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

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

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

Best anaesthetic drug strategy for morbidly obese patients

Purpose of review: The purpose of this review is to describe an evidence-based drug strategy applicable to any obese patient, rather than to present one standard ideal' anaesthetic drug combination. The ultimate choice of specific drugs in any given situation will depend upon clinician experience, patient specifics, and drug availability. The fundamental principle in anaesthesia for the obese patient is to use the shortest acting, least fat soluble agents to ensure rapid recovery to safe levels of alertness and mobility. Recent findings: No new drugs have been introduced over the past few years, but we have seen an introduction of enhanced recovery after surgery-based protocols into bariatric surgery. Our understanding of how obesity affects pharmacokinetics/dynamics of our drugs is improving, with new and better use of established drugs. Allometric scaling is being tested in the different pharmacokinetic/dynamic models used in target controlled infusion devices, with improved performance as a result. Obstructive sleep apnoea has a significant impact upon outcome and utilization of clinical resources, including critical care beds. If an improved drug dosing strategy will reduce this impact, then this would be a step forward. Summary: This review introduces newer findings to help us use anaesthetic and analgesic drugs more safely in the morbidly obese. However, there remain many areas of uncertainty with a lack of consensus on many issues

Perioperative management of obstructive sleep apnea in bariatric surgery: a consensus guideline

BACKGROUND: The frequency of metabolic and bariatric surgery (MBS) is increasing worldwide, with over 500,000 cases performed every year. Obstructive sleep apnea (OSA) is present in 35%-94% of MBS patients. Nevertheless, consensus regarding the perioperative management of OSA in MBS patients is not established. OBJECTIVES: To provide consensus based guidelines utilizing current literature and, when in the absence of supporting clinical data, expert opinion by organizing a consensus meeting of experts from relevant specialties. SETTING: The meeting was held in Amsterdam, the Netherlands. METHODS: A panel of 15 international experts identified 75 questions covering preoperative screening, treatment, postoperative monitoring, anesthetic care and follow-up. Six researchers reviewed the literature systematically. During this meeting, the "Amsterdam Delphi Method" was utilized including controlled acquisition of feedback, aggregation of responses and iteration. RESULTS: Recommendations or statements were provided for 58 questions. In the judgment of the experts, 17 questions provided no additional useful information and it was agreed to exclude them. With the exception of 3 recommendations (64%, 66%, and 66% respectively), consensus (>70%) was reached for 55 statements and recommendations. Several highlights: polysomnography is the gold standard for diagnosing OSA; continuous positive airway pressure is recommended for all patients with moderate and severe OSA; OSA patients should be continuously monitored with pulse oximetry in the early postoperative period; perioperative usage of sedatives and opioids should be minimized. CONCLUSION: This first international expert meeting provided 58 statements and recommendations for a clinical consensus guideline regarding the perioperative management of OSA patients undergoing MBS.status: publishe

Perioperative management of obstructive sleep apnea in bariatric surgery : a consensus guideline

Background: The frequency of metabolic and bariatric surgery (MBS) is increasing worldwide, with over 500,000 cases performed every year. Obstructive sleep apnea (OSA) is present in 35%–94% of MBS patients. Nevertheless, consensus regarding the perioperative management of OSA in MBS patients is not established. Objectives: To provide consensus based guidelines utilizing current literature and, when in the absence of supporting clinical data, expert opinion by organizing a consensus meeting of experts from relevant specialties. Setting: The meeting was held in Amsterdam, the Netherlands. Methods: A panel of 15 international experts identified 75 questions covering preoperative screening, treatment, postoperative monitoring, anesthetic care and follow-up. Six researchers reviewed the literature systematically. During this meeting, the “Amsterdam Delphi Method” was utilized including controlled acquisition of feedback, aggregation of responses and iteration. Results: Recommendations or statements were provided for 58 questions. In the judgment of the experts, 17 questions provided no additional useful information and it was agreed to exclude them. With the exception of 3 recommendations (64%, 66%, and 66% respectively), consensus (>70%) was reached for 55 statements and recommendations. Several highlights: polysomnography is the gold standard for diagnosing OSA; continuous positive airway pressure is recommended for all patients with moderate and severe OSA; OSA patients should be continuously monitored with pulse oximetry in the early postoperative period; perioperative usage of sedatives and opioids should be minimized. Conclusion: This first international expert meeting provided 58 statements and recommendations for a clinical consensus guideline regarding the perioperative management of OSA patients undergoing MBS