Short-term physical exercise impacts on the human holobiont obtained by a randomised intervention study

Background Human well-being has been linked to the composition and functional capacity of the intestinal microbiota. As regular exercise is known to improve human health, it is not surprising that exercise was previously described to positively modulate the gut microbiota, too. However, most previous studies mainly focused on either elite athletes or animal models. Thus, we conducted a randomised intervention study that focused on the effects of different types of training (endurance and strength) in previously physically inactive, healthy adults in comparison to controls that did not perform regular exercise. Overall study duration was ten weeks including six weeks of intervention period. In addition to 16S rRNA gene amplicon sequencing of longitudinally sampled faecal material of participants (six time points), detailed body composition measurements and analysis of blood samples (at baseline and after the intervention) were performed to obtain overall physiological changes within the intervention period. Activity tracker devices (wrist-band wearables) provided activity status and sleeping patterns of participants as well as exercise intensity and heart measurements. Conclusions We could show that different types of exercise have distinct but moderate effects on the overall physiology of humans and very distinct microbial changes in the gut. The observed overall changes during the intervention highlight the importance of physical activity on well-being. Future studies should investigate the effect of exercise on a longer timescale, investigate different training intensities and consider high-resolution shotgun metagenomics technology. Trial registration DRKS, DRKS00015873 . Registered 12 December 2018; Retrospectively registered

Impella versus extracorporal life support in cardiogenic shock: a propensity score adjusted analysis

Aims: The mortality in cardiogenic shock (CS) is high. The role of specific mechanical circulatory support (MCS) systems is unclear. We aimed to compare patients receiving Impella versus ECLS (extracorporal life support) with regard to baseline characteristics, feasibility, and outcomes in CS. Methods and results: This is a retrospective cohort study including CS patients over 18 years with a complete follow-up of the primary endpoint and available baseline lactate level, receiving haemodynamic support either by Impella 2.5 or ECLS from two European registries. The decision for device implementation was made at the discretion of the treating physician. The primary endpoint of this study was all-cause mortality at 30 days. A propensity score for the use of Impella was calculated, and multivariable logistic regression was used to obtain adjusted odds ratios (aOR). In total, 149 patients were included, receiving either Impella (n = 73) or ECLS (n = 76) for CS. The feasibility of device implantation was high (87%) and similar (aOR: 3.14; 95% CI: 0.18–56.50; P = 0.41) with both systems. The rates of vascular injuries (aOR: 0.95; 95% CI: 0.10–3.50; P = 0.56) and bleedings requiring transfusions (aOR: 0.44; 95% CI: 0.09–2.10; P = 0.29) were similar in ECLS patients and Impella patients. The use of Impella or ECLS was not associated with increased odds of mortality (aOR: 4.19; 95% CI: 0.53–33.25; P = 0.17), after correction for propensity score and baseline lactate level. Baseline lactate level was independently associated with increased odds of 30 day mortality (per mmol/L increase; OR: 1.29; 95% CI: 1.14–1.45; P < 0.001). Conclusions: In CS patients, the adjusted mortality rates of both ECLS and Impella were high and similar. The baseline lactate level was a potent predictor of mortality and could play a role in patient selection for therapy in future studies. In patients with profound CS, the type of device is likely to be less important compared with other parameters including non-cardiac and neurological factors

Sarcoma classification by DNA methylation profiling

Sarcomas are malignant soft tissue and bone tumours affecting adults, adolescents and children. They represent a morphologically heterogeneous class of tumours and some entities lack defining histopathological features. Therefore, the diagnosis of sarcomas is burdened with a high inter-observer variability and misclassification rate. Here, we demonstrate classification of soft tissue and bone tumours using a machine learning classifier algorithm based on array-generated DNA methylation data. This sarcoma classifier is trained using a dataset of 1077 methylation profiles from comprehensively pre-characterized cases comprising 62 tumour methylation classes constituting a broad range of soft tissue and bone sarcoma subtypes across the entire age spectrum. The performance is validated in a cohort of 428 sarcomatous tumours, of which 322 cases were classified by the sarcoma classifier. Our results demonstrate the potential of the DNA methylation-based sarcoma classification for research and future diagnostic applications

The Polygenic and Monogenic Basis of Blood Traits and Diseases

Blood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant global health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including data for 563,085 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering a range of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell trait GWAS to interrogate clinically meaningful variants across a wide allelic spectrum of human variation. Analysis of blood cell traits in the UK Biobank and other cohorts illuminates the full genetic architecture of hematopoietic phenotypes, with evidence supporting the omnigenic model for complex traits and linking polygenic burden with monogenic blood diseases

NASH limits anti-tumour surveillance in immunotherapy-treated HCC.

Hepatocellular carcinoma (HCC) can have viral or non-viral causes1-5. Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need6,7. Here we report the progressive accumulation of exhausted, unconventionally activated CD8+PD1+ T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8+PD1+ T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH-HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8+PD1+CXCR6+, TOX+, and TNF+ T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8+ T cells or TNF neutralization, suggesting that CD8+ T cells help to induce NASH-HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8+PD1+ T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH-HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment

Changing perioperative prophylaxis during antibiotic therapy and iterative debridement for orthopedic infections?

BACKGROUND Perioperative antibiotic prophylaxis in non-infected orthopedic surgery is evident, in contrast to prophylaxis during surgery for infection. Epidemiological data are lacking for this particular situation. METHODS AND FINDINGS It is a single-center cohort on iterative surgical site infections (SSIs) in infected orthopedic patients. We included 2480 first episodes of orthopedic infections (median age 56 years and 833 immune-suppressed): implant-related infections (n = 648), osteoarticular infections (1153), and 1327 soft tissue infections. The median number of debridement was 1 (range, 1-15 interventions). Overall, 1617 infections (65%) were debrided once compared to 862 cases that were operated multiple times (35%). Upon iterative intraoperative tissue sampling, we detected pathogens in 507 cases (507/862; 59%), of which 241 (242/507; 48%) corresponded to the initial species at the first debridement. We witnessed 265 new SSIs (11% of the cohort) that were resistant to current antibiotic therapy in 174 cases (7% of the cohort). In multivariate analysis, iterative surgical debridements that were performed under current antibiotic administration were associated with new SSIs (odds ratio 1.6, 95%CI 1.2-2.2); mostly occurring after the 2nd debridement. However, we failed to define an ideal hypothetic prophylaxis during antibiotic therapy to prevent further SSIs. CONCLUSIONS Selection of new pathogens resistant to ongoing antibiotic therapy occurs frequently during iterative debridement in orthopedic infections, especially after the 2nd debridement. The new pathogens are however unpredictable. The prevention, if feasible, probably relies on surgical performance and wise indications for re-debridement instead of new maximal prophylactic antibiotic coverage in addition to current therapeutic regimens

Changing perioperative prophylaxis during antibiotic therapy and iterative debridement for orthopedic infections?

BackgroundPerioperative antibiotic prophylaxis in non-infected orthopedic surgery is evident, in contrast to prophylaxis during surgery for infection. Epidemiological data are lacking for this particular situation.Methods and findingsIt is a single-center cohort on iterative surgical site infections (SSIs) in infected orthopedic patients. We included 2480 first episodes of orthopedic infections (median age 56 years and 833 immune-suppressed): implant-related infections (n = 648), osteoarticular infections (1153), and 1327 soft tissue infections. The median number of debridement was 1 (range, 1-15 interventions). Overall, 1617 infections (65%) were debrided once compared to 862 cases that were operated multiple times (35%). Upon iterative intraoperative tissue sampling, we detected pathogens in 507 cases (507/862; 59%), of which 241 (242/507; 48%) corresponded to the initial species at the first debridement. We witnessed 265 new SSIs (11% of the cohort) that were resistant to current antibiotic therapy in 174 cases (7% of the cohort). In multivariate analysis, iterative surgical debridements that were performed under current antibiotic administration were associated with new SSIs (odds ratio 1.6, 95%CI 1.2-2.2); mostly occurring after the 2nd debridement. However, we failed to define an ideal hypothetic prophylaxis during antibiotic therapy to prevent further SSIs.ConclusionsSelection of new pathogens resistant to ongoing antibiotic therapy occurs frequently during iterative debridement in orthopedic infections, especially after the 2nd debridement. The new pathogens are however unpredictable. The prevention, if feasible, probably relies on surgical performance and wise indications for re-debridement instead of new maximal prophylactic antibiotic coverage in addition to current therapeutic regimens

Changes in Body Weight and Composition Are Associated With Changes in Left Ventricular Geometry and Function in the General Population

Background-The different effects of total body weight (TBW), fat-free mass (FFM), and fat mass (FM) on left ventricular (LV) geometry and function are complex. We investigated the associations of changes over time in TBW, FM, and FFM with changes in LV geometry and function. Methods and Results-We analyzed data from 1189 subjects (694 women), aged 44 to 86 years, from the baseline and the 5-year follow-up examination of the population-based SHIP (Study of Health in Pomerania). TBW was measured, and FFM and FM were calculated based on height-weight models derived from bioelectrical impedance studies. Echocardiographic measurements of LV geometry and function were performed according to the guidelines of the American Society of Echocardiography. Changes in body composition measures were associated with changes in LV geometry and function by multivariable-adjusted linear regression models. A 1-kg increase/decrease in TBW or FM was associated, respectively, with an increase/decrease of 0.89 g or 1.84 g in LV mass, whereas there was no such association on changes in FFM. Moreover, an increase in FM was associated with LV concentric remodeling and impairment of systolic and diastolic function parameters, whereas an increase in FFM was associated with LV eccentric remodeling and improved systolic and diastolic functional variables. Conclusions-Our findings indicate that changes in LV morphology and function depend on the type of body mass composition. Prospective data need to address whether specific changes in body composition over time may affect the risk for heart dysfunction more precisely than the change in TBW

Glucose and insulin levels are associated with arterial stiffness and concentric remodeling of the heart

Background Mortality attributable to heart failure remains high. The prevalence of heart failure in patients with diabetes mellitus ranges from 19 to 26%. It is estimated that up to 21.1 million adults in the United States have diagnosed diabetes mellitus and around 80.8 million have impaired fasting glucose. We investigated the associations of fasting glucose (FG) and fasting insulin (FI), the homeostasis model assessment-insulin resistance index (HOMA-IR) and 2-h postload glucose (2HG) and insulin (2HI) with parameters of left ventricular geometry and function and arterial stiffness determined by magnetic resonance imaging in individuals without diagnosed type 2 diabetes. Methods Cross-sectional analyses of 1001 individuals (453 women, 45.3%), aged 21 to 80 years, from two independent population-based studies, the Study of Health in Pomerania (SHIP-TREND-0) and KORA FF4 Study. FG, FI, HOMA-IR, 2HG and 2HI, as well as glucose tolerance categories, were analyzed for associations with heart and arterial parameters using multivariable-adjusted linear regression models. Results In total, 390 individuals (39%) had prediabetes (isolated impaired fasting glucose, isolated glucose tolerance or both), and 49 (4.9%) were found to have unknown type 2 diabetes. In the multivariable-adjusted analysis, positive linear associations of FG, FI, HOMA-IR, 2HG and 2HI with arterial stiffness index and left ventricular wall-thickness and concentricity and inverse linear associations with left ventricular end-diastolic volume were observed. A 1 mmol/l higher FG was associated with a 1.18 ml/m(2.7) (1.80 to 0.57; p &lt; 0.001) lower left ventricular end-diastolic volume index, a 0.042 mm/m(2.7) (0.014 to 0.070) higher left ventricular wall-thickness index, a 0.12 mmHg m(2.7)/ml (0.06 to 0.17; p &lt; 0.001) greater arterial stiffness index and a 0.037 g/ml (0.018 to 0.056; p &lt; 0.001) higher left ventricular concentricity. Conclusions Our findings suggest that higher glucose levels in the prediabetic range and insulin resistance might lead to higher arterial stiffness and concentric remodeling of the heart

Association between hepatic steatosis and serum liver enzyme levels with atrial fibrillation in the general population

Background: Hepatic steatosis (HS) affects up to 35% of adults in the general population. Atrial fibrillation (AF) is the most prevalent sustained arrhythmia and has a substantial impact on healthcare costs. We analyzed cross-sectional associations of HS and serum liver enzyme levels with prevalent AF in a general population sample. Methods: We analyzed data from 3090 women and men, aged 20-81 years, from the population-based Study of Health in Pomerania. HS was determined by ultrasonography. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyltranspeptidase (GGT) were measured photometrically. AF was determined by automatic electrocardiographic analysis software. Results: The prevalences of HS and AF were 30.3% and 1.49%, respectively. ALT, AST and GGT showed a positive linear association with the risk of prevalent AF, after multivariable adjustment. The adjusted odds ratios for AF per 1-standard deviation increment in log-transformed serum liver enzyme levels were 1.65 (95% confidence interval [CI]: 1.16 to 2.35; p = 0.006) for ALT, 1.47 (95% CI: 1.07 to 2.02; p = 0.017) for AST and 2.17 (95% CI: 1.64 to 2.87; p < 0.001) for GGT. In contrast, ultrasonographic HS was not associated with AF. Conclusions: Our findings indicate that moderately elevated serum liver enzymes, but not sonographic liver hyperechogenicity, were associated with increased AF prevalence in the general adult population. The hepatic release of increased levels of serum liver enzymes might be accompanied by higher levels o