Cyclic GMP-AMP synthase contributes to epithelial homeostasis in intestinal inflammation via Beclin-1-mediated autophagy.

Inflammatory bowel disease (IBD) represents a set of idiopathic and chronic inflammatory diseases of the gastrointestinal tract. Central to the pathogenesis of IBD is a dysregulation of normal intestinal epithelial homeostasis. cGAS is a DNA-sensing receptor demonstrated to promote autophagy, a mechanism that removes dysfunctional cellular components. Beclin-1 is a crucial protein involved in the initiation of autophagy. We hypothesized that cGAS plays a key role in intestinal homeostasis by upregulating Beclin-1-mediated autophagy. We evaluated intestinal cGAS levels in humans with IBD and in murine colonic tissue after performing a 2% dextran sulfate sodium (DSS) colitis model. Autophagy and cell death mechanisms were studied in cGAS KO and WT mice via qPCR, WB analysis, H&E, IF, and TUNEL staining. Autophagy was measured in stimulated intestinal epithelial cells (IECs) via WB analysis. Our data demonstrates cGAS to be upregulated during human and murine colitis. Furthermore, cGAS deficiency leads to worsened colitis and decreased levels of autophagy proteins including Beclin-1 and LC3-II. Co-IP demonstrates a direct binding between cGAS and Beclin-1 in IECs. Transfection of cGAS in stimulated HCT-116 cells leads to increased autophagy. IECs isolated from cGAS KO have diminished autophagic flux. cGAS KO mice subjected to DSS have increased cell death and cleaved caspase-3. Lastly, treatment of cGAS KO mice with rapamycin decreased the severity of colitis. Our data suggest that cGAS maintains intestinal epithelial homeostasis during human IBD and murine colitis by upregulating Beclin-1-mediated autophagy and preventing IEC death. Rescue of autophagy can attenuate the severity of colitis associated with cGAS deficiency.

Insights into effects of algae on decay and distribution of bacterial pathogens in recreational water: Implications for microbial risk management.

The decay and distribution of bacterial pathogens in water is an important information for the health risk assessment to guide water safety management, and suspended algae might affect bacterial pathogens in water. This study established microcosms to investigate the effects of algae-related factors on the representative indicators and opportunistic pathogen species in water. We found that suspended algae increased the persistence of targeted species by 1-2 orders of magnitude of concentrations compared to microcosms without algae; and the effect of algae on microbial survival was affected by water nutrient levels (i.e., carbon, nitrogen and phosphorus), as the increased microbial persistence were correlated to the increased algae concentrations with more nutrient supplies. Moreover, decay and distribution profiles of representative species were determined. The three opportunistic pathogen species (Pseudomonas aeruginosa, Aeromonas hydrophila and Staphylococcus aureus) showed lower decay rates (0.82-0.98/day, 0.76-0.98/day, 0.63-0.87/day) largely affected by algae-related factors, while the enteric species (Escherichia coli and Enterococcus faecalis) had higher decay rates (0.94-1.31/day, 0.89-1.21/day) with little association with algae, indicating the propensity for attachment to algae is an important parameter in microbial fate. Together results suggest suspended algae played an evident role in the decay and distribution of bacterial pathogens, providing important implications regarding microbial safety in recreational water.

Evaluation and improvement of the National Early Warning Score (NEWS2) for COVID-19: a multi-hospital study.

BACKGROUND: The National Early Warning Score (NEWS2) is currently recommended in the UK for the risk stratification of COVID-19 patients, but little is known about its ability to detect severe cases. We aimed to evaluate NEWS2 for the prediction of severe COVID-19 outcome and identify and validate a set of blood and physiological parameters routinely collected at hospital admission to improve upon the use of NEWS2 alone for medium-term risk stratification. METHODS: Training cohorts comprised 1276 patients admitted to King's College Hospital National Health Service (NHS) Foundation Trust with COVID-19 disease from 1 March to 30 April 2020. External validation cohorts included 6237 patients from five UK NHS Trusts (Guy's and St Thomas' Hospitals, University Hospitals Southampton, University Hospitals Bristol and Weston NHS Foundation Trust, University College London Hospitals, University Hospitals Birmingham), one hospital in Norway (Oslo University Hospital), and two hospitals in Wuhan, China (Wuhan Sixth Hospital and Taikang Tongji Hospital). The outcome was severe COVID-19 disease (transfer to intensive care unit (ICU) or death) at 14 days after hospital admission. Age, physiological measures, blood biomarkers, sex, ethnicity, and comorbidities (hypertension, diabetes, cardiovascular, respiratory and kidney diseases) measured at hospital admission were considered in the models. RESULTS: A baseline model of 'NEWS2 + age' had poor-to-moderate discrimination for severe COVID-19 infection at 14 days (area under receiver operating characteristic curve (AUC) in training cohort = 0.700, 95% confidence interval (CI) 0.680, 0.722; Brier score = 0.192, 95% CI 0.186, 0.197). A supplemented model adding eight routinely collected blood and physiological parameters (supplemental oxygen flow rate, urea, age, oxygen saturation, C-reactive protein, estimated glomerular filtration rate, neutrophil count, neutrophil/lymphocyte ratio) improved discrimination (AUC = 0.735; 95% CI 0.715, 0.757), and these improvements were replicated across seven UK and non-UK sites. However, there was evidence of miscalibration with the model tending to underestimate risks in most sites. CONCLUSIONS: NEWS2 score had poor-to-moderate discrimination for medium-term COVID-19 outcome which raises questions about its use as a screening tool at hospital admission. Risk stratification was improved by including readily available blood and physiological parameters measured at hospital admission, but there was evidence of miscalibration in external sites. This highlights the need for a better understanding of the use of early warning scores for COVID.

Morbidity and Mortality After Burr Hole Craniostomy Versus Craniotomy for Chronic Subdural Hematoma Evacuation: A Single-Center Experience.

BACKGROUND: Chronic subdural hematomas (cSDHs) are common neurosurgical pathological entities and typically occur after trauma in elderly patients. The 2 most commonly used strategies for treatment have included burr hole drainage and craniotomy with decompression. However, the choice of these procedures has remained controversial and has been primarily determined by surgeon preference. We designed a matched-cohort analysis to compare these 2 procedures and identify the risk factors associated with the postoperative outcomes. Thus, we compared the rates of reoperation and mortality for patients who had undergone craniotomy versus burr hole evacuation for cSDH. METHODS: A retrospective review examining the data from 299 consecutive patients with cSHDs from 2002 to 2015 was performed. We compared the following endpoints between the 2 procedures: 30-day mortality, discharge to a skilled nursing facility, and the need for reoperation. We also compared the potential risk factors in the patients with different primary outcomes. RESULTS: Patients undergoing craniotomy had a decreased need for reoperation compared with patients treated with burr hole evacuation (7.5% vs. 15.7%; P = 0.044). Older age was associated with both increased disposition to a nursing facility and increased 30-day mortality in both groups. Increased 30-day mortality was associated with aspirin usage in patients who had undergone craniotomy and with warfarin (Coumadin) in patients who had undergone burr hole evacuation. CONCLUSIONS: Our study identified an increased need for reoperation for patients treated with burr hole evacuation compared with those undergoing craniotomy. Older age and low Glasgow coma scale scores were associated with worse outcomes in both groups. Certain methods of anticoagulation were also associated with worse outcomes, which varied between the 2 groups. We recommend that surgeons individualize the choice of procedure according to the specific patient characteristics with consideration of these findings.

Diversity of potential antibiotic-resistant bacterial pathogens and the effect of suspended particles on the spread of antibiotic resistance in urban recreational water.

Evidence of the increasing incidence of antibiotic resistance in watersheds has attracted worldwide attention. Limited in formation is available on the occurrences of health-related antibiotic-resistant bacterial pathogens (ARBPs) in recreational waters. The effects of certain environmental factors (e.g., suspended particles) on the spread of resistance also has not been characterized to date. In this study, a combination of culture and molecular methods was employed to comprehensively investigate the patterns of microbial resistance to representative antibiotics in samples from three recreational lakes in Beijing. The antibiotic resistance index (ARI) based on the gradient concentration assay revealed that samples showed high resistance to penicillin-G, moderate resistance to ampicillin, vancomycin and erythromycin and low resistance to ceftriaxone, gentamycin, tetracycline and chloramphenicol. Antibiotic-resistant bacteria (ARB) were cultured and collected, and the diversity of potential ARBP species was further explored using next-generation sequencing (NGS). The results showed that most of the identified ARBPs were environmental opportunistic pathogens with emerging clinical concerns, e.g., the multidrug-resistant Acinetobacter junii. Furthermore, particle-attached (PA) fractions presented higher ARI values than free-floating (FL) fractions did, indicating that the PA fractions were more resistant to selected antibiotics. And the NGS results revealed that the PA fractions showed higher similarity in the screened ARB community compositions in comparison with the FL fractions, primarily due to a protective effect provided by the particles. Accordingly, ARBPs could persist for a longer time in protective particle matrices. However, quantification of antibiotic-resistant genes (ARGs) by qPCR showed no significant abundance differences between the two fractions. Overall, these findings suggest a potential health risk from the prevalence of ARBPs in recreational waters and provides a better understanding of the contribution of particles in the spread of antibiotic resistance in aquatic systems, with implications for the control of excessive suspended particles by water management.