Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Oxygen reduction reaction features in neutral media on glassy carbon electrode functionalized by chemically prepared gold nanoparticles

Gold nanoparticles (AuNPs) were prepared by chemical route using 4 different protocols by varying reducer, stabilizing agent and solvent mixture. The obtained AuNPs were characterized by transmission electronic microscopy (TEM), UV-Visible and zeta potential measurements. From these latter surface charge densities were calculated to evidence the effect of the solvent mixture on AuNPs stability. The AuNPs were then deposited onto glassy carbon (GC) electrodes by drop-casting and the resulting deposits were characterized by cyclic voltammetry (CV) in H2SO4 and field emission gun scanning electron microscopy (FEG-SEM). The electrochemical kinetic parameters of the 4 different modified electrodes towards oxygen reduction reaction (ORR) in neutral NaCl-NaHCO3 media (0.15 M / 0.028 M, pH 7.4) were evaluated by rotating disk electrode voltammetry and subsequent Koutecky-Levich treatment. Contrary to what we previously obtained with electrodeposited AuNPs [Gotti et al., Electrochim. Acta 2014], the highest cathodic transfer coefficients were not obtained on the smallest particles, highlighting the influence of the stabilizing ligand together with the deposits morphology on the ORR kinetics

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Intubation in burns patients:a 5-year review of the Manchester regional burns centre experience

Despite criteria to guide intubation from the American Burn Association (ABA), concerns remain regarding over-intubation of burns patients. The purpose of this study was to review appropriateness of intubation at a UK regional burns centre over a 5-year period.A 5-year retrospective review of adult patients admitted to the Manchester Burns Centre who underwent intubation at or prior to admission was performed. Intubations for non-burn indications or burns >40%TBSA were excluded. Patient demographic and burn characteristics data were extracted from medical records. Indications for intubation were compared to ABA and Denver criteria.47 patients were identified, of which 40 met inclusion criteria for analysis. 72.5% and 95% of these patients met ABA or Denver criteria respectively. 30.8% of patients were extubated within 48 h. 50% patients extubated within 48 h had ≤1 indication for intubation or negative laryngoscopy. Complications related to intubation and ventilation were noted in 37.5% of patients, with ventilation associated pneumonia (VAP) being the most common occurring in 27.5%.95% of patients fulfilled recognised criteria for intubation. However, 30% were extubated within 48 h, suggesting potentially avoidable intubation. This study suggests current intubation criteria may over-estimate risk of airway compromise and supports results from non-UK studies that a proportion of patients may be suitable for close observation rather than early intubation

Microvascular coaptation methods: device manufacture and computational simulation

The practice of joining blood vessels has been ongoing since the late nineteenth century, although it was initially restricted to animal studies and experimental techniques. At this time, fine silk thread and curved needles had been introduced (1), which was a significant advancement on previous suture materials such as leather, tendon and catgut (2) – although these were used for wound closure rather than vascular repair. It was not until the mid twentieth century, circa World War II, that vascular anastomoses were performed whilst repairing or reconstructing traumatic injuries (3). The natural progression from repairing vascular injuries was to perform these procedures in smaller and smaller vessels. Of course, this necessitated use of an operating microscope and development and manufacture of finer suture materials, needles, and more delicate instruments. This chapter aims to provide details of the common microvascular anastomotic devices and their manufacture

Uncovering genetic mechanisms of hypertension through multi-omic analysis of the kidney.

From PubMed via Jisc Publications RouterHistory: received 2020-01-10, accepted 2021-03-04Publication status: ppublishFunder: U.S. Department of Health & Human Services | National Institutes of Health (NIH); Grant(s): R01 DK117445-01A1Funder: NIDDK NIH HHS; Grant(s): R01 DK108805, R01 DK119380, R01 DK108805, R01 DK119380Funder: Kidney Research UK; Grant(s): RP_017_20180302Funder: Gates Cambridge Trust; Grant(s): OPP1144Funder: British Heart Foundation (BHF); Grant(s): PG/19/16/34270, CH/13/2/30154, PG/19/84/34771Funder: Wellcome Trust (Wellcome); Grant(s): WT206194Funder: RCUK | Medical Research Council (MRC); Grant(s): MR/R010900/1Funder: EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: "Ideas" Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013)); Grant(s): ERC-CoG-Inflammatension 726318The kidney is an organ of key relevance to blood pressure (BP) regulation, hypertension and antihypertensive treatment. However, genetically mediated renal mechanisms underlying susceptibility to hypertension remain poorly understood. We integrated genotype, gene expression, alternative splicing and DNA methylation profiles of up to 430 human kidneys to characterize the effects of BP index variants from genome-wide association studies (GWASs) on renal transcriptome and epigenome. We uncovered kidney targets for 479 (58.3%) BP-GWAS variants and paired 49 BP-GWAS kidney genes with 210 licensed drugs. Our colocalization and Mendelian randomization analyses identified 179 unique kidney genes with evidence of putatively causal effects on BP. Through Mendelian randomization, we also uncovered effects of BP on renal outcomes commonly affecting patients with hypertension. Collectively, our studies identified genetic variants, kidney genes, molecular mechanisms and biological pathways of key relevance to the genetic regulation of BP and inherited susceptibility to hypertension