Postoperative continuous positive airway pressure to prevent pneumonia, re-intubation, and death after major abdominal surgery (PRISM): a multicentre, open-label, randomised, phase 3 trial

Background: Respiratory complications are an important cause of postoperative morbidity. We aimed to investigate whether continuous positive airway pressure (CPAP) administered immediately after major abdominal surgery could prevent postoperative morbidity. Methods: PRISM was an open-label, randomised, phase 3 trial done at 70 hospitals across six countries. Patients aged 50 years or older who were undergoing elective major open abdominal surgery were randomly assigned (1:1) to receive CPAP within 4 h of the end of surgery or usual postoperative care. Patients were randomly assigned using a computer-generated minimisation algorithm with inbuilt concealment. The primary outcome was a composite of pneumonia, endotracheal re-intubation, or death within 30 days after randomisation, assessed in the intention-to-treat population. Safety was assessed in all patients who received CPAP. The trial is registered with the ISRCTN registry, ISRCTN56012545. Findings: Between Feb 8, 2016, and Nov 11, 2019, 4806 patients were randomly assigned (2405 to the CPAP group and 2401 to the usual care group), of whom 4793 were included in the primary analysis (2396 in the CPAP group and 2397 in the usual care group). 195 (8\ub71%) of 2396 patients in the CPAP group and 197 (8\ub72%) of 2397 patients in the usual care group met the composite primary outcome (adjusted odds ratio 1\ub701 [95% CI 0\ub781-1\ub724]; p=0\ub795). 200 (8\ub79%) of 2241 patients in the CPAP group had adverse events. The most common adverse events were claustrophobia (78 [3\ub75%] of 2241 patients), oronasal dryness (43 [1\ub79%]), excessive air leak (36 [1\ub76%]), vomiting (26 [1\ub72%]), and pain (24 [1\ub71%]). There were two serious adverse events: one patient had significant hearing loss and one patient had obstruction of their venous catheter caused by a CPAP hood, which resulted in transient haemodynamic instability. Interpretation: In this large clinical effectiveness trial, CPAP did not reduce the incidence of pneumonia, endotracheal re-intubation, or death after major abdominal surgery. Although CPAP has an important role in the treatment of respiratory failure after surgery, routine use of prophylactic post-operative CPAP is not recommended

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