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  The mobile vaccine equity enhancement program–a model program for enhancing equity in vaccine availability based at a large health care system

  Broach, John; Brown, Olga; McEachern, Caitlin; Forget, Janell; Lancette, Peter; Soucie, Norman; Inzerillo, Julie; Klugman, Robert; Tosi, Stephen; Haddad, Abraham; et al. (2023-10-17)

  The SARS CoV-2 (COVID-19) pandemic presented unprecedented challenges as communities attempted to respond to the administration of a novel vaccine that faced cold chain logistical requirements and vaccine hesitancy among many, as well as complicated phased rollout plans that changed frequently as availability of the vaccine waxed and waned. The COVID-19 pandemic also disproportionately affected communities of color and communities with barriers to accessing healthcare. In the setting of these difficulties, a program was created specifically to address inequity in vaccine administration with a focus on communities of color and linguistic diversity as well as those who had technological barriers to online sign-up processes common at mass vaccination sites. This effort, the Mobile Vaccine Equity Enhancement Program (MVeeP), delivered over 12,000 vaccines in 24 months through a reproducible set of practices that can inform equity-driven vaccine efforts in future pandemics.
• Effectiveness of various COVID-19 vaccine regimens among 10.4 million patients from the National COVID Cohort Collaborative during Pre-Delta to Omicron periods - United States, 11 December 2020 to 30 June 2022

  Fu, Yuanyuan; Wu, Kaipeng; Wang, Zhanwei; Yang, Hua; Chen, Yu; Wu, Lang; Yanagihara, Richard; Hedges, Jerris R; Wang, Hongwei; Deng, Youping (2023-09-22)

  Objective: This study reports the vaccine effectiveness (VE) of COVID-19 vaccine regimens in the United States, based on the National COVID Cohort Collaborative (N3C) database. Methods: Data from 10.4 million adults, enrolled in the N3C from 11 December 2020 to 30 June 2022, were analyzed. VE against infection and death outcomes were evaluated across 13 vaccine regimens in recipient cohorts during the Pre-Delta, Delta, and Omicron periods. VE was estimated as (1-odds ratio) × 100% by multivariate logistic regression, using the unvaccinated cohort as reference. Results: Natural immunity showed a highly protective effect (70.33%) against re-infection, but the mortality risk among the unvaccinated population was increased after re-infection; vaccination following infection reduced the risk of re-infection and death. mRNA-1273 full vaccination plus mRNA-1273 booster showed the highest anti-infection effectiveness (47.59%) (95% CI, 46.72-48.45) in the overall cohort. In the type 2 diabetes cohort, VE against infection was highest with BNT162b2 full vaccination plus mRNA-1273 booster (61.19%) (95% CI, 53.73-67.75). VE against death was also highest with BNT162b2 full vaccination plus mRNA-1273 booster (89.56%) (95% CI, 85.75-92.61). During the Pre-Delta period, all vaccination regimens showed an anti-infection effect; during the Delta period, only boosters, mixed vaccines, and Ad26.COV2.S vaccination exhibited an anti-infection effect; during the Omicron period, none of the vaccine regimens demonstrated an anti-infection effect. Irrespective of the variant period, even a single dose of mRNA vaccine offered protection against death, thus demonstrating survival benefit, even in the presence of infection or re-infection. Similar patterns were observed in patients with type 2 diabetes. Conclusions: Although the anti-infection effect declined as SARS-CoV-2 variants evolved, all COVID-19 mRNA vaccines had sustained effectiveness against death. Vaccination was crucial for preventing re-infection and reducing the risk of death following SARS-CoV-2 infection.
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  Association of neighborhood-level sociodemographic factors with Direct-to-Consumer (DTC) distribution of COVID-19 rapid antigen tests in 5 US communities

  Herbert, Carly; Shi, Qiming; Baek, Jonggyu; Wang, Biqi; Kheterpal, Vik; Nowak, Christopher; Suvarna, Thejas; Singh, Aditi; Hartin, Paul; Durnam, Basyl; et al. (2023-09-22)

  Background: Many interventions for widescale distribution of rapid antigen tests for COVID-19 have utilized online, direct-to-consumer (DTC) ordering systems; however, little is known about the sociodemographic characteristics of home-test users. We aimed to characterize the patterns of online orders for rapid antigen tests and determine geospatial and temporal associations with neighborhood characteristics and community incidence of COVID-19, respectively. Methods: This observational study analyzed online, DTC orders for rapid antigen test kits from beneficiaries of the Say Yes! Covid Test program from March to November 2021 in five communities: Louisville, Kentucky; Indianapolis, Indiana; Fulton County, Georgia; O'ahu, Hawaii; and Ann Arbor/Ypsilanti, Michigan. Using spatial autoregressive models, we assessed the geospatial associations of test kit distribution with Census block-level education, income, age, population density, and racial distribution and Census tract-level Social Vulnerability Index. Lag association analyses were used to measure the association between online rapid antigen kit orders and community-level COVID-19 incidence. Results: In total, 164,402 DTC test kits were ordered during the intervention. Distribution of tests at all sites were significantly geospatially clustered at the block-group level (Moran's I: p < 0.001); however, education, income, age, population density, race, and social vulnerability index were inconsistently associated with test orders across sites. In Michigan, Georgia, and Kentucky, there were strong associations between same-day COVID-19 incidence and test kit orders (Michigan: r = 0.89, Georgia: r = 0.85, Kentucky: r = 0.75). The incidence of COVID-19 during the current day and the previous 6-days increased current DTC orders by 9.0 (95% CI = 1.7, 16.3), 3.0 (95% CI = 1.3, 4.6), and 6.8 (95% CI = 3.4, 10.2) in Michigan, Georgia, and Kentucky, respectively. There was no same-day or 6-day lagged correlation between test kit orders and COVID-19 incidence in Indiana. Conclusions: Our findings suggest that online ordering is not associated with geospatial clustering based on sociodemographic characteristics. Observed temporal preferences for DTC ordering can guide public health messaging around DTC testing programs.
• Outpatient Treatment of Confirmed COVID-19: Living, Rapid Practice Points From the American College of Physicians (Version 2)

  Qaseem, Amir; Yost, Jennifer; Abraham, George M; Andrews, Rebecca; Jokela, Janet A; Miller, Matthew C; Humphrey, Linda L; Dunn, Andrew; Haeme, Ray; Lee, Rachael; et al. (2023-09-19)

  Description: Evidence for the use of outpatient treatments in adults with confirmed COVID-19 continues to evolve with new data. This is version 2 of the American College of Physicians (ACP) living, rapid practice points focusing on 22 outpatient treatments for COVID-19, specifically addressing the dominant SARS-CoV-2 Omicron variant. Methods: The Population Health and Medical Science Committee (formerly the Scientific Medical Policy Committee) developed this version of the living, rapid practice points on the basis of a living, rapid review done by the ACP Center for Evidence Reviews at Cochrane Austria at the University for Continuing Education Krems (Danube University Krems). This topic will be maintained as living and rapid by continually monitoring and assessing the impact of new evidence. Practice point 1: Consider molnupiravir to treat symptomatic patients with confirmed mild to moderate COVID-19 in the outpatient setting who are within 5 days of the onset of symptoms and at a high risk for progressing to severe disease. Practice point 2: Consider nirmatrelvir-ritonavir combination therapy to treat symptomatic patients with confirmed mild to moderate COVID-19 in the outpatient setting who are within 5 days of the onset of symptoms and at a high risk for progressing to severe disease. Practice point 3: Do not use ivermectin to treat patients with confirmed mild to moderate COVID-19 in the outpatient setting. Practice point 4: Do not use sotrovimab to treat patients with confirmed mild to moderate COVID-19 in the outpatient setting.
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  On a path toward a broad-spectrum anti-viral: inhibition of HIV-1 and coronavirus replication by SR kinase inhibitor harmine

  Dahal, Subha; Clayton, Kiera; Cabral, Tyler; Cheng, Ran; Jahanshahi, Shahrzad; Ahmed, Choudhary; Koirala, Amrit; Villasmil Ocando, Alonso; Malty, Ramy; Been, Terek; et al. (2023-09-14)

  RNA processing plays a key role in gene expression, allowing for increased protein diversity and functional complexity. Consequently, modulating RNA processing can impact gene function. Given HIV-1's reliance on host RNA processing machinery for viral protein production/replication, modulators of this process could serve as novel anti-virals to complement and/or enhance existing therapies. In this study, screening of several serine-arginine-rich (SR) kinase inhibitors for their impact on HIV-1 gene expression identified harmine as an inhibitor of HIV-1 gene expression in several cell lines and primary CD4+ T cells/macrophages at low micromolar concentrations with limited cell toxicity. Harmine induced a loss of viral structural protein expression associated with reduced HIV-1 unspliced and singly-spliced HIV-1 RNA levels but limited impact on multiply spliced RNAs. Although harmine is a known inhibitor of both DYRK1A and monoaminoxidase A (MAO A), neither DYRK1A depletion nor other MAO A inhibitors had any effect on HIV-1 expression. However, the compound altered the expression of several other SR kinases in primary CD4+ T cells, increasing CLK1 and reducing CLK2 kinase levels, effects known to regulate HIV-1 expression. Harmine was also unique among the SR kinase inhibitors tested for its ability to suppress replication of a seasonal coronavirus, human coronavirus (HCoV)-229E, and multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, reducing viral protein expression and virus release. Harmine acts post-entry, arresting virus replication even after the onset of viral protein production. At doses required to suppress HIV-1 replication, harmine had limited impact on the host transcriptome, alternative splicing, or alterative polyadenylation as assessed by RNA-Seq. Together, our study demonstrates the feasibility of targeting host RNA processing to inhibit a range of viruses with minimal impact on the host cell. IMPORTANCE This study highlights the crucial role RNA processing plays in regulating viral gene expression and replication. By targeting SR kinases, we identified harmine as a potent inhibitor of HIV-1 as well as coronavirus (HCoV-229E and multiple SARS-CoV-2 variants) replication. Harmine inhibits HIV-1 protein expression and reduces accumulation of HIV-1 RNAs in both cell lines and primary CD4+ T cells. Harmine also suppresses coronavirus replication post-viral entry by preferentially reducing coronavirus sub-genomic RNA accumulation. By focusing on host factors rather than viral targets, our study offers a novel approach to combating viral infections that is effective against a range of unrelated viruses. Moreover, at doses required to inhibit virus replication, harmine had limited toxicity and minimal effect on the host transcriptome. These findings support the viability of targeting host cellular processes as a means of developing broad-spectrum anti-virals.
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  Who is pregnant? Defining real-world data-based pregnancy episodes in the National COVID Cohort Collaborative (N3C)

  Jones, Sara E; Bradwell, Katie R; Chan, Lauren E; McMurry, Julie A; Olson-Chen, Courtney; Tarleton, Jessica; Wilkins, Kenneth J; Ly, Victoria; Ljazouli, Saad; Qin, Qiuyuan; et al. (2023-08-16)

  Objectives: To define pregnancy episodes and estimate gestational age within electronic health record (EHR) data from the National COVID Cohort Collaborative (N3C). Materials and methods: We developed a comprehensive approach, named Hierarchy and rule-based pregnancy episode Inference integrated with Pregnancy Progression Signatures (HIPPS), and applied it to EHR data in the N3C (January 1, 2018-April 7, 2022). HIPPS combines: (1) an extension of a previously published pregnancy episode algorithm, (2) a novel algorithm to detect gestational age-specific signatures of a progressing pregnancy for further episode support, and (3) pregnancy start date inference. Clinicians performed validation of HIPPS on a subset of episodes. We then generated pregnancy cohorts based on gestational age precision and pregnancy outcomes for assessment of accuracy and comparison of COVID-19 and other characteristics. Results: We identified 628 165 pregnant persons with 816 471 pregnancy episodes, of which 52.3% were live births, 24.4% were other outcomes (stillbirth, ectopic pregnancy, abortions), and 23.3% had unknown outcomes. Clinician validation agreed 98.8% with HIPPS-identified episodes. We were able to estimate start dates within 1 week of precision for 475 433 (58.2%) episodes. 62 540 (7.7%) episodes had incident COVID-19 during pregnancy. Discussion: HIPPS provides measures of support for pregnancy-related variables such as gestational age and pregnancy outcomes based on N3C data. Gestational age precision allows researchers to find time to events with reasonable confidence. Conclusion: We have developed a novel and robust approach for inferring pregnancy episodes and gestational age that addresses data inconsistency and missingness in EHR data.
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  Immunopeptidome profiling of human coronavirus OC43-infected cells identifies CD4 T-cell epitopes specific to seasonal coronaviruses or cross-reactive with SARS-CoV-2

  Becerra-Artiles, Aniuska; Nanaware, Padma P; Muneeruddin, Khaja; Weaver, Grant; Shaffer, Scott A; Calvo-Calle, J Mauricio; Stern, Lawrence J (2023-07-27)

  Seasonal "common-cold" human coronaviruses are widely spread throughout the world and are mainly associated with mild upper respiratory tract infections. The emergence of highly pathogenic coronaviruses MERS-CoV, SARS-CoV, and most recently SARS-CoV-2 has prompted increased attention to coronavirus biology and immunopathology, but the T-cell response to seasonal coronaviruses remains largely uncharacterized. Here we report the repertoire of viral peptides that are naturally processed and presented upon infection of a model cell line with seasonal coronavirus OC43. We identified MHC-bound peptides derived from each of the viral structural proteins (spike, nucleoprotein, hemagglutinin-esterase, membrane, and envelope) as well as non-structural proteins nsp3, nsp5, nsp6, and nsp12. Eighty MHC-II bound peptides corresponding to 14 distinct OC43-derived epitopes were identified, including many at very high abundance within the overall MHC-II peptidome. Fewer and less abundant MHC-I bound OC43-derived peptides were observed, possibly due to MHC-I downregulation induced by OC43 infection. The MHC-II peptides elicited low-abundance recall T-cell responses in most donors tested. In vitro assays confirmed that the peptides were recognized by CD4+ T cells and identified the presenting HLA alleles. T-cell responses cross-reactive between OC43, SARS-CoV-2, and the other seasonal coronaviruses were confirmed in samples of peripheral blood and peptide-expanded T-cell lines. Among the validated epitopes, spike protein S903-917 presented by DPA1*01:03/DPB1*04:01 and S1085-1099 presented by DRB1*15:01 shared substantial homology to other human coronaviruses, including SARS-CoV-2, and were targeted by cross-reactive CD4 T cells. Nucleoprotein N54-68 and hemagglutinin-esterase HE128-142 presented by DRB1*15:01 and HE259-273 presented by DPA1*01:03/DPB1*04:01 are immunodominant epitopes with low coronavirus homology that are not cross-reactive with SARS-CoV-2. Overall, the set of naturally processed and presented OC43 epitopes comprise both OC43-specific and human coronavirus cross-reactive epitopes, which can be used to follow CD4 T-cell cross-reactivity after infection or vaccination, and to guide selection of epitopes for inclusion in pan-coronavirus vaccines.
• Abatacept, Cenicriviroc, or Infliximab for Treatment of Adults Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial

  O'Halloran, Jane A; Ko, Emily R; Anstrom, Kevin J; Kedar, Eyal; McCarthy, Matthew W; Panettieri, Reynold A; Maillo, Martin; Nunez, Patricia Segura; Lachiewicz, Anne M; Gonzalez, Cynthia; et al. (2023-07-25)

  Importance: Immune dysregulation contributes to poorer outcomes in COVID-19. Objective: To investigate whether abatacept, cenicriviroc, or infliximab provides benefit when added to standard care for COVID-19 pneumonia. Design, setting, and participants: Randomized, double-masked, placebo-controlled clinical trial using a master protocol to investigate immunomodulators added to standard care for treatment of participants hospitalized with COVID-19 pneumonia. The results of 3 substudies are reported from 95 hospitals at 85 clinical research sites in the US and Latin America. Hospitalized patients 18 years or older with confirmed SARS-CoV-2 infection within 14 days and evidence of pulmonary involvement underwent randomization between October 2020 and December 2021. Interventions: Single infusion of abatacept (10 mg/kg; maximum dose, 1000 mg) or infliximab (5 mg/kg) or a 28-day oral course of cenicriviroc (300-mg loading dose followed by 150 mg twice per day). Main outcomes and measures: The primary outcome was time to recovery by day 28 evaluated using an 8-point ordinal scale (higher scores indicate better health). Recovery was defined as the first day the participant scored at least 6 on the ordinal scale. Results: Of the 1971 participants randomized across the 3 substudies, the mean (SD) age was 54.8 (14.6) years and 1218 (61.8%) were men. The primary end point of time to recovery from COVID-19 pneumonia was not significantly different for abatacept (recovery rate ratio [RRR], 1.12 [95% CI, 0.98-1.28]; P = .09), cenicriviroc (RRR, 1.01 [95% CI, 0.86-1.18]; P = .94), or infliximab (RRR, 1.12 [95% CI, 0.99-1.28]; P = .08) compared with placebo. All-cause 28-day mortality was 11.0% for abatacept vs 15.1% for placebo (odds ratio [OR], 0.62 [95% CI, 0.41-0.94]), 13.8% for cenicriviroc vs 11.9% for placebo (OR, 1.18 [95% CI 0.72-1.94]), and 10.1% for infliximab vs 14.5% for placebo (OR, 0.59 [95% CI, 0.39-0.90]). Safety outcomes were comparable between active treatment and placebo, including secondary infections, in all 3 substudies. Conclusions and relevance: Time to recovery from COVID-19 pneumonia among hospitalized participants was not significantly different for abatacept, cenicriviroc, or infliximab vs placebo. Trial registration: ClinicalTrials.gov Identifier: NCT04593940.
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  Seizure as Presenting Symptom of Multisystem Inflammatory Syndrome in Children

  D'Ambrosio, Eleonora S; Gauguet, Stefanie; Miller, Christine; McMahon, Erin; Driscoll, Christopher; Mohanty, Mugdha; Guggina, Thomas (2023-07-08)

  We describe the case of a 13-year-old girl who presented with a new-onset seizure and fever and subsequently developed severe cardiac dysfunction, coronary artery dilation, and shock due to the surprising diagnosis of multisystem inflammatory syndrome in children (MIS-C). Although the clinical entity we now call MIS-C was first mentioned in the medical literature in April 2020, the full picture of this disease process is still evolving. Neurologic involvement has been described in cases with MIS-C; however, seizures are not a typical presenting symptom. Additionally, because children infected with SARS-CoV-2 are often asymptomatic, a documented preceding COVID-19 infection might not be available to raise suspicion of MIS-C early on. Febrile seizures, meningitis, and encephalitis are childhood illnesses that pediatricians are generally familiar with, but associating these clinical pictures with MIS-C is uncommon. Given the possibility of rapid clinical cardiogenic decline, as seen in our patient, a prompt diagnosis and appropriate monitoring and treatment are of utmost importance. This case report aims to raise awareness that new-onset seizures with fevers can be early or the first presenting symptoms in children with MIS-C, and further workup and close monitoring may be required.
• Performance of Rapid Antigen Tests to Detect Symptomatic and Asymptomatic SARS-CoV-2 Infection : A Prospective Cohort Study

  Soni, Apurv; Herbert, Carly; Lin, Honghuang; Yan, Yi; Pretz, Caitlin; Stamegna, Pamela; Wang, Biqi; Orwig, Taylor; Wright, Colton; Tarrant, Seanan; et al. (2023-07-04)

  Background: The performance of rapid antigen tests (Ag-RDTs) for screening asymptomatic and symptomatic persons for SARS-CoV-2 is not well established. Objective: To evaluate the performance of Ag-RDTs for detection of SARS-CoV-2 among symptomatic and asymptomatic participants. Design: This prospective cohort study enrolled participants between October 2021 and January 2022. Participants completed Ag-RDTs and reverse transcriptase polymerase chain reaction (RT-PCR) testing for SARS-CoV-2 every 48 hours for 15 days. Setting: Participants were enrolled digitally throughout the mainland United States. They self-collected anterior nasal swabs for Ag-RDTs and RT-PCR testing. Nasal swabs for RT-PCR were shipped to a central laboratory, whereas Ag-RDTs were done at home. Participants: Of 7361 participants in the study, 5353 who were asymptomatic and negative for SARS-CoV-2 on study day 1 were eligible. In total, 154 participants had at least 1 positive RT-PCR result. Measurements: The sensitivity of Ag-RDTs was measured on the basis of testing once (same-day), twice (after 48 hours), and thrice (after a total of 96 hours). The analysis was repeated for different days past index PCR positivity (DPIPPs) to approximate real-world scenarios where testing initiation may not always coincide with DPIPP 0. Results were stratified by symptom status. Results: Among 154 participants who tested positive for SARS-CoV-2, 97 were asymptomatic and 57 had symptoms at infection onset. Serial testing with Ag-RDTs twice 48 hours apart resulted in an aggregated sensitivity of 93.4% (95% CI, 90.4% to 95.9%) among symptomatic participants on DPIPPs 0 to 6. When singleton positive results were excluded, the aggregated sensitivity on DPIPPs 0 to 6 for 2-time serial testing among asymptomatic participants was lower at 62.7% (CI, 57.0% to 70.5%), but it improved to 79.0% (CI, 70.1% to 87.4%) with testing 3 times at 48-hour intervals. Limitation: Participants tested every 48 hours; therefore, these data cannot support conclusions about serial testing intervals shorter than 48 hours. Conclusion: The performance of Ag-RDTs was optimized when asymptomatic participants tested 3 times at 48-hour intervals and when symptomatic participants tested 2 times separated by 48 hours. Primary funding source: National Institutes of Health RADx Tech program.
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  Unvaccinated Adolescents' COVID-19 Vaccine Intentions: Implications for Public Health Messaging

  Ryan, Grace W; Askelson, Natoshia M; Woodworth, Kate R; Lindley, Megan C; Gedlinske, Amber; Parker, Andrew M; Gidengil, Courtney A; Petersen, Christine A; Scherer, Aaron M (2023-07-03)

  Purpose: COVID-19 vaccine uptake remains low for US adolescents and contributes to excess morbidity and mortality. Most research has assessed parental intention to vaccinate their children. We explored differences between vaccine-acceptant and vaccine-hesitant unvaccinated US adolescents using national survey data. Methods: A nonprobability, quota-based sample of adolescents, aged 13-17 years, was recruited through an online survey panel in April 2021. One thousand nine hundred twenty seven adolescents were screened for participation and the final sample included 985 responses. We assessed responses from unvaccinated adolescents (n = 831). Our primary measure was COVID-19 vaccination intent ("vaccine-acceptant" defined as "definitely will" get a COVID-19 vaccine and any other response classified as "vaccine-hesitant") and secondary measures included reasons for intending or not intending to get vaccinated and trusted sources of COVID-19 vaccine information. We calculated descriptive statistics and chi-square tests to explore differences between vaccine-acceptant and vaccine-hesitant adolescents. Results: Most (n = 831; 70.9%) adolescents were hesitant, with more hesitancy observed among adolescents with low levels of concern about COVID-19 and high levels of concern about side effects of COVID-19 vaccination. Among vaccine-hesitant adolescents, reasons for not intending to get vaccinated included waiting for safety data and having parents who would make the vaccination decision. Vaccine-hesitant adolescents had a lower number of trusted information sources than vaccine-acceptant adolescents. Discussion: Differences identified between vaccine-acceptant and vaccine-hesitant adolescents can inform message content and dissemination. Messages should include accurate, age-appropriate information about side effects and risks of COVID-19 infection. Prioritizing dissemination of these messages through family members, state and local government officials, and healthcare providers may be most effective.
• Systematic Analyses of the Resistance Potential of Drugs Targeting SARS-CoV-2 Main Protease

  Flynn, Julia M; Huang, Qiu Yu J; Zvornicanin, Sarah N; Schneider-Nachum, Gila; Shaqra, Ala M; Yilmaz, Nese Kurt; Moquin, Stephanie A; Dovala, Dustin; Schiffer, Celia A; Bolon, Daniel N A (2023-06-30)

  Drugs that target the main protease (Mpro) of SARS-CoV-2 are effective therapeutics that have entered clinical use. Wide-scale use of these drugs will apply selection pressure for the evolution of resistance mutations. To understand resistance potential in Mpro, we performed comprehensive surveys of amino acid changes that can cause resistance to nirmatrelvir (Pfizer), and ensitrelvir (Xocova) in a yeast screen. We identified 142 resistance mutations for nirmatrelvir and 177 for ensitrelvir, many of which have not been previously reported. Ninety-nine mutations caused apparent resistance to both inhibitors, suggesting likelihood for the evolution of cross-resistance. The mutation with the strongest drug resistance score against nirmatrelvir in our study (E166V) was the most impactful resistance mutation recently reported in multiple viral passaging studies. Many mutations that exhibited inhibitor-specific resistance were consistent with the distinct interactions of each inhibitor in the substrate binding site. In addition, mutants with strong drug resistance scores tended to have reduced function. Our results indicate that strong pressure from nirmatrelvir or ensitrelvir will select for multiple distinct-resistant lineages that will include both primary resistance mutations that weaken interactions with drug while decreasing enzyme function and compensatory mutations that increase enzyme activity. The comprehensive identification of resistance mutations enables the design of inhibitors with reduced potential of developing resistance and aids in the surveillance of drug resistance in circulating viral populations.
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  Pediatricians' perspectives on COVID-19 and HPV vaccine hesitancy

  Ryan, Grace W; Miotto, Mary Beth; McReynolds, Cynthia; Lemon, Stephenie C; Pbert, Lori; Trivedi, Michelle (2023-06-22)

  Rises in parental vaccine hesitancy, observed during the COVID-19 pandemic, threaten public health. This is especially concerning for vaccines not typically required for school-entry, such as the vaccines for COVID-19 and human papillomavirus (HPV), both of which also have much lower rates of completion compared to other adolescent vaccines. Pediatricians are well-positioned to address vaccine hesitancy and can offer insights into parents' perspectives in this area. There is evidence that pediatricians' sharing their own vaccine stories may help to address parents' concerns; yet we have little information on pediatricians' or their children's COVID-19 vaccine uptake. To address these gaps, we conducted a cross-sectional survey about Massachusetts pediatricians' behaviors and perspectives on vaccines that face significant resistance: HPV and COVID-19 vaccines. A total of 144 people initiated the survey, and 109 participants were eligible and completed the survey. Participants reported high levels of COVID-19 vaccine uptake for themselves (97%) and their children (98%). Similarities in parents' resistance toward both vaccines were identified: fear of side effects; general vaccine resistance. Pediatricians reported a rise in vaccine hesitancy since the beginning of the COVID-19 pandemic. Future research should focus on identifying strategies to build overall vaccine confidence and streamline these efforts for pediatricians.
• Telemedicine impact on post-stroke outpatient follow-up in an academic healthcare network during the COVID-19 pandemic

  Alabyad, Darwish; Lemuel-Clarke, Manet; Antwan, Marlyn; Henriquez, Laura; Belagaje, Samir; Rangaraju, Srikant; Mosley, Ashlee; Cabral, Jacqueline; Walczak, Teri; Ido, Moges; et al. (2023-06-21)

  Background: The expansion of telemedicine associated with the COVID-19 pandemic has influenced outpatient medical care. The objective of our study was to determine the impact of telemedicine on post-acute stroke clinic follow-up. Methods: We retrospectively evaluated the impact of telemedicine in Emory Healthcare, an academic healthcare system of comprehensive and primary stroke centers in Atlanta, Georgia, on post-hospital stroke clinic follow-up. We compared the frequency of 90-day follow-up in a centralized subspecialty stroke clinic among patients hospitalized before the local COVID-19 pandemic (January 1, 2019- February 28, 2020), during (March 1- April 30, 2020) and after telemedicine implementation (May 1- December 31, 2020). A comparison was made across hospitals less than 1 mile, 10 miles, and 25 miles from the stroke clinic. Results: Of 1096 ischemic stroke patients discharged home or to a rehab facility during the study period, 342 (31%) had follow-up in the Emory Stroke Clinic (comprehensive stroke center 46%, primary stroke center 10 miles away 18%, primary stroke center 25 miles away 14%). Overall, 90-day follow-up increased from 19% to 41% after telemedicine implementation (p<0.001) with telemedicine appointments amounting for up to 28% of all follow-up visits. In multivariable analysis, factors associated with teleneurology follow-up (vs no follow-up) included discharge from the comprehensive stroke center, thrombectomy treatment, private insurance, private transport to the hospital, NIHSS 0-5 and history of dyslipidemia. Conclusions: Despite telemedicine implementation at an academic healthcare network successfully increasing post-stroke discharge follow-up in a centralized subspecialty stroke clinic, the majority of patients did not complete 90-day follow-up during the COVID-19 pandemic.
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  Changes in postpartum contraception utilization rates during the early stage of the COVID-19 pandemic

  Chin, Emily; Leung, Katherine; Moore Simas, Tiffany A; Kumaraswami, Tara (2023-06-19)

  Background: The first wave of the COVID-19 pandemic was associated with restricted access to reproductive care including delayed abortion and female sterilization procedures, in addition to altered maternity care experiences. Given high rates of unintended and short-interval pregnancies in the United States in general and negative obstetric outcomes specifically associated with COVID-19, access to all effective pregnancy prevention methods during the pandemic was crucial. Objectives: To investigate changes in contraception utilization rates prior to delivery discharge, at outpatient postpartum visits, and at 10 weeks' postpartum, at the largest healthcare system in Central Massachusetts, during the first wave of the COVID-19 pandemic (15 March to 15 May 2020), compared to the same period in 2019. Design: Retrospective cohort review. Methods: Compared perinatal individuals (n = 495) who received prenatal care and delivered at UMass Memorial Medical Center from mid-March to mid-May in both 2019 (non-pandemic) and 2020 (COVID-19 pandemic). Receipt of contraception prior to delivery discharge and at outpatient postpartum visit was estimated and compared between the two time periods using the Chi-square test for categorical variables (or Fisher's exact test when cell counts were < 5) and Student's t-test for continuous variables. Multivariable logistic regression was performed to adjust for confounders. Results: The proportion of individuals who used long-acting reversible contraception before delivery discharge was 4% in 2019 and 13% in 2020 (p = 0.01). Modes of outpatient postpartum visit contraception did not vary from 2019 to 2020, (p = 0.06). Overall, there were no differences in contraception utilization rates at 10 weeks' postpartum from 2019 to 2020, (p = 0.50). Conclusion: Compared to a year prior, immediate postpartum long-acting reversible contraception use increased during the first wave of the COVID-19 pandemic, while overall contraception use at 10 weeks' postpartum remained unchanged. The evaluation of contraceptive use during the most restrictive time of COVID-19 pandemic can help identify opportunities to increase access to effective contraception, such as the immediate postpartum period prior to hospital discharge.
• Empowering Youth Vaccine Ambassadors to Promote COVID-19 Vaccination in Local Communities: A 7-Step Approach

  Minkah, Princilla; Borg, Amy; Ryan, Grace W; Goulding, Melissa; Perrone, Domenica; Castiel, Matilde; Rosal, Milagros C; Lemon, Stephenie C (2023-06-11)

  Despite the availability of COVID-19 vaccines for youth since 2021, vaccine hesitancy has resulted in suboptimal uptake. Public health campaigns that empower local youth ambassadors as trusted messengers who share their personal narratives related to getting vaccinated hold promise for promoting COVID-19 vaccination. We used a seven-step approach to develop, implement, and evaluate a youth-led ambassador campaign to promote COVID-19 vaccine uptake in communities experiencing COVID-19 disparities in Worcester, MA. The seven steps included (1) engaging with key partners; (2) determining a community of focus; (3) identifying trusted sources; (4) determining campaign components; (5) training the vaccine ambassadors; (6) disseminating the campaign; and (7) evaluating the campaign. We trained nine youth as vaccine ambassadors. Ambassadors were guided through self-reflection of motivations for COVID-19 vaccination and the resulting personal narratives became the campaign messaging. English/Spanish vaccine messages developed by youth ambassadors were disseminated through social media platforms (n = 3), radio (n = 2), local TV (n = 2), flyers (n = 2,086), posters (n = 386), billboards (n = 10), and local bus ads (n = 40). Qualitative youth feedback indicate participation in the campaign was a positive and empowering experience which reinforces the importance of engaging youth in public health messaging. Youth empowerment through personal narratives (and storytelling) holds promise for future public health campaigns.
• COVID-19-induced Esophageal Necrosis Requiring Emergent Total Esophagectomy in a Vaccinated Patient

  Patil, Tanmay; Dickson, Kevin M; Viera, Matthew; Bludevich, Bryce M; Akalin, Ali; Uy, Karl; Lou, Feiran; Maxfield, Mark W (2023-06-09)

  Acute esophageal necrosis may be a potential complication of Coronavirus Disease 2019 (COVID-19). COVID-19 has been associated with a variety of sequelae, including acute respiratory distress syndrome, myocarditis, and thromboembolic events. Here, we present a case of a 43-year-old male who was admitted for acute necrotizing pancreatitis and found to have COVID-19 pneumonia. He subsequently developed acute esophageal necrosis requiring a total esophagectomy. Currently, there are at least five other reported cases of esophageal necrosis with concomitant COVID-19 infection. This case is the first requiring esophagectomy. Future studies may establish esophageal necrosis as a known complication of COVID-19.
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  Factors affecting the implementation of employee whole health in the veterans health administration: a qualitative evaluation

  Adjognon, Omonyêlé L; Cohen-Bearak, Adena; Kaitz, Jenesse; Bokhour, Barbara G; Chatelain, Leslie; Charns, Martin P; Mohr, David C (2023-06-08)

  Background: There is increasing recognition of the need to focus on the health and well-being of healthcare employees given high rates of burnout and turnover. Employee wellness programs are effective at addressing these issues; however, participation in these programs is often a challenge and requires large scale organizational transformation. The Veterans Health Administration (VA) has begun to roll out their own employee wellness program-Employee Whole Health (EWH)-focused on the holistic needs of all employees. This evaluation's goal was to use the Lean Enterprise Transformation (LET) model for organizational transformation to identify key factors-facilitators and barriers-affecting the implementation of VA EWH. Methods: This cross-sectional qualitative evaluation based on the action research model reflects on the organizational implementation of EWH. Semi-structured 60-minute phone interviews were conducted in February-April 2021 with 27 key informants (e.g., EWH coordinator, wellness/occupational health staff) knowledgeable about EWH implementation across 10 VA medical centers. Operational partner provided a list of potential participants, eligible because of their involvement in EWH implementation at their site. The interview guide was informed by the LET model. Interviews were recorded and professionally transcribed. Constant comparative review with a combination of a priori coding based on the model and emergent thematic analysis was used to identify themes from transcripts. Matrix analysis and rapid turnaround qualitative methods were used to identify cross-site factors to EWH implementation. Results: Eight common factors in the conceptual model were found to facilitate and/or hinder EWH implementation efforts: [1] EWH initiatives, [2] multilevel leadership support, [3] alignment, [4] integration, [5] employee engagement, [6] communication, [7] staffing, and [8] culture. An emergent factor was [9] the impact of the COVID-19 pandemic on EWH implementation. Conclusions: As VA expands its EWH cultural transformation nationwide, evaluation findings can (a) enable existing programs to address known implementation barriers, and (b) inform new sites to capitalize on known facilitators, anticipate and address barriers, and leverage evaluation recommendations through concerted implementation at the organization, process, and employee levels to jump-start their EWH program implementation.
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  Matching medical staff to long term care facilities to respond to COVID-19 outbreak

  Zarei, Hamid Reza; Ghanbarpour Mamaghani, Mahsa; Ergun, Ozlem; Yu, Patricia; Winchester, Leanne; Chen, Elizabeth (2023-06-07)

  Background: Staff shortage is a long-standing issue in long term care facilities (LTCFs) that worsened with the COVID-19 outbreak. Different states in the US have employed various tools to alleviate this issue in LTCFs. We describe the actions taken by the Commonwealth of Massachusetts to assist LTCFs in addressing the staff shortage issue and their outcomes. Therefore, the main question of this study is how to create a central mechanism to allocate severely limited medical staff to healthcare centers during emergencies. Methods: For the Commonwealth of Massachusetts, we developed a mathematical programming model to match severely limited available staff with LTCF demand requests submitted through a designed portal. To find feasible matches and prioritize facility needs, we incorporated restrictions and preferences for both sides. For staff, we considered maximum mileage they are willing to travel, available by date, and short- or long-term work preferences. For LTCFs, we considered their demand quantities for different positions and the level of urgency for their demand. As a secondary goal of this study, by using the feedback entries data received from the LTCFs on their matches, we developed statistical models to determine the most salient features that induced the LTCFs to submit feedback. Results: We used the developed portal to complete about 150 matching sessions in 14 months to match staff to LTCFs in Massachusetts. LTCFs provided feedback for 2,542 matches including 2,064 intentions to hire the matched staff during this time. Further analysis indicated that nursing homes and facilities that entered higher levels of demand to the portal were more likely to provide feedback on the matches and facilities that were prioritized in the matching process due to whole facility testing or low staffing levels were less likely to do so. On the staffing side, matches that involved more experienced staff and staff who can work afternoons, evenings, and overnight were more likely to generate feedback from the facility that they were matched to. Conclusion: Developing a central matching framework to match medical staff to LTCFs at the time of a public health emergency could be an efficient tool for responding to staffing shortages. Such central approaches that help allocate a severely limited resource efficiently during a public emergency can be developed and used for different resource types, as well as provide crucial demand and supply information in different regions and/or demographics.
• Rising to the Occasion: A National Nursing Home Study Documenting Attempts to Address Social Isolation During the COVID-19 Pandemic

  Lapane, Kate L; Lim, Emily; Mack, Deborah S; Hargraves, J Lee; Cosenza, Carol; Dubé, Catherine E (2023-05-30)

  Objectives: COVID-19-related policies introduced extraordinary social disruption in nursing homes. In response, nursing facilities implemented strategies to alleviate their residents' loneliness. This study sought to describe interventions nursing homes used, document the perceived effectiveness of efforts, and determine barriers to implementing strategies to mitigate social isolation and loneliness. Design: National survey of nursing homes sampled in strata defined by facility size (beds: 30-99, 100+) and quality ratings (1, 2-4, 5). Settings and participants: US Nursing Home Directors of Nursing/Administrators (n = 1676). Methods: The survey was conducted between February and May 2022 (response rate: 30%; n = 504, weighted n = 14,506). Weighted analyses provided nationally representative results. Results: One-third were extremely concerned about their home's ability to meet residents' medical and social needs during COVID-19 before vaccines were available and 13% after vaccines. Nearly all reported trying to mitigate residents' social isolation during the pandemic. Efforts tried, and perceived as most useful, included using technology (tablets, phones, emails), assigning staff as a family contact, and more staff time with residents. Most frequently cited barriers to implementation were related to staffing issues. Conclusions and implications: Despite multiple challenges, nearly all nursing homes tried to implement many different approaches to address residents' social needs, with some (eg, having an assigned family contact, use of tablets and phones) perceived as more useful than others. Staffing issues presented barriers for addressing the social needs of nursing home residents. Many strategies for addressing social isolation placed more demands on a workforce already stretched to the limit. While concerns about resident social isolation reduced after vaccine availability, administrators remained extremely concerned about staff burnout and mental health.

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