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

Antibody induced injury to podocytes with proteinuria and foot process swelling in a transgenic (T16) mouse

T16 mice contain a human 3′ untranslated sequence of the Thy 1.1 gene. Unlike normal mice they express Thy 1.1 protein on the podocytes which was immuno-localized to podocyte apical and basal plasma membranes and filtration slit. When monoclonal anti-Thy 1.1 antibody (OX7) was injected in nonproteinuric heterozygous mice there was rapid podocyte foot process swelling and proteinuria. Immunofluorescence showed granular glomerular OX7 binding at one hour. Progressive loss of pedicels occurred with 17.9 ± 2.5, 14.4 ± 1.1 and 10.5 ± 3.5 per 10 nm glomerular basement membrane (GBM) remaining 1, 6 and 24 hours, respectively, after 1 mg OX7, vs 32.2 ± 2.0 in T16 mice given saline. Twenty-four hour proteinuria was OX7 dose-dependent, peaked at 1–3 days and reduced to near basal levels 9–11 days thereafter. Proteinuria was nonselective except at very low doses (0.1 mg OX7) where microalbuminuria was seen. F(ab′)2 OX7 administration also caused proteinuria in T16 mice. One milligram F(ab′)1 OX7 caused diffuse foot process swelling without manifest proteinuria in T16 mice. Anti-Thy 1.1 IgM monoclonal antibody did not produce the effects of OX7 in T16 mice. Foot process swelling was not modified by histamine or 5-hydroxytryptamine antagonists. OX7 did not cause complement activation or leucocyte infiltration, hence glomerular injury appeared to be mediated directly by the antibody

Chemical composition and antibacterial activity of Gongronema latifolium

Chemical composition of Gongronema latifolium leaves was determined using standard methods. Aqueous and methanol G. latifolium extracts were tested against thirteen pathogenic bacterial isolates. Crude protein, lipid extract, ash, crude fibre and nitrogen free extractives obtained are: 27.2%, 6.07%, 11.6%, 10.8% and 44.3% dry matter respectively. Potassium, sodium, calcium, phosphorus and cobalt contents are 332, 110, 115, 125 and 116 mg/kg respectively. Dominant essential amino acids are leucine, valine and phenylalanine. Aspartic acid, glutamic acid and glycine are 13.8%, 11.9% and 10.3% respectively of total amino acid. Saturated and unsaturated fatty acids are 50.2% and 39.4% of the oil respectively. Palmitic acid makes up 36% of the total fatty acid. Extracts show no activity against E. faecalis, Y. enterolytica, E. aerogenes, B. cereus and E. agglomerans. Methanol extracts were active against S. enteritidis, S. cholerasius ser typhimurium and P. aeruginosa (minimum inhibitory concentration (MIC) 1 mg; zone of growth inhibition 7, 6.5 and 7 mm respectively). Aqueous extracts show activity against E. coli (MIC 5 mg) and P. aeruginosa (MIC 1 mg) while methanol extracts are active against P. aeruginosa and L. monocytogenes. G. latifolium has potential food and antibacterial uses