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

Partial recovery of a eutrophic reservoir through managed phosphorus limitation and unmanaged macrophyte growth

Recovery from an algal to a macrophyte-dominated state in a freshwater system can require both nutrient reduction and a switch to initiate the change. Despite ferric dosing of pumped inputs since 1983 to reduce external phosphorus loading and forced mixing of the main basin by helices since 1985, Alton Water reservoir, Suffolk, UK suffered from increasing planktonic chlorophyll a concentrations in the main basin, from construction in 1981 until 1992. From 1987 blooms of cyanobacteria were increasingly frequent, with a major bloom of Woronichinia ( originally Coelosphaerium) in 1992, resulting in water supply problems. Since 1993 a partial recovery from a eutrophic to mesotrophic state occurred. Studies of chlorophyll a, orthophosphate (OP), total phosphorus (TP), Alkaline Phosphatase Activity (APA) and response of phytoplankton to in situ phosphate addition experiments between 1995 and 1997, revealed gradients indicative of increasing phosphorus limitation of phytoplankton along the length of the reservoir, away from the pumped input. From 1993 to 1997 no algal blooms occurred in the main basin of the reservoir and extensive macrophyte growth was observed around the reservoir periphery, principally Elodea spp. This corresponded with an increase in weed-eating birds, such as coot (Fulica atra) and tufted duck (Aythya fuligula). The partial recovery of the main basin was attributed to bottom-up control through phosphorus limitation as a result of management in the form of ferric dosing, as well as competition for nutrients and light by the extensive macrophyte beds. Increased macrophyte growth was probably induced by changes in the reservoir ecology following the cyanobacterial bloom and associated fish kill in 1992.</p

The potential for phosphorus release across the sediment-water interface in an eutrophic reservoir dosed with ferric sulphate.

Alton Water, Suffolk, UK is a pumped storage reservoir that has a history of cyanobacterial blooms. Dosing of the input water with ferric sulphate to control external phosphorus loading has occurred since 1983. A detailed study of the sediment chemistry of the site was carried out between May 1995 and July 1997. Sequential phosphorus fraction analysis indicated a decrease along the length of the reservoir in sediment labile phosphorus content from 0.62 to 0.08 mg P g(-1) dw and iron-bound phosphorus content from 3.22 to 0.46 mg P g(-1) dw. These gradients positively correlated with water column chlorophyll rr concentrations reported in a parallel study. Labile and iron-bound sediment phosphorus contents were in a dynamic equilibrium due to diffusional release, contributing to internal loading to the water column. Equilibrium phosphorus concentrations (EPC) determined from phosphorus adsorption capacity (PAC) experiments were lower inside the bunded region (0.01-0.03 mg P-PO4 l(-1)) where iron content was greatest compared to outside the bund (0.15-0.20 mg P-PO4 l(-1)) suggesting greater potential for diffusional release of phosphorus at the latter site. PAC experiments indicated that anaerobic and pH-mediated loadings were of less importance than diffusional release, although the latter map have contributed to internal loading in the main reservoir. Sulphate concentrations may act to increase the potential for anaerobic internal loading near to the pumped input in microstratified sediment. Sediment iron content decreased from 250 +/- 13.1 to 51 +/- 4.0 mg Fe g(-1) dw across the line of a constructed bund at the north-west end near to the pumped input, which indicated successful control of dispersal of the fine ferric floc. The management implications with regard to phosphorus loadings indicated by these results are discussed. (C) 2001 Elsevier Science Ltd. All rights reserved</p

Partial recovery of a eutrophic reservoir through managed phosphorus limitation and unmanaged macrophyte growth

Recovery from an algal to a macrophyte-dominated state in a freshwater system can require both nutrient reduction and a switch to initiate the change. Despite ferric dosing of pumped inputs since 1983 to reduce external phosphorus loading and forced mixing of the main basin by helices since 1985, Alton Water reservoir, Suffolk, UK suffered from increasing planktonic chlorophyll a concentrations in the main basin, from construction in 1981 until 1992. From 1987 blooms of cyanobacteria were increasingly frequent, with a major bloom of Woronichinia ( originally Coelosphaerium) in 1992, resulting in water supply problems. Since 1993 a partial recovery from a eutrophic to mesotrophic state occurred. Studies of chlorophyll a, orthophosphate (OP), total phosphorus (TP), Alkaline Phosphatase Activity (APA) and response of phytoplankton to in situ phosphate addition experiments between 1995 and 1997, revealed gradients indicative of increasing phosphorus limitation of phytoplankton along the length of the reservoir, away from the pumped input. From 1993 to 1997 no algal blooms occurred in the main basin of the reservoir and extensive macrophyte growth was observed around the reservoir periphery, principally Elodea spp. This corresponded with an increase in weed-eating birds, such as coot (Fulica atra) and tufted duck (Aythya fuligula). The partial recovery of the main basin was attributed to bottom-up control through phosphorus limitation as a result of management in the form of ferric dosing, as well as competition for nutrients and light by the extensive macrophyte beds. Increased macrophyte growth was probably induced by changes in the reservoir ecology following the cyanobacterial bloom and associated fish kill in 1992.</p

Reduction in photosynthetic efficiency of <i>Cladophora glomerata</i>, induced by overlying canopies of Lemna spp.

The duckweeds Lemna minor L. and L. minuscula Herter reduced PSII quantum efficiency (F'(q)/F'(m)) of the filamentous green alga Cladophora glomerata Kutzing by up to 42% over seven days when floating above mats of C. glomerata in containers. Dissolved oxygen (DO) increased by 23% at 30degreesC in containers with C. glomerata over controls. But when the water surface in the containers was covered with Lemna spp. floating above C. glomerata, DO was 83% lower at 30degreesC over seven days than in control samples with no duckweed or alga. Dissolved oxygen was lower beneath a thick mat (1 cm) of either Lemna spp. covering the surface than under a thin layer (single-frond canopy). PAM fluorimetry showed that maximum PSII efficiency (F-v/F-m) of C. glomerata in containers was reduced under a canopy of L. minor by 17% over seven days, and under L. minuscula by 22%. F'(q)/F'(m) of C. glomerata in containers exposed to 51 mumol m(-2)s(-1) PPFD decreased under a canopy of L. minor by 16% over seven days, and under L. minuscula by 19% compared to controls. When light response curves were compared, F'(q)/F'(m) was significantly reduced under canopies of L. minor at the highest temperatures tested (28degreesC and 30degreesC). L. minor significantly reduced relative electron transport rate (rel. ETR) of the controls by up to 71% at 30degreesC. Relative electron transport rate did not reach light saturation point (E-sat) except at 28degrees and 30degreesC under mats of L. minor. Whereas the highest rate of production (rel. ETRmax) and E-sat increased with temperature in controls, under a canopy of Lemna, decreases were observed. It is suggested that, during periods of high summer temperature and irradiance, shading inhibits oxygenic photosynthesis in mats of C. glomerata beneath canopies of Lemna spp. This results in less oxygen being produced by the C. glomerata (oxygen produced by Lemna spp. is not released into the water), and this may further inhibit the C. glomerata by limiting oxygen-dependent electron transport and/or photo respiration. This feedback loop could lead to the eventual senescence of the C. glomerata. The combination of low oxygen, high temperature and stressed filamentous algae, particularly in slow or standing water, may help to explain sudden collapses in DO concentration, with detrimental effects on water quality downstream. (C) 2002 Elsevier Science Ltd. All rights reserved.</p