Summary SARS-CoV-2 Spike protein is critical for virus infection via engagement of ACE2 1 , and is a major antibody target. Here we report chronic SARS-CoV-2 with reduced sensitivity to neutralising antibodies in an immune suppressed individual treated with convalescent plasma, generating whole genome ultradeep sequences over 23 time points spanning 101 days. Little change was observed in the overall viral population structure following two courses of remdesivir over the first 57 days. However, following convalescent plasma therapy we observed large, dynamic virus population shifts, with the emergence of a dominant viral strain bearing D796H in S2 and ΔH69/ΔV70 in the S1 N-terminal domain NTD of the Spike protein. As passively transferred serum antibodies diminished, viruses with the escape genotype diminished in frequency, before returning during a final, unsuccessful course of convalescent plasma. In vitro , the Spike escape double mutant bearing ΔH69/ΔV70 and D796H conferred modestly decreased sensitivity to convalescent plasma, whilst maintaining infectivity similar to wild type. D796H appeared to be the main contributor to decreased susceptibility but incurred an infectivity defect. The ΔH69/ΔV70 single mutant had two-fold higher infectivity compared to wild type, possibly compensating for the reduced infectivity of D796H. These data reveal strong selection on SARS-CoV-2 during convalescent plasma therapy associated with emergence of viral variants with evidence of reduced susceptibility to neutralising antibodies.

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Many current applications use recommendations in order to modify the natural user behavior, such as to increase the number of sales or the time spent on a website. This results in a gap between the final recommendation objective and the classical setup where recommendation candidates are evaluated by their coherence with past user behavior, by predicting either the missing entries in the user-item matrix, or the most likely next event. To bridge this gap, we optimize a recommendation policy for the task of increasing the desired outcome versus the organic user behavior. We show this is equivalent to learning to predict recommendation outcomes under a fully random recommendation policy. To this end, we propose a new domain adaptation algorithm that learns from logged data containing outcomes from a biased recommendation policy and predicts recommendation outcomes according to random exposure. We compare our method against state-of-the-art factorization methods, in addition to new approaches of causal recommendation and show significant improvements.

Writing Committee for the REMAP-CAP Investigators IMPORTANCE The evidence for benefit of convalescent plasma for critically ill patients with COVID-19 is inconclusive.OBJECTIVE To determine whether convalescent plasma would improve outcomes for critically ill adults with COVID-19. DESIGN, SETTING, AND PARTICIPANTSThe ongoing Randomized, Embedded, Multifactorial, Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) enrolled and randomized 4763 adults with suspected or confirmed COVID-19 between March 9, 2020, and January 18, 2021, within at least 1 domain; 2011 critically ill adults were randomized to open-label interventions in the immunoglobulin domain at 129 sites in 4 countries. Follow-up ended on April 19, 2021. INTERVENTIONSThe immunoglobulin domain randomized participants to receive 2 units of high-titer, ABO-compatible convalescent plasma (total volume of 550 mL ± 150 mL) within 48 hours of randomization (n = 1084) or no convalescent plasma (n = 916). MAIN OUTCOMES AND MEASURESThe primary ordinal end point was organ support-free days (days alive and free of intensive care unit-based organ support) up to day 21 (range, −1 to 21 days; patients who died were assigned -1 day). The primary analysis was an adjusted bayesian cumulative logistic model. Superiority was defined as the posterior probability of an odds ratio (OR) greater than 1 (threshold for trial conclusion of superiority >99%). Futility was defined as the posterior probability of an OR less than 1.2 (threshold for trial conclusion of futility >95%). An OR greater than 1 represented improved survival, more organ support-free days, or both. The prespecified secondary outcomes included in-hospital survival; 28-day survival; 90-day survival; respiratory support-free days; cardiovascular support-free days; progression to invasive mechanical ventilation, extracorporeal mechanical oxygenation, or death; intensive care unit length of stay; hospital length of stay; World Health Organization ordinal scale score at day 14; venous thromboembolic events at 90 days; and serious adverse events. RESULTS Among the 2011 participants who were randomized (median age, 61 [IQR, 52 to 70] years and 645/1998 [32.3%] women), 1990 (99%) completed the trial. The convalescent plasma intervention was stopped after the prespecified criterion for futility was met. The median number of organ support-free days was 0 (IQR, -1 to 16) in the convalescent plasma group and 3 (IQR, -1 to 16) in the no convalescent plasma group. The in-hospital mortality rate was 37.3% (401/1075) for the convalescent plasma group and 38.4% (347/904) for the no convalescent plasma group and the median number of days alive and free of organ support was 14 (IQR, 3 to 18) and 14 (IQR, 7 to 18), respectively. The median-adjusted OR was 0.97 (95% credible interval, 0.83 to 1.15) and the posterior probability of futility (OR <1.2) was 99.4% for the convalescent plasma group compared with the no convalescent plasma group. The treatment effects were consistent across the primary outcome and the 11...

BackgroundEarly physical rehabilitation in the intensive care unit (ICU) has been shown to improve short-term clinical outcomes but long-term benefit has not been proven and the optimum intensity of rehabilitation is not known.MethodsWe conducted a randomised, parallel-group, allocation-concealed, assessor-blinded, controlled trial in patients who had received at least 48 hours of invasive or non-invasive ventilation. Participants were randomised in a 1:1 ratio, stratified by admitting ICU, admission type and level of independence. The intervention group had a target of 90 min physical rehabilitation per day, the control group a target of 30 min per day (both Monday to Friday). The primary outcome was the Physical Component Summary (PCS) measure of SF-36 at 6 months.ResultsWe recruited 308 participants over 34 months: 150 assigned to the intervention and 158 to the control group. The intervention group received a median (IQR) of 161 (67–273) min of physical rehabilitation on ICU compared with 86 (31–139) min in the control group. At 6 months, 62 participants in the intervention group and 54 participants in the control group contributed primary outcome data. In the intervention group, 43 had died, 11 had withdrawn and 34 were lost to follow-up, while in the control group, 56 had died, 5 had withdrawn and 43 were lost to follow-up. There was no difference in the primary outcome at 6 months, mean (SD) PCS 37 (12.2) in the intervention group and 37 (11.3) in the control group.ConclusionsIn this study, ICU-based physical rehabilitation did not appear to improve physical outcomes at 6 months compared with standard physical rehabilitation.Trial registration numberISRCTN 20436833.