Human oral isolate Lactobacillus fermentum AGR1487 induces a proinflammatory response in germ-free rat colons

Lactobacilli are thought to be beneficial for human health, with lactobacilli-associated infections being confined to immune-compromised individuals. However, Lactobacillus fermentum AGR1487 negatively affects barrier integrity in vitro so we hypothesized that it caused a pro-inflammatory response in the host. We compared germ-free rats inoculated with AGR1487 to those inoculated with another L. fermentum strain, AGR1485, which does not affect in vitro barrier integrity. We showed that rats inoculated with AGR1487 had more inflammatory cells in their colon, higher levels of inflammatory biomarkers, and increased colonic gene expression of pro-inflammatory pathways. In addition, our in vitro studies showed that AGR1487 had a greater capacity to activate TLR signaling and induce pro-inflammatory cytokines in immune cells. This study indicates the potential of strains of the same species to differentially elicit inflammatory responses in the host and highlights the importance of strain characterization in probiotic approaches to treat inflammatory disorders

Volunteer Bias in Recruitment, Retention, and Blood Sample Donation in a Randomised Controlled Trial Involving Mothers and Their Children at Six Months and Two Years: A Longitudinal Analysis

BACKGROUND: The vulnerability of clinical trials to volunteer bias is under-reported. Volunteer bias is systematic error due to differences between those who choose to participate in studies and those who do not. METHODS AND RESULTS: This paper extends the applications of the concept of volunteer bias by using data from a trial of probiotic supplementation for childhood atopy in healthy dyads to explore 1) differences between a) trial participants and aggregated data from publicly available databases b) participants and non-participants as the trial progressed 2) impact on trial findings of weighting data according to deprivation (Townsend) fifths in the sample and target populations. 1) a) Recruits (n = 454) were less deprived than the target population, matched for area of residence and delivery dates (n = 6,893) (mean [SD] deprivation scores 0.09[4.21] and 0.79[4.08], t = 3.44, df = 511, p<0.001). b) i) As the trial progressed, representation of the most deprived decreased. These participants and smokers were less likely to be retained at 6 months (n = 430[95%]) (OR 0.29,0.13-0.67 and 0.20,0.09-0.46), and 2 years (n = 380[84%]) (aOR 0.68,0.50-0.93 and 0.55,0.28-1.09), and consent to infant blood sample donation (n = 220[48%]) (aOR 0.72,0.57-0.92 and 0.43,0.22-0.83). ii) Mothers interested in probiotics or research or reporting infants' adverse events or rashes were more likely to attend research clinics and consent to skin-prick testing. Mothers participating to help children were more likely to consent to infant blood sample donation. 2) In one trial outcome, atopic eczema, the intervention had a positive effect only in the over-represented, least deprived group. Here, data weighting attenuated risk reduction from 6.9%(0.9-13.1%) to 4.6%(-1.4-+10.5%), and OR from 0.40(0.18-0.91) to 0.56(0.26-1.21). Other findings were unchanged. CONCLUSIONS: Potential for volunteer bias intensified during the trial, due to non-participation of the most deprived and smokers. However, these were not the only predictors of non-participation. Data weighting quantified volunteer bias and modified one important trial outcome. TRIAL REGISTRATION: This randomised, double blind, parallel group, placebo controlled trial is registered with the International Standard Randomised Controlled Trials Register, Number (ISRCTN) 26287422. Registered title: Probiotics in the prevention of atopy in infants and children

A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes

dentification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 x 10(-8)) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD.Peer reviewe

Chronic pain after groin hernia repair: pain characteristics and impact on quality of life

Background: Chronic postsurgical pain (CPSP) after hernia repair research has mainly relied on unconfirmed self-reporting. We aimed to describe confirmed CPSP incidence, management, and quality of life (QoL) in a 2-year prospective study. Methods: Multicenter study (GENDOLCAT) of 3890 patients undergoing 4 common surgical procedures in 23 hospitals to develop a risk model for CPSP; 2352 men underwent open hernia repair. Patients with pain were identified by telephone at 1 and 3 months and referred to the hospital 4 months after surgery for a physical examination to confirm CPSP. Three validated tools were used: the Brief Pain Inventory (BPI) for severity, analgesic use, and interference with activities; the SF-12 questionnaire for QoL (validated Spanish version), and the Douleur Neuropathique 4 (DN4). Patients with CPSP were called again at 1 and 2 years. Results: In 1761 patients who underwent hernia repair and were eligible for physical examination for CPSP, the incidence of confirmed pain at 4 months was 13.6% (patient-reported pain, 6.2% at 1 year and 4.0% at 2 years). Neuropathic pain was diagnosed in 38.5% of the CPSP patients at 4 months. The incidences of neuropathic CPSP in patients with mesh or non-mesh repairs were similar (38.6 and 33.3%, respectively). SF-12 physical component scores changed little in all patients, whether or not they developed CPSP. The SF-12 mental component decreased significantly in all patients, but the decrease was clinically significant only in CPSP patients. CPSP interfered with activities (18%), work (15.6%), walking (15%) and mood (10.2%). At 2 years 52.1% of CPSP patients had moderate/intense pain and 28.2% took analgesics. Conclusion: CPSP affects QoL-related activities, and although it diminishes over the course of 2 years after surgery, many patients continue to have moderate/intense pain and take analgesics. CPSP and neuropathic pain rates seem to be similar after mesh and non-mesh repair. BPI and SF-12 mental component scores detect effects on QoL