Background Norovirus infection is the leading cause of acute non-bacterial gastroenteritis. Histoblood group antigens (HBGA) are host susceptibility determinants for Norwalk virus (NV) infection. We hypothesized that antibodies that block NV-HBGA binding are associated with protection from clinical illness following NV exposure. Methods We developed an HBGA blocking assay to examine the ability of human serum to block the interaction of NV virus-like particles with H type 1 and H type 3 glycans. Sera from persons experimentally challenged with NV were evaluated. Results There was a high correlation between the H type 1 and H type 3 synthetic glycan assays(r=0.977, p<0.0001); the H type 1 assay had higher quantitative sensitivity (p<0.0001). Among 18 infected secretor-positive individuals, blocking titers peaked by day 28 post-challenge and were higher for individuals who did not develop gastroenteritis than for those who did at days 0,14,28, and 180 (p<0.05 for each). Additionally, 6/6 without gastroenteritis had measurable blocking titers (>25)compared to 2/12 with gastroenteritis (p=0.0015). Conclusions Blocking antibodies correlate with protection against clinical NV gastroenteritis. This knowledge will help guide the evaluation of new vaccine strategies, and elucidation of the nature of immunity to the virus.

Given the considerable lack of evidence supporting its efficacy, we recommend against routine performance of DRE to screen for prostate cancer in the primary care setting.

The transport properties (adsorption and aggregation behavior) of virus-like particles (VLPs) of two strains of norovirus (“Norwalk” GI.1 and “Houston” GII.4) were studied in a variety of solution chemistries. GI.1 and GII.4 VLPs were found to be stable against aggregation at pH 4.0–8.0. At pH 9.0, GI.1 VLPs rapidly disintegrated. The attachment efficiencies (α) of GI.1 and GII.4 VLPs to silica increased with increasing ionic strength in NaCl solutions at pH 8.0. The attachment efficiency of GI.1 VLPs decreased as pH was increased above the isoelectric point (pH 5.0), whereas at and below the isoelectric point, the attachment efficiency was erratic. Ca2+ and Mg2+ dramatically increased the attachment efficiencies of GI.1 and GII.4 VLPs, which may be due to specific interactions with the VLP capsids. Bicarbonate decreased attachment efficiencies for both GI.1 and GII.4 VLPs, whereas phosphate decreased the attachment efficiency of GI.1, while increasing GII.4 attachment efficiency. The observed differences in GI.1 and GII.4 VLP attachment efficiencies in response to solution chemistry may be attributed to differential responses of the unique arrangement of exposed amino acid residues on the capsid surface of each VLP strain.

Background: Burnout among postgraduate medical trainees (PMTs) is increasingly being recognized as a crisis in the medical profession. We aimed to establish the prevalence of burnout among PMTs, identify risk and protective factors, and assess whether burnout varied by country of training, year of study and specialty of practice. Methods: We systematically searched MEDLINE, Embase, PsycINFO, the Cochrane Database of Systematic Reviews, Web of Science and Education Resources Information Center from their inception to Aug. 21, 2018, for studies of burnout among PMTs. The primary objective was to identify the global prevalence of burnout among PMTs. Our secondary objective was to evaluate the association between burnout and country of training, year of study, specialty of training and other sociodemographic factors commonly thought to be related to burnout. We employed random-effects meta-analysis and meta-regression techniques to estimate a pooled prevalence and conduct secondary analyses. Results: In total, 8505 published studies were screened, 196 met eligibility and 114 were included in the meta-analysis. The pooled prevalence of burnout was 47.3% (95% confidence interval 43.1% to 51.5%), based on studies published over 20 years involving 31 210 PMTs from 47 countries. The prevalence of burnout remained unchanged over the past 2 decades. Burnout varied by region, with PMTs of European countries experiencing the lowest level. Burnout rates among medical and surgical PMTs were similar. Interpretation: Current wellness efforts and policies have not changed the prevalence of burnout worldwide. Future research should focus on understanding systemic factors and leveraging these findings to design interventions to combat burnout. Study registration: PROSPERO no. CRD42018108774

Epidemiological evidence shows that regular physical activity is associated with reduced risk of primary and recurrent colon cancer. However, the underlying mechanisms of action are poorly understood. We evaluated the effects of stimulating a human colon cancer cell line (LoVo) with human serum collected before and after an acute exercise bout vs nonexercise control serum on cancer cell proliferation. We also measured exercise-induced changes in serum cytokines and intracellular protein expression to explore potential biological mechanisms. Blood samples were collected from 16 men with lifestyle risk factors for colon cancer (age ≥50 years; body mass index ≥25 kg/m 2 ; physically inactive) before and immediately after an acute bout of moderate-intensity aerobic interval exercise (6 Â 5 minutes intervals at 60% heart rate reserve) and a nonexercise control condition. Stimulating LoVo cells with serum obtained immediately after exercise reduced cancer cell proliferation compared to control (À5.7%; P = .002). This was accompanied by a decrease in LoVo cell γ-H2AX expression (À24.6%; P = .029), indicating a reduction in DNA damage. Acute exercise also increased serum IL-6 (24.6%, P = .002). Furthermore, stimulating LoVo cells with recombinant IL-6 reduced γ-H2AX expression (β = À22.7%; P < .001) and cell proliferation (β = À5.3%; P < .001) in a linear dose-dependent manner, mimicking the effect of exercise. These findings suggest that the systemic responses to acute aerobic exercise inhibit colon cancer cell proliferation in vitro, and this may be driven by IL-6-induced regulation of DNA damage and repair. This mechanism of action may partly underlie epidemiological associations linking regular physical activity with reduced colon cancer risk.

Rotavirus nonstructural protein 4 (NSP4) is a protein with pleiotropic properties. It functions in rotavirus morphogenesis, pathogenesis, and is the first described viral enterotoxin. Since many bacterial toxins function as potent mucosal adjuvants, we evaluated whether baculovirus-expressed recombinant simian rotavirus SA11 NSP4 possesses adjuvant activity by co-administering NSP4 with keyhole limpethemocyanin (KLH), tetanus toxoid (TT) or ovalbumin (OVA) as model antigens in mice. Following intranasal immunization, NSP4 significantly enhanced both systemic and mucosal immune responses to model immunogens, as compared to the control group, in an antigen-specific manner. Both full-length and a cleavage product of SA11 NSP4 had adjuvant activity, localizing this activity to the C-terminus of the protein. NSP4 forms from virulent and avirulent porcine rotavirus OSU strain, and SA11 NSP4 localized withina 2/6 -virus like particle (VLP) also exhibited adjuvant effects. These studies suggest that the rotavirus enterotoxin NSP4 can function as an adjuvant to enhance immune responses for a co-administered antigen.

Rapid immunoanalytical screening of food and environmental samples for small molecular weight (hapten) biotoxin contaminations requires the production of antibody reagents that possess the requisite sensitivity and specificity. To date animal-derived polyclonal (pAb) and monoclonal (mAb) antibodies have provided the binding element of the majority of these assays but recombinant antibodies (rAb) isolated from in vitro combinatorial phage display libraries are an exciting alternative due to (1) circumventing the need for experimental animals, (2) speed of production in commonly used in vitro expression systems and (3) subsequent molecular enhancement of binder performance. Short chain variable fragments (scFv) have been the most commonly employed rAb reagents for hapten biotoxin detection over the last two decades but antibody binding fragments (Fab) and single domain antibodies (sdAb) are increasing in popularity due to increased expression efficiency of functional binders and superior resistance to solvents. rAb-based immunochromatographic assays and surface plasmon resonance (SPR) biosensors have been reported to detect sub-regulatory levels of fungal (mycotoxins), marine (phycotoxins) and aquatic biotoxins in a wide range of food and environmental matrices, however this technology has yet to surpass the performances of the equivalent mAb- and pAb-based formats. As such the full potential of rAb technology in hapten biotoxin detection has yet to be achieved, but in time the inherent advantages of engineered rAb are set to provide the next generation of ultra-high performing binder reagents for the rapid and specific detection of hapten biotoxins.

Background Noroviruses (NoVs) are the most common cause of epidemic gastroenteritis, responsible for at least 50% of all gastroenteritis outbreaks worldwide and were recently identified as a leading cause of travelers’ diarrhea (TD) in U.S. and European travelers to Mexico, Guatemala and India. Methods Serum and diarrheic stool samples were collected from 75 US student travelers to Cuernavaca, Mexico, who developed TD. NoV RNA was detected in acute diarrheic stool samples using RT-PCR. Serology assays were performed using GI.1 Norwalk virus (NV) and GII.4 Houston virus (HOV) virus-like particles (VLP) to measure serum levels of IgA and IgG by Dissociation-Enhanced Lanthanide Fluorescent Immunoassay (DELFIA); serum IgM was measured by capture ELISA, and the 50% antibody blocking titer (BT50) was determined by a carbohydrate-blocking assay. Results NoV infection was identified in 12 (16%; 9 GI-NoV and 3 GII-NoV) of 75 travelers by either RT-PCR or ≥4-fold rise in antibody titer. Significantly more individuals had detectable pre-existing IgA antibodies against HOV (62/75, 83%) than against NV (49/75, 65%) (p=0.025) VLPs. A significant difference was observed between NV- and HOV-specific preexisting IgA antibody levels (p=0.0037), IgG (p=0.003) and BT50 (p=<0.0001). None of the NoV-infected TD travelers had BT50 >200, a level that has been described previously as a possible correlate of protection. Conclusions We found that GI-NoVs are commonly associated with TD cases identified in U.S. adults traveling to Mexico, and seroprevalence rates and geometric mean antibody levels to a GI-NoV were lower than to a GII-NoV strain.