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

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

The effect of stratification of microplankton communities in the northern Strait of Georgia

The northern Strait of Georgia (NSG) and adjacent Malaspina Complex of inlets (MC) were studied to determine the effect of stratification on microplankton communities. The NSG was dominated by nanoflagellates in spring. There was no evidence of a vernal diatom bloom in the Strait, perhaps due to wind turbulence or microzooplankton grazing. In early summer regimes were conducive to diatom growth but the northern Strait was experiencing a "mild" red tide. By late summer, diatoms bloomed and prevailed, presumably, till the fall decline. Stratification was greatest in late summer, due chiefly to temperature, with reduced surface salinities on the east side from Fraser River runoff. At this time biological partitioning was pronounced, resulting in a mosaic of organismal groups. Although stratification had declined by early autumn, the mosaicism was maintained and strengthened. Diatoms were most abundant in the north and on the west side where stratification was least, in areas of tidal turbulence. Photosynthetic nanoflagellates and photosynthetic dinoflagellates favoured the more stratified east side. Ciliate distributions mirrored those of the nanoflagellates. The MC was thought to be a more stratified version of the NSG but it was found to be a fairly mixed water body due to tidal action. It was sheltered from winds which allowed the early blooming of diatoms. These were maintained for several months by a tidal jet through Malaspina Inlet that probably injected nutrients into the junction of Malaspina, Okeover, and Lancelot Inlets. Principal components analysis was used to reduce the dimensionality of the biological dataset, and canonical correlation analysis allowed the coupling of environmental data to the biological principal components. It was found that PCI reflected general biomass while PC's II and III were most often related to depth and location. These latter two were utilised to resolve the species information in three-dimensions. In general, nanoflagellates populated surface waters whereas diatoms tended to occupy deeper depths. Multiple regression analysis was performed on organismal groups to explore how biomass was affected by stratification, pycnocline depth, surface temperature (seasonality), nitrate, and grazing.Science, Faculty ofEarth, Ocean and Atmospheric Sciences, Department ofGraduat

Precise control of interface anisotropy during deposition of Co/Pd multilayers

We demonstrate the control of perpendicular magnetic anisotropy (PMA) in multilayer films without modification of either the microstructure or saturation magnetization by tuning the Ar+ ion energy using remote plasma sputtering. We show that for [Co/Pd]8 multilayer films, increasing the Ar+ ion energy results in a strong decrease in PMA through an increase in interfacial roughness determined by X-ray reflectivity measurements. X-ray diffraction and transmission electron microscope image data show that the microstructure is independent of Ar+ energy. This opens a different approach to the in-situ deposition of graded exchange springs and for control of the polarizing layer in hybrid spin transfer torque devices