A population survey of bowel habits in urban Swiss men

The aim of this study was to determine the prevalence of symptoms related to constipation in urban Swiss men and to identify associated sociodemographic factors and health habits. A sample of 773 men aged between 35 and 74 years randomly selected from the Geneva population answered a questionnaire on bowel habits during a personal interview in a mobile epidemiological unit. ‘Constipation' was reported by more than 6% of subjects, difficulties in stool evacuation by approximately 5% and less than three stools per week by approximately 2%. These symptoms appeared less prevalent in subjects with post-baccalaureate education (the excess prevalence of self-reported constipation, difficulty in stool evacuation and frequent daily defecation was greater than 5%). Smokers were more likely to have a frequency of 3-7 stools per week and were less affected by frequent daily defecation. Self-reported constipation was more prevalent in subjects with a higher dietary fibre intake. No statistically significant effects of age, nationality, dietary fat or physical activity were observed. These results are consistent with national surveys in US populations. Factors related to socioeconomic status or education may be a cause of constipation in men, but they still need to be elucidate

A high-dose pharmacokinetic study of a new IgG4 monoclonal antibody temelimab/GNbAC1 antagonist of an endogenous retroviral protein pHERV-W Env

PURPOSE : Temelimab/GNbAC1 is a humanized immunoglobulin G4 monoclonal antibody antagonist of the human endogenous retrovirus W envelope protein, which is associated with multiple sclerosis (MS) pathophysiology and possibly with other autoimmune disorders. Human endogenous retrovirus W envelope protein is expressed in the central nervous system of patients with MS, and sufficient amount of temelimab must reach the target. The safety of very high dosages of temelimab should be tested to support further clinical trials in MS. METHODS : This randomized, placebo-controlled, dose-escalation study evaluated the safety and pharmacokinetic profile of temelimab in 24 healthy volunteers after a single intravenous infusion at doses of 36, 60, 85, and 110 mg/kg administered sequentially. FINDINGS : Temelimab was well tolerated, with no particular adverse drug reactions at any dose. The maximal dose of 110 mg/kg could be administered, and no antidrug antibodies were induced. After administration of 36–110 mg/kg, mean temelimab Cmax increased from 859 to 2450 μg/mL, and AUC values increased from 319,900 to 1,030,000 μg·h/mL. There was an approximate dose-proportional increase in exposure, similar to observations at lower doses. IMPLICATIONS : The favorable data in terms of safety and pharmacokinetic variables support temelimab use at high doses in future MS trials to optimally neutralize the temelimab target in the central nervous system. ClinicalTrials.gov identifier: NCT03574428.GeNeuro SAhttps://www.journals.elsevier.com/clinical-therapeutics2020-09-01hj2020Pharmacolog

A new therapeutic approach for type 1 diabetes : rationale for GNbAC1, an anti‐HERV‐W‐Env monoclonal antibody

We describe a newly identified therapeutic target for type 1 diabetes (T1D): an envelope protein of endogenous retroviral origin, human endogenous retrovirus W envelope (HERV‐W‐Env). HERV‐W‐Env was found to be detected in the blood of ~60% of patients with T1D and is expressed in acinar pancreatic cells of 75% of patients with T1D at post mortem examination. Preclinical experiments showed that this protein displays direct cytotoxicity on human β‐islet cells. In vivo HERV‐W‐Env impairs the insulin and glucose metabolism in transgenic mice expressing HERV‐W‐Env. GNbAC1, an IgG4 monoclonal antibody, has been developed to specifically target HERV‐W‐Env and to neutralize the effect of HERV‐W‐Env in vitro and in vivo. GNbAC1 is currently in clinical development for multiple sclerosis and > 300 subjects have been administered with GNbAC1 so far. GNbAC1 is now being tested in T1D in the RAINBOW‐T1D study, which is a randomized placebo‐controlled study with the objective of showing the safety and pharmacodynamic response of GNbAC1 in patients who have had T1D with a maximum of 4 years' duration. GNbAC1 is being tested vs placebo at the dose of 6 mg/kg in 60 patients during six repeated administrations for 6 months; a 6‐month open‐label extension will follow. The primary endpoint is to assess safety, and secondary endpoints are the pharmacodynamic responses to GNbAC1. GNbAC1 targeting HERV‐W‐Env is currently in clinical development in T1D, with the first safety and pharmacodynamic study. If the study results are positive, this may open the door to the development of an innovative non‐immunomodulatory disease‐modifying treatment for T1D.The RAINBOW-T1D study is financed by GeNeuro Australia Pty Ltd, a subsidiary of GeNeuro SA, Switzerland.http://wileyonlinelibrary.com/journal/dom2019-09-01hj2018Pharmacolog

Carotid plaque surface echogenicity predicts cerebrovascular events: An Echographic Multicentric Swiss Study.

BACKGROUND AND PURPOSE To determine the prognostic value for ischemic stroke or transitory ischemic attack (TIA) of plaque surface echogenicity alone or combined to degree of stenosis in a Swiss multicenter cohort METHODS: Patients with ≥60% asymptomatic or ≥50% symptomatic carotid stenosis were included. Grey-scale based colour mapping was obtained of the whole plaque and of its surface defined as the regions between the lumen and respectively 0-0.5, 0-1, 0-1.5, and 0-2 mm of the outer border of the plaque. Red, yellow and green colour represented low, intermediate or high echogenicity. Proportion of red color on surface (PRCS) reflecting low echogenictiy was considered alone or combined to degree of stenosis (Risk index, RI). RESULTS We included 205 asymptomatic and 54 symptomatic patients. During follow-up (median/mean 24/27.7 months) 27 patients experienced stroke or TIA. In the asymptomatic group, RI ≥0.25 and PRCS ≥79% predicted stroke or TIA with a hazard ratio (HR) of respectively 8.7 p = 0.0001 and 10.2 p < 0.0001. In the symptomatic group RI ≥0.25 and PRCS ≥81% predicted stroke or TIA occurrence with a HR of respectively 6.1 p = 0.006 and 8.9 p = 0.001. The best surface parameter was located at 0-0.5mm. Among variables including age, sex, degree of stenosis, stenosis progression, RI, PRCS, grey median scale values and clinical baseline status, only PRCS independently prognosticated stroke (p = 0.005). CONCLUSION In this pilot study including patients with at least moderate degree of carotid stenosis, PRCS (0-0.5mm) alone or combined to degree of stenosis strongly predicted occurrence of subsequent cerebrovascular events

Meta-analyses involving cross-over trials: methodological issues.

BACKGROUND: Meta-analysis of randomized controlled trials (RCTs) is usually based on trials where patients are randomized individually into two different, parallel, treatment groups. This paper concentrates on RCTs of a different design-two-period, two-treatment cross-over trials. METHODS: The characteristics of these trials are outlined, with detailed examples of methods for analysis for both continuous and binary data. These case studies are then extended into the context of a meta-analysis. The Cochrane Library was surveyed to assess current practice for synthesis. RESULTS: Methods are described for continuous and binary data for use both when the necessary paired data are given and also when they need to be calculated or imputed, and some suggestions are provided to help people wishing to synthesize data from cross-over trials into meta-analyses. The survey suggested that about 8% of the trials in the Cochrane library were cross-over trials and 18% of the reviews referred to such trials, although there was no consistent approach to their inclusion into the reviews. CONCLUSIONS: Methods do exist for including valuable information from two-period, two-treatment cross-over trials into quantitative reviews. However, poor reporting of cross-over trials will often impede attempts to perform a meta-analysis using the available methods

Fms-Like Tyrosine Kinase 3 Ligand Recruits Plasmacytoid Dendritic Cells to the Brain

The lack of professional afferent APCs in naive brain parenchyma contributes to the systemic immune ignorance to Ags localized exclusively within the brain. Dendritic cells (DCs) appear within the brain as a consequence of inflammation, but no molecular mechanisms accounting for this influx have been described. In this study we demonstrate that Fms-like tyrosine kinase 3 ligand (Flt3L) recruits plasmacytoid DCs (pDCs; >50-fold; p < 0.001) to the brain parenchyma. These pDCs expressed IFN-alpha, the hallmark cytokine produced by pDCs, indicating recruitment and activation in situ of bona fide pDCs within the brain parenchyma. Flt3L did not increase the numbers of conventional DCs, macrophages, or B, T, NK, NKT, or microglial cells within the brain. Our data demonstrate that Flt3L reconstitutes a crucial afferent component of the immune response, namely, professional APCs within the brain parenchyma, and this could counteract the intrinsic systemic immune ignorance to Ags localized exclusively within the brain