Publications by authors named "Michael J Joyner"

437 Publications

Convalescent plasma for COVID-19. TSUNAMI is not the final word.

Eur J Intern Med 2022 Jan 7. Epub 2022 Jan 7.

Immunohaematology and Transfusion Service, Fondazione IRCCS Policlinico San Matteo Pavia, Italy.

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http://dx.doi.org/10.1016/j.ejim.2022.01.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8739393PMC
January 2022

Are convalescent plasma stocks collected during former COVID-19 waves still effective against current SARS-CoV-2 variants?

Vox Sang 2022 Jan 12. Epub 2022 Jan 12.

Department of Medicine, Johns Hopkins School of Public Health and School of Medicine, Baltimore, Maryland, USA.

COVID-19 convalescent plasma (CCP) was among the few frontline therapies used to treat COVID-19. After large randomized controlled trials (RCTs) relying on late use in hospitalized patients and/or low antibody titres failed to meet their predefined primary endpoint, the infectious disease community reduced usage of CCP in favour of monoclonal antibodies. Consequently, there are CCP stocks at most transfusion centres worldwide, although scattered usage continues. Further, better designed RCTs are also being launched. The urgent question here is: should we use CCP units collected months before given the largely changed viral variant landscape? We review here in vitro evidence that discourages usage of such CCP units against Delta and other variants of concern. CCP collections should be continued in order to update the armamentarium of therapeutics against vaccine breakthrough infections or in unvaccinated patients and is especially relevant in next-generation RCTs.
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http://dx.doi.org/10.1111/vox.13239DOI Listing
January 2022

Coagulation profile of human COVID-19 convalescent plasma.

Sci Rep 2022 01 12;12(1):637. Epub 2022 Jan 12.

Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.

Convalescent plasma is used to treat COVID-19. There are theoretical concerns about the impact of pro-coagulant factors in convalescent plasma on the coagulation cascade particularly among patients with severe COVID-19. The aim of this study was to evaluate the coagulation profile of COVID-19 convalescent plasma. Clotting times and coagulation factor assays were compared between fresh frozen plasma, COVID-19 convalescent plasma, and pathogen-reduced COVID-19 convalescent plasma. Measurements included prothrombin time, activated partial thromboplastin time, thrombin time, fibrinogen, D-dimer, von Willebrand factor activity, von Willebrand factor antigen, coagulation factors II, V, VII-XII, protein S activity, protein C antigen, and alpha-2 plasmin inhibitor. Clotting times and coagulation factor assays were not different between COVID-19 convalescent plasma and fresh frozen plasma, except for protein C antigen. When compared to fresh frozen plasma and regular convalescent plasma, pathogen reduction treatment increased activated partial thromboplastin time and thrombin time, while reducing fibrinogen, coagulation factor II, V, VIII, IX, X, XI, XII, protein S activity, and alpha-2 plasmin inhibitor. The coagulation profiles of human COVID-19 convalescent plasma and standard fresh frozen plasma are not different. Pathogen reduced COVID-19 convalescent plasma is associated with reduction of coagulation factors and a slight prolongation of coagulation times, as anticipated. A key limitation of the study is that the COVID-19 disease course of the convalesced donors was not characterized.
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http://dx.doi.org/10.1038/s41598-021-04670-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8755772PMC
January 2022

Concerns about estimating relative risk of death associated with convalescent plasma for COVID-19.

Nat Med 2022 Jan 10. Epub 2022 Jan 10.

Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.

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http://dx.doi.org/10.1038/s41591-021-01638-6DOI Listing
January 2022

Access to and safety of COVID-19 convalescent plasma in the United States Expanded Access Program: A national registry study.

PLoS Med 2021 12 20;18(12):e1003872. Epub 2021 Dec 20.

Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, Minnesota, United States of America.

Background: The United States (US) Expanded Access Program (EAP) to coronavirus disease 2019 (COVID-19) convalescent plasma was initiated in response to the rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19. While randomized clinical trials were in various stages of development and enrollment, there was an urgent need for widespread access to potential therapeutic agents. The objective of this study is to report on the demographic, geographical, and chronological characteristics of patients in the EAP, and key safety metrics following transfusion of COVID-19 convalescent plasma.

Methods And Findings: Mayo Clinic served as the central institutional review board for all participating facilities, and any US physician could participate as a local physician-principal investigator. Eligible patients were hospitalized, were aged 18 years or older, and had-or were at risk of progression to-severe or life-threatening COVID-19; eligible patients were enrolled through the EAP central website. Blood collection facilities rapidly implemented programs to collect convalescent plasma for hospitalized patients with COVID-19. Demographic and clinical characteristics of all enrolled patients in the EAP were summarized. Temporal patterns in access to COVID-19 convalescent plasma were investigated by comparing daily and weekly changes in EAP enrollment in response to changes in infection rate at the state level. Geographical analyses on access to convalescent plasma included assessing EAP enrollment in all national hospital referral regions, as well as assessing enrollment in metropolitan areas and less populated areas that did not have access to COVID-19 clinical trials. From April 3 to August 23, 2020, 105,717 hospitalized patients with severe or life-threatening COVID-19 were enrolled in the EAP. The majority of patients were 60 years of age or older (57.8%), were male (58.4%), and had overweight or obesity (83.8%). There was substantial inclusion of minorities and underserved populations: 46.4% of patients were of a race other than white, and 37.2% of patients were of Hispanic ethnicity. Chronologically and geographically, increases in the number of both enrollments and transfusions in the EAP closely followed confirmed infections across all 50 states. Nearly all national hospital referral regions enrolled and transfused patients in the EAP, including both in metropolitan and in less populated areas. The incidence of serious adverse events was objectively low (<1%), and the overall crude 30-day mortality rate was 25.2% (95% CI, 25.0% to 25.5%). This registry study was limited by the observational and pragmatic study design that did not include a control or comparator group; thus, the data should not be used to infer definitive treatment effects.

Conclusions: These results suggest that the EAP provided widespread access to COVID-19 convalescent plasma in all 50 states, including for underserved racial and ethnic minority populations. The study design of the EAP may serve as a model for future efforts when broad access to a treatment is needed in response to an emerging infectious disease.

Trial Registration: ClinicalTrials.gov NCT#: NCT04338360.
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http://dx.doi.org/10.1371/journal.pmed.1003872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8730442PMC
December 2021

Filling in the Spaces in Cardiovascular Epidemiology.

Epidemiology 2022 Jan;33(1):34-36

Chair, Molecular Microbiology & Immunology, Alfred & Jill Sommer Professor and Chair, Bloomberg Distinguished Professor, Department of Molecular Microbiology and Immunology, Johns Hopkins University School of Medicine, Baltimore, MD.

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http://dx.doi.org/10.1097/EDE.0000000000001435DOI Listing
January 2022

COVID-19 Convalescent Plasma Is More than Neutralizing Antibodies: A Narrative Review of Potential Beneficial and Detrimental Co-Factors.

Viruses 2021 08 11;13(8). Epub 2021 Aug 11.

Department of Medicine, Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.

COVID-19 convalescent plasma (CCP) is currently under investigation for both treatment and post-exposure prophylaxis. The active component of CCP mediating improved outcome is commonly reported as specific antibodies, particularly neutralizing antibodies, with clinical efficacy characterized according to the level or antibody affinity. In this review, we highlight the potential role of additional factors in CCP that can be either beneficial (e.g., AT-III, alpha-1 AT, ACE2+ extracellular vesicles) or detrimental (e.g., anti-ADAMTS13, anti-MDA5 or anti-interferon autoantibodies, pro-coagulant extracellular vesicles). Variations in these factors in CCP may contribute to varied outcomes in patients with COVID-19 and undergoing CCP therapy. We advise careful, retrospective investigation of such co-factors in randomized clinical trials that use fresh frozen plasma in control arms. Nevertheless, it might be difficult to establish a causal link between these components and outcome, given that CCP is generally safe and neutralizing antibody effects may predominate.
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http://dx.doi.org/10.3390/v13081594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8402718PMC
August 2021

Mortality in individuals treated with COVID-19 convalescent plasma varies with the geographic provenance of donors.

Nat Commun 2021 08 11;12(1):4864. Epub 2021 Aug 11.

Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, MN, USA.

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.
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http://dx.doi.org/10.1038/s41467-021-25113-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357797PMC
August 2021

In Reply-How Safe Is COVID-19 Convalescent Plasma?

Mayo Clin Proc 2021 08 25;96(8):2281-2282. Epub 2021 Jun 25.

Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, FL.

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http://dx.doi.org/10.1016/j.mayocp.2021.06.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8226061PMC
August 2021

Association of Varying Clinical Manifestations and Positive Anti-SARS-CoV-2 IgG Antibodies: A Cross-Sectional Observational Study.

J Allergy Clin Immunol Pract 2021 09 15;9(9):3331-3338.e2. Epub 2021 Jul 15.

Department of Pathology, Johns Hopkins University, Baltimore, Md. Electronic address:

Background: The complex relationship between clinical manifestations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and individual immune responses is not fully elucidated.

Objective: To examine phenotypes of symptomatology and their relationship with positive anti-SARS-CoV-2 IgG antibody responses.

Methods: An observational study was performed of adults (≥18 years) from 5 US states. Participants completed an electronic survey and underwent testing to anti-SARS-CoV-2 nucleocapsid protein IgG antibody between May and July 2020. Latent class analysis was used to identify characteristic symptom clusters.

Results: Overall, 9507 adults (mean age, 39.6 ± 15.0 years) completed the survey; 6665 (70.1%) underwent antibody testing for anti-SARS-CoV-2 IgG. Positive SARS-CoV-2 antibodies were associated with self-reported positive SARS-CoV-2 nasal swab result (bivariable logistic regression; odds ratio [95% CI], 5.98 [4.83-7.41]), household with 6 or more members (1.27 [1.14-1.41]) and sick contact (3.65 [3.19-4.17]), and older age (50-69 years: 1.55 [1.37-1.76]; ≥70 years: 1.52 [1.16-1.99]), but inversely associated with female sex (0.61 [0.55-0.68]). Latent class analysis revealed 8 latent classes of symptoms. Latent classes 1 (all symptoms) and 4 (fever, cough, muscle ache, anosmia, dysgeusia, and headache) were associated with the highest proportion (62.0% and 57.4%) of positive antibodies, whereas classes 6 (fever, cough, muscle ache, headache) and 8 (anosmia, dysgeusia) had intermediate proportions (48.2% and 40.5%), and classes 3 (headache, diarrhea, stomach pain) and 7 (no symptoms) had the lowest proportion (7.8% and 8.5%) of positive antibodies.

Conclusions: SARS-CoV-2 infections manifest with substantial diversity of symptoms, which are associated with variable anti-SARS-CoV-2 IgG antibody responses. Prolonged fever, anosmia, and receiving supplemental oxygen therapy had strongest associations with positive SARS-CoV-2 IgG.
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http://dx.doi.org/10.1016/j.jaip.2021.06.046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279919PMC
September 2021

Take a Deep, Resisted, Breath.

J Am Heart Assoc 2021 07 29;10(13):e022203. Epub 2021 Jun 29.

Mayo Clinic Rochester MN.

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http://dx.doi.org/10.1161/JAHA.121.022203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8403307PMC
July 2021

SARS-CoV-2 Serologic Assays Dependent on Dual-Antigen Binding Demonstrate Diverging Kinetics Relative to Other Antibody Detection Methods.

J Clin Microbiol 2021 08 18;59(9):e0123121. Epub 2021 Aug 18.

Department of Laboratory Medicine and Pathology, Mayo Clinicgrid.66875.3a, Rochester, Minnesota, USA.

Longitudinal studies assessing durability of the anti-severe acute respiratory syndrome coronavirus 2 (anti-SARS-CoV-2) humoral immune response have generated conflicting results. This has been proposed to be due to differences in patient populations, the lack of standardized methodologies, and the use of assays that measure distinct aspects of the humoral response. SARS-CoV-2 antibodies were serially measured in sera from a cohort of 44 well-characterized convalescent plasma donors over 120 days post-COVID-19 symptom onset, utilizing eight assays, which varied according to antigen source, the detected antibody isotype, and the activity measured (i.e., binding, blocking, or neutralizing). While the majority of assays demonstrated a gradual decline in antibody titers over the course of 120 days, the two electrochemiluminescence immunoassay Roche assays (Roche Diagnostics Elecsys anti-SARS-CoV-2 [qualitative, nucleocapsid based] and Roche Diagnostics Elecsys anti-SARS-CoV-2 S [semiquantitative, spike based]), which utilize dual-antigen binding for antibody detection, demonstrated stable and/or increasing antibody titers over the study period. This study is among the first to assess longitudinal, rather than cross-sectional, SARS-CoV-2 antibody profiles among convalescent COVID-19 patients, primarily using commercially available serologic assays with Food and Drug Administration emergency use authorization. We show that SARS-CoV-2 antibody detection is dependent on the serologic method used, which has implications for future assay utilization and clinical value.
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http://dx.doi.org/10.1128/JCM.01231-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8373029PMC
August 2021

Convalescent Plasma Therapy for COVID-19: A Graphical Mosaic of the Worldwide Evidence.

Front Med (Lausanne) 2021 7;8:684151. Epub 2021 Jun 7.

Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, MN, United States.

Convalescent plasma has been used worldwide to treat patients hospitalized with coronavirus disease 2019 (COVID-19) and prevent disease progression. Despite global usage, uncertainty remains regarding plasma efficacy, as randomized controlled trials (RCTs) have provided divergent evidence regarding the survival benefit of convalescent plasma. Here, we argue that during a global health emergency, the mosaic of evidence originating from multiple levels of the epistemic hierarchy should inform contemporary policy and healthcare decisions. Indeed, worldwide matched-control studies have generally found convalescent plasma to improve COVID-19 patient survival, and RCTs have demonstrated a survival benefit when transfused early in the disease course but limited or no benefit later in the disease course when patients required greater supportive therapies. RCTs have also revealed that convalescent plasma transfusion contributes to improved symptomatology and viral clearance. To further investigate the effect of convalescent plasma on patient mortality, we performed a meta-analytical approach to pool daily survival data from all controlled studies that reported Kaplan-Meier survival plots. Qualitative inspection of all available Kaplan-Meier survival data and an aggregate Kaplan-Meier survival plot revealed a directionally consistent pattern among studies arising from multiple levels of the epistemic hierarchy, whereby convalescent plasma transfusion was generally associated with greater patient survival. Given that convalescent plasma has a similar safety profile as standard plasma, convalescent plasma should be implemented within weeks of the onset of future infectious disease outbreaks.
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http://dx.doi.org/10.3389/fmed.2021.684151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215127PMC
June 2021

Impact of Pharmacologically Left Shifting the Oxygen-Hemoglobin Dissociation Curve on Arterial Blood Gases and Pulmonary Gas Exchange During Maximal Exercise in Hypoxia.

High Alt Med Biol 2021 09 21;22(3):249-262. Epub 2021 Jun 21.

Human Integrative and Environmental Physiology Laboratory, Department of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota, USA.

Stewart, Glenn M., Troy J. Cross, Michael J. Joyner, Steven C. Chase, Timothy Curry, Josh Lehrer-Graiwer, Kobina Dufu, Nicholas E. Vlahakis, and Bruce D. Johnson. Impact of pharmacologically left shifting the oxygen-hemoglobin dissociation curve on arterial blood gases and pulmonary gas exchange during maximal exercise in hypoxia. . 22:249-262, 2021. Physiological and pathological conditions, which reduce the loading of oxygen onto hemoglobin (Hb), can impair exercise capacity and cause debilitating symptoms. Accordingly, this study examined the impact of pharmacologically left shifting the oxygen-hemoglobin dissociation curve (ODC) on arterial oxygen saturation (SaO) and exercise capacity. Eight healthy subjects completed a maximal incremental exercise test in hypoxia (FO: 0.125) and normoxia (FO: 0.21) before (Day 1) and after (Day 15) daily ingestion of 900 mg of voxelotor (an oxygen/Hb affinity modulator). Pulmonary gas exchange and arterial blood gases were assessed throughout exercise and at peak. Data for a 1,500 mg daily drug dose are reported in a limited cohort ( = 3). Fourteen days of drug administration left shifted the ODC (p50 measured under standard conditions, Day 1: 28.0 ± 2.1 mmHg vs. Day 15: 26.1 ± 1.8 mmHg,  < 0.05). Throughout incremental exercise in hypoxia, SaO was systematically higher after drug (peak exercise SaO on Day 1: 71 ± 2 vs. Day 15: 81% ± 2%,  < 0.001), whereas oxygen extraction (Ca-vO diff) and consumption (VO) were similar (peak exercise Ca-vO diff on Day 1: 11.5 ± 1.7 vs. Day 15: 11.0 ± 1.8 ml/100 ml blood,  = 0.417; peak VO on Day 1: 2.59 ± 0.39 vs. Day 15: 2.47 ± 0.43 l/min,  = 0.127). Throughout incremental exercise in normoxia, SaO was systematically higher after drug, whereas peak VO was reduced (peak exercise SaO on Day 1: 93.9 ± 1.8 vs. Day 15: 95.8% ± 1.0%,  = 0.008; peak VO on Day 1: 3.62 ± 0.55 vs. Day 15: 3.26 ± 52 l/min,  = 0.001). Pharmacologically increasing the affinity of Hb for oxygen improved SaO during hypoxia without impacting exercise capacity; however, left shifting the ODC in healthy individuals appears detrimental to exercise capacity in normoxia. Left shifting the ODC to different magnitudes and under more chronic forms of hypoxia warrants further study.
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http://dx.doi.org/10.1089/ham.2020.0159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8665803PMC
September 2021

Association of Convalescent Plasma Therapy With Survival in Patients With Hematologic Cancers and COVID-19.

JAMA Oncol 2021 06 17. Epub 2021 Jun 17.

Departments of Medicine and Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee.

Importance: COVID-19 is a life-threatening illness for many patients. Prior studies have established hematologic cancers as a risk factor associated with particularly poor outcomes from COVID-19. To our knowledge, no studies have established a beneficial role for anti-COVID-19 interventions in this at-risk population. Convalescent plasma therapy may benefit immunocompromised individuals with COVID-19, including those with hematologic cancers.

Objective: To evaluate the association of convalescent plasma treatment with 30-day mortality in hospitalized adults with hematologic cancers and COVID-19 from a multi-institutional cohort.

Design, Setting, And Participants: This retrospective cohort study using data from the COVID-19 and Cancer Consortium registry with propensity score matching evaluated patients with hematologic cancers who were hospitalized for COVID-19. Data were collected between March 17, 2020, and January 21, 2021.

Exposures: Convalescent plasma treatment at any time during hospitalization.

Main Outcomes And Measures: The main outcome was 30-day all-cause mortality. Cox proportional hazards regression analysis with adjustment for potential confounders was performed. Hazard ratios (HRs) are reported with 95% CIs. Secondary subgroup analyses were conducted on patients with severe COVID-19 who required mechanical ventilatory support and/or intensive care unit admission.

Results: A total of 966 individuals (mean [SD] age, 65 [15] years; 539 [55.8%] male) were evaluated in this study; 143 convalescent plasma recipients were compared with 823 untreated control patients. After adjustment for potential confounding factors, convalescent plasma treatment was associated with improved 30-day mortality (HR, 0.60; 95% CI, 0.37-0.97). This association remained significant after propensity score matching (HR, 0.52; 95% CI, 0.29-0.92). Among the 338 patients admitted to the intensive care unit, mortality was significantly lower in convalescent plasma recipients compared with nonrecipients (HR for propensity score-matched comparison, 0.40; 95% CI, 0.20-0.80). Among the 227 patients who required mechanical ventilatory support, mortality was significantly lower in convalescent plasma recipients compared with nonrecipients (HR for propensity score-matched comparison, 0.32; 95% CI, 0.14-0.72).

Conclusions And Relevance: The findings of this cohort study suggest a potential survival benefit in the administration of convalescent plasma to patients with hematologic cancers and COVID-19.
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http://dx.doi.org/10.1001/jamaoncol.2021.1799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8377563PMC
June 2021

Convalescent plasma use in the USA was inversely correlated with COVID-19 mortality.

Elife 2021 06 4;10. Epub 2021 Jun 4.

Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, United States.

Background: 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.

Methods: We tracked the number of CCP units dispensed to hospitals by blood banking organizations and correlated that usage with hospital admission and mortality data.

Results: 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.

Conclusions: 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.

Funding: 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.
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http://dx.doi.org/10.7554/eLife.69866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205484PMC
June 2021

Simple Bodyweight Training Improves Cardiorespiratory Fitness with Minimal Time Commitment: A Contemporary Application of the 5BX Approach.

Int J Exerc Sci 2021 1;14(3):93-100. Epub 2021 Apr 1.

Department of Kinesiology, McMaster University, Hamilton, ON, CANADA.

Bodyweight training (BWT) is a style of interval exercise based on classic principles of physical education. Limited research, however, has examined the efficacy of BWT on cardiorespiratory fitness. This is especially true for simple BWT protocols that do not require extraordinarily high levels of effort. We examined the effect of a BWT protocol, modelled after the original "Five Basic Exercises" (5BX) plan, on peak oxygen uptake (VO) in healthy, inactive adults (20 ± 1 y; body mass index: 20 ± 5 kg/m; mean ± SD). Participants were randomized to a training group that performed 18 sessions over six weeks (n=9), or a non-training control group ( = 10). The 11-minute session involved five exercises (burpees, high knees, split squat jumps, high knees, squat jumps), each performed for 60-seconds at a self-selected "challenging" pace, interspersed with active recovery periods (walking). Mean intensity during training was 82 ± 5% of maximal heart rate, rating of perceived exertion was 14 ± 3 out of 20, and compliance was 100%. ANCOVA revealed a significant difference between groups after the intervention, such that VO was higher in the training group compared to control (34.2 ± 6.4 vs 30.3 ± 11.1 ml/kg/min; = 0.03). Peak power output during the VO test was also higher after training compared to control (211 ± 43 vs 191 ±50 W, = 0.004). There were no changes in leg muscular endurance, handgrip strength or vertical jump height in either group. We conclude that simple BWT- requiring minimal time commitment and no specialized equipment - can enhance cardiorespiratory fitness in inactive adults. These findings have relevance for individuals seeking practical, time-efficient approaches to exercise.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8136567PMC
April 2021

Use of convalescent plasma in COVID-19 patients with immunosuppression.

Transfusion 2021 08 1;61(8):2503-2511. Epub 2021 Jun 1.

Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, Minnesota, USA.

In the absence of effective countermeasures, human convalescent plasma has been widely used to treat severe acute respiratory syndrome coronavirus 2, the causative agent of novel coronavirus disease 19 (COVID-19), including among patients with innate or acquired immunosuppression. However, the association between COVID-19-associated mortality in patients with immunosuppression and therapeutic use of convalescent plasma is unknown. We review 75 reports, including one large matched-control registry study of 143 COVID-19 patients with hematological malignancies, and 51 case reports and 23 case series representing 238 COVID-19 patients with immunosuppression. We review clinical features and treatment protocols of COVID-19 patients with immunosuppression after treatment with human convalescent plasma. We also discuss the time course and clinical features of recovery. The available data from case reports and case series provide evidence suggesting a mortality benefit and rapid clinical improvement in patients with several forms of immunosuppression following COVID-19 convalescent plasma transfusion. The utility of convalescent plasma or other forms of antibody therapy in immune-deficient and immune-suppressed patients with COVID-19 warrants further investigation.
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http://dx.doi.org/10.1111/trf.16525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8242637PMC
August 2021

Technological advances in elite marathon performance.

J Appl Physiol (1985) 2021 06 13;130(6):2002-2008. Epub 2021 May 13.

Exercise Science Program, Department of Physical Therapy, Marquette University, Milwaukee, Wisconsin.

There is scientific and legal controversy about recent technological advances in performance running shoes that reduce the energetic cost of running and may provide a distinct competitive advantage. To better understand the potential performance-enhancing effects of technological advancements in marathon racing shoes, we examined the finishing times and racing shoes of the top 50 male and 50 female runners from the World Marathon Major series in the 2010s before and after the introduction of new Nike shoe models (4%, NEXT%, Alphafly, and other prototypes; herein referred to as "neoteric Nikes"). Data for racing shoes were available for 3,886 of the 3,900 performances recorded at the four annual marathons in Boston, London, Chicago, and New York. In full cohort analyses, marathon finishing times were 2.0% or 2.8 min (138.5 ± 8.1 min vs. 141.3 ± 7.4 min, < 0.001) faster for male runners wearing neoteric Nikes compared with other shoes. For females, marathon finishing times were 2.6% or 4.3 min (159.1 ± 10.0 min vs. 163.4 ± 10.7 min, < 0.001) faster for runners wearing neoteric Nikes. In a subset of within-runner changes in marathon performances (males, = 138; females, = 101), marathon finishing times improved by 0.8% or 1.2 min for males wearing neoteric Nikes relative to the most recent marathon in which other shoes were worn, and this performance-enhancing effect was greater among females who demonstrated 1.6% or 3.7 min improvement ( = 0.002). Our results demonstrate that marathon performances are substantially faster when world-class athletes, and particularly females, wear marathon racing shoes with technological advancements. World-class athletes are substantively faster, wearing marathon racing shoes with technological advancements than other shoes when competing in the marathon. Our findings suggest that technological advances in footwear contributed to the recent improvements in marathon finishing times among elite runners and in record-setting marathon performances. This investigation highlights the importance of sports analytics and may have broad implications for the regulation of running footwear during competition.
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http://dx.doi.org/10.1152/japplphysiol.00002.2021DOI Listing
June 2021

The Effect of Convalescent Plasma Therapy on Mortality Among Patients With COVID-19: Systematic Review and Meta-analysis.

Mayo Clin Proc 2021 05 17;96(5):1262-1275. Epub 2021 Feb 17.

Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, MN. Electronic address:

To determine the effect of COVID-19 convalescent plasma on mortality, we aggregated patient outcome data from 10 randomized clinical trials, 20 matched control studies, 2 dose-response studies, and 96 case reports or case series. Studies published between January 1, 2020, and January 16, 2021, were identified through a systematic search of online PubMed and MEDLINE databases. Random effects analyses of randomized clinical trials and matched control data demonstrated that patients with COVID-19 transfused with convalescent plasma exhibited a lower mortality rate compared with patients receiving standard treatments. Additional analyses showed that early transfusion (within 3 days of hospital admission) of higher titer plasma is associated with lower patient mortality. These data provide evidence favoring the efficacy of human convalescent plasma as a therapeutic agent in hospitalized patients with COVID-19.
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http://dx.doi.org/10.1016/j.mayocp.2021.02.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7888247PMC
May 2021

Sex-based limits to running speed in the human, horse and dog: The role of sexual dimorphisms.

FASEB J 2021 05;35(5):e21562

Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, MN, USA.

Elite performing men continue to record faster record times in running events compared to women. These sex-based differences in running speed and endurance in humans are expected based on sexual dimorphisms that contribute to differences in the determinants of aerobic performance. Comparatively, the sexual dimorphisms contributing to sex-based differences in elite aerobic performance are not ubiquitous across other species that compete in running events. The purpose of this review is to offer a framework and model for ongoing discussions of the physiological determinants and ultimately limits of physical performance. The records for average running speed of champion athletes were delineated by sex for thoroughbred horses, greyhound dogs, and humans. Male and female performances within each of these species are being optimized by training, nutrition, and financial incentives, and are approaching a performance maximum. For horses and greyhounds breeding also plays a role. Analysis of athletic records shows that there is a sex-related difference of ~10% or more in elite athletic performance for humans; however, the upper limit of performance does not appear to be different between sexes for thoroughbred horses and greyhound dogs. In the context of the nil sex differences in running performance in thoroughbreds and greyhounds, we discuss the physiological role of sexual dimorphisms on sex-specific limits to running performance. We highlight that studies on both human and animal performance in athletic events stimulate critical physiological questions and drive novel research.
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http://dx.doi.org/10.1096/fj.202100161RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8444096PMC
May 2021

Convalescent Plasma Use in the United States was inversely correlated with COVID-19 Mortality: Did Plasma Hesitancy cost lives?

medRxiv 2021 Apr 16. Epub 2021 Apr 16.

Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, FL.

Background: The US Food and Drug Administration authorized 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 US.

Methods: We tracked the number of CCP units dispensed to hospitals by blood banking organizations and correlated that usage with hospital admission and mortality data.

Results: 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 two weeks after admission, and this finding was robust to examination of deaths taking place one, two or three 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.

Conclusions: 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.
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http://dx.doi.org/10.1101/2021.04.07.21255089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043483PMC
April 2021

Program and patient characteristics for the United States Expanded Access Program to COVID-19 convalescent plasma.

medRxiv 2021 Apr 10. Epub 2021 Apr 10.

Background: The United States (US) Expanded Access Program (EAP) to COVID-19 convalescent plasma was initiated in response to the rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease-2019 (COVID-19). While randomized clinical trials were in various stages of development and enrollment, there was an urgent need for widespread access to potential therapeutic agents particularly for vulnerable racial and ethnic minority populations who were disproportionately affected by the pandemic. The objective of this study is to report on the demographic, geographic, and chronological access to COVID-19 convalescent plasma in the US via the EAP.

Methods And Findings: Mayo Clinic served as the central IRB for all participating facilities and any US physician could participate as local physician-principal investigator. Registration occurred through the EAP central website. Blood banks rapidly developed logistics to provide convalescent plasma to hospitalized patients with COVID-19. Demographic and clinical characteristics of all enrolled patients in the EAP were summarized. Temporal trends in access to COVID-19 convalescent plasma were investigated by comparing daily and weekly changes in EAP enrollment in response to changes in infection rate on a state level. Geographical analyses on access to convalescent plasma included assessing EAP enrollment in all national hospital referral regions as well as assessing enrollment in metropolitan and less populated areas which did not have access to COVID-19 clinical trials.From April 3 to August 23, 2020, 105,717 hospitalized patients with severe or life-threatening COVID-19 were enrolled in the EAP. A majority of patients were older than 60 years of age (57.8%), male (58.4%), and overweight or obese (83.8%). There was substantial inclusion of minorities and underserved populations, including 46.4% of patients with a race other than White, and 37.2% of patients were of Hispanic ethnicity. Severe or life-threatening COVID-19 was present in 61.8% of patients and 18.9% of patients were mechanically ventilated at time of convalescent plasma infusion. Chronologically and geographically, increases in enrollment in the EAP closely followed confirmed infections across all 50 states. Nearly all national hospital referral regions enrolled patients in the EAP, including both in metropolitan and less populated areas.

Conclusions: The EAP successfully provided widespread access to COVID-19 convalescent plasma in all 50 states, including for underserved racial and ethnic minority populations. The efficient study design of the EAP may serve as an example framework for future efforts when broad access to a treatment is needed in response to a dynamic disease affecting demographic groups and areas historically underrepresented in clinical studies.
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http://dx.doi.org/10.1101/2021.04.08.21255115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043472PMC
April 2021

Liver transplantation for acute liver failure in a SARS-CoV-2 PCR-positive patient.

Am J Transplant 2021 08 5;21(8):2890-2894. Epub 2021 May 5.

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.

Current guidelines recommend deferring liver transplantation (LT) in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection until clinical improvement occurs and two PCR tests collected at least 24 hours apart are negative. We report a case of an 18-year-old, previously healthy African-American woman diagnosed with COVID-19, who presents with acute liver failure (ALF) requiring urgent LT in the context of SARS-CoV-2 polymerase chain reaction (PCR) positivity. The patient was thought to have acute Wilsonian crisis on the basis of hemolytic anemia, alkaline phosphatase:bilirubin ratio <4, AST:ALT ratio >2.2, elevated serum copper, and low uric acid, although an unusual presentation of COVID-19 causing ALF could not be excluded. After meeting criteria for status 1a listing, the patient underwent successful LT, despite ongoing SARS-CoV-2 PCR positivity. Remdesivir was given immediately posttransplant, and mycophenolate mofetil was withheld initially and the SARS-CoV-2 PCR test eventually became negative. Three months following transplantation, the patient has made a near-complete recovery. This case highlights that COVID-19 with SARS-CoV-2 PCR positivity may not be an absolute contraindication for transplantation in ALF. Criteria for patient selection and timing of LT amid the COVID-19 pandemic need to be validated in future studies.
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http://dx.doi.org/10.1111/ajt.16582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251077PMC
August 2021

The Oxygen Cascade During Exercise in Health and Disease.

Mayo Clin Proc 2021 04 11;96(4):1017-1032. Epub 2021 Mar 11.

Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, MN. Electronic address:

The oxygen transport cascade describes the physiological steps that bring atmospheric oxygen into the body where it is delivered and consumed by metabolically active tissue. As such, the oxygen cascade is fundamental to our understanding of exercise in health and disease. Our narrative review will highlight each step of the oxygen transport cascade from inspiration of atmospheric oxygen down to mitochondrial consumption in both healthy active males and females along with clinical conditions. We will focus on how different steps interact along with principles of homeostasis, physiological redundancies, and adaptation. In particular, we highlight some of the parallels between elite athletes and clinical conditions in terms of the oxygen cascade.
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http://dx.doi.org/10.1016/j.mayocp.2020.06.063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026750PMC
April 2021

SARS-CoV-2 Seroprevalence and Symptom Onset in Culturally Linked Orthodox Jewish Communities Across Multiple Regions in the United States.

JAMA Netw Open 2021 03 1;4(3):e212816. Epub 2021 Mar 1.

Department of Dermatology, George Washington University, Washington, DC.

Importance: Data on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) seroprevalence in the United States are still emerging.

Objective: To elucidate SARS-CoV-2 seroprevalence and symptom onset in a culturally linked community across 5 states in the United States.

Design, Setting, And Participants: This cross-sectional study included adults (aged ≥18 years) recruited from the orthodox Jewish community across 5 states (California, Connecticut, Michigan, New Jersey, and New York) in 3 geographically distinct areas of the United States between May 13 and July 6, 2020. Participants completed an online survey and underwent SARS-CoV-2 antibody testing.

Main Outcomes And Measures: Seroprevalence and date of symptom onset of SARS-CoV-2.

Results: Overall, 9507 adults (mean [SD] age, 39.6 [15.0] years; 3777 [39.7%] women) completed the SARS-CoV-2 survey, of whom 6665 (70.1%) had immunoglobin G anti-SARS-CoV-2 antibody levels assessed. A high seroprevalence of SARS-CoV-2 antibodies was observed across all communities, with the highest proportion of positive testing observed in New Jersey (1080 of 3323 [32.5%]) and New York (671 of 2196 [30.6%]). Most individuals with a positive SARS-CoV-2 immunoglobin G antibody test reported a date of symptom-onset between March 9 and March 31, 2020 (California: 135 of 154 [87.7%]; Connecticut: 32 of 34 [94.1%]; Michigan: 44 of 50 [88.0%]; New Jersey: 964 of 1168 [82.5%]; New York: 571 of 677 [84.3%]). This start date was coincident with the Jewish festival of Purim, celebrated March 9 to 10, 2020, with extensive intracommunity spread in the weeks following (mean and mode of peak symptom onset, March 20, 2020), occurring in the absence of strong general and culture-specific public health directives.

Conclusions And Relevance: This cross-sectional study of orthodox Jewish adults across the US found that socioculturally bound communities experienced early parallel outbreaks in discrete locations, notably prior to substantive medical and governmental directives. Further research should clarify optimal national, local, community-based, and government policies to prevent outbreaks in social and cultural communities that traditionally gather for holidays, assemblies, and festivals.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.2816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948060PMC
March 2021

The Principles of Antibody Therapy for Infectious Diseases with Relevance for COVID-19.

mBio 2021 03 2;12(2). Epub 2021 Mar 2.

Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, Minnesota, USA.

Antibody therapies such as convalescent plasma and monoclonal antibodies have emerged as major potential therapeutics for coronavirus disease 2019 (COVID-19). Immunoglobulins differ from conventional antimicrobial agents in that they mediate direct and indirect antimicrobial effects that work in concert with other components of the immune system. The field of infectious diseases pioneered antibody therapies in the first half of the 20th century but largely abandoned them with the arrival of conventional antimicrobial therapy. Consequently, much of the knowledge gained from the historical development and use of immunoglobulins such as serum and convalescent antibody therapies was forgotten; principles and practice governing their use were not taught to new generations of medical practitioners, and further development of this modality stalled. This became apparent during the COVID-19 pandemic in the spring of 2020 when convalescent plasma was initially deployed as salvage therapy in patients with severe disease. In retrospect, this was a stage of disease when it was less likely to be effective. Lessons of the past tell us that antibody therapy is most likely to be effective when used early in respiratory diseases. This article puts forth three principles of antibody therapy, namely, specificity, temporal, and quantitative principles, connoting that antibody efficacy requires the administration of specific antibody, given early in course of disease in sufficient amount. These principles are traced to the history of serum therapy for infectious diseases. The application of the specificity, temporal, and quantitative principles to COVID-19 is discussed in the context of current use of antibody therapy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
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http://dx.doi.org/10.1128/mBio.03372-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092292PMC
March 2021

SARS-CoV-2 variants and convalescent plasma: reality, fallacies, and opportunities.

J Clin Invest 2021 04;131(7)

Departments of Medicine and Microbiology and Immunology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, USA.

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http://dx.doi.org/10.1172/JCI148832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011895PMC
April 2021
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