Human genetic variation in VAC14 regulates Salmonella invasion and typhoid fever through modulation of cholesterol.

Risk, severity, and outcome of infection depend on the interplay of pathogen virulence and host susceptibility. Systematic identification of genetic susceptibility to infection is being undertaken through genome-wide association studies, but how to expeditiously move from genetic differences to functional mechanisms is unclear. Here, we use genetic association of molecular, cellular, and human disease traits and experimental validation to demonstrate that genetic variation affects expression of VAC14, a phosphoinositide-regulating protein, to influence susceptibility to Salmonella enterica serovar Typhi (S Typhi) infection. Decreased VAC14 expression increased plasma membrane cholesterol, facilitating Salmonella docking and invasion. This increased susceptibility at the cellular level manifests as increased susceptibility to typhoid fever in a Vietnamese population. Furthermore, treating zebrafish with a cholesterol-lowering agent, ezetimibe, reduced susceptibility to S Typhi. Thus, coupling multiple genetic association studies with mechanistic dissection revealed how VAC14 regulates Salmonella invasion and typhoid fever susceptibility and may open doors to new prophylactic/therapeutic approaches.

Perturbation of placental protein glycosylation by endoplasmic reticulum stress promotes maladaptation of maternal hepatic glucose metabolism.

Placental hormones orchestrate maternal metabolic adaptations to support pregnancy. We hypothesized that placental ER stress, which characterizes early-onset pre-eclampsia (ePE), compromises glycosylation, reducing hormone bioactivity and these maladaptations predispose the mother to metabolic disease in later life. We demonstrate ER stress reduces the complexity and sialylation of trophoblast protein N-glycosylation, while aberrant glycosylation of vascular endothelial growth factor reduced its bioactivity. ER stress alters the expression of 66 of the 146 genes annotated with "protein glycosylation" and reduces the expression of sialyltransferases. Using mouse placental explants, we show ER stress promotes the secretion of mis-glycosylated glycoproteins. Pregnant mice carrying placentas with junctional zone-specific ER stress have reduced blood glucose, anomalous hepatic glucose metabolism, increased cellular stress and elevated DNA methyltransferase 3A. Using pregnancy-specific glycoproteins as a readout, we also demonstrate aberrant glycosylation of placental proteins in women with ePE, thus providing a mechanistic link between ePE and subsequent maternal metabolic disorders.

Improving the Timeliness of Discharge Summary Communication: A Quality Improvement Project.

Introduction A recognised problem in the Royal Devon & Exeter Hospital and across the NHS is that discharge summaries are often sent to general practitioners (GP) long after the patient is discharged, or not at all. This is a safety issue when for example the summary includes time-sensitive requests for the GP or information relevant to ongoing care. Methods A quality improvement project was devised to tackle this important problem. First, the Royal Devon & Exeter Hospital's electronic patient record system was used to construct a report allowing measurement of the scale of this problem and stratification by factors such as discharging department or ward. This report identified that 22.6% (12,965/57,367) of discharge summaries are sent outside the Trust's target (two working days from discharge). A three-pronged approach was devised targeting discharges of deceased patients using educational material, discharges from a medical ward using an automated list, and finally optimising the technical steps required to send a discharge summary to attempt to reduce the delay. Results Plan, do, study and act (PDSA) cycles were implemented, one targeting discharges for deceased patients and another targeting discharges from a medical ward. Though not sustained, the former resulted in a six-week increase in the percentage of discharge summaries sent within the target from 50% to 80%. The latter did not lead to improvement due to a number of factors including workload in the midst of a global pandemic and other factors explored in a root cause analysis. The most ambitious intervention aimed to automate an administrative step, which proved challenging due to software and human factors. As such this intervention was not completed during the study period. Conclusion The sending of discharge summaries is often delayed and this has potential consequences for patient care. This study has used the hospital's electronic patient record system to create a report which provides detailed information on areas with the most potential for improvement. Though the targeted interventions were respectively nonsustained, unsuccessful and not implemented, this data can suggest reasons behind poor performance and therefore targets for future interventions, illustrating great sustainability.

Metabolic adverse events associated with systemic corticosteroid therapy-a systematic review and meta-analysis.

OBJECTIVES: To assess the risk of new-onset or worsening hyperglycaemia, hypertension, weight gain and hyperlipidaemia with systemic corticosteroid therapy (CST) as reported in published randomised control trial (RCT) studies. DATA SOURCES: Literature search using MEDLINE, EMBASE, Cochrane library, Web of Science and Scopus STUDY ELIGIBILITY CRITERIA: Published articles on results of RCT with a systemic CST arm with numerical data presented on adverse effect (AE). PARTICIPANTS AND INTERVENTIONS: Reports of hyperglycaemia, hypertension, weight gain and hyperlipidaemia associated with systemic CST in patients or healthy volunteer's ≥17 years of age. STUDY APPRAISAL METHODS: Risk of bias tool, assessment at the level of AE and key study characteristics. RESULTS: A total of 5446 articles were screened to include 118 studies with 152 systemic CST arms (total participants=17 113 among which 8569 participants treated with CST). Pooled prevalence of hyperglycaemia in the CST arms within the studies was 10% (95% CI 7% to 14%), with the highest prevalence in respiratory illnesses at 22% (95% CI 9% to 35%). Pooled prevalence of severe hyperglycaemia, hypertension, weight gain and hyperlipidaemia within the corticosteroid arms was 5% (95% CI 2% to 9%), 6% (95% CI 4% to 8%), 13% (95% CI 8% to 18%), 8% (95% CI 4% to 17%), respectively. CST was significantly associated hyperglycaemia, hypertension and weight gain as noted in double-blinded placebo-controlled parallel-arms studies: OR of 2.13 (95% CI 1.66 to 2.72), 1.68 (95% CI 0.96 to 2.95) and 5.20 (95% CI 2.10 to 12.90), respectively. Intravenous therapy posed higher risk than oral therapy: OR of 2.39 (95% CI 1.16 to 4.91). LIMITATIONS: There was significant heterogeneity in the AE definitions and quality of AE reporting in the primary studies and patient populations in the studies. The impact of cumulative dose effect on incidental AE could not be calculated. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: Systemic CST use is associated with increased risk of metabolic AEs, which differs for each disease group and route of administration. PROSPERO REGISTRATION NUMBER: CRD42020161270.

Seasonal variability of sediment controls of carbon cycling in an agricultural stream.

Streams and rivers are 'active pipelines' where high rates of carbon (C) turnover can lead to globally important emissions of carbon dioxide (CO2) and methane (CH4) from surface waters to the atmosphere. Streambed sediments are particularly important in affecting stream chemistry, with rates of biogeochemical activity, and CO2 and CH4 concentrations far exceeding those in surface waters. Despite an increase in research on CO2 and CH4 in streambed sediments there is a lack of knowledge and insight on seasonal dynamics. In this study the seasonally variable effect of sediment type (sand-dominated versus gravel-dominated) on porewater C cycling, including CO2 and CH4 concentrations, was investigated. We found high concentrations of CO2 and CH4 in the streambed of a small agricultural stream. Sand-dominated sediments were characterised by higher microbial activity and CO2 and CH4 concentrations than gravel-dominated sediments, with CH4:CO2 ratios higher in sand-dominated sediments but rates of recalcitrant C uptake highest in gravel-dominated sediments. CO2 and CH4 concentrations were unexpectedly high year-round, with little variation in concentrations among seasons. Our results indicate that small, agricultural streams, which generally receive large amounts of fine sediment and organic matter (OM), may contribute greatly to annual C cycling in freshwater systems. These results should be considered in future stream management plans where the removal of sandy sediments may perform valuable ecosystem services, reducing C turnover, CO2 and CH4 concentrations, and mitigating greenhouse gas (GHG) production.