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

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

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Unveiling new degradation intermediates/pathways from the photocatalytic degradation of microcystin-lr

Mass spectrometry was utilized for structural identification ofthe intermediates formed during the photocatalytic degradation of the cyanotoxin, microcystin-LR with immobilized TiO2 photocatalysts at neutral pH. Most of the intermediates reported herein have not been found in prior studies. Results indicate that MC-LR degradation is initiated at four sites of the toxin; three on the Adda amino acid (aromatic ring, methoxy group, and conjugated double bonds) and one on the cyclic structure (Mdha amino acid). Several intermediates gave multiple peaks in the TIC (m/z = 1011.5, 1029.5, 1063.5), which were deduced to be geometrical or constitutional isomers. This is the first study that reports the hydroxylation of the aromatic ring and the demethoxylation of MC-LR with TiO2 photocatalysis. The most targeted site was the conjugated diene bonds because of their location in the MC-LR structure. Isomerization at the C4-C5 and C 6-C7 of the diene bond of the Adda chain was a direct result of hydroxyl radical addition/substitution. Based on the above, we concluded that oxidation and isomerization of the diene bonds of MC-LR occurred simultaneously. Other steps included hydroxyl substitution, further oxidation, and bond cleavage. As the reaction time progressed, simultaneous oxidation of the Adda chain and the cyclic structure occurred

LC/MS/MS structure elucidation of reaction intermediates formed during the TiO2 photocatalysis of microcystin-lr

Microcystin-LR (MC-LR), a cyanotoxin and emerging drinking water contaminant, was treated with TiO2 photocatalysts immobilized on stainless steel plates as an alternative to nanoparticles in slurry. The reaction intermediates of MC-LR were identified with mass spectrometry (MS) at pH of Milli-Q water (pHsq=5.7). Eleven new [M+H]+ were observed in the liquid chromatography mass spectrometry (LC/MS) chromatogram with some of them giving multiple peaks. Most of these reaction intermediates have not been reported from previous studies employing TiO2 nanoparticles at acidic conditions (pH=4.0). Investigating the effects of pH (for 3.0<pH<7.0), toxin adsorption and initial toxin concentration on the degradation efficiency of the TiO2 photocatalytic films showed that acidic conditions are preferable for the degradation. Combined with the limited surface area of the films and the absence of additional oxidants (i.e., H2O2) the degradation was slower and more intermediate steps were identified. Possible structures of the intermediates (formed at neutral pH) after analyzing the corresponding MS/MS spectra are reported. The collision-induced dissociation of the [M+H]+ of MC-LR and the intermediates 1011.5 and 1029.5 are discussed and possible fragmentation pathways and mechanisms are also proposed. Analysis of the MS/MS spectra indicates that the fragmentation of some amino acids is less favorable because of internal interaction with free groups of adjacent amino acids. The MS/MS spectra assisted in determining hydroxylation sites, by the formation or alteration of specific product ions such as m/z 599

Degradation of microcystin-lr using sulfate radicals generated through photolysis, thermolysis and e- transfer mechanisms

This study explores the potential use of sulfate radical-based advanced oxidation technologies (SR-AOTs) for the degradation of the naturally occurring hepatotoxin, microcystin-LR (MC-LR). The generation of sulfate radicals was achieved by activation of the oxidants persulfate (PS) and peroxymonosulfate (PMS) through electrophilic transition metal cations (Ag+ and Co2+, respectively), radiation (UV 300 Fe2+/H2O2 ≫ Ag+/PS, which we believe is associated with the energy of the lower unoccupied molecular orbital of the oxidants. When UV (300 < λ < 400 nm) radiation was used, the PS system was more efficient than PMS and H2O2 at all different oxidant concentrations. Since, the UV lamps used in the study emit light at a range of wavelengths (300 < λ < 400 nm), the activation of the oxidants is believed to be caused by the emission spectra and not just λmax = 365 nm. At acidic conditions, the PS/UV (300 < λ < 400 nm)/pH 3 and PMS/UV/pH 3 systems were most efficient and required the least amount of energy to reduce the toxin concentration by one order of magnitude. When thermal activation was used, PMS yielded the highest degradation efficiency (∼77%) compared to 52% for the PS and less then 2.5% for H2O2

Cyanotoxins: New generation of water contaminants

Cyanobacteria, more commonly known as blue-green algae, are found worldwide in various aquatic environments as well as in water distribution systems (Atikovic 2003; Carmichael 1994; Madigan et al. 2003). Blooms of cyanobacteria have recently become spatially and temporally more prevalent in the United States and worldwide as a consequence of increasing nutrient levels such as nitrates and phosphates from fertilizers and detergents. Cyanobacterial blooms impart color, odor, and taste problems in water. More importantly, such blooms produce and release toxic compounds that dramatically impair the quality of water bodies. Up to 50% of the recorded blooms can be expected to contain toxins (Carmichael 1992). These compounds have severe and sometimes irreversible effects on mammalian health. Episodes of human and animal poisoning by consumption of water contaminated with cyanobacterial toxins have been reported since the late 1800s (Carmichael 1994). Exposure to cyanobacterial toxins can affect the number and diversity of wild animal populations, cause bioaccumulation of toxins in the tissues of fish and shellfish, and indirectly affect other organisms through the food chain. Moreover, the presence of cyanobacteria and cyanobacterial toxins in sources of drinking water supply has raised major concerns. Another major issue is the lack of guidelines or regulations of cyanobacteria and cyanotoxins in terms of maximum contaminant level (MCL) and analytical detection methods. In the past few years, major research effort has been targeted toward the treatment of these toxins, especially the hepatotoxin microcystin-LR (MC-LR)