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BACKGROUND. Convalescent plasma is the only antibody-based therapy currently available for patients with coronavlrus disease 2019 (COVID-19). It has robust historical precedence and sound biological plausibility. Although promising, convalescent plasma has not yet been shown to be safe as a treatment for COVID-19. METHODS. Thus, we analyzed key safety metrics after transfusion of ABO-compatible human COVID-19 convalescent plasma in 5000 hospitalized adults with severe or life-threatening COVID-19, with 66% in the intensive care unit, as part of the US FDA expanded access program for COVID-19 convalescent plasma. RESULTS. The incidence of all serious adverse events (SAEs), including mortality rate (0.3%), in the first 4 hours after transfusion was <1%. Of the 36 reported SAEs, there were 25 reported incidences of related SAEs, including mortality (n = 4), transfusion-associated circulatory overload (n = 7), transfusion-related acute lung injury (n = 11), and severe allergic transfusion reactions (n = 3). However, only 2 of 36 SAEs were judged as definitely related to the convalescent plasma transfusion by the treating physician. The 7-day mortality rate was 14.9%. CONCLUSION. Given the deadly nature of COVID-19 and the large population of critically ill patients included in these analyses, the mortality rate does not appear excessive. These early indicators suggest that transfusion of convalescent plasma is safe in hospitalized patients with COVID-19. TRIAL REGISTRATION. ClinicalTrials.gov NCT04338360. FUNDING. Mayo Clinic, Biomedical Advanced Research and Development Authority (75A50120C00096), National Center for Advancing Translational Sciences (UL1TR002377), National Heart, Lung, and Blood Institute (5R35HL139854 and R01 HL059842), National Institute of Diabetes and Digestive and Kidney Diseases (5T32DK07352), Natural Sciences and Engineering Research Council of Canada (PDF-532926-2019), National Institute of Allergy and Infectious Disease (R21 AI145356, R21 AI152318, and AI152078), Schwab Charitable Fund, United Health Group, National Basketball Association, Millennium Pharmaceuticals, and Octapharma USA Inc.

The timing and magnitude of sex differences in athletic performance during early human development, prior to adulthood, is unknown. To compare swimming velocity of boys and girls for all Olympic-length freestyle swimming events to determine the age of divergence in swimming performance. We collected the all-time top 100 U.S. freestyle swimming performance times of boys and girls age 5 to 18 years for the 50m to 1500m events. Swimming performance improved with increasing age for boys and girls (p<0.001) until reaching a plateau, which initiated at a younger age for girls (15 years) than boys (17 years; sex×age; p<0.001). Prior to age 10, the top 5 swimming records for girls were 3% faster than the top boys (p<0.001). For the 10th-50th places, however, there were no sex-related differences in swimming performance prior to age 10 (p = 0.227). For both the top 5 and 10th-50th places, the sex difference in performance increased from age 10 (top 5, 2.5%; 10th-50th places, 1.0%) until age 17 (top 5, 7.6%; 10th-50th places, 8.0%). For all places, the sex difference in performance at age 18 was larger for sprint events (9.6%; 50-200m) than endurance events (7.1%; 400-1500m; p<0.001). Additionally, the sex-related difference in performance increased across age and US ranking from 2.4% for 1st place to 4.3% for 100th place (p<0.001), indicating less depth of performance in girls than boys. However, annual participation was ~20% higher in girls than boys for all ages (p<0.001). The top 5 girls demonstrated faster swimming velocities and the 10th-50th place girls demonstrated similar swimming velocities than boys (until ~10 years). After age 10, however, boys demonstrated increasingly faster swimming velocities than girls until 17 years. Collectively, these data suggest girls are faster, or at least not slower, than boys prior to the performance-enhancing effects of puberty.

During infectious disease emergencies, it may be necessary to deploy new therapies without conclusive evidence for their effectiveness. During the SARS-CoV-2 pandemic, several countries used registries to track the use of COVID-19 convalescent plasma (CCP). Those registries provided evidence that CCP was effective when used early and with high titer.

Females likely experience larger performance benefits from androgenic‐anabolic steroids than males. We set out to determine if there were temporal differences in select athletics (track and field) records between females and males. Exploratory aims included: (1) evaluating the improvements in female and male world records over time, and (2) investigating the influence of doping programs on male and female world records before and after 1990, when sports governing bodies began to implement random out‐of‐competition and systematic in‐competition drug testing. We collected the top 500 performances of all time for both sexes from an online database (worldathletics.org) in four running events (100, 200, 400 and 800 m) and two throwing events (discus throw and shot‐put). Data were stratified into quintiles based on world record ranking (1st to 100th, 101st to 200th, etc.). The temporal distribution of the top 100 female performers was significantly earlier than the top 100 male performers (year: 2000 ± 1 vs. 2005 ± 1, respectively; P < 0.0001). Within the event, the top performances occurred significantly earlier for females in the 800 m (year: 1995 ± 15 vs. 2003 ± 12; P = 0.0007) and shot‐put (year: 1992 ± 14 vs. 2003 ± 17; P = 0.0004). Among females, world records rapidly improved through the 1980s, but following 1990, the world records ceased to improve. Geographically, there was a greater representation of countries with state‐sponsored doping programs, specifically among female performances. We postulate these sex differences in the temporal distribution of top performances are likely associated with enhanced effectiveness of exogenous androgens (steroid doping) among female athletes with lower endogenous androgen hormones compared to males. What is the central question of this study? Despite a longstanding notion that top performance in athletics occurred earlier for females compared to males, likely due to the larger performance benefits of androgenic‐anabolic steroids, no study has compared this temporal relation: what is the temporal distribution of select athletics events between females and males? What is the main finding and its importance? The top‐100 female performances occurred earlier than the top‐100 male performances. The sex‐related temporal differences were particularly notable for the shot‐put and 800 m. Furthermore, there was a greater representation of countries with known state‐sponsored doping programs, specifically among females. The analyses suggest that androgenic‐anabolic steroids played a greater role in the world's best female athletics performances.

The US Food and Drug Administration authorized COVID-19 convalescent plasma (CCP) therapy for hospitalized COVID-19 patients via the Expanded Access Program (EAP) and the Emergency Use Authorization (EUA), leading to use in about 500,000 patients during the first year of the pandemic for the USA. We tracked the number of CCP units dispensed to hospitals by blood banking organizations and correlated that usage with hospital admission and mortality data. CCP usage per admission peaked in Fall 2020, with more than 40% of inpatients estimated to have received CCP between late September and early November 2020. However, after randomized controlled trials failed to show a reduction in mortality, CCP usage per admission declined steadily to a nadir of less than 10% in March 2021. We found a strong inverse correlation (r = -0.52, p=0.002) between CCP usage per hospital admission and deaths occurring 2 weeks after admission, and this finding was robust to examination of deaths taking place 1, 2, or 3 weeks after admission. Changes in the number of hospital admissions, SARS-CoV-2 variants, and age of patients could not explain these findings. The retreat from CCP usage might have resulted in as many as 29,000 excess deaths from mid-November 2020 to February 2021. A strong inverse correlation between CCP use and mortality per admission in the USA provides population-level evidence consistent with the notion that CCP reduces mortality in COVID-19 and suggests that the recent decline in usage could have resulted in excess deaths. There was no specific funding for this study. AC was supported in part by RO1 HL059842 and R01 AI1520789; MJJ was supported in part by 5R35HL139854. This project has been funded in whole or in part with Federal funds from the Department of Health and Human Services; Office of the Assistant Secretary for Preparedness and Response; Biomedical Advanced Research and Development Authority under Contract No. 75A50120C00096.

Exercise intolerance and exertional dyspnoea are the cardinal symptoms of heart failure with reduced ejection fraction (HFrEF). In HFrEF, abnormal autonomic and cardiopulmonary responses arising from locomotor muscle group III/IV afferent feedback is one of the primary mechanisms contributing to exercise intolerance. HFrEF patients also have pulmonary system and respiratory muscle abnormalities that impair exercise tolerance. Thus, the primary impetus for this review was to describe the mechanistic consequences of locomotor muscle group III/IV afferent feedback and respiratory muscle work in HFrEF. To address this, we first discuss the abnormal autonomic and cardiopulmonary responses mediated by locomotor muscle afferent feedback in HFrEF. Next, we outline how respiratory muscle work impairs exercise tolerance in HFrEF through its effects on locomotor muscle O2 delivery. We then discuss the direct and indirect evidence supporting an interaction between locomotor muscle group III/IV afferent feedback and respiratory muscle work during exercise in HFrEF. Last, we outline future research directions related to locomotor and respiratory muscle abnormalities to progress the field forward in understanding the pathophysiology of exercise intolerance in HFrEF. New Findings What is the topic of this review? This review is focused on understanding the role that locomotor muscle group III/IV afferent feedback and respiratory muscle work play in the pathophysiology of exercise intolerance in patients with heart failure. What advances does it highlight? This review proposes that the concomitant effects of locomotor muscle afferent feedback and respiratory muscle work worsen exercise tolerance and exacerbate exertional dyspnoea in patients with heart failure.

Successful therapeutics and vaccines for coronavirus disease 2019 (COVID-19) have harnessed the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Evidence that SARS-CoV-2 exists as locally evolving variants suggests that immunological differences may impact the effectiveness of antibody-based treatments such as convalescent plasma and vaccines. Considering that near-sourced convalescent plasma likely reflects the antigenic composition of local viral strains, we hypothesize that convalescent plasma has a higher efficacy, as defined by death within 30 days of transfusion, when the convalescent plasma donor and treated patient were in close geographic proximity. Results of a series of modeling techniques applied to approximately 28,000 patients from the Expanded Access to Convalescent Plasma program (ClinicalTrials.gov number: NCT04338360) support this hypothesis. This work has implications for the interpretation of clinical studies, the ability to develop effective COVID-19 treatments, and, potentially, for the effectiveness of COVID-19 vaccines as additional locally-evolving variants continue to emerge. Regional differences in SARS-CoV-2 variants may affect treatment outcome. Here, the authors show that near-sourced convalescent plasma has higher efficacy, as defined by death within 30 days of transfusion, than plasma sourced more than 150 miles away.

Men outperform women in many athletic endeavors due to physiological and anatomical differences (e.g. larger and faster muscle); however, the observed sex differences in elite athletic performance are typically larger than expected, and may reflect sex-related differences in opportunity or incentives. As collegiate rowing in the United States has been largely incentivized for women over the last 20 years, but not men, the purpose of this study was to examine sex differences in elite rowing performance over that timeframe. Finishing times from grand finale races for collegiate championship on-water performances (n = 480) and junior indoor performances (n = 1,280) were compared between men and women across 20 years (1997-2016), weight classes (heavy vs. lightweight) and finishing place. Participation of the numbers of men and women rowers were also quantified across years. Men were faster than women across all finishing places, weight classes and years of competition and performance declined across finishing place for both men and women (P<0.001). Interestingly, the reduction in performance time across finishing place was greater (P<0.001) for collegiate men compared to women in the heavyweight division. This result is opposite to other sports (e.g. running and swimming), and to lightweight rowing in this study, which provides women fewer incentives than in heavyweight rowing. Correspondingly, participation in collegiate rowing has increased by ~113 women per year (P<0.001), with no change (P = 0.899) for collegiate men. These results indicate that increased participation and incentives within collegiate rowing for women vs. men contribute to sex differences in athletic performance.