The efficacy of convalescent plasma for coronavirus disease 2019 (COVID-19) is unclear. Although most randomized controlled trials have shown negative results, uncontrolled studies have suggested that the antibody content could influence patient outcomes. We conducted an open-label, randomized controlled trial of convalescent plasma for adults with COVID-19 receiving oxygen within 12 d of respiratory symptom onset (NCT04348656). Patients were allocated 2:1 to 500 ml of convalescent plasma or standard of care. The composite primary outcome was intubation or death by 30 d. Exploratory analyses of the effect of convalescent plasma antibodies on the primary outcome was assessed by logistic regression. The trial was terminated at 78% of planned enrollment after meeting stopping criteria for futility. In total, 940 patients were randomized, and 921 patients were included in the intention-to-treat analysis. Intubation or death occurred in 199/614 (32.4%) patients in the convalescent plasma arm and 86/307 (28.0%) patients in the standard of care arm—relative risk (RR) = 1.16 (95% confidence interval (CI) 0.94–1.43, P = 0.18). Patients in the convalescent plasma arm had more serious adverse events (33.4% versus 26.4%; RR = 1.27, 95% CI 1.02–1.57, P = 0.034). The antibody content significantly modulated the therapeutic effect of convalescent plasma. In multivariate analysis, each standardized log increase in neutralization or antibody-dependent cellular cytotoxicity independently reduced the potential harmful effect of plasma (odds ratio (OR) = 0.74, 95% CI 0.57–0.95 and OR = 0.66, 95% CI 0.50–0.87, respectively), whereas IgG against the full transmembrane spike protein increased it (OR = 1.53, 95% CI 1.14–2.05). Convalescent plasma did not reduce the risk of intubation or death at 30 d in hospitalized patients with COVID-19. Transfusion of convalescent plasma with unfavorable antibody profiles could be associated with worse clinical outcomes compared to standard care.

Background Elevated proinflammatory cytokines are associated with greater COVID-19 severity. We aimed to assess safety and efficacy of sarilumab, an interleukin-6 receptor inhibitor, in patients with severe (requiring supplemental oxygen by nasal cannula or face mask) or critical (requiring greater supplemental oxygen, mechanical ventilation, or extracorporeal support) COVID-19. Methods We did a 60-day, randomised, double-blind, placebo-controlled, multinational phase 3 trial at 45 hospitals in Argentina, Brazil, Canada, Chile, France, Germany, Israel, Italy, Japan, Russia, and Spain. We included adults (≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection and pneumonia, who required oxygen supplementation or intensive care. Patients were randomly assigned (2:2:1 with permuted blocks of five) to receive intravenous sarilumab 400 mg, sarilumab 200 mg, or placebo. Patients, care providers, outcome assessors, and investigators remained masked to assigned intervention throughout the course of the study. The primary endpoint was time to clinical improvement of two or more points (seven point scale ranging from 1 [death] to 7 [discharged from hospital]) in the modified intention-to-treat population. The key secondary endpoint was proportion of patients alive at day 29. Safety outcomes included adverse events and laboratory assessments. This study is registered with ClinicalTrials.gov , NCT04327388 ; EudraCT, 2020-001162-12; and WHO, U1111-1249-6021. Findings Between March 28 and July 3, 2020, of 431 patients who were screened, 420 patients were randomly assigned and 416 received placebo (n=84 [20%]), sarilumab 200 mg (n=159 [38%]), or sarilumab 400 mg (n=173 [42%]). At day 29, no significant differences were seen in median time to an improvement of two or more points between placebo (12·0 days [95% CI 9·0 to 15·0]) and sarilumab 200 mg (10·0 days [9·0 to 12·0]; hazard ratio [HR] 1·03 [95% CI 0·75 to 1·40]; log-rank p=0·96) or sarilumab 400 mg (10·0 days [9·0 to 13·0]; HR 1·14 [95% CI 0·84 to 1·54]; log-rank p=0·34), or in proportions of patients alive (77 [92%] of 84 patients in the placebo group; 143 [90%] of 159 patients in the sarilumab 200 mg group; difference −1·7 [−9·3 to 5·8]; p=0·63 vs placebo; and 159 [92%] of 173 patients in the sarilumab 400 mg group; difference 0·2 [−6·9 to 7·4]; p=0·85 vs placebo). At day 29, there were numerical, non-significant survival differences between sarilumab 400 mg (88%) and placebo (79%; difference +8·9% [95% CI −7·7 to 25·5]; p=0·25) for patients who had critical disease. No unexpected safety signals were seen. The rates of treatment-emergent adverse events were 65% (55 of 84) in the placebo group, 65% (103 of 159) in the sarilumab 200 mg group, and 70% (121 of 173) in the sarilumab 400 mg group, and of those leading to death 11% (nine of 84) were in the placebo group, 1...

Human attention is normally conceived as a limited capacity process that can be controlled in either an exogenous, reflexive manner or an endogenous, volitional manner (Broadbent, 1971;Posner, 1978). For several decades, the attention-cuing paradigm has provided a simple methodology for engaging and measuring these two forms of orienting (Posner, 1980;Posner, Snyder, & Davidson, 1980). Typically, reflexive attention has been triggered by a peripheral flash that does not predict where a visual target will appear. This attentional cue is followed by a target, demanding a manual detection response, appearing either at the cued location or at a noncued location. The usual result is that if the cue-target stimulus onset asynchrony (SOA) is less than 300 msec, reaction time (RT) is shorter when a target appears at a cued location versus a noncued location. Because attended items are processed more efficiently than nonattended items, the facilitation effect at the cued location is taken as evidence that the abrupt onset attracted attention to its location. And because the facilitation effect emerged rapidly in response to a cue that did not predict where the target would appear, the attention effect is considered to be reflexive in nature. For SOAs greater than 300 msec, RT becomes longer for targets appearing at the cued location than for those appearing at the noncued locations, reflecting the inhibition-of-return phenomenon. This inhibition effect at the cued location is taken as evidence that attention was withdrawn from the cued location and is inhibited in returning there (Posner & Cohen, 1984).The cuing methodology for volitional orienting is similar to the above, with two important exceptions. First, instead of an attentional cue being flashed in the periphery, a central directional cue, usually an arrow, points toward the cued location. Second, the arrow cue predicts where the target is most likely to appear. The usual result when this central predictive cuing methodology is used is that an RT advantage emerges relatively slowly at the cued location and then persists across the long cue-target SOAs, since there is little reason to shift attention away from where the target is most likely to appear (e.g., Jonides, 1981).Recently, a number of studies have shown that central directional cues do not need to be spatially predictive in Recent evidence indicates that central directional stimuli, such as eyes and arrows, trigger rapid, reflexive shifts of spatial attention. A study by Fischer, Castel, Dodd, and Pratt (2003) suggested that a similar effect might also apply to central numbers, as if a digit's meaning causes attention to be oriented to its relative position on a left-to-right mental number line. However, unlike central eyes and arrows, the orienting effect for central digits emerges slowly, suggesting that top-down endogenous processes may be mediating this effect. Here, we report a series of three experiments that strongly support this hypothesis. Experiment 1 replicated Fischer et al.'s left-to-right n...

A wealth of data indicate that central spatially nonpredictive eyes and arrows trigger very similar reflexive spatial orienting, although the effects of eyes may be more strongly reflexive (e.g., Friesen, Ristic, & Kingstone, 2004). Pratt and Hommel (2003) recently reported that the orienting effect for arrows is sensitive to arbitrary cue-target color contingencies; for example, an attentional orienting effect for blue colored arrows is evident only for blue targets. We reasoned that if the orienting effect elicited by eye direction is more strongly reflexive than the orienting effect elicited by arrow direction, it follows that eyes, unlike arrows, may trigger orienting effects that generalize across congruent and incongruent cue-target color contingencies. Replicating Pratt and Hommel (2003), we found that the reflexive attention effect elicited by arrows is specific to color-congruent target stimuli. The attention effect triggered by eyes, however, generalizes across color-congruent and color-incongruent target stimuli. These data support the hypothesis that eye direction and arrow direction trigger similar reflexive shifts in spatial attention, but that the attention effect triggered by eye direction is more strongly reflexive.

BackgroundEvidence-based priority setting is increasingly important for rationally distributing scarce health resources and for guiding future health research. We sought to quantify the contribution of a wide range of infectious diseases to the overall infectious disease burden in a high-income setting.Methodology/Principal FindingsWe used health-adjusted life years (HALYs), a composite measure comprising premature mortality and reduced functioning due to disease, to estimate the burden of 51 infectious diseases and associated syndromes in Ontario using 2005–2007 data. Deaths were estimated from vital statistics data and disease incidence was estimated from reportable disease, healthcare utilization, and cancer registry data, supplemented by local modeling studies and national and international epidemiologic studies. The 51 infectious agents and associated syndromes accounted for 729 lost HALYs, 44.2 deaths, and 58,987 incident cases per 100,000 population annually. The most burdensome infectious agents were: hepatitis C virus, Streptococcus pneumoniae, Escherichia coli, human papillomavirus, hepatitis B virus, human immunodeficiency virus, Staphylococcus aureus, influenza virus, Clostridium difficile, and rhinovirus. The top five, ten, and 20 pathogens accounted for 46%, 67%, and 75% of the total infectious disease burden, respectively. Marked sex-specific differences in disease burden were observed for some pathogens. The main limitations of this study were the exclusion of certain infectious diseases due to data availability issues, not considering the impact of co-infections and co-morbidity, and the inability to assess the burden of milder infections that do not result in healthcare utilization.Conclusions/SignificanceInfectious diseases continue to cause a substantial health burden in high-income settings such as Ontario. Most of this burden is attributable to a relatively small number of infectious agents, for which many effective interventions have been previously identified. Therefore, these findings should be used to guide public health policy, planning, and research.