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

New approaches for assessing site formation of submerged lithic scatters

This study investigates the hydrodynamic processes that affect site formation of a submerged lithic scatter located at Cape Bruguieres Channel (CBC) in the NW of Western Australia through a combination of in situ, experimental and modelling approaches. A pressure sensor and current meter were deployed on the site and recorded hydrodynamic data over a three month period with maximum current speeds of 0.55 m/s recorded during spring tides. To test the potential for artefacts to be transported away from their original depositional context, a representative selection of submerged archaeological artefacts collected from the site and natural stone were subjected to a range of current speeds within a controlled flume environment. This demonstrated that all artefacts and natural stone remained stable within the flume even when experiencing current speeds approaching the maximum current velocities recorded at the site, regardless of lithic orientation relative to the current direction. In addition it was seen that mass alone did not control the hydrodynamic stability of the lithics tested, rather the hydrodynamic properties of a lithic are highly dependent on both its shape and orientation relative to current flow direction. This is a significant finding and suggests that the smaller the mass of a lithic does not necessarily correspond with preferential transport by currents caused by tides or waves. To test the potential for lithics to be transported during extreme cyclone events, a fine 30 m resolution bathymetric grid was constructed for CBC and current speeds modelled for Tropical Cyclone (TC) Damien which crossed the archipelago as a Category 3 (severe tropical cyclone) in February 2020. Modelled currents during this event reached a maximum velocity of 0.8 m/s and would be capable of transporting the smallest mass lithic but only if it was orientated in its most hydrodynamically unstable position relative to the current direction. These results suggest the Cape Bruguieres lithic scatter site has effectively remained in situ following sea level inundation at approximately 7,000 years BP