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1.
J Am Chem Soc ; 143(46): 19306-19310, 2021 11 24.
Article in English | MEDLINE | ID: covidwho-1510556

ABSTRACT

The 68-kDa homodimeric 3C-like protease of SARS-CoV-2, Mpro (3CLpro/Nsp5), is a promising antiviral drug target. We evaluate the concordance of models generated by the newly introduced AlphaFold2 structure prediction program with residual dipolar couplings (RDCs) measured in solution for 15N-1HN and 13C'-1HN atom pairs. The latter were measured using a new, highly precise TROSY-AntiTROSY Encoded RDC (TATER) experiment. Three sets of AlphaFold2 models were evaluated: (1) MproAF, generated using the standard AlphaFold2 input structural database; (2) MproAFD, where the AlphaFold2 implementation was modified to exclude all candidate template X-ray structures deposited after Jan 1, 2020; and (3) MproAFS, which excluded all structures homologous to coronaviral Mpro. Close agreement between all three sets of AlphaFold models and experimental RDC data is found for most of the protein. For residues in well-defined secondary structure, the agreement decreases somewhat upon Amber relaxation. For these regions, MproAF agreement exceeds that of most high-resolution X-ray structures. Residues from domain 2 that comprise elements of both the active site and the homo-dimerization interface fit less well across all structures. These results indicate novel opportunities for combining experimentation with molecular dynamics simulations, where solution RDCs provide highly precise input for QM/MM simulations of substrate binding/reaction trajectories.


Subject(s)
Coronavirus 3C Proteases/chemistry , Crystallography, X-Ray/methods , SARS-CoV-2 , COVID-19 , Catalytic Domain , Magnetic Resonance Spectroscopy , Molecular Conformation , Molecular Dynamics Simulation , Protein Conformation , Protein Folding , Software , X-Rays
2.
Biophys J ; 120(6): 994-1000, 2021 03 16.
Article in English | MEDLINE | ID: covidwho-1081171

ABSTRACT

The seasonality of respiratory diseases has been linked, among other factors, to low outdoor absolute humidity and low indoor relative humidity, which increase evaporation of water in the mucosal lining of the respiratory tract. We demonstrate that normal breathing results in an absorption-desorption cycle inside facemasks, in which supersaturated air is absorbed by the mask fibers during expiration, followed by evaporation during inspiration of dry environmental air. For double-layered cotton masks, which have considerable heat capacity, the temperature of inspired air rises above room temperature, and the effective increase in relative humidity can exceed 100%. We propose that the recently reported, disease-attenuating effect of generic facemasks is dominated by the strong humidity increase of inspired air. This elevated humidity promotes mucociliary clearance of pathogens from the lungs, both before and after an infection of the upper respiratory tract has occurred. Effective mucociliary clearance can delay and reduce infection of the lower respiratory tract, thus mitigating disease severity. This mode of action suggests that masks can benefit the wearer even after an infection in the upper respiratory tract has occurred, complementing the traditional function of masks to limit person-to-person disease transmission. This potential therapeutical use should be studied further.


Subject(s)
COVID-19/pathology , COVID-19/prevention & control , Masks/virology , Respiratory System/virology , Severity of Illness Index , COVID-19/virology , Humans , Humidity , SARS-CoV-2/physiology
3.
Open Forum Infect Dis ; 8(2): ofaa638, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-1069293

ABSTRACT

BACKGROUND: Older adults and people from certain racial and ethnic groups are disproportionately represented in coronavirus disease 2019 (COVID-19) hospitalizations and deaths. METHODS: Using data from the Premier Healthcare Database on 181 813 hospitalized adults diagnosed with COVID-19 during March-September 2020, we applied multivariable log-binomial regression to assess the associations between age and race/ethnicity and COVID-19 clinical severity (intensive care unit [ICU] admission, invasive mechanical ventilation [IMV], and death) and to determine whether the impact of age on clinical severity differs by race/ethnicity. RESULTS: Overall, 84 497 (47%) patients were admitted to the ICU, 29 078 (16%) received IMV, and 27 864 (15%) died in the hospital. Increased age was strongly associated with clinical severity when controlling for underlying medical conditions and other covariates; the strength of this association differed by race/ethnicity. Compared with non-Hispanic White patients, risk of death was lower among non-Hispanic Black patients (adjusted risk ratio, 0.96; 95% CI, 0.92-0.99) and higher among Hispanic/Latino patients (risk ratio [RR], 1.15; 95% CI, 1.09-1.20), non-Hispanic Asian patients (RR, 1.16; 95% CI, 1.09-1.23), and patients of other racial and ethnic groups (RR, 1.13; 95% CI, 1.06-1.21). Risk of ICU admission and risk of IMV were elevated among some racial and ethnic groups. CONCLUSIONS: These results indicate that age is a driver of poor outcomes among hospitalized persons with COVID-19. Additionally, clinical severity may be elevated among patients of some racial and ethnic minority groups. Public health strategies to reduce severe acute respiratory syndrome coronavirus 2 infection rates among older adults and racial and ethnic minorities are essential to reduce poor outcomes.

4.
MMWR Morb Mortal Wkly Rep ; 70(5): 155-161, 2021 Feb 05.
Article in English | MEDLINE | ID: covidwho-1063528

ABSTRACT

Exposure to lead, a toxic metal, can result in severe effects in children, including decreased ability to learn, permanent neurologic damage, organ failure, and death. CDC and other health care organizations recommend routine blood lead level (BLL) testing among children as part of well-child examinations to facilitate prompt identification of elevated BLL, eliminate source exposure, and provide medical and other services (1). To describe BLL testing trends among young children during the coronavirus disease 2019 (COVID-19) pandemic, CDC analyzed data reported from 34 state and local health departments about BLL testing among children aged <6 years conducted during January-May 2019 and January-May 2020. Compared with testing in 2019, testing during January-May 2020 decreased by 34%, with 480,172 fewer children tested. An estimated 9,603 children with elevated BLL were missed because of decreased BLL testing. Despite geographic variability, all health departments reported fewer children tested for BLL after the national COVID-19 emergency declaration (March-May 2020). In addition, health departments reported difficulty conducting medical follow-up and environmental investigations for children with elevated BLLs because of staffing shortages and constraints on home visits associated with the pandemic. Providers and public health agencies need to take action to ensure that children who missed their scheduled blood lead screening test, or who required follow-up on an earlier high BLL, be tested as soon as possible and receive appropriate care.


Subject(s)
COVID-19/epidemiology , Diagnostic Tests, Routine/statistics & numerical data , Lead/blood , Child, Preschool , Humans , Infant , United States/epidemiology
5.
MMWR Morb Mortal Wkly Rep ; 69(35): 1210-1215, 2020 Sep 04.
Article in English | MEDLINE | ID: covidwho-745358

ABSTRACT

Hydroxychloroquine and chloroquine, primarily used to treat autoimmune diseases and to prevent and treat malaria, received national attention in early March 2020, as potential treatment and prophylaxis for coronavirus disease 2019 (COVID-19) (1). On March 20, the Food and Drug Administration (FDA) issued an emergency use authorization (EUA) for chloroquine phosphate and hydroxychloroquine sulfate in the Strategic National Stockpile to be used by licensed health care providers to treat patients hospitalized with COVID-19 when the providers determine the potential benefit outweighs the potential risk to the patient.* Following reports of cardiac and other adverse events in patients receiving hydroxychloroquine for COVID-19 (2), on April 24, 2020, FDA issued a caution against its use† and on June 15, rescinded its EUA for hydroxychloroquine from the Strategic National Stockpile.§ Following the FDA's issuance of caution and EUA rescindment, on May 12 and June 16, the federal COVID-19 Treatment Guidelines Panel issued recommendations against the use of hydroxychloroquine or chloroquine to treat COVID-19; the panel also noted that at that time no medication could be recommended for COVID-19 pre- or postexposure prophylaxis outside the setting of a clinical trial (3). However, public discussion concerning the effectiveness of these drugs on outcomes of COVID-19 (4,5), and clinical trials of hydroxychloroquine for prophylaxis of COVID-19 continue.¶ In response to recent reports of notable increases in prescriptions for hydroxychloroquine or chloroquine (6), CDC analyzed outpatient retail pharmacy transaction data to identify potential differences in prescriptions dispensed by provider type during January-June 2020 compared with the same period in 2019. Before 2020, primary care providers and specialists who routinely prescribed hydroxychloroquine, such as rheumatologists and dermatologists, accounted for approximately 97% of new prescriptions. New prescriptions by specialists who did not typically prescribe these medications (defined as specialties accounting for ≤2% of new prescriptions before 2020) increased from 1,143 prescriptions in February 2020 to 75,569 in March 2020, an 80-fold increase from March 2019. Although dispensing trends are returning to prepandemic levels, continued adherence to current clinical guidelines for the indicated use of these medications will ensure their availability and benefit to patients for whom their use is indicated (3,4), because current data on treatment and pre- or postexposure prophylaxis for COVID-19 indicate that the potential benefits of these drugs do not appear to outweigh their risks.


Subject(s)
Chloroquine/therapeutic use , Hydroxychloroquine/therapeutic use , Practice Patterns, Physicians'/statistics & numerical data , Specialization/statistics & numerical data , COVID-19/drug therapy , Coronavirus Infections/drug therapy , Female , Humans , Male , Treatment Outcome , United States
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