanical ventilation, and vasopressor and renal replacement therapy did not differ between groups. Levels of interleukin-1ß and interleukin-18 at the end of integration of hemoadsorption to cardiopulmonary bypass were significantly lower in the hemoadsorption than in the control group. CONCLUSIONS: This randomized trial failed to demonstrate a reduction in postoperative organ dysfunction through intraoperative hemoadsorption in patients undergoing cardiac surgery for IE. Although hemoadsorption reduced plasma cytokines at the end of cardiopulmonary bypass, there was no difference in any of the clinically relevant outcome measures. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03266302.

Non-patient-related SARS-CoV-2 exposure from colleagues and household members poses the highest infection risk for hospital employees in a German university hospital: follow-up of the prospective Co-HCW seroprevalence study.

PURPOSE: The Co-HCW study is a prospective, longitudinal, single-center observational study that aims to assess the SARS-CoV-2 seroprevalence and infection status in staff members of Jena University Hospital (JUH) in Jena, Germany. METHODS: This follow-up study covers the observation period from 19th May 2020 to 22nd June 2021. At each of the three voluntary study visits, participants filled out a questionnaire regarding their SARS-CoV-2 exposure and provided serum samples to detect specific SARS-CoV-2 antibodies. Participants who were tested positive for antibodies against nucleocapsid and/or spike protein without previous vaccination and/or reported a positive SARS-CoV-2 PCR test were regarded to have been infected with SARS-CoV-2. Multivariable logistic regression modeling was applied to identify potential risk factors for infected compared to non-infected participants. RESULTS: Out of 660 participants that were included during the first study visit, 406 participants (61.5%) were eligible for the final analysis as their COVID-19 risk area (high-risk n = 76; intermediate-risk n = 198; low-risk n = 132) did not change during the study. Forty-four participants [10.8%, 95% confidence interval (95%CI) 8.0-14.3%] had evidence of a current or past SARS-CoV-2 infection detected by serology (n = 40) and/or PCR (n = 28). No association between SARS-CoV-2 infection and the COVID-19 risk group according to working place was detected. However, exposure to a SARS-CoV-2 positive household member [adjusted OR (AOR) 4.46, 95% CI 2.06-9.65] or colleague (AOR 2.30, 95%CI 1.10-4.79) was found to significantly increase the risk of a SARS-CoV-2 infection. CONCLUSION: Our results demonstrate that non-patient-related SARS-CoV-2 exposure posed the highest infection risk for hospital staff members of JUH.

Comparison of fatigue, cognitive dysfunction and psychological disorders in post-COVID patients and patients after sepsis: is there a specific constellation?

BACKGROUND: Sequelae of COVID-19 can be severe and longlasting. We compared frequencies of fatigue, depression and cognitive dysfunction in survivors of SARS-CoV-2-infection and sepsis. METHODS: We performed a prospective cohort study of 355 symptomatic post-COVID patients who visited our out-patient clinic for post-COVID-19 care. We compared them with 272 symptomatic patients from the Mid-German Sepsis Cohort, which investigates the long-term courses of sepsis survivors. Possible predictors for frequent clinical findings (fatigue, signs of depression, cognitive dysfunction) in post-COVID were investigated with multivariable logistic regression. RESULTS: Median age of the post-COVID patients was 51 years (range 17-86), 60.0% were female, and 31.8% required hospitalization during acute COVID-19. In the post-COVID patients (median follow-up time: 163 days) and the post-sepsis patients (180 days), fatigue was found in 93.2% and 67.8%, signs of depression were found in 81.3% and 10.9%, and cognitive dysfunction was found in 23.5% and 21.3%, respectively. In post-COVID, we did not observe an association between fatigue or depression and the severity of acute COVID-19. In contrast, cognitive dysfunction was associated with hospitalization (out-patient versus in-patient) and more frequent in post-COVID patients treated on an ICU compared to the MSC patients. CONCLUSION: In post-COVID patients, fatigue and signs of depression are more common than in sepsis survivors, independent from the acute SARS-CoV-2-infection. In contrast, cognitive dysfunction is associated with hospitalization. Despite the differences in frequencies, owing to the similarity of post-COVID and post-sepsis sequelae, this knowledge may help in implementing follow-up approaches after SARS-CoV-2 infection.

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

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 (n = 25) or sternotomy (n = 239). Propensity score matching was used for outcome comparisons. RESULTS: Of the 264 patients, 25 (age: 72 ± 10 years; 72% male) underwent double (n = 19) and triple valve surgery (n = 6) through RMT and 239 (age: 71 ± 11 years; 54% male) underwent double (n = 176) and triple valve surgery (n = 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; p < 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: n = 2 vs. sternotomy: n = 2) and there were no significant differences in other outcomes. During 5-year follow-up, reoperation was required in sternotomy patients only (n = 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; p = 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.

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.

Association between sepsis incidence and regional socioeconomic deprivation and health care capacity in Germany - an ecological study.

BACKGROUND: Sepsis is a substantial health care burden. Data on regional variation in sepsis incidence in Germany and any possible associations with regional socioeconomic deprivation and health care capacity is lacking. METHODS: Ecological study based on the nationwide hospital Diagnosis-related Groups (DRG) statistics data of 2016. We identified sepsis by ICD-10-codes and calculated crude and age-standardized incidence proportions in the 401 administrative German districts. Associations between socioeconomic and health care capacity indicators and crude and age-adjusted sepsis incidence were investigated by simple and multiple negative binomial (NB) regressions. RESULTS: In 2016, sepsis incidence was 178 per 100,000 inhabitants and varied 10-fold between districts. We found that the rate of students leaving school without certificate was significantly associated with crude and age-standardized explicit sepsis incidence in the simple and multiple NB regressions. While we observed no evidence for an association to the capacity of hospital beds and general practitioners, the distance to the nearest pharmacy was associated with crude- and age-standardized sepsis incidence. In the multiple regression analyses, an increase of the mean distance + 1000 m was associated with an expected increase by 21.6 [95% CI, 10.1, 33.0] (p < 0.001), and 11.1 [95% CI, 1.0, 21.2]/100,000 population (p = .026) after adjusting for age differences between districts. CONCLUSIONS: Residence in districts with lower socioeconomic status (e.g., less education) and further distance to pharmacies are both associated with an increased sepsis incidence. This warrants further research with individual-level patient data to better model and understand such dependencies and to ultimately design public health interventions to address the burden of sepsis in Germany.

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.

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) .

[Period Prevalence of SARS-CoV-2 in an Unselected Sample of Pregnant Women in Jena, Thuringia]. / Periodenprävalenz von SARS-CoV-2 in einer unselektierten Stichprobe schwangerer Frauen in Jena, Thüringen.

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%).

Do adolescents with extreme obesity differ according to previous treatment seeking behavior? The Youth with Extreme obesity Study (YES) cohort.

OBJECTIVES: Adolescent extreme obesity is associated with somatic and psychiatric comorbidity, low quality of life, and social dysfunction. Nevertheless, few adolescents seek obesity treatment, thus many may elope appropriate care. We examine whether previous treatment seeking relates to disease burden, and whether previously non-treatment seeking adolescents accept diagnostic and therapeutic offers. This information is important to inform intervention strategies. METHODS: The Youth with Extreme obesity Study (YES) is a prospective, multicenter cohort study. We developed a novel recruitment strategy to span medical and vocational ascertainment settings and directly compare previously treatment seeking and non-treatment seeking youth. Participants aged 14-24 years; BMI ≥ 30 kg/m2 were enrolled at four medical- and one job centers. We present comorbidity and psycho-social baseline data by sex, obesity WHO grade I-III, and treatment-seeking status, defined as self-reported previous participation in a weight-loss program. RESULTS: Of 431 participants, 47% were male; mean age 16.6 (standard deviation 2.3) years, BMI 39.2 (7.5) kg/m2. Somatic comorbidity increased with obesity grade, p < 0.05: hypertension (42, 55, 64%), dyslipidemia (28, 24, 37%,), dysglycemia (9, 19, 20%,), elevated transaminases (15, 26, 30%). Quality of life (EQ5 D) decreased (74, 71, 70). Rates of psychiatric disorders were stable: depression 11%, attention deficit disorder 6%, substance use disorder 2%, self-injurious behavior 5%, suicide attempt 3%. Only 63% (56, 64, 69%) reported previous treatment seeking. Acceptance of the diagnostic (89%) or therapeutic (28%) program, medical or psychosocial situation did not differ by treatment seeking status. Acceptance of the therapeutic program was generally low, but high at the job center (92%). CONCLUSION: Irrespective of previous treatment seeking, adolescent extreme obesity was associated with high comorbidity and psychosocial burden. Acceptance of the diagnostic program overall and the therapeutic program at the job center were high. This underscores the need of innovative, accessible programs beyond the currently offered care.

The risk of infections in multiple myeloma before and after the advent of novel agents: a 12-year survey.

Infections represent a major cause of morbidity and mortality in multiple myeloma and are linked to both therapy- and disease-related factors. Although it has been suggested that the rate of infections increased since the introduction of novel agents, controversies still exist. To better assess the risk factors associated with infections in the era of novel agents, we conducted a large retrospective analysis of 479 myeloma patients treated at Jena University Hospital over a period of 12 years. During their disease history, 65% of patients developed at least one infection, and 37% of therapies were associated with at least one infectious episode. The rate of infections was constant over the years, with no increase in infectious complications after the routine implementation of novel agents. Infections were mainly bacterial and strongly associated with high disease burden, relapsed disease, and treatment with high-dose chemotherapy. Varicella zoster virus (VZV) reactivations occurred late during treatment (median time between high-dose chemotherapy and VZV reactivation 6 months, range 0-44 months), and fewer patients developed a VZV reactivation after 2009 (p = 0.001). Infections are still one of the major causes of morbidity in myeloma patients, and prophylactic measures are urgently needed to reduce this potentially lethal complication.

Chronic Critical Illness from Sepsis Is Associated with an Enhanced TCR Response.

Sepsis is characterized by a disproportionate host response to infection that often culminates in multiple organ failure. Current concepts invoke a deregulated immune reaction involving features of hyperinflammation, as well as protracted immune suppression. However, owing to the scarcity of human data, the precise origin of a long-term suppression of adaptive immunity remains doubtful. We report on an explorative clinical study of chronic critical illness (CCI) patients aimed at assessing the long-term consequences of sepsis on T cell function. Blood was drawn from 12 male CCI patients (median age 67 y, range 48-79 y) receiving continuous mechanical ventilation and renal replacement therapy in a long-term care hospital who had been treated in an external acute care hospital for severe sepsis. T cells were purified and subjected to flow cytometric immune-phenotyping and functional assays. We found that T cells from CCI patients featured higher basal levels of activation and stronger expression of the inhibitory surface receptor programmed cell death 1 compared with controls. However, T cells from CCI patients exhibited no suppressed TCR response at the level of proximal TCR signaling (activation/phosphorylation of PLCγ, Erk, Akt, LAT), activation marker upregulation (CD69, CD25, CD154, NUR77), IL-2 production, or clonal expansion. Rather, our data illustrate an augmented response in T cells from CCI patients in response to TCR/coreceptor (CD3/CD28) challenge. Thus, the present findings reveal that CCI sepsis patients feature signs of immune suppression but that their T cells exhibit a primed, rather than a suppressed, phenotype in their TCR response, arguing against a generalized T cell paralysis as a major cause of protracted immune suppression from sepsis.

[Psychosocial Characteristic and Health Care for Unemployed Youths with Extreme Obesity - A Model Project]. / Psychosoziale Charakterisierung und Integrative Versorgung arbeitsloser Jugendlicher mit extremer Adipositas ­ ein Modellprojekt.

INTRODUCTION: In clinical care, unemployed youths have limited access to available obesity treatments including obesity surgery. With the implementation of a specialized obesity outpatient unit in cooperation with five German job-centers we aim to prove whether unemployed youths are interested in obesity treatment and how they adhere to a multilevel obesity treatment in terms of participation rates. MATERIALS AND METHODS: Youths (aged 15.0-24.9 years) with a body-mass-index (BMI) ≥30 kg/m2 were initially offered an individualized patient information concerning obesity treatment on the premises of the job-center. If interested, youths were included in the multicomponent treatment program (6 sessions). Those who participated in a minimum of 5 out of 6 treatment sessions were offered access to a preparation course (4 sessions) and an individualized evaluation of the indication for obesity surgery. RESULTS: Between 2012 and 2017, 83 youths (mean age 21.1 years, BMI 48.1 kg/m2, BMI 35.0-39.9 kg/m2: N=7, ≥40 kg/m2: N=71) were enrolled in the treatment program. 34 participated in ≥5/6 sessions in the multicomponent obesity treatment and 20 expressed an interest in obesity surgery. To date, 11 adolescents underwent obesity surgery with a mean BMI reduction of 14.3 kg/m2 between 3 and 36 months after obesity surgery (excess weight loss 27.3%) vs. 3.8 kg/m2 between 6 and 48 months after treatment initiation in the group of youths who did not receive obesity surgery. 13 youths were integrated in the primary labor market. DISCUSSION: Several unemployed youths accepted our treatment program and improved their health and vocational status in the course of their participation. CONCLUSIONS: The implementation of a specialized obesity outpatient unit within German job-centers is a successful strategy to characterize this high-risk-group and to determine their individual treatment needs. This finding must be confirmed with a larger sample size and by evaluating the long-term course of treatment.

[The role of biostatistics in institutional review boards]. / Biometrische Aspekte in Ethikkommissionen.

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.

[Scientific and ethical evaluation of projects in data-driven medicine]. / Wissenschaftliche und ethische Bewertung von Projekten in der datengetriebenen Medizin.

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.

[Current challenges in the assessment of ethical proposals-aspects of digitalization and personalization in the healthcare system]. / Aktuelle Herausforderungen bei der Bewertung von Ethikanträgen ­ Aspekte der Digitalisierung und Personalisierung im Gesundheitswesen.

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.

Clinical course, treatment and outcome of Pneumocystis pneumonia in immunocompromised adults: a retrospective analysis over 17 years.

BACKGROUND: Despite modern intensive care with standardized strategies against acute respiratory distress syndrome (ARDS), Pneumocystis pneumonia (PcP) remains a life-threatening disease with a high mortality rate. Here, we analyzed a large mixed cohort of immunocompromised patients with PcP, with regard to clinical course and treatment, and aimed at identifying predictors of outcome. METHODS: This was a single-center retrospective analysis in a tertiary care institution across 17 years. Diagnosis of PcP required typical clinical features and microbiological confirmation of Pneumocystis jirovecii. Epidemiological, clinical, laboratory and outcome data were collected from patient records. RESULTS: A total of 52,364 specimens from 7504 patients were sent for microbiological assessment (3653 with clinical suspicion of Pneumocystis pneumonia). PcP was confirmed in 240 patients, about half of them HIV positive (52%). The remaining subjects were either solid organ transplant recipients (16.3%) or suffered from malignancy (15.8%) or autoimmune diseases (11.7%). Of note, 95% of patients with PcP were not receiving chemoprophylaxis. Overall in-hospital mortality was 25.4%, increasing to 58% if ICU admission was required. Multivariable regression identified lactate dehydrogenase (LDH) as predictor of in-hospital mortality (adjusted OR 1.17 (95% CI 1.09-1.27), p < 0.0001). Mortality in LDH quartiles increased from 8% to 49%, and a cutoff value of 495 U/L predicted mortality with sensitivity and specificity of 70%. With regard to treatment, 40% of patients received trimethoprim-sulfamethoxazole at doses that were lower than recommended, and these patients had a higher mortality risk (HR 1.80 (95% CI 1.10-3.44), p = 0.02). CONCLUSIONS: PcP remains a life-threatening disease among immunocompromised patients. About half of patients with PcP do not have HIV infection. Initial LDH values might serve as a stratifying tool to identify those patients at high risk of death among patients with HIV and without HIV infection.

Dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human.

Free fatty acids provide an important energy source as nutrients, and act as signalling molecules in various cellular processes. Several G-protein-coupled receptors have been identified as free-fatty-acid receptors important in physiology as well as in several diseases. GPR120 (also known as O3FAR1) functions as a receptor for unsaturated long-chain free fatty acids and has a critical role in various physiological homeostasis mechanisms such as adipogenesis, regulation of appetite and food preference. Here we show that GPR120-deficient mice fed a high-fat diet develop obesity, glucose intolerance and fatty liver with decreased adipocyte differentiation and lipogenesis and enhanced hepatic lipogenesis. Insulin resistance in such mice is associated with reduced insulin signalling and enhanced inflammation in adipose tissue. In human, we show that GPR120 expression in adipose tissue is significantly higher in obese individuals than in lean controls. GPR120 exon sequencing in obese subjects reveals a deleterious non-synonymous mutation (p.R270H) that inhibits GPR120 signalling activity. Furthermore, the p.R270H variant increases the risk of obesity in European populations. Overall, this study demonstrates that the lipid sensor GPR120 has a key role in sensing dietary fat and, therefore, in the control of energy balance in both humans and rodents.