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SummaryBackgroundStaphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection.MethodsIn this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants.FindingsBetween Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18–45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference −1·4%, 95% CI −7·0 to 4·3; hazard ratio 0·96, 0·68–1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3–4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005).InterpretationAdjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia.FundingUK National Institute for Health Research Health Technology Assessment.

Initial data from the Formosa Satellite‐7/Constellation Observing System for Meteorology Ionosphere and Climate (FORMOSAT‐7/COSMIC‐2, hereafter C2), a recently launched equatorial constellation of six satellites carrying advanced radio occultation receivers, exhibit high signal‐to‐noise ratio, precision, and accuracy, and the ability to provide high vertical resolution profiles of bending angles and refractivity, which contain information on temperature and water vapor in the challenging tropical atmosphere. After an initial calibration/validation phase, over 100,000 soundings of bending angles and refractivity that passed quality control in October 2019 are compared with independent data, including radiosondes, model forecasts, and analyses. The comparisons show that C2 data meet expectations of high accuracy, precision, and capability to detect superrefraction. When fully operational, the C2 satellites are expected to produce ~5,000 soundings per day, providing freely available observations that will enable improved forecasts of weather, including tropical cyclones, and weather, space weather, and climate research.

Coronaviruses are the causative agents of respiratory disease in humans and animals, including severe acute respiratory syndrome. Fusion of coronaviruses is generally thought to occur at neutral pH, although there is also evidence for a role of acidic endosomes during entry of a variety of coronaviruses. Therefore, the molecular basis of coronavirus fusion during entry into host cells remains incompletely defined. Here, we examined coronavirus-cell fusion and entry employing the avian coronavirus infectious bronchitis virus (IBV). Virus entry into cells was inhibited by acidotropic bases and by other inhibitors of pH-dependent endocytosis. We carried out fluorescence-dequenching fusion assays of R18-labeled virions and show that for IBV, coronaviruscell fusion occurs in a low-pH-dependent manner, with a half-maximal rate of fusion occurring at pH 5.5. Fusion was reduced, but still occurred, at lower temperatures (20°C). We observed no effect of inhibitors of endosomal proteases on the fusion event. These data are the first direct measure of virus-cell fusion for any coronavirus and demonstrate that the coronavirus IBV employs a direct, low-pH-dependent virus-cell fusion activation reaction. We further show that IBV was not inactivated, and fusion was unaffected, by prior exposure to pH 5.0 buffer. Virions also showed evidence of reversible conformational changes in their surface proteins, indicating that aspects of the fusion reaction may be reversible in nature.For all enveloped viruses, a critical event during entry into cells is the fusion of the viral envelope with the membrane of the host cell (13). Our current understanding of viral fusion has been driven by fundamental problems first solved with influenza hemagglutinin (HA) (50). Whereas the trigger for HA-mediated fusion is the low pH of the endosome, other viruses (e.g., paramyxoviruses and most retroviruses) undergo a receptor-primed fusion with the plasma membrane at neutral pH (13).Coronaviruses (CoV) have recently received much attention due to the outbreak of severe acute respiratory syndrome (SARS) (22, 28), but there is little consensus as to whether coronavirus entry and fusion occur following endocytosis or at the plasma membrane (6,16,21,43). Coronaviruses are enveloped positive-strand RNA viruses that replicate in the cytoplasm (28). They have a distinctive set of club-shaped spikes on their envelope, and the spike protein (S) is the primary determinant of cell tropism and pathogenesis, being responsible (and apparently sufficient) for receptor binding and fusion (16). However, other envelope proteins are present: the M protein, the E protein, and (in some coronaviruses) an HE protein (28). The coronavirus S protein is categorized as a class I fusion protein, based on the presence of characteristic heptad repeats (3, 9, 26); as such, it shows features of the fusion proteins of influenza virus (HA), retroviruses (Env), and paramyxoviruses (F and HN), for which there is extensive characterization at the structural and biophysical levels (11).Al...