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

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Pseudo-Bouveret's Syndrome

We report a patient with gastric outlet obstruction due to gallstone, with clinical and imaging features mimicking Bouveret's syndrome. However, the obstruction was simply due to extrinsic compression by a gallstone without cholecystoduodenal fistula formation. Laparoscopic cholecystectomy cured the patient

Complexes of silver(I) with peptides and proteins as produced in electrospray mass spectrometry

Silver(I) forms aqueous phase complexes with both sulfur and nonsulfur containing peptides and proteins. These complexes were introduced into the gas phase via electrospray, and their structures probed by means of tandem mass spectrometry. Experiments with di-, tri-, and oligopeptides show that the abundance of silver(I)-containing ions increases relative to that of proton-containing ions as peptide length increases. This increase is much more dramatic for methionine-containing peptides. Collision-induced dissociation of silver-peptide complexes yields a multitude of product ions that are silver containing. However, even for methionine-containing peptides, very few of these product ions contain the methionine residue. The solution- phase structure and the gas-phase structure of the silver/peptide complex are not identical. The methionine sulfur acts as the silver anchoring point in solution. Desolvation in the gas phase leads to a rearrangement of the silver/peptide complex such that the silver ion becomes chelated to the nitrogen and oxygen atom on the peptide backbone in addition to the methionine sulfur. This rearrangement decreases the importance of the silver/sulfur bond to the extent that it is frequently broken upon collision activation and leads to the formation of silver/peptide product ions that are nonsulfur bearing

Broad-Line Reverberation in the \u3ci\u3eKepler\u3c/i\u3e-Field Seyfert Galaxy Zw 220-015

The Seyfert 1 galaxy Zw 229-015 is among the brightest active galaxies being monitored by the Kepler mission. In order to determine the black hole mass in Zw 229-015 from Hβ reverberation mapping, we have carried out nightly observations with the Kast Spectrograph at the Lick 3 m telescope during the dark runs from 2010 June through December, obtaining 54 spectroscopic observations in total. We have also obtained nightly V-band imaging with the Katzman Automatic Imaging Telescope at Lick Observatory and with the 0.9 m telescope at the Brigham Young University West Mountain Observatory over the same period. We detect strong variability in the source, which exhibited more than a factor of two change in broad Hβ flux. From cross-correlation measurements, we find that the Hβ light curve has a rest-frame lag of 3.86+0.69 –0.90 days with respect to the V-band continuum variations. We also measure reverberation lags for Hα and Hγ and find an upper limit to the Hδ lag. Combining the Hβ lag measurement with a broad Hβ width of σline = 1590 ± 47 km s–1 measured from the rms variability spectrum, we obtain a virial estimate of M BH = 1.00+0.19 –0.24 × 107 M ☉ for the black hole in Zw 229-015. As a Kepler target, Zw 229-015 will eventually have one of the highest-quality optical light curves ever measured for any active galaxy, and the black hole mass determined from reverberation mapping will serve as a benchmark for testing relationships between black hole mass and continuum variability characteristics in active galactic nuclei