Interaction-based Mendelian randomization with measured and unmeasured gene-by-covariate interactions

Studies leveraging gene-environment (GxE) interactions within Mendelian randomization (MR) analyses have prompted the emergence of two similar methodologies: MR-GxE and MR-GENIUS. Such methods are attractive in allowing for pleiotropic bias to be corrected when using individual instruments. Specifically, MR-GxE requires an interaction to be explicitly identified, while MR-GENIUS does not. We critically examine the assumptions of MR-GxE and MR-GENIUS in the absence of a pre-defined covariate, and propose sensitivity analyses to evaluate their performance. Finally, we explore the effect of body mass index (BMI) upon systolic blood pressure (SBP) using data from the UK Biobank, finding evidence of a positive effect of BMI on SBP. We find both approaches share similar assumptions, though differences between the approaches lend themselves to differing research settings. Where a suitable gene-by-covariate interaction is observed MR-GxE can produce unbiased causal effect estimates. MR-GENIUS can circumvent the need to identify interactions, but as a consequence relies on either the MR-GxE assumptions holding globally, or additional information with respect to the distribution of pleiotropic effects in the absence of an explicitly defined interaction covariate

Decreased levels of alpha-1-acid glycoprotein are related to the mortality of septic patients in the emergency department

OBJECTIVE: To determine the validity of alpha-1-acid glycoprotein as a novel biomarker for mortality in patients with severe sepsis. METHODS: We prospectively included patients with severe sepsis or septic shock at the emergency department at a single tertiary referral teaching hospital. All of the patients were enrolled within the first 24 hours of emergency department admission, and clinical data and blood samples were obtained. As the primary outcome, we investigated the association of serum levels of alpha-1-acid glycoprotein and 96-hour mortality with logistic regression analysis and generalized estimating equations adjusted for age, sex, shock status and Acute Physiology and Chronic Health Evaluation II score. RESULTS: Patients with septic shock had lower alpha-1-acid glycoprotein levels at the time of emergency department admission compared to patients without shock (respectively, 149.1 ±42.7 vs. 189.8 ±68.6; p = 0.005). Similarly, non-survivors in the first 96 hours were also characterized by lower levels of alpha-1-acid glycoprotein at the time of emergency department admission compared to survivors (respectively, 132.18 ±50.2 vs. 179.8 ±61.4; p = 0.01). In an adjusted analysis, alpha-1-acid glycoprotein levels ≤120 mg/dL were significantly associated with 96-hour mortality (odds ratio = 14.37; 95% confidence interval = 1.58 to 130.21). CONCLUSION: Septic shock patients exhibited lower circulating alpha-1-acid glycoprotein levels than patients without shock. Alpha-1-acid glycoprotein levels were independently associated with 96-hour mortality in individuals with severe sepsis

Post infectious IBS: defining its clinical features and prognosis using an internet-based survey

Background: Gastrointestinal infection is an important risk factor for developing IBS. Our aim was to characterise postinfectious IBS (PI-IBS) compared to other IBS patients. Methods: An internet survey of IBS patients using Rome III diagnostic questionnaire, Hospital Anxiety & Depression Scale (HADS) and Patient Health Questionnaire-12 somatic symptom score (PHQ12-SS) documenting the mode of onset. Results: 7811 participants, 63.2% female of whom 1004 (13.3%) met criteria for PI-IBS. 70% of PI-IBS described sudden onset, 35% onset while travelling, 49.6% vomiting, 49.9 fever and 20.3% bloody diarrhoea. Compared to other IBS, PI-IBS was significantly associated with living in Northern Europe and North America, having a hysterectomy, not having an appendectomy, higher PHQ12-SS score and having more than one toilet in the family home. PI-IBS patients had more frequent stools. At 1 year recovery rate in PI-IBS and non-PI-IBS group was 19.7% and 22.2%, p=0.15. Recovery rates were lower for females (20.7%) versus males (38.8%), those with somatisation ( 23.0%) versus those without (33.2%) and living in North America or Northern Europe (21.1%) versus living elsewhere (33.9%) p=<0.001. Conclusion: PI-IBS accounts for around 13% of all IBS in this internet sample, with some distinctive features but a similar prognosis to the remainder

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements