Background: Obesity is common in patients with coronavirus disease 2019 (COVID-19). The effects of obesity on clinical outcomes of COVID-19 warrant systematical investigation. Objective: This study explores the effects of obesity with the risk of severe disease among patients with COVID-19. Methods: Body mass index (BMI) and degree of visceral adipose tissue (VAT) accumulation were used as indicators for obesity status. Publication databases including preprints were searched up to August 10, 2020. Clinical outcomes of severe COVID-19 included hospitalization, a requirement for treatment in an intensive care unit (ICU), invasive mechanical ventilation (IMV), and mortality. Risks for severe COVID-19 outcomes are presented as odds ratios (OR) and 95% confidence interval (95%CI) for cohort studies with BMI-defined obesity, and standardized mean difference (SMD) and 95%CI for controlled studies with VAT-defined excessive adiposity. Results: A total of 45, 650 participants from 30 studies with BMI-defined obesity and 3 controlled studies with VAT-defined adiposity were included for assessing the risk of severe COVID-19. Univariate analyses showed significantly higher ORs of severe COVID
Peri-operative SARS-CoV-2 infection increases postoperative mortality. The aim of this study was to determine the optimal duration of planned delay before surgery in patients who have had SARS-CoV-2 infection. This international, multicentre, prospective cohort study included patients undergoing elective or emergency surgery during October 2020. Surgical patients with pre-operative SARS-CoV-2 infection were compared with those without previous SARS-CoV-2 infection. The primary outcome measure was 30-day postoperative mortality. Logistic regression models were used to calculate adjusted 30-day mortality rates stratified by time from diagnosis of SARS-CoV-2 infection to surgery. Among 140,231 patients (116 countries), 3127 patients (2.2%) had a pre-operative SARS-CoV-2 diagnosis. Adjusted 30-day mortality in patients without SARS-CoV-2 infection was 1.5% (95%CI 1.4-1.5). In patients with a pre-operative SARS-CoV-2 diagnosis, mortality was increased in patients having surgery within 0-2 weeks, 3-4 weeks and 5-6 weeks of the diagnosis (odds ratio (95%CI) 4.1 (3.3-4.8), 3.9 (2.6-5.1) and 3.6 (2.0-5.2), respectively). Surgery performed ≥ 7 weeks after SARS-CoV-2 diagnosis was associated with a similar mortality risk to baseline (odds ratio (95%CI) 1.5 (0.9-2.1)). After a ≥ 7 week delay in undertaking surgery following SARS-CoV-2 infection, patients with ongoing symptoms had a higher mortality than patients whose symptoms had resolved or who had been asymptomatic (6.0% (95%CI 3.2-8.7) vs. 2.4% (95%CI 1.4-3.4) vs. 1.3% (95%CI 0.6-2.0), respectively). Where possible, surgery should be delayed for at least 7 weeks following SARS-CoV-2 infection. Patients with ongoing symptoms ≥ 7 weeks from diagnosis may benefit from further delay.
SUMMARY Signaling in the ancestral branch of the unfolded protein response (UPR) is initiated by unconventional splicing of HAC1/XBP1 mRNA during endoplasmic reticulum (ER) stress. In mammals, IRE1α has been known to cleave the XBP1 intron. However, the enzyme responsible for ligation of two XBP1 exons remains unknown. Using an XBP1 splicing-based synthetic circuit, we identify RtcB as the primary UPR RNA ligase. In RtcB knockout cells, XBP1 mRNA splicing is defective during ER stress. Genetic rescue and in vitro splicing show that the RNA ligase activity of RtcB is directly required for the splicing of XBP1 mRNA. Taken together, these data demonstrate that RtcB is the long sought RNA ligase that catalyzes unconventional RNA splicing during the mammalian UPR.
Genetic studies demonstrate that ␥-protocadherins (PCDH-␥) are required for the survival and synaptic connectivity in neuronal subpopulations of the central nervous system. However, the intracellular signaling mechanisms for PCDH-␥ are poorly understood. Here, we show that PCDH-␥ binds two tyrosine kinases, PYK2 and focal adhesion kinase (FAK), and interaction with PCDH-␥ inhibits kinase activity. Consistent with this, PYK2 activity is abnormally up-regulated in the Pcdh-␥-deficient neurons. Overexpression of PYK2 induces apoptosis in the chicken spinal cord. Thus, negative regulation of PYK2 activity by PCDH could contribute to the survival of subsets of neurons. Surprisingly, we found that PCDH-␣ interacts similarly with PYK2 and FAK despite containing a distinct cytoplasmic domain. In neural tissue, PCDH-␥, together with PCDH-␣, forms functional complexes with PYK2 and/or FAK. Therefore, the identification of common intracellular effectors for PCDH-␥ and PCDH-␣ suggests that dozens of protocadherins generated by Pcdh-␣ and Pcdh-␥ gene clusters can converge different extracellular signals into common intracellular pathways.
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