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Background In the COVID-STEROID 2 trial there was suggestion of heterogeneity of treatment effects (HTE) between patients enrolled from Europe vs. India on the primary outcome. Whether there was HTE for the remaining patient-centred outcomes is unclear. Methods In this post hoc analysis of the COVID-STEROID 2 trial, which compared 12 mg vs. 6 mg dexamethasone in adults with COVID-19 and severe hypoxemia, we evaluated HTE by geographical region (Europe vs. India) for secondary outcomes with analyses adjusted for stratification variables. Results are presented as risk differences (RDs) or mean differences (MDs) with 99% confidence intervals (CIs) and P-values from interaction tests. Findings There were differences in mortality at day 28 (RD for Europe −8.3% (99% CI: −17.7 to 1.0) vs. India 0.1% (99% CI: −10.0 to 10.0)), mortality at day 90 (RD for Europe −7.4% (99% CI: −17.1 to 2.0) vs. India −1.4% (99% CI: −12.8 to 9.8)), mortality at day 180 (RD for Europe −6.7% (99% CI: −16.4 to 2.9) vs. India −1.0% (99% CI: −12.3 to 10.3)), and number of days alive without life support at day 90 (MD for Europe 6.1 days (99% CI: −1.3 to 13.4) vs. India 1.7 days (99% CI: −8.4 to 11.8)). For serious adverse reactions, the direction was reversed (RD for Europe −1.0% (99% CI: −7.1 to 5.2) vs. India −5.3% (99% CI: −16.2 to 5.0). Interpretation Our analysis suggests higher dose dexamethasone may have less beneficial effects for patients in India as compared with those in Europe; however, the evidence is weak, and this could represent a chance finding., Background: In the COVID-STEROID 2 trial there was suggestion of heterogeneity of treatment effects (HTE) between patients enrolled from Europe vs. India on the primary outcome. Whether there was HTE for the remaining patient-centred outcomes is unclear. Methods: In this post hoc analysis of the COVID-STEROID 2 trial, which compared 12 mg vs. 6 mg dexamethasone in adults with COVID-19 and severe hypoxemia, we evaluated HTE by geographical region (Europe vs. India) for secondary outcomes with analyses adjusted for stratification variables. Results are presented as risk differences (RDs) or mean differences (MDs) with 99% confidence intervals (CIs) and P-values from interaction tests. Findings: There were differences in mortality at day 28 (RD for Europe −8.3% (99% CI: −17.7 to 1.0) vs. India 0.1% (99% CI: −10.0 to 10.0)), mortality at day 90 (RD for Europe −7.4% (99% CI: −17.1 to 2.0) vs. India −1.4% (99% CI: −12.8 to 9.8)), mortality at day 180 (RD for Europe −6.7% (99% CI: −16.4 to 2.9) vs. India −1.0% (99% CI: −12.3 to 10.3)), and number of days alive without life support at day 90 (MD for Europe 6.1 days (99% CI: −1.3 to 13.4) vs. India 1.7 days (99% CI: −8.4 to 11.8)). For serious adverse reactions, the direction was reversed (RD for Europe −1.0% (99% CI: −7.1 to 5.2) vs. India −5.3% (99% CI: −16.2 to 5.0). Interpretation: Our analysis suggests higher dose dexamethasone may have less beneficial effects for patients in India as compared with those in Europe; however, the evidence is weak, and this could represent a chance finding. Funding: None for this analysis. The COVID STEROID 2 trial was funded by The Novo Nordisk Foundation and supported by Rigshospitalet's Research Council.

Background: Low-serum levels of magnesium, phosphate, and zinc are observed in many intensive care unit (ICU) patients, but clinical equipoise exists regarding supplementation strategies. We aimed to assess the desirable and undesirable effects of supplementation with magnesium, phosphate, or zinc in adult ICU patients. Methods: We conducted a systematic review with meta-analysis of randomised clinical trials assessing the effects of supplementation with magnesium, phosphate, or zinc in adult ICU patients. Primary outcomes were mortality and duration of mechanical ventilation. We registered the protocol, followed the Preferred Reporting Items for Systematic Review and Meta-Analysis statement, used the Cochrane risk of bias 2 tool, and the grading of recommendations, assessment, development and evaluation (GRADE) approach for assessing the certainty of the evidence. Results: We identified no low risk of bias trials. For magnesium supplementation, we included three trials (n = 235); the relative risk (RR) for mortality was 0.54, 95% confidence interval (CI) 0.30–0.96 compared to no supplementation (very low certainty of evidence). For zinc supplementation, two trials were included (n = 168); the RR for mortality was 0.73, 95% CI 0.41–1.28 compared to control. No trials assessed the effects of phosphate supplementation on mortality. For outcomes other than mortality, only zero or one trial was available. Conclusions: In adult ICU patients, the certainty of evidence for the effects of supplementation with magnesium, phosphate, or zinc was very low. High-quality trials are needed to assess the value of supplementation strategies in these patients.

Background Non-coding genetic variants that influence gene transcription in pancreatic islets play a major role in the susceptibility to type 2 diabetes (T2D), and likely also contribute to type 1 diabetes (T1D) risk. For many loci, however, the mechanisms through which non-coding variants influence diabetes susceptibility are unknown. Results We examine splicing QTLs (sQTLs) in pancreatic islets from 399 human donors and observe that common genetic variation has a widespread influence on the splicing of genes with established roles in islet biology and diabetes. In parallel, we profile expression QTLs (eQTLs) and use transcriptome-wide association as well as genetic co-localization studies to assign islet sQTLs or eQTLs to T2D and T1D susceptibility signals, many of which lack candidate effector genes. This analysis reveals biologically plausible mechanisms, including the association of T2D with an sQTL that creates a nonsense isoform in ERO1B ,a regulator of ER-stress and proinsulin biosynthesis. The expanded list of T2D risk effector genes reveals overrepresented pathways, including regulators of G-protein-mediated cAMP production. The analysis of sQTLs also reveals candidate effector genes for T1D susceptibility such as DCLRE1B ,a senescence regulator, and lncRNA MEG3 .Conclusions These data expose widespread effects of common genetic variants on RNA splicing in pancreatic islets. The results support a role for splicing variation in diabetes susceptibility, and offer a new set of genetic targets with potential therapeutic benefit., info:eu-repo/semantics/published

Importance A daily dose with 6 mg of dexamethasone is recommended for up to 10 days in patients with severe and critical COVID-19, but a higher dose may benefit those with more severe disease. Objective To assess the effects of 12 mg/d vs 6 mg/d of dexamethasone in patients with COVID-19 and severe hypoxemia. Design, Setting, and Participants A multicenter, randomized clinical trial was conducted between August 2020 and May 2021 at 26 hospitals in Europe and India and included 1000 adults with confirmed COVID-19 requiring at least 10 L/min of oxygen or mechanical ventilation. End of 90-day follow-up was on August 19, 2021. Interventions Patients were randomized 1:1 to 12 mg/d of intravenous dexamethasone (n = 503) or 6 mg/d of intravenous dexamethasone (n = 497) for up to 10 days. Main Outcomes and Measures The primary outcome was the number of days alive without life support (invasive mechanical ventilation, circulatory support, or kidney replacement therapy) at 28 days and was adjusted for stratification variables. Of the 8 prespecified secondary outcomes, 5 are included in this analysis (the number of days alive without life support at 90 days, the number of days alive out of the hospital at 90 days, mortality at 28 days and at 90 days, and ≥1 serious adverse reactions at 28 days). Results Of the 1000 randomized patients, 982 were included (median age, 65 [IQR, 55-73] years; 305 [31%] women) and primary outcome data were available for 971 (491 in the 12 mg of dexamethasone group and 480 in the 6 mg of dexamethasone group). The median number of days alive without life support was 22.0 days (IQR, 6.0-28.0 days) in the 12 mg of dexamethasone group and 20.5 days (IQR, 4.0-28.0 days) in the 6 mg of dexamethasone group (adjusted mean difference, 1.3 days [95% CI, 0-2.6 days]; P = .07). Mortality at 28 days was 27.1% in the 12 mg of dexamethasone group vs 32.3% in the 6 mg of dexamethasone group (adjusted relative risk, 0.86

Genome-scale human protein-protein interaction networks are critical to understanding cell biology and interpreting genomic data, but challenging to produce experimentally. Through data integration and quality control, we provide a scored human protein-protein interaction network (InWeb_InBioMap, or InWeb_IM) with severalfold more interactions (>500,000) and better functional biological relevance than comparable resources. We illustrate that InWeb_InBioMap enables functional interpretation of >4,700 cancer genomes and genes involved in autism.

Udgivelsesdato: 2010-null, Eukaryotic cells replicate by a complex series of evolutionarily conserved events that are tightly regulated at defined stages of the cell division cycle. Progression through this cycle involves a large number of dedicated protein complexes and signaling pathways, and deregulation of this process is implicated in tumorigenesis. We applied high-resolution mass spectrometry-based proteomics to investigate the proteome and phosphoproteome of the human cell cycle on a global scale and quantified 6027 proteins and 20,443 unique phosphorylation sites and their dynamics. Co-regulated proteins and phosphorylation sites were grouped according to their cell cycle kinetics and compared to publicly available messenger RNA microarray data. Most detected phosphorylation sites and more than 20% of all quantified proteins showed substantial regulation, mainly in mitotic cells. Kinase-motif analysis revealed global activation during S phase of the DNA damage response network, which was mediated by phosphorylation by ATM or ATR or DNA-dependent protein kinases. We determined site-specific stoichiometry of more than 5000 sites and found that most of the up-regulated sites phosphorylated by cyclin-dependent kinase 1 (CDK1) or CDK2 were almost fully phosphorylated in mitotic cells. In particular, nuclear proteins and proteins involved in regulating metabolic processes have high phosphorylation site occupancy in mitosis. This suggests that these proteins may be inactivated by phosphorylation in mitotic cells.