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

Development of a model for high precursor conversion efficiency pulsed-pressure chemical vapor deposition (PP-CVD) processing

A model of the movement of precursor particles in the unsteady Pulsed-Pressure Chemical Vapour Deposition (PP-CVD) process is developed to study the high conversion efficiencies observed experimentally in this process. Verification of the modelling procedures was conducted through a study of velocity persistence in an equilibrium gas and through Direct Simulation Monte Carlo (DSMC) simulations of unsteady self-diffusion processes. The model results demonstrate that in the PP-CVD process the arrival time for precursor particles at the deposition surface is much less than the reactor pump-down time, resulting in high precursor conversion efficiencies. Higher conversion efficiency was found to correlate with smaller size solvent molecules and moderate reactor peak pressure

Implementation of Unsteady Sampling Procedures for the Parallel Direct Simulation Monte Carlo Method

accepted for publication 7th March 2008 JCOMP-D-07-00498R1An unsteady sampling routine for a general parallel Direct Simulation Monte Carlo method called PDSC is introduced, allowing the simulation of time-dependent flow problems in the near continuum range. A post-processing procedure called DSMC Rapid Ensemble Averaging Method (DREAM) is developed to improve the statistical scatter in the results while minimising both memory and simulation time. This method builds an ensemble average of repeated runs over small number of sampling intervals prior to the sampling point of interest by restarting the flow using either a Maxwellian distribution based on macroscopic properties for near equilibrium flows (DREAM-I) or output instantaneous particle data obtained by the original unsteady sampling of PDSC for strongly non-equilibrium flows (DREAM-II). The method is validated by simulating shock tube flow and the development of simple Couette flow. Unsteady PDSC is found to accurately predict the flow field in both cases with significantly reduced run-times over single processor code and DREAM greatly reduces the statistical scatter in the results while maintaining accurate particle velocity distributions. Simulations are then conducted of two applications involving the interaction of shocks over wedges. The results of these simulations are compared to experimental data and simulations from the literature where there these are available. In general it was found that ten ensembled runs of DREAM processing could reduce the statistical uncertainty in the raw PDSC data by 2.5-3.3 times, based on the limited number of cases in the present study

Microbial effects on transport processes (BioTran) : anaerobic flow-through experiments using crushed Diorite and Pseudomonas aeruginosa (April 2008-March 2009)

Risk assessments for landfills and geological repositories for radioactive waste are primarily based on the precepts of contaminant transport; and are concerned with understanding the movement of gas, wastes and solutes through engineered barriers and natural groundwater systems, within the concept of ‘Source’, ‘Pathway’, and ‘Receptor’. The emphasis on solute migration for landfill investigations is reflected in the theoretical development used during numerical simulation. However, microbes living in such environments can have an impact on transport processes (Bateman et al., 2006; Chapelle 2000; Cunningham et al., 1997; Fredrickson et al., 1989; Keith-Loach and Livens 2002; West and Chilton 1997). Microbial activity in any environment is generally located on chemical or physical interfaces, usually within biofilms, and the impacts can be both physical (e.g. altering porosity) and/or chemical (e.g. changing pH, redox conditions) and may result in intracellular or extracellular mineral formation or degradation (Beveridge et al., 1997; Ehrlich 1999; Konhauser et al., 1998; Milodowski et al., 1990; Tuck et al., 2006). These processes could all impact on fluid flow through fractures and porous media by, for example, blocking of constrictions in fracture flow pathways and pore throats. The BioTran project was initiated to examine the effects of microbes on transport processes, especially in the context of contaminant properties of host rocks. An understanding of these microbial processes will also be relevant to other areas such as bioremediation of contaminated land, borehole and reservoir clogging and enhanced oil recovery. More broadly, these processes impinge on aquifer recharge, pathogen survival, and ultimately on groundwater protection. To date, the project has comprehensively reviewed the available literature and developed methodologies for experimental studies to provide information and data for existing transport models (Bateman et al., 2006; Coombs et al., 2008; Wagner et al., 2007). The BioTran project has focussed on materials from the Äspö Underground Research Laboratory (URL) in the context of the geological containment of radioactive waste in hard rock (diorite) environments (Banwart et al., 1995). Early experimental work simulated the interactions of indigenous microbes with mineralogical surfaces associated with groundwater flow systems at Äspö (Hama et al., 2001); and ascertained that these microbes can either concentrate relevant chemical species for mineral formation in localised microenvironments or accelerate clay formation, the implications of this being that local hydrological conditions can be changed by microbial activity (Tuck et al., 2006). ). It has also been shown that minerals precipitated biogenically are chemically and physically very stable and persist in the system long after the original biofilm has decayed or been removed (Brydie et al., 2005). As a result of these studies, the BioTran project undertook a pilot study to examine the influences of biofilm growth by growing the bacterium Pseudomonas aeruginosa aerobically on groundwater flowing though crushed diorite taken from the Äspö Hard Rock Laboratory, Sweden (West et al., 2008). The results of this study demonstrated that biofilms could be grown in both flow cells and flow-through columns within a few days on a diorite substrate through which artificial groundwater containing minimal nutrients was passed. Also, biofilm development could be successfully imaged in several ways, including by visible and UV light microscopy and cryogenic scanning electron microscopy (cryoSEM). The flow-through column experiment has now been repeated in this current study but under anaerobic conditions over an extended experimental period of 147 days (3524 hours). The experiment showed that: • P. aeruginosa biofilms can be grown anaerobically using diorite and synthetic Äspö groundwater as a growth medium, although the rate of growth is significantly slower. The respiratory metabolism of P. aeruginosa is essentially aerobic; it is however known to grow in the absence of oxygen if nitrate is available as a respiratory electron acceptor. The Äspö groundwater used in this column experiment had negligible nitrate, the fact that growth was observed under anaerobic conditions demonstrates the metabolic versatility and minimal nutritional requirements of the P. aeruginosa strain; • Numbers of P. aeruginosa decreased over the duration of the experiment but were able to survive up to 2684 hours; • CryoSEM observations of the experimental column material showed that biofilm was formed during the course of the experiment; • Biofilm only developed in the first 0 cm to 4 cm of the column as demonstrated by direct observations and by petrographic analysis of the experimental column at cessation of the investigation; • Observations of bacteria-free control columns were vitally important as the experimental column material revealed many features that could easily have been superficially identified as being of biological origin; • The presence of porewater salt caused considerable ambiguity in the identification of biofilaments and biofilm because the salt structures often closely resembled amorphous features anticipated for biofilm development filaments; • No change in pH was observed during the course of the experiment; • The growth of biofilm in the anaerobic environment was insufficient to effect pressure and fluid flow through either column; • The fluid chemistry data shows a rapid reduction in both Mn and Ba concentrations despite no appreciable levels of Mn or Ba being detectable in the groundwater. It was therefore assumed that Mn and Ba ions were present in the inoculant or had originated from the column itself. Future investigations will move away from dioritic sand-packed columns and focus on biofilm growth within complete sandstone rock cores under representative in-situ conditions of pressure and groundwater chemistry

Diagnosis and management of β cell chronic lymphocytic leukaemia in a cat

A four-year-old, female neutered domestic shorthair cat had a history of chronic intermittent vomiting and lymphocytosis. B cell chronic lymphocytic leukaemia was diagnosed by flow cytometry, which revealed abnormally large numbers of mature B lymphocytes in the peripheral blood. The cat was treated conservatively with antiemetic drugs and remained stable without chemotherapy for over a year