Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Three-component stereoselective enzymatic synthesis of amino diols and amino-polyols

Amino polyols represent attractive chemical building blocks but can be challenging to synthesize because of the high density of asymmetric functionalities and the need for extensive protection group strategies. Here we present a three-component strategy for the stereoselective enzymatic synthesis of amino diols and amino polyols using a diverse set of prochiral aldehydes, hydroxy ketones and amines as starting materials. We were able to combine biocatalytic aldol reactions, using variants of D-fructose-6-phosphate aldolase (FSA), with reductive aminations catalyzed by IRED-259, identified from a metagenomic library. A two-step process, without the need for intermediate isolation, was developed to avoid cross-reactivity of the carbonyl components. Stereoselective formation of the (R),(R),(R) enantiomers of amino polyols was observed and confirmed by x-ray crystallography

Three-Component Stereoselective Enzymatic Synthesis of Amino-Diols and Amino-Polyols

Amino-polyols represent attractive chemical building blocks but can be challenging to synthesize because of the high density of asymmetric functionalities and the need for extensive protecting-group strategies. Here we present a three-component strategy for the stereoselective enzymatic synthesis of amino-diols and amino-polyols using a diverse set of prochiral aldehydes, hydroxy ketones, and amines as starting materials. We were able to combine biocatalytic aldol reactions, using variants of d-fructose-6-phosphate aldolase (FSA), with reductive aminations catalyzed by IRED-259, identified from a metagenomic library. A two-step process, without the need for intermediate isolation, was developed to avoid cross-reactivity of the carbonyl components. Stereoselective formation of the 2R,3R,4R enantiomers of amino-polyols was observed and confirmed by X-ray crystallography.We kindly acknowledge financial support from the European Research Council (788231-ProgrES-ERC-2017-ADG to S.L.F.; BIO-H-BORROW to N.J.T.). J.R.M. acknowledges the Industrial Biotechnology Innovation Centre (IBioIC) and BBSRC funding through a CASE studentship with Prozomix Ltd. P.C. acknowledges financial support from the project RTI2018-094637-BI00 funded by MCIN/AEI/10.13039/501100011033 and by “ERDF A way of making Europe” and project PCI2018-092937 MCIN/AEI/10.13039/501100011033 cofunded by the UE under the ERACoBioTech Tralaminol (European Union’s Horizon 2020 research and innovation programme grant agreement no. 722361).Peer reviewe

Appendicitis risk prediction models in children presenting with right iliac fossa pain (RIFT study): a prospective, multicentre validation study.

Background Acute appendicitis is the most common surgical emergency in children. Differentiation of acute appendicitis from conditions that do not require operative management can be challenging in children. This study aimed to identify the optimum risk prediction model to stratify acute appendicitis risk in children. Methods We did a rapid review to identify acute appendicitis risk prediction models. A prospective, multicentre cohort study was then done to evaluate performance of these models. Children (aged 5\u201315 years) presenting with acute right iliac fossa pain in the UK and Ireland were included. For each model, score cutoff thresholds were systematically varied to identify the best achievable specificity while maintaining a failure rate (ie, proportion of patients identified as low risk who had acute appendicitis) less than 5%. The normal appendicectomy rate was the proportion of resected appendixes found to be normal on histopathological examination. Findings 15 risk prediction models were identified that could be assessed. The cohort study enrolled 1827 children from 139 centres, of whom 630 (34\ub75%) underwent appendicectomy. The normal appendicectomy rate was 15\ub79% (100 of 630 patients). The Shera score was the best performing model, with an area under the curve of 0\ub784 (95% CI 0\ub782\u20130\ub786). Applying score cutoffs of 3 points or lower for children aged 5\u201310 years and girls aged 11\u201315 years, and 2 points or lower for boys aged 11\u201315 years, the failure rate was 3\ub73% (95% CI 2\ub70\u20135\ub72; 18 of 539 patients), specificity was 44\ub73% (95% CI 41\ub74\u201347\ub72; 521 of 1176), and positive predictive value was 41\ub74% (38\ub75\u201344\ub74; 463 of 1118). Positive predictive value for the Shera score with a cutoff of 6 points or lower (72\ub76%, 67\ub74\u201377\ub74) was similar to that of ultrasound scan (75\ub70%, 65\ub73\u201383\ub71). Interpretation The Shera score has the potential to identify a large group of children at low risk of acute appendicitis who could be considered for early discharge. Risk scoring does not identify children who should proceed directly to surgery. Medium-risk and high-risk children should undergo routine preoperative ultrasound imaging by operators trained to assess for acute appendicitis, and MRI or low-dose CT if uncertainty remains. Funding None

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

Altres ajuts: Department of Health and Social Care (DHSC); Illumina; LifeArc; Medical Research Council (MRC); UKRI; Sepsis Research (the Fiona Elizabeth Agnew Trust); the Intensive Care Society, Wellcome Trust Senior Research Fellowship (223164/Z/21/Z); BBSRC Institute Program Support Grant to the Roslin Institute (BBS/E/D/20002172, BBS/E/D/10002070, BBS/E/D/30002275); UKRI grants (MC_PC_20004, MC_PC_19025, MC_PC_1905, MRNO2995X/1); UK Research and Innovation (MC_PC_20029); the Wellcome PhD training fellowship for clinicians (204979/Z/16/Z); the Edinburgh Clinical Academic Track (ECAT) programme; the National Institute for Health Research, the Wellcome Trust; the MRC; Cancer Research UK; the DHSC; NHS England; the Smilow family; the National Center for Advancing Translational Sciences of the National Institutes of Health (CTSA award number UL1TR001878); the Perelman School of Medicine at the University of Pennsylvania; National Institute on Aging (NIA U01AG009740); the National Institute on Aging (RC2 AG036495, RC4 AG039029); the Common Fund of the Office of the Director of the National Institutes of Health; NCI; NHGRI; NHLBI; NIDA; NIMH; NINDS.Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care or hospitalization 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