A community effort in SARS-CoV-2 drug discovery.

peer reviewedThe COVID-19 pandemic continues to pose a substantial threat to human lives and is likely to do so for years to come. Despite the availability of vaccines, searching for efficient small-molecule drugs that are widely available, including in low- and middle-income countries, is an ongoing challenge. In this work, we report the results of an open science community effort, the "Billion molecules against Covid-19 challenge", to identify small-molecule inhibitors against SARS-CoV-2 or relevant human receptors. Participating teams used a wide variety of computational methods to screen a minimum of 1 billion virtual molecules against 6 protein targets. Overall, 31 teams participated, and they suggested a total of 639,024 molecules, which were subsequently ranked to find 'consensus compounds'. The organizing team coordinated with various contract research organizations (CROs) and collaborating institutions to synthesize and test 878 compounds for biological activity against proteases (Nsp5, Nsp3, TMPRSS2), nucleocapsid N, RdRP (only the Nsp12 domain), and (alpha) spike protein S. Overall, 27 compounds with weak inhibition/binding were experimentally identified by binding-, cleavage-, and/or viral suppression assays and are presented here. Open science approaches such as the one presented here contribute to the knowledge base of future drug discovery efforts in finding better SARS-CoV-2 treatments.R-AGR-3826 - COVID19-14715687-CovScreen (01/06/2020 - 31/01/2021) - GLAAB Enric

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

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

X-ray spectroscopic diagnostics of magnetically confined plasmas: Instrumentation and techniques.

This thesis reports several advances in x-ray crystal spectroscopic techniques for the diagnosis of high-temperature magnetically confined plasmas. Two complementary spectrometers have been developed, and have been demonstrated in a wide range of experiments on the Culham Laboratory DITE and COMPASS tokamaks, and on the Joint European JET tokamak. A Bragg rotor' spectrometer uses a combination of crystals and multilayers to give complete coverage of the spectrum between 1 A and 100 A. Developments were made to extend the coverage from 25 A to 100 A, using multilayer mirrors and organic crystals. The success of the instrument depends largely on the development of a high-rate ( 107 count/s) gas proportional counter system, capable of covering the energy range from 100 eV to 10 keV. A Johann spectrometer uses a novel four-pillar jig to bend' crystals to typically 1 m radius. A large-area cooled x-ray CCD array is used in the focus, resulting in a compact high-resolution instrument. This allows line profile and ratio measurements with a time resolution of ~1 ms. Observations using the Bragg rotor spectrometer include impurity monitoring under various plasma and limiter configurations. Temperature and density sensitive line ratios were measured under known plasma conditions and compared with theory, adding confidence to their use for less well diagnosed plasmas such as those observed in astrophysics. A major application has been the study of a switch (controlled by the refuelling rate) between long and short impurity confinement times in the DITE tokamak. Trace impurities were injected by laser ablation, and their subsequent temporal and spatial behavour studied spectroscopically. Weak lines, due to radiative recombination into excited states of H- and He-like ions, were observed in the outer plasma. The radial profiles of these "radiative recombination lines" were governed by a balance between transport and, recombination, and allowed the effective diffusion coefficient to be measured locally. It was shown that the transport changes occurred in the outer half of the plasma, and that conditions in the core were unchanged. The suitability of Bragg spectroscopy for a reactor-relevant plasma was demonstrated during the JET preliminary tritium experiment (PTE). A double- reflection instrument was used, with a tritium-compatible radiation-shielded beamline. Based on this operational experience, a soft x-ray spectroscopy system for a next-step device such as ITER is proposed

Modeling of bremsstrahlung emission from the confined runaway electrons and applications to the hard x-ray monitor of ITER

International audienc

Novel dual-reflection design applied for ITER core x-ray spectrometer

A novel dual-reflection configuration is introduced for the International Tokamak Experimental Reactor (ITER) core x-ray spectrometer to fit the allocated space where it will be placed accompanied by moving the detectors backward to reduce the incident radiation dose. The highly oriented pyrolytic graphite, which has a mosaic structure of microscopic crystallites, is chosen for the front reflector motivated by higher x-ray throughput and stronger misalignment tolerance compared to the perfect crystal reflector. In the ITER core x-ray spectrometer, a combination of several reflector-deflected Lines of Sight (LOSs) and a direct LOS is proposed for the first time named X-Ray Crystal Spectroscopy Core (XRCS-Core). The system is optimized to observe lines from externally seeded xenon and the intrinsic tungsten impurity, meeting both port integration needs and measurement requirements. Its spectral performance is simulated using an analytical-raytracing mixed code——XRSA, showing good imaging quality with a spectral resolution higher than 8000. The XRCS-Core system is thought to be applicable in various ITER scenarios through the assessment taking into account the spectrometers’ specifications and the chosen lines’ emissivity in different plasma parameters

Effect of wall light reflection in ITER diagnostics

The reflection of light from walls will result in parasitic signals for various optical diagnostics and can be a serious issue in ITER. In this study, we show recent progress in the assessment of the effects of wall reflections in ITER based on ray tracing simulation results. Four different diagnostics in ITER were chosen for the simulation, i.e. visible spectroscopy, infrared thermography, edge laser Thomson scattering, and charge exchange recombination spectroscopy