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49 Research products, page 1 of 5

  • COVID-19
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  • Open Access English
    Authors: 
    Yuping Ren; Eun-Jin Choi; Ke Zhang; Yu Chen; Sha Ye; Xiaoling Deng; Kangling Zhang; Xiaoyong Bao;
    Publisher: Multidisciplinary Digital Publishing Institute
    Project: NIH | Functional Portraits of t... (1R21AI113771-01A1), NIH | UTMB Clinical and Transla... (3UL1TR001439-04S2), NIH | Characterization of tRNA-... (1R56AI107033-01A1)

    Human metapneumovirus (hMPV) is a leading cause of lower respiratory infection in pediatric populations globally. This study examined proteomic profile changes in A549 cells infected with hMPV and two attenuated mutants with deleted PDZ domain-binding motif(s) in the M2-2 protein. These motifs are involved in the interruption of antiviral signaling, namely the interaction between the TNF receptor associated factor (TRAF) and mitochondrial antiviral-signaling (MAVS) proteins. The aim of this study was to provide insight into the overall and novel impact of M2-2 motifs on cellular responses via an unbiased comparison. Tandem mass tagging, stable isotope labeling, and high-resolution mass spectrometry were used for quantitative proteomic analysis. Using quantitative proteomics and Venn analysis, 1248 common proteins were detected in all infected samples of both technical sets. Hierarchical clustering of the differentiated proteome displayed distinct proteomic signatures that were controlled by the motif(s). Bioinformatics and experimental analysis confirmed the differentiated proteomes, revealed novel cellular biological events, and implicated key pathways controlled by hMPV M2-2 PDZ domain-binding motif(s). This provides further insight for evaluating M2-2 mutants as potent vaccine candidates.

  • Open Access English
    Authors: 
    Meike Dittmann; Hans-Heinrich Hoffmann; Margaret A. Scull; Rachel H. Gilmore; Kierstin L. Bell; Michael J. Ciancanelli; Sam J. Wilson; Stefania Crotta; Yingpu Yu; Brenna Flatley; +5 more
    Publisher: Cell Press
    Country: United Kingdom
    Project: NIH | Transforming Translationa... (3UL1TR000043-07S1), NIH | Multi-Center Blinded Anal... (3U54AI057158-08S1), NIH | Type I interferon-stimula... (5R01AI091707-05)

    Summary Interferon-stimulated genes (ISGs) act in concert to provide a tight barrier against viruses. Recent studies have shed light on the contribution of individual ISG effectors to the antiviral state, but most have examined those acting on early, intracellular stages of the viral life cycle. Here, we applied an image-based screen to identify ISGs inhibiting late stages of influenza A virus (IAV) infection. We unraveled a directly antiviral function for the gene SERPINE1, encoding plasminogen activator inhibitor 1 (PAI-1). By targeting extracellular airway proteases, PAI-1 inhibits IAV glycoprotein cleavage, thereby reducing infectivity of progeny viruses. This was biologically relevant for IAV restriction in vivo. Further, partial PAI-1 deficiency, attributable to a polymorphism in human SERPINE1, conferred increased susceptibility to IAV in vitro. Together, our findings reveal that manipulating the extracellular environment to inhibit the last step in a virus life cycle is an important mechanism of the antiviral response. Highlights • SERPINE1/PAI-1 was identified as an unconventional ISG that acts extracellularly • PAI-1 inhibits influenza A virus (IAV) spread by inhibiting glycoprotein cleavage • Endogenous PAI-1 blocks IAV spread in human and murine cells, ex vivo and in vivo • PAI-1 potentially inhibits other viruses requiring extracellular maturation Plasminogen activator inhibitor (PAI-1) blocks surface glycoprotein maturation of influenza A virus, thus reducing virus spread in the airways and revealing that the innate immune system, driven by type I IFN, uses modulation of the extracellular environment to inhibit viruses. Graphical Abstract

  • Open Access English
    Authors: 
    Rohan Khera; Callahan Clark; Yuan Lu; Yinglong Guo; Sheng Ren; Brandon Truax; Erica S. Spatz; Karthik Murugiah; Zhenqiu Lin; Saad B. Omer; +2 more
    Publisher: Cold Spring Harbor Laboratory
    Project: NIH | SCH: INT: A Context-aware... (1R01EB028106-01), NIH | UT Southwestern Center fo... (4UL1TR001105-04), NIH | Yale Transdisciplinary Co... (1U54MD010711-01), NIH | Yale Scholars in Implemen... (1K12HL138037-01)

    Background: Whether angiotensin-converting enzyme (ACE) Inhibitors and angiotensin receptor blockers (ARBs) mitigate or exacerbate SARS-CoV-2 infection remains uncertain. In a national study, we evaluated the association of ACE inhibitors and ARB with coronavirus disease-19 (COVID-19) hospitalization and mortality among individuals with hypertension. Methods: Among Medicare Advantage and commercially insured individuals, we identified 2,263 people with hypertension, receiving ≥1 antihypertensive agents, and who had a positive outpatient SARS-CoV-2 test (outpatient cohort). In a propensity score-matched analysis, we determined the association of ACE inhibitors and ARBs with the risk of hospitalization for COVID-19. In a second study of 7,933 individuals with hypertension who were hospitalized with COVID-19 (inpatient cohort), we tested the association of these medications with in-hospital mortality. We stratified all our assessments by insurance groups. Results: Among individuals in the outpatient and inpatient cohorts, 31.9% and 29.8%, respectively, used ACE inhibitors and 32.3% and 28.1% used ARBs. In the outpatient study, over a median 30.0 (19.0 - 40.0) days after testing positive, 12.7% were hospitalized for COVID-19. In propensity score-matched analyses, neither ACE inhibitors (HR, 0.77 [0.53, 1.13], P = 0.18), nor ARBs (HR, 0.88 [0.61, 1.26], P = 0.48), were significantly associated with risk of hospitalization. In analyses stratified by insurance group, ACE inhibitors, but not ARBs, were associated with a significant lower risk of hospitalization in the Medicare group (HR, 0.61 [0.41, 0.93], P = 0.02), but not the commercially insured group (HR: 2.14 [0.82, 5.60], P = 0.12; P-interaction 0.09). In the inpatient study, 14.2% died, 59.5% survived to discharge, and 26.3% had an ongoing hospitalization. In propensity score-matched analyses, neither use of ACE inhibitor (0.97 [0.81, 1.16]; P = 0.74) nor ARB (1.15 [0.95, 1.38]; P = 0.15) was associated with risk of in-hospital mortality, in total or in the stratified analyses. Conclusions: The use of ACE inhibitors and ARBs was not associated with the risk of hospitalization or mortality among those infected with SARS-CoV-2. However, there was a nearly 40% lower risk of hospitalization with the use of ACE inhibitors in the Medicare population. This finding merits a clinical trial to evaluate the potential role of ACE inhibitors in reducing the risk of hospitalization among older individuals, who are at an elevated risk of adverse outcomes with the infection.

  • Open Access English
    Authors: 
    Frederick R. Adler; Chris Stockmann; Kwabena Krow Ampofo; Andrew T. Pavia; Carrie L. Byington;
    Publisher: Public Library of Science (PLoS)
    Project: NIH | Risk Stratification and D... (5R01AI125642-02), NIH | University of Utah Center... (3UL1TR001067-04S2), NIH | Decision Support for Eval... (5K24HD047249-05), NIH | STI and Respiratory Patho... (5U01AI082482-03), NIH | Explanatory models of CF ... (1R01HL125520-01A1)

    Background Common cold viruses create significant health and financial burdens, and understanding key loci of transmission would help focus control strategies. This study (1) examines factors that influence when individuals transition from a negative to positive test (acquisition) or a positive to negative test (loss) of rhinovirus (HRV) and other respiratory tract viruses in 26 households followed weekly for one year, (2) investigates evidence for intrahousehold and interhousehold transmission and the characteristics of individuals implicated in transmission, and (3) builds data-based simulation models to identify factors that most strongly affect patterns of prevalence. Methods We detected HRV, coronavirus, paramyxovirus, influenza and bocavirus with the FilmArray polymerase chain reaction (PCR) platform (BioFire Diagnostics, LLC). We used logistic regression to find covariates affecting acquisition or loss of HRV including demographic characteristics of individuals, their household, their current infection status, and prevalence within their household and across the population. We apply generalized linear mixed models to test robustness of results. Results Acquisition of HRV was less probable in older individuals and those infected with a coronavirus, and higher with a higher proportion of other household members infected. Loss of HRV is reduced with a higher proportion of other household members infected. Within households, only children and symptomatic individuals show evidence for transmission, while between households only a higher number of infected older children (ages 5-19) increases the probability of acquisition. Coronaviruses, paramyxoviruses and bocavirus also show evidence of intrahousehold transmission. Simulations show that age-dependent susceptibility and transmission have the largest effects on mean HRV prevalence. Conclusions Children are most likely to acquire and most likely to transmit HRV both within and between households, with infectiousness concentrated in symptomatic children. Simulations predict that the spread of HRV and other respiratory tract viruses can be reduced but not eliminated by practices within the home.

  • Open Access English
    Authors: 
    Jordana E. Hoppe; Brandie D. Wagner; Scott D. Sagel; Frank J. Accurso; Edith T. Zemanick;
    Publisher: BMC
    Project: NIH | Colorado Clinical and Tra... (5UL1TR001082-05), NIH | Airway Microbiome in Cyst... (5K23HL114883-04)

    Background Pulmonary exacerbations (PEx) in school aged children and adults with cystic fibrosis (CF) lead to increased morbidity and lung function decline. However, the effect of exacerbations in young children with CF is not fully understood. We sought to characterize the frequency and clinical impact of PEx in a pilot study of infants and pre-school aged children with CF. Methods Thirty young children with CF [median (range) 1.5 years (0.2–4.9)] were prospectively followed for 2 years. Exacerbation frequency (hospitalizations and outpatient antibiotic use) was determined. Chest radiographs were performed at enrollment and study completion and assigned a Brasfield score. Lung function at age 7 years was assessed in a subset of children. The association between PEx frequency, chest radiograph score, and lung function was determined using Spearman correlation coefficients and corresponding 95% confidence intervals. Correlations with an absolute magnitude of 0.3 or greater were considered clinically significant. Results Over 2 years, participants experienced a median of two PEx (range 0–13). Chest radiograph scores at enrollment and study completion were inversely associated with PEx frequency (R = −0.48 and R = −0.44, respectively). The association between frequency of PEx and lung function [forced expiratory volume in 1 s (FEV1)] at age 7 years was small (R = 0.20). Higher forced vital capacity (FVC) at 7 years was associated with more frequent PEx during the study (R = 0.44). Conclusions Children with worse chest radiograph scores had more frequent PEx over the subsequent 2 years, suggesting a group of patients at higher risk for PEx. Frequent PEx in infants and young children with CF were not associated with lower FEV1 and FVC at 7 years, although spirometry in this age group may not be a sensitive marker of mild lung disease and disease progression. Electronic supplementary material The online version of this article (10.1186/s12890-017-0546-8) contains supplementary material, which is available to authorized users.

  • Open Access English
    Authors: 
    Sean Ekins; Thomas J. Lane; Peter B. Madrid;
    Publisher: Springer US
    Project: NIH | Repurposing pyronaridine ... (1R21TR001718-01), NIH | Centralized assay dataset... (2R44GM122196-02A1)

    For the last 50 years we have known of a broad-spectrum agent tilorone dihydrochloride (Tilorone). This is a small-molecule orally bioavailable drug that was originally discovered in the USA and is currently used clinically as an antiviral in Russia and the Ukraine. Over the years there have been numerous clinical and non-clinical reports of its broad spectrum of antiviral activity. More recently we have identified additional promising antiviral activities against Middle East Respiratory Syndrome, Chikungunya, Ebola and Marburg which highlights that this old drug may have other uses against new viruses. This may in turn inform the types of drugs that we need for virus outbreaks such as for the new coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Tilorone has been long neglected by the west in many respects but it deserves further reassessment in light of current and future needs for broad-spectrum antivirals.

  • Publication . Other literature type . Preprint . 2020
    Open Access English
    Authors: 
    Dongmei Li; Daniel P. Croft; Deborah J. Ossip; Zidian Xie;
    Publisher: Cold Spring Harbor Laboratory
    Project: NIH | The University of Rochest... (3UL1TR002001-02S1)

    AbstractBackgroundCOVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was declared a global pandemic in March 2020. Electronic cigarette use (vaping) rapidly gained popularity in the US in recent years. Whether electronic cigarette users (vapers) are more susceptible to COVID-19 infection is unknown.MethodsUsing integrated data in each US state from the 2018 Behavioral Risk Factor Surveillance System (BRFSS), United States Census Bureau and the 1Point3Acres.com website, generalized estimating equation (GEE) models with negative binomial distribution assumption and log link functions were used to examine the association of weighted proportions of vapers with number of COVID-19 infections and deaths in the US.ResultsThe weighted proportion of vapers who used e-cigarettes every day or some days ranged from 2.86% to 6.42% for US states. Statistically significant associations were observed between the weighted proportion of vapers and number of COVID-19 infected cases as well as COVID-19 deaths in the US after adjusting for the weighted proportion of smokers and other significant covariates in the GEE models. With every one percent increase in weighted proportion of vapers in each state, the number of COVID-19 infected cases increase by 0.3139 (95% CI: 0.0554 –0.5723) and the number of COVID-19 deaths increase by 0.3705 (95% CI: 0.0623 – 0.6786) in log scale in each US state.ConclusionsThe positive associations between the proportion of vapers and the number of COVID-19 infected cases and deaths in each US state suggest an increased susceptibility of vapers to COVID-19 infections and deaths.

  • Open Access English
    Authors: 
    Zost, Seth J; Gilchuk, Pavlo; Chen, Rita; Case, James Brett; Reidy, Joseph X; Trivette, Andrew; Nargi, Rachel S; Sutton, Rachel E; Suryadevara, Naveen; Chen, Elaine C; +19 more
    Publisher: Cold Spring Harbor Laboratory
    Project: NIH | Infectious Disease Pathog... (5T32AI007151-28), NIH | The Vanderbilt Institute ... (6UL1TR000445-11), NIH | Illumina Genome Analyzer ... (1S10RR028106-01A1), NIH | The Vanderbilt Institute ... (3UL1RR024975-03S4), NIH | Childhood Infections Rese... (5T32AI095202-09)

    Antibodies are a principal determinant of immunity for most RNA viruses and have promise to reduce infection or disease during major epidemics. The novel coronavirus SARS-CoV-2 has caused a global pandemic with millions of infections and hundreds of thousands of deaths to date1,2. In response, we used a rapid antibody discovery platform to isolate hundreds of human monoclonal antibodies (mAbs) against the SARS-CoV-2 spike (S) protein. We stratify these mAbs into five major classes based on their reactivity to subdomains of S protein as well as their cross-reactivity to SARS-CoV. Many of these mAbs inhibit infection of authentic SARS-CoV-2 virus, with most neutralizing mAbs recognizing the receptor-binding domain (RBD) of S. This work defines sites of vulnerability on SARS-CoV-2 S and demonstrates the speed and robustness of new antibody discovery methodologies.

  • Open Access English
    Authors: 
    Rohan Khera; Lovedeep Singh Dhingra; Snigdha Jain; Harlan M. Krumholz;
    Publisher: Cold Spring Harbor Laboratory
    Project: NIH | UT Southwestern Center fo... (4UL1TR001105-04)

    BackgroundThe coronavirus disease-19 (COVID-19) pandemic threatens to overwhelm the healthcare resources of the country, but also poses a personal hazard to healthcare workers, including physicians. To address the potential impact of excluding physicians with a high risk of adverse outcomes based on age, we evaluated the current patterns of age of licensed physicians across the United States.MethodsWe compiled information from the 2018 database of actively licensed physicians in the Federation of State Medical Boards (FSMB) across the US. Both at a national- and the state-level, we assessed the number and proportion of physicians who would be at an elevated risk due to age over 60 years.ResultsOf the 985,026 licensed physicians in the US, 235857 or 23.9% were aged 25-40 years, 447052 or 45.4% are 40-60 years, 191794 or 19.5% were 60-70 years, and 106121 or 10.8% were 70 years or older. Age was not reported in 4202 or 0.4% of physicians. Overall, 297915 or 30.2% of physicians were 60 years of age or older, 246167 (25.0%) 65 years and older, and 106121 (10.8%) 70 years or older. States in the US reported that a median 5470 licensed physicians (interquartile range [IQR], 2394 to 10108) were 60 years of age or older. Notably, states of North Dakota (n=1180) and Vermont (n = 1215) had the lowest and California (n=50786) and New York (n=31582) the highest number of physicians over the age of 60 years (Figure 1). Across states, the median proportion of physicians aged 60 years and older was 28.9% (IQR, 27.2%, 31.4%), and ranged between 25.9% for Nebraska to 32.6% for New Mexico (Figure 2).DiscussionOlder physicians represent a large proportion of the US physician workforce, particularly in states with the worst COVID-19 outbreak. Therefore, their exclusion from patient care will be impractical. Optimizing care practices by limiting direct patient contact of physicians vulnerable to adverse outcomes from COVID-19, potentially by expanding their participation in telehealth may be a strategy to protect them.

  • Publication . Preprint . Other literature type . 2020
    Open Access English
    Authors: 
    Michael J. Joyner; R. Scott Wright; DeLisa Fairweather; Jonathon W. Senefeld; Katelyn A. Bruno; Stephen A. Klassen; Rickey E. Carter; Allan M. Klompas; Chad C. Wiggins; John R. A. Shepherd; +24 more
    Publisher: Cold Spring Harbor Laboratory
    Project: NIH | Variant Hemoglobin and Ca... (1R35HL139854-01), NIH | Mayo Clinic Center for cl... (3UL1TR002377-02S1), NIH | Diabetes and Metabolism (5T32DK007352-38), NSERC

    Background: Convalescent plasma is the only antibody based therapy currently available for COVID-19 patients. 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 5,000 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) in the first four hours after transfusion was <1%, including mortality rate (0.3%). Of the 36 reported SAEs, there were 25 reported incidences of related SAEs, including mortality (n=4), transfusion-associated circulatory overload (TACO; n=7), transfusion-related acute lung injury (TRALI; 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 seven-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.

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The following results are related to COVID-19. Are you interested to view more results? Visit OpenAIRE - Explore.
49 Research products, page 1 of 5
  • Open Access English
    Authors: 
    Yuping Ren; Eun-Jin Choi; Ke Zhang; Yu Chen; Sha Ye; Xiaoling Deng; Kangling Zhang; Xiaoyong Bao;
    Publisher: Multidisciplinary Digital Publishing Institute
    Project: NIH | Functional Portraits of t... (1R21AI113771-01A1), NIH | UTMB Clinical and Transla... (3UL1TR001439-04S2), NIH | Characterization of tRNA-... (1R56AI107033-01A1)

    Human metapneumovirus (hMPV) is a leading cause of lower respiratory infection in pediatric populations globally. This study examined proteomic profile changes in A549 cells infected with hMPV and two attenuated mutants with deleted PDZ domain-binding motif(s) in the M2-2 protein. These motifs are involved in the interruption of antiviral signaling, namely the interaction between the TNF receptor associated factor (TRAF) and mitochondrial antiviral-signaling (MAVS) proteins. The aim of this study was to provide insight into the overall and novel impact of M2-2 motifs on cellular responses via an unbiased comparison. Tandem mass tagging, stable isotope labeling, and high-resolution mass spectrometry were used for quantitative proteomic analysis. Using quantitative proteomics and Venn analysis, 1248 common proteins were detected in all infected samples of both technical sets. Hierarchical clustering of the differentiated proteome displayed distinct proteomic signatures that were controlled by the motif(s). Bioinformatics and experimental analysis confirmed the differentiated proteomes, revealed novel cellular biological events, and implicated key pathways controlled by hMPV M2-2 PDZ domain-binding motif(s). This provides further insight for evaluating M2-2 mutants as potent vaccine candidates.

  • Open Access English
    Authors: 
    Meike Dittmann; Hans-Heinrich Hoffmann; Margaret A. Scull; Rachel H. Gilmore; Kierstin L. Bell; Michael J. Ciancanelli; Sam J. Wilson; Stefania Crotta; Yingpu Yu; Brenna Flatley; +5 more
    Publisher: Cell Press
    Country: United Kingdom
    Project: NIH | Transforming Translationa... (3UL1TR000043-07S1), NIH | Multi-Center Blinded Anal... (3U54AI057158-08S1), NIH | Type I interferon-stimula... (5R01AI091707-05)

    Summary Interferon-stimulated genes (ISGs) act in concert to provide a tight barrier against viruses. Recent studies have shed light on the contribution of individual ISG effectors to the antiviral state, but most have examined those acting on early, intracellular stages of the viral life cycle. Here, we applied an image-based screen to identify ISGs inhibiting late stages of influenza A virus (IAV) infection. We unraveled a directly antiviral function for the gene SERPINE1, encoding plasminogen activator inhibitor 1 (PAI-1). By targeting extracellular airway proteases, PAI-1 inhibits IAV glycoprotein cleavage, thereby reducing infectivity of progeny viruses. This was biologically relevant for IAV restriction in vivo. Further, partial PAI-1 deficiency, attributable to a polymorphism in human SERPINE1, conferred increased susceptibility to IAV in vitro. Together, our findings reveal that manipulating the extracellular environment to inhibit the last step in a virus life cycle is an important mechanism of the antiviral response. Highlights • SERPINE1/PAI-1 was identified as an unconventional ISG that acts extracellularly • PAI-1 inhibits influenza A virus (IAV) spread by inhibiting glycoprotein cleavage • Endogenous PAI-1 blocks IAV spread in human and murine cells, ex vivo and in vivo • PAI-1 potentially inhibits other viruses requiring extracellular maturation Plasminogen activator inhibitor (PAI-1) blocks surface glycoprotein maturation of influenza A virus, thus reducing virus spread in the airways and revealing that the innate immune system, driven by type I IFN, uses modulation of the extracellular environment to inhibit viruses. Graphical Abstract

  • Open Access English
    Authors: 
    Rohan Khera; Callahan Clark; Yuan Lu; Yinglong Guo; Sheng Ren; Brandon Truax; Erica S. Spatz; Karthik Murugiah; Zhenqiu Lin; Saad B. Omer; +2 more
    Publisher: Cold Spring Harbor Laboratory
    Project: NIH | SCH: INT: A Context-aware... (1R01EB028106-01), NIH | UT Southwestern Center fo... (4UL1TR001105-04), NIH | Yale Transdisciplinary Co... (1U54MD010711-01), NIH | Yale Scholars in Implemen... (1K12HL138037-01)

    Background: Whether angiotensin-converting enzyme (ACE) Inhibitors and angiotensin receptor blockers (ARBs) mitigate or exacerbate SARS-CoV-2 infection remains uncertain. In a national study, we evaluated the association of ACE inhibitors and ARB with coronavirus disease-19 (COVID-19) hospitalization and mortality among individuals with hypertension. Methods: Among Medicare Advantage and commercially insured individuals, we identified 2,263 people with hypertension, receiving ≥1 antihypertensive agents, and who had a positive outpatient SARS-CoV-2 test (outpatient cohort). In a propensity score-matched analysis, we determined the association of ACE inhibitors and ARBs with the risk of hospitalization for COVID-19. In a second study of 7,933 individuals with hypertension who were hospitalized with COVID-19 (inpatient cohort), we tested the association of these medications with in-hospital mortality. We stratified all our assessments by insurance groups. Results: Among individuals in the outpatient and inpatient cohorts, 31.9% and 29.8%, respectively, used ACE inhibitors and 32.3% and 28.1% used ARBs. In the outpatient study, over a median 30.0 (19.0 - 40.0) days after testing positive, 12.7% were hospitalized for COVID-19. In propensity score-matched analyses, neither ACE inhibitors (HR, 0.77 [0.53, 1.13], P = 0.18), nor ARBs (HR, 0.88 [0.61, 1.26], P = 0.48), were significantly associated with risk of hospitalization. In analyses stratified by insurance group, ACE inhibitors, but not ARBs, were associated with a significant lower risk of hospitalization in the Medicare group (HR, 0.61 [0.41, 0.93], P = 0.02), but not the commercially insured group (HR: 2.14 [0.82, 5.60], P = 0.12; P-interaction 0.09). In the inpatient study, 14.2% died, 59.5% survived to discharge, and 26.3% had an ongoing hospitalization. In propensity score-matched analyses, neither use of ACE inhibitor (0.97 [0.81, 1.16]; P = 0.74) nor ARB (1.15 [0.95, 1.38]; P = 0.15) was associated with risk of in-hospital mortality, in total or in the stratified analyses. Conclusions: The use of ACE inhibitors and ARBs was not associated with the risk of hospitalization or mortality among those infected with SARS-CoV-2. However, there was a nearly 40% lower risk of hospitalization with the use of ACE inhibitors in the Medicare population. This finding merits a clinical trial to evaluate the potential role of ACE inhibitors in reducing the risk of hospitalization among older individuals, who are at an elevated risk of adverse outcomes with the infection.

  • Open Access English
    Authors: 
    Frederick R. Adler; Chris Stockmann; Kwabena Krow Ampofo; Andrew T. Pavia; Carrie L. Byington;
    Publisher: Public Library of Science (PLoS)
    Project: NIH | Risk Stratification and D... (5R01AI125642-02), NIH | University of Utah Center... (3UL1TR001067-04S2), NIH | Decision Support for Eval... (5K24HD047249-05), NIH | STI and Respiratory Patho... (5U01AI082482-03), NIH | Explanatory models of CF ... (1R01HL125520-01A1)

    Background Common cold viruses create significant health and financial burdens, and understanding key loci of transmission would help focus control strategies. This study (1) examines factors that influence when individuals transition from a negative to positive test (acquisition) or a positive to negative test (loss) of rhinovirus (HRV) and other respiratory tract viruses in 26 households followed weekly for one year, (2) investigates evidence for intrahousehold and interhousehold transmission and the characteristics of individuals implicated in transmission, and (3) builds data-based simulation models to identify factors that most strongly affect patterns of prevalence. Methods We detected HRV, coronavirus, paramyxovirus, influenza and bocavirus with the FilmArray polymerase chain reaction (PCR) platform (BioFire Diagnostics, LLC). We used logistic regression to find covariates affecting acquisition or loss of HRV including demographic characteristics of individuals, their household, their current infection status, and prevalence within their household and across the population. We apply generalized linear mixed models to test robustness of results. Results Acquisition of HRV was less probable in older individuals and those infected with a coronavirus, and higher with a higher proportion of other household members infected. Loss of HRV is reduced with a higher proportion of other household members infected. Within households, only children and symptomatic individuals show evidence for transmission, while between households only a higher number of infected older children (ages 5-19) increases the probability of acquisition. Coronaviruses, paramyxoviruses and bocavirus also show evidence of intrahousehold transmission. Simulations show that age-dependent susceptibility and transmission have the largest effects on mean HRV prevalence. Conclusions Children are most likely to acquire and most likely to transmit HRV both within and between households, with infectiousness concentrated in symptomatic children. Simulations predict that the spread of HRV and other respiratory tract viruses can be reduced but not eliminated by practices within the home.

  • Open Access English
    Authors: 
    Jordana E. Hoppe; Brandie D. Wagner; Scott D. Sagel; Frank J. Accurso; Edith T. Zemanick;
    Publisher: BMC
    Project: NIH | Colorado Clinical and Tra... (5UL1TR001082-05), NIH | Airway Microbiome in Cyst... (5K23HL114883-04)

    Background Pulmonary exacerbations (PEx) in school aged children and adults with cystic fibrosis (CF) lead to increased morbidity and lung function decline. However, the effect of exacerbations in young children with CF is not fully understood. We sought to characterize the frequency and clinical impact of PEx in a pilot study of infants and pre-school aged children with CF. Methods Thirty young children with CF [median (range) 1.5 years (0.2–4.9)] were prospectively followed for 2 years. Exacerbation frequency (hospitalizations and outpatient antibiotic use) was determined. Chest radiographs were performed at enrollment and study completion and assigned a Brasfield score. Lung function at age 7 years was assessed in a subset of children. The association between PEx frequency, chest radiograph score, and lung function was determined using Spearman correlation coefficients and corresponding 95% confidence intervals. Correlations with an absolute magnitude of 0.3 or greater were considered clinically significant. Results Over 2 years, participants experienced a median of two PEx (range 0–13). Chest radiograph scores at enrollment and study completion were inversely associated with PEx frequency (R = −0.48 and R = −0.44, respectively). The association between frequency of PEx and lung function [forced expiratory volume in 1 s (FEV1)] at age 7 years was small (R = 0.20). Higher forced vital capacity (FVC) at 7 years was associated with more frequent PEx during the study (R = 0.44). Conclusions Children with worse chest radiograph scores had more frequent PEx over the subsequent 2 years, suggesting a group of patients at higher risk for PEx. Frequent PEx in infants and young children with CF were not associated with lower FEV1 and FVC at 7 years, although spirometry in this age group may not be a sensitive marker of mild lung disease and disease progression. Electronic supplementary material The online version of this article (10.1186/s12890-017-0546-8) contains supplementary material, which is available to authorized users.

  • Open Access English
    Authors: 
    Sean Ekins; Thomas J. Lane; Peter B. Madrid;
    Publisher: Springer US
    Project: NIH | Repurposing pyronaridine ... (1R21TR001718-01), NIH | Centralized assay dataset... (2R44GM122196-02A1)

    For the last 50 years we have known of a broad-spectrum agent tilorone dihydrochloride (Tilorone). This is a small-molecule orally bioavailable drug that was originally discovered in the USA and is currently used clinically as an antiviral in Russia and the Ukraine. Over the years there have been numerous clinical and non-clinical reports of its broad spectrum of antiviral activity. More recently we have identified additional promising antiviral activities against Middle East Respiratory Syndrome, Chikungunya, Ebola and Marburg which highlights that this old drug may have other uses against new viruses. This may in turn inform the types of drugs that we need for virus outbreaks such as for the new coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Tilorone has been long neglected by the west in many respects but it deserves further reassessment in light of current and future needs for broad-spectrum antivirals.

  • Publication . Other literature type . Preprint . 2020
    Open Access English
    Authors: 
    Dongmei Li; Daniel P. Croft; Deborah J. Ossip; Zidian Xie;
    Publisher: Cold Spring Harbor Laboratory
    Project: NIH | The University of Rochest... (3UL1TR002001-02S1)

    AbstractBackgroundCOVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was declared a global pandemic in March 2020. Electronic cigarette use (vaping) rapidly gained popularity in the US in recent years. Whether electronic cigarette users (vapers) are more susceptible to COVID-19 infection is unknown.MethodsUsing integrated data in each US state from the 2018 Behavioral Risk Factor Surveillance System (BRFSS), United States Census Bureau and the 1Point3Acres.com website, generalized estimating equation (GEE) models with negative binomial distribution assumption and log link functions were used to examine the association of weighted proportions of vapers with number of COVID-19 infections and deaths in the US.ResultsThe weighted proportion of vapers who used e-cigarettes every day or some days ranged from 2.86% to 6.42% for US states. Statistically significant associations were observed between the weighted proportion of vapers and number of COVID-19 infected cases as well as COVID-19 deaths in the US after adjusting for the weighted proportion of smokers and other significant covariates in the GEE models. With every one percent increase in weighted proportion of vapers in each state, the number of COVID-19 infected cases increase by 0.3139 (95% CI: 0.0554 –0.5723) and the number of COVID-19 deaths increase by 0.3705 (95% CI: 0.0623 – 0.6786) in log scale in each US state.ConclusionsThe positive associations between the proportion of vapers and the number of COVID-19 infected cases and deaths in each US state suggest an increased susceptibility of vapers to COVID-19 infections and deaths.

  • Open Access English
    Authors: 
    Zost, Seth J; Gilchuk, Pavlo; Chen, Rita; Case, James Brett; Reidy, Joseph X; Trivette, Andrew; Nargi, Rachel S; Sutton, Rachel E; Suryadevara, Naveen; Chen, Elaine C; +19 more
    Publisher: Cold Spring Harbor Laboratory
    Project: NIH | Infectious Disease Pathog... (5T32AI007151-28), NIH | The Vanderbilt Institute ... (6UL1TR000445-11), NIH | Illumina Genome Analyzer ... (1S10RR028106-01A1), NIH | The Vanderbilt Institute ... (3UL1RR024975-03S4), NIH | Childhood Infections Rese... (5T32AI095202-09)

    Antibodies are a principal determinant of immunity for most RNA viruses and have promise to reduce infection or disease during major epidemics. The novel coronavirus SARS-CoV-2 has caused a global pandemic with millions of infections and hundreds of thousands of deaths to date1,2. In response, we used a rapid antibody discovery platform to isolate hundreds of human monoclonal antibodies (mAbs) against the SARS-CoV-2 spike (S) protein. We stratify these mAbs into five major classes based on their reactivity to subdomains of S protein as well as their cross-reactivity to SARS-CoV. Many of these mAbs inhibit infection of authentic SARS-CoV-2 virus, with most neutralizing mAbs recognizing the receptor-binding domain (RBD) of S. This work defines sites of vulnerability on SARS-CoV-2 S and demonstrates the speed and robustness of new antibody discovery methodologies.

  • Open Access English
    Authors: 
    Rohan Khera; Lovedeep Singh Dhingra; Snigdha Jain; Harlan M. Krumholz;
    Publisher: Cold Spring Harbor Laboratory
    Project: NIH | UT Southwestern Center fo... (4UL1TR001105-04)

    BackgroundThe coronavirus disease-19 (COVID-19) pandemic threatens to overwhelm the healthcare resources of the country, but also poses a personal hazard to healthcare workers, including physicians. To address the potential impact of excluding physicians with a high risk of adverse outcomes based on age, we evaluated the current patterns of age of licensed physicians across the United States.MethodsWe compiled information from the 2018 database of actively licensed physicians in the Federation of State Medical Boards (FSMB) across the US. Both at a national- and the state-level, we assessed the number and proportion of physicians who would be at an elevated risk due to age over 60 years.ResultsOf the 985,026 licensed physicians in the US, 235857 or 23.9% were aged 25-40 years, 447052 or 45.4% are 40-60 years, 191794 or 19.5% were 60-70 years, and 106121 or 10.8% were 70 years or older. Age was not reported in 4202 or 0.4% of physicians. Overall, 297915 or 30.2% of physicians were 60 years of age or older, 246167 (25.0%) 65 years and older, and 106121 (10.8%) 70 years or older. States in the US reported that a median 5470 licensed physicians (interquartile range [IQR], 2394 to 10108) were 60 years of age or older. Notably, states of North Dakota (n=1180) and Vermont (n = 1215) had the lowest and California (n=50786) and New York (n=31582) the highest number of physicians over the age of 60 years (Figure 1). Across states, the median proportion of physicians aged 60 years and older was 28.9% (IQR, 27.2%, 31.4%), and ranged between 25.9% for Nebraska to 32.6% for New Mexico (Figure 2).DiscussionOlder physicians represent a large proportion of the US physician workforce, particularly in states with the worst COVID-19 outbreak. Therefore, their exclusion from patient care will be impractical. Optimizing care practices by limiting direct patient contact of physicians vulnerable to adverse outcomes from COVID-19, potentially by expanding their participation in telehealth may be a strategy to protect them.

  • Publication . Preprint . Other literature type . 2020
    Open Access English
    Authors: 
    Michael J. Joyner; R. Scott Wright; DeLisa Fairweather; Jonathon W. Senefeld; Katelyn A. Bruno; Stephen A. Klassen; Rickey E. Carter; Allan M. Klompas; Chad C. Wiggins; John R. A. Shepherd; +24 more
    Publisher: Cold Spring Harbor Laboratory
    Project: NIH | Variant Hemoglobin and Ca... (1R35HL139854-01), NIH | Mayo Clinic Center for cl... (3UL1TR002377-02S1), NIH | Diabetes and Metabolism (5T32DK007352-38), NSERC

    Background: Convalescent plasma is the only antibody based therapy currently available for COVID-19 patients. 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 5,000 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) in the first four hours after transfusion was <1%, including mortality rate (0.3%). Of the 36 reported SAEs, there were 25 reported incidences of related SAEs, including mortality (n=4), transfusion-associated circulatory overload (TACO; n=7), transfusion-related acute lung injury (TRALI; 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 seven-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.