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

Background: In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg–800 mg (depending on weight) given intravenously. A second dose could be given 12–24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). Findings: Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76–0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12–1·33; p<0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77–0·92; p<0·0001). Interpretation: In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

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

Background: Many patients with COVID-19 have been treated with plasma containing anti-SARS-CoV-2 antibodies. We aimed to evaluate the safety and efficacy of convalescent plasma therapy in patients admitted to hospital with COVID-19. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. The trial is underway at 177 NHS hospitals from across the UK. Eligible and consenting patients were randomly assigned (1:1) to receive either usual care alone (usual care group) or usual care plus high-titre convalescent plasma (convalescent plasma group). The primary outcome was 28-day mortality, analysed on an intention-to-treat basis. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936. Findings: Between May 28, 2020, and Jan 15, 2021, 11558 (71%) of 16287 patients enrolled in RECOVERY were eligible to receive convalescent plasma and were assigned to either the convalescent plasma group or the usual care group. There was no significant difference in 28-day mortality between the two groups: 1399 (24%) of 5795 patients in the convalescent plasma group and 1408 (24%) of 5763 patients in the usual care group died within 28 days (rate ratio 1·00, 95% CI 0·93–1·07; p=0·95). The 28-day mortality rate ratio was similar in all prespecified subgroups of patients, including in those patients without detectable SARS-CoV-2 antibodies at randomisation. Allocation to convalescent plasma had no significant effect on the proportion of patients discharged from hospital within 28 days (3832 [66%] patients in the convalescent plasma group vs 3822 [66%] patients in the usual care group; rate ratio 0·99, 95% CI 0·94–1·03; p=0·57). Among those not on invasive mechanical ventilation at randomisation, there was no significant difference in the proportion of patients meeting the composite endpoint of progression to invasive mechanical ventilation or death (1568 [29%] of 5493 patients in the convalescent plasma group vs 1568 [29%] of 5448 patients in the usual care group; rate ratio 0·99, 95% CI 0·93–1·05; p=0·79). Interpretation: In patients hospitalised with COVID-19, high-titre convalescent plasma did not improve survival or other prespecified clinical outcomes. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

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

Continued expansion of the Wedge-tailed Shearwater, Puffinus pacificus, nesting colonies on Rottnest Island, Western Australia

The areas and burrow densities of Wedge-tailed Shearwater, Puffinus pacificus, colonies on Rottnest Island, Western Australia, were measured in April 2002. In the 10 years since the previous survey on Rottnest Island, two new colonies have been established. Summed over all colonies, there was an increase of 46% in the total area of colonies, to 45785 m2, and a doubling of the total number of burrows, to 11745 ± 1320 (s.e.). Burrow densities differed significantly between colonies and vegetation type. Burrow densities were lowest on the edge of the colonies, where the heath plant Olearia axillaris was present. The growth of the Wedge-tailed Shearwater colonies is consistent with the increase in reproductive effort observed in many other tropical, colonial-nesting seabirds in south-western Western Australian waters

Burrowing seabirds drive decreased diversity and structural complexity, and increased productivity in insular-vegetation communities

Burrow-nesting seabirds, such as the wedge-tailed shearwater (Puffinus pacificus (Gmelin)) physically and chemically engineer the soil of their colonies in a manner that is likely to affect plant growth and ecology. We examined this functional interaction by measuring the diversity, vertical structure and productivity of vegetation in shearwater colonies on Rottnest Island, Western Australia, and by comparing these with those in the adjacent, non-colonised heath. The colony supported a distinct, less diverse vegetation community and was dominated by short-lived, succulent exotics. An ecotone was present between the two communities. Across all species, vegetation was shorter and denser in the colony and individual species that co-occurred in both locations were stunted in the colony. The percentage of bare soil in the colony was double that of the heath. The productivity of a phytometer (Rhagodia baccata) was significantly higher in colony soil than in heath soil. In a glasshouse experiment, cuttings grown in colony soil had 337% of the root mass and 537% of the foliage mass of plants grown in heath soil. Field measurements demonstrated increased leaf set and foliage extension in colony plants. Seed germination from the colony soil (2674 seedlings m -2) greatly exceeded that of the heath (59 seedlings m -2). Dense, productive and species-poor colony vegetation supports the assemblage-level thinning hypothesis as the mechanism for vegetation change, but we argue that prominent colony species are simply better adapted to high nutrient loads and frequent disturbance. A model of vegetation succession is also proposed

Burrow building in seabird colonies: a soil-forming process in island ecosystems

Soil modification via biopedturbation by burrow-building seabirds was examined in a Mediterranean, island ecosystem. Physical and chemical soil properties were compared between a colony of Wedge-tailed Shearwaters (Puffinus pacificus) and adjacent heath across a 14-month period. When compared to heath soil, the biopedturbated soil was 28% drier (6.04±5.40 vol%), had increased bulk density (by 29% to 1.30±0.11 g cm -3, 51% porosity), wetting capacity (by 83% to 0.55±0.83 molarity of ethanol droplet), hydraulic conductivity (by 266% to 398.91±252.04 mm h -1), and a greater range in soil surface temperature (31.7±6.2°C diurnally to 18.3±3.2°C nocturnally). Soil penetration resistance was reduced by 26% at a depth of 0-100 mm (326.5±122.4 kPa) and by 55% at 500-600 mm (1116.8±465.0 kPa). Colony soil also had increased levels of nitrate (by 470%), phosphorous (118%), ammonium (102%), sulphur (69%), and potassium (34%), decreased levels of iron (by 50%) and organic carbon (61%), was more alkaline, and had a 78% greater conductivity. Shearwaters deposited guano at a rate of 234.4 kg ha -1 yr -1 (dry mass). Chemical analysis of guano equated this to 50.9, 5.7, 5.5, and 3.6 kg ha -1 yr -1 of nitrogen, potassium, sulphur, and phosphorous, respectively. Experimentally constructed burrows demonstrated that digging alone can alter physical and chemical soil factors, but that changes in the nutrient profile of colony soils are predominantly guano-driven. We argue that the physical impact of seabirds on soil should not be overlooked as a soil-forming and ecosystem-shaping factor in island ecosystems, and that biopedturbation can exert major bottom-up influences on insular plant and animal communitie

Burrow entrance attrition rate in wedge-tailed shearwater Puffinus pacificus colonies on Rottnest Island, Western Australia

Shearwaters (Puffinus spp.) appear to select burrow-nest sites to minimise the risk of burrow collapse and are known to clear and re-excavate damaged burrows, yet empirical evidence on the incidence of burrow collapse is lacking. We provide preliminary data on rates of burrow entrance collapse in a colony of Wedge-tailed Shearwaters (P. pacificus) on Rottnest Island, Western Australia. Entrances to 67.8% of burrows that were active during the laying phase of the 2002/03 breeding season had collapsed by the beginning of the next season. The attrition rate was linear over time, and collapsed portions had a mean length of 17.9 ± 2.7 cm (standard error). Burrow entrances overlain with shallow-rooted, annual plants (89.7% collapse rate) were more than twice as likely to collapse as those located beneath deeper-rooting, perennial shrubs (40.9% collapse rate). Three quarters of collapsed entrances were re-excavated the following season, and at least 11.5 t ha -1 yr -1 (8.5 m 3 ha -1 yr -1) of soil was displaced through this process. Of marker posts that were placed at the entrances of burrows in 1992 (n = 264), 22% were found in 2003. Of the posts that were found, 19% remained associated with a burrow entrance. We consider that most entrance collapses in this study reflect abandonment of burrows by the birds. Our data predict that, if a current increase in shallow-rooted vegetation in colony areas continues, the rate of entrance collapse and colony erosion will increase. Although we did not attempt to quantify the effect that burrow entrance collapse has on the reproductive biology of the shearwaters, we hope that our work will catalyse future investigation in this field

Impact of Phytophthora-dieback on birds in Banksia woodlands in south west Western Australia

Invasive plant pathogens have impacted forest and woodland systems globally and can negatively impact biodiversity. The soil-borne plant pathogen Phytophthora cinnamomi is listed as one of the world's worst invasive species and alters plant community composition and habitat structure. Few studies have examined how these Phytophthora-induced habitat changes affect faunal communities. We examined bird communities in Banksia woodland with, and without, Phytophthora dieback in a biodiversity hotspot, southwestern Australia. Seven sites along dieback fronts, with paired 1-ha plots in diseased and healthy vegetation, were surveyed monthly for birds over seven months. Vegetation assessments showed that diseased sites had reduced plant species richness, litter, shrub, tree and canopy cover, high bare ground and significantly lower flowering scores, than healthy sites. Bird community composition differed significantly between diseased and healthy sites, although total bird abundance, total species richness and foraging guilds, did not. Average species richness of birds per survey and the abundance of brown honeyeaters, western spinebills and silvereyes was lower in diseased than healthy sites. The tawny-crowned honeyeater had higher abundances in diseased sites. Similarity matrices of habitat structure, flowering scores and bird assemblages were congruent, indicating that habitat structural differences were influencing bird community composition. Our results suggest that this pathogen is potentially a serious threat to avian biodiversity and especially for nectarivores, and populations in fragmented landscapes. Since elimination of the pathogen is not currently possible, management should focus on methods of preventing its spread until techniques to eliminate the pathogen are developed

SUPPRESSION OF MOLECULAR IONS IN SECONDARY ION MASS SPECTRA

Des perfectionnements dans l'élimination des ions moléculaires dans les spectres SIMS ont été obtenus à l'aide d'un analyseur ionique : Cameca IMS-3F. Cette étude montre une diminution du nombre d'ions moléculaires d'un facteur 10 à 100 par rapport aux techniques classiques utilisant un décalage d'énergie.Improved suppression of molecular ions in SIMS spectra has been obtained using a Cameca IMS-3F ion microscope. The approach described results in the suppression of molecular ions by factors of 10-100 fold more than by classical "energy offset"