Browsing by Subject "SARS-CoV-2"
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Item Open Access A genetically engineered, stem-cell-derived cellular vaccine.(Cell reports. Medicine, 2022-12) Cooper, Amanda; Sidaway, Adam; Chandrashekar, Abishek; Latta, Elizabeth; Chakraborty, Krishnendu; Yu, Jingyou; McMahan, Katherine; Giffin, Victoria; Manickam, Cordelia; Kroll, Kyle; Mosher, Matthew; Reeves, R Keith; Gam, Rihab; Arthofer, Elisa; Choudhry, Modassir; Henley, Tom; Barouch, Dan HDespite rapid clinical translation of COVID-19 vaccines in response to the global pandemic, an opportunity remains for vaccine technology innovation to address current limitations and meet challenges of inevitable future pandemics. We describe a universal vaccine cell (UVC) genetically engineered to mimic natural physiological immunity induced upon viral infection of host cells. Cells engineered to express the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike as a representative viral antigen induce robust neutralizing antibodies in immunized non-human primates. Similar titers generated in this established non-human primate (NHP) model have translated into protective human neutralizing antibody levels in SARS-CoV-2-vaccinated individuals. Animals vaccinated with ancestral spike antigens and subsequently challenged with SARS-CoV-2 Delta variant in a heterologous challenge have an approximately 3 log decrease in viral subgenomic RNA in the lungs. This cellular vaccine is designed as a scalable cell line with a modular poly-antigenic payload, allowing for rapid, large-scale clinical manufacturing and use in an evolving viral variant environment.Item Open Access A Multi-Center International Analysis of Lung Transplantation Outcomes in Patients With COVID-19.(Clinical transplantation, 2024-09) Kashem, Mohammed Abul; Loor, Gabriel; Emtiazjoo, Amir; Hartwig, Matthew; Van Raemdonck, Dirk; Calvelli, Hannah; Leon Pena, Andres; Salan-Gomez, Marcelo; Zhao, Huaqing; Warnick, Michael; Villavicencio, Mauricio; Ius, Fabio; Ghadimi, Kamrouz; Salman, Jawad; Chandrashekaran, Satish; Machuca, Tiago; Sanchez, Pablo G; Subramaniam, Kathirvel; Neyrinck, Arne; Huddleston, Stephen; Ceulemans, Laurens; Osho, Asishana; D'Silva, Ethan; Ramamurthy, Uma; Shaffer, Andrew; Langer, Nathaniel; Toyoda, YoshiyaIntroduction
Lung transplantation has become increasingly utilized in patients with COVID-19. While several single-center and UNOS database studies have been published on lung transplants (LTs) for end-stage lung disease (ESLD) from Coronavirus disease 2019 (COVID-19), there is a lack of multi-center and international data.Methods
This is a multicenter analysis from 11 high-volume lung transplant centers in the United States and Europe. Data were collected through the Multi-Institutional ECLS Registry and stratified by ESLD due to COVID-19 versus other etiologies. Demographics and clinical variables were compared using Chi-square test and Fisher's exact test. Survival was assessed by Kaplan-Meier curves and compared by log-rank test with propensity score matching.Results
Of 1606 lung transplant recipients, 46 (2.9%) were transplanted for ESLD from COVID-19 compared to 1560 (97.1%) without a history of COVID-19. Among COVID-19 patients, 30 (65.2%) had COVID-19-associated ARDS and 16 (34.8%) had post-COVID-19 fibrosis. COVID-19 patients had higher lung allocation scores (78.0 vs. 44.4, p < 0.0001), had severely limited functional status (37.0% vs. 2.9%, p < 0.0001), had higher preoperative ECMO usage (65.2% vs. 5.4%, p < 0.0001), and spent less time on the waitlist (32 vs. 137 days, p < 0.0001). A 30-day survival was comparable between COVID-19 and non-COVID-19 patients before (100% vs. 98.7%, p = 0.39) and after propensity matching (p = 0.15).Conclusions
Patients who received LTs due to COVID-19 had short-term survival comparable to that of patients without COVID-19. Our findings support the idea that lung transplantation should be considered for select patients with ESLD due to COVID-19.Item Open Access A survey and panel discussion of the effects of the COVID-19 pandemic on paediatric urological productivity, guideline adherence and provider stress.(Journal of pediatric urology, 2020-08) O'Kelly, Fardod; Sparks, Scott; Seideman, Casey; Gargollo, Patricio; Granberg, Candace; Ko, Joan; Malhotra, Neha; Hecht, Sarah; Swords, Kelly; Rowe, Courtney; Whittam, Ben; Spinoit, Anne-Francoise; Dudley, Anne; Ellison, Jonathan; Chu, David; Routh, Jonathan; Cannon, Glenn; Kokorowski, Paul; Koyle, Martin; Silay, Mesrur Selcuk; APAUC (Academic Paediatric and Adolescent Urology Collaborative) and the YAU (Young Academic Urologists) GroupIntroduction
The COVID-19 pandemic has led to an unprecedented need to re-organise and re-align priorities for all surgical specialties. Despite the current declining numbers globally, the direct effects of the pandemic on institutional practices and on personal stress and coping mechanisms remains unknown. The aims of this study were to assess the effect of the pandemic on daily scheduling and work balances, its effects on stress, and to determine compliance with guidelines and to assess whether quarantining has led to other areas of increased productivity.Methods
A trans-Atlantic convenience sample of paediatric urologists was created in which panellists (Zoom) discussed the direct effects of the COVID-19 pandemic on individual units, as well as creating a questionnaire using a mini-Delphi method to provide current semi-quantitative data regarding practice, and adherence levels to recently published risk stratification guidelines. They also filled out a Perceived Stress Scale (PSS) questionnaire to assess contemporary pandemic stress levels.Results
There was an 86% response rate from paediatric urologists. The majority of respondents reported near complete disruption to planned operations (70%), and trainee education (70%). They were also worried about the effects of altered home-lives on productivity (≤90%), as well as a lack of personal protective equipment (57%). The baseline stress rate was measured at a very high level (PSS) during the pandemic. Adherence to recent operative guidelines for urgent cases was 100%.Conclusion
This study represents a panel discussion of a number of practical implications for paediatric urologists, and is one of the few papers to assess more pragmatic effects and combines opinions from both sides of the Atlantic. The impact of the pandemic has been very significant for paediatric urologists and includes a decrease in the number of patients seen and operated on, decreased salary, increased self-reported stress levels, substantially increased telemedicine usage, increased free time for various activities, and good compliance with guidelines and hospital management decisions.Item Open Access A Systematic Framework to Rapidly Obtain Data on Patients with Cancer and COVID-19: CCC19 Governance, Protocol, and Quality Assurance.(Cancer cell, 2020-12) COVID-19 and Cancer Consortium. Electronic address: jeremy.warner@vumc.org; COVID-19 and Cancer ConsortiumWhen the COVID-19 pandemic began, formal frameworks to collect data about affected patients were lacking. The COVID-19 and Cancer Consortium (CCC19) was formed to collect granular data on patients with cancer and COVID-19 at scale and as rapidly as possible. CCC19 has grown from five initial institutions to 125 institutions with >400 collaborators. More than 5,000 cases with complete baseline data have been accrued. Future directions include increased electronic health record integration for direct data ingestion, expansion to additional domestic and international sites, more intentional patient involvement, and granular analyses of still-unanswered questions related to cancer subtypes and treatments.Item Open Access Abatacept, Cenicriviroc, or Infliximab for Treatment of Adults Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial.(JAMA, 2023-07) 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; Smith, P Brian; de Tai, Sabina Mendivil-Tuchia; Khan, Akram; Lora, Alfredo J Mena; Salathe, Matthias; Capo, Gerardo; Gonzalez, Daniel Rodríguez; Patterson, Thomas F; Palma, Christopher; Ariza, Horacio; Lima, Maria Patelli; Blamoun, John; Nannini, Esteban C; Sprinz, Eduardo; Mykietiuk, Analia; Alicic, Radica; Rauseo, Adriana M; Wolfe, Cameron R; Witting, Britta; Wang, Jennifer P; Parra-Rodriguez, Luis; Der, Tatyana; Willsey, Kate; Wen, Jun; Silverstein, Adam; O'Brien, Sean M; Al-Khalidi, Hussein R; Maldonado, Michael A; Melsheimer, Richard; Ferguson, William G; McNulty, Steven E; Zakroysky, Pearl; Halabi, Susan; Benjamin, Daniel K; Butler, Sandra; Atkinson, Jane C; Adam, Stacey J; Chang, Soju; LaVange, Lisa; Proschan, Michael; Bozzette, Samuel A; Powderly, William G; ACTIV-1 IM Study Group MembersImportance
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.Item Open Access Activity of Galidesivir in a Hamster Model of SARS-CoV-2.(Viruses, 2021-12-21) Taylor, Ray; Bowen, Richard; Demarest, James F; DeSpirito, Michael; Hartwig, Airn; Bielefeldt-Ohmann, Helle; Walling, Dennis M; Mathis, Amanda; Babu, Yarlagadda SCoronavirus disease 2019 (COVID-19) has claimed the lives of millions of people worldwide since it first emerged. The impact of the COVID-19 pandemic on public health and the global economy has highlighted the medical need for the development of broadly acting interventions against emerging viral threats. Galidesivir is a broad-spectrum antiviral compound with demonstrated in vitro and in vivo efficacy against several RNA viruses of public health concern, including those causing yellow fever, Ebola, Marburg, and Rift Valley fever. In vitro studies have shown that the antiviral activity of galidesivir also extends to coronaviruses. Herein, we describe the efficacy of galidesivir in the Syrian golden hamster model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Treatment with galidesivir reduced lung pathology in infected animals compared with untreated controls when treatment was initiated 24 h prior to infection. These results add to the evidence of the applicability of galidesivir as a potential medical intervention for a range of acute viral illnesses, including coronaviruses.Item Open Access Age-related model for estimating the symptomatic and asymptomatic transmissibility of COVID-19 patients.(Biometrics, 2023-09) Tan, Jianbin; Shen, Ye; Ge, Yang; Martinez, Leonardo; Huang, HuiEstimation of age-dependent transmissibility of COVID-19 patients is critical for effective policymaking. Although the transmissibility of symptomatic cases has been extensively studied, asymptomatic infection is understudied due to limited data. Using a dataset with reliably distinguished symptomatic and asymptomatic statuses of COVID-19 cases, we propose an ordinary differential equation model that considers age-dependent transmissibility in transmission dynamics. Under a Bayesian framework, multi-source information is synthesized in our model for identifying transmissibility. A shrinkage prior among age groups is also adopted to improve the estimation behavior of transmissibility from age-structured data. The added values of accounting for age-dependent transmissibility are further evaluated through simulation studies. In real-data analysis, we compare our approach with two basic models using the deviance information criterion (DIC) and its extension. We find that the proposed model is more flexible for our epidemic data. Our results also suggest that the transmissibility of asymptomatic infections is significantly lower (on average, 76.45% with a credible interval (27.38%, 88.65%)) than that of symptomatic cases. In both symptomatic and asymptomatic patients, the transmissibility mainly increases with age. Patients older than 30 years are more likely to develop symptoms with higher transmissibility. We also find that the transmission burden of asymptomatic cases is lower than that of symptomatic patients.Item Open Access An Agile Systems Modeling Framework for Bed Resource Planning During COVID-19 Pandemic in Singapore.(Frontiers in public health, 2022-01) Lam, Sean Shao Wei; Pourghaderi, Ahmad Reza; Abdullah, Hairil Rizal; Nguyen, Francis Ngoc Hoang Long; Siddiqui, Fahad Javaid; Ansah, John Pastor; Low, Jenny G; Matchar, David Bruce; Ong, Marcus Eng HockBackground
The COVID-19 pandemic has had a major impact on health systems globally. The sufficiency of hospitals' bed resource is a cornerstone for access to care which can significantly impact the public health outcomes.Objective
We describe the development of a dynamic simulation framework to support agile resource planning during the COVID-19 pandemic in Singapore.Materials and methods
The study data were derived from the Singapore General Hospital and public domain sources over the period from 1 January 2020 till 31 May 2020 covering the period when the initial outbreak and surge of COVID-19 cases in Singapore happened. The simulation models and its variants take into consideration the dynamic evolution of the pandemic and the rapidly evolving policies and processes in Singapore.Results
The models were calibrated against historical data for the Singapore COVID-19 situation. Several variants of the resource planning model were rapidly developed to adapt to the fast-changing COVID-19 situation in Singapore.Conclusion
The agility in adaptable models and robust collaborative management structure enabled the quick deployment of human and capital resources to sustain the high level of health services delivery during the COVID-19 surge.Item Open Access An Analysis of Public Interest in Elective Neurosurgical Procedures During the COVID-19 Pandemic Through Online Search Engine Trends.(World neurosurgery, 2021-04) Feng, Austin Y; Garcia, Cesar A; Jin, Michael C; Ho, Allen L; Li, Gordon; Grant, Gerald; Ratliff, John; Skirboll, Stephen LObjective
In the wake of the COVID-19 pandemic, the Centers for Medicare & Medicaid Services (CMS) has recommended the temporary cessation of all elective surgeries. The effects on patients' interest of elective neurosurgical procedures are currently unexplored.Methods
Using Google Trends, search terms of 7 different neurosurgical procedure categories (trauma, spine, tumor, movement disorder, epilepsy, endovascular, and miscellaneous) were assessed in terms of relative search volume (RSV) between January 2015 and September 2020. Analyses of search terms were performed for over the short term (February 18, 2020, to April 18, 2020), intermediate term (January 1, 2020, to May 31, 2020), and long term (January 2015 to September 2020). State-level interest during phase I reopening (April 28, 2020, to May 31, 2020) was also evaluated.Results
In the short term, RSVs of 4 categories (epilepsy, movement disorder, spine, and tumor) were significantly lower in the post-CMS announcement period. In the intermediate term, RSVs of 5 categories (miscellaneous, epilepsy, movement disorder, spine, and tumor) were significantly lower in the post-CMS announcement period. In the long term, RSVs of nearly all categories (endovascular, epilepsy, miscellaneous, movement disorder, spine, and tumor) were significantly lower in the post-CMS announcement period. Only the movement disorder procedure category had significantly higher RSV in states that reopened early.Conclusions
With the recommendation for cessation of elective surgeries, patient interests in overall elective neurosurgical procedures have dropped significantly. With gradual reopening, there has been a resurgence in some procedure types. Google Trends has proven to be a useful tracker of patient interest and may be used by neurosurgical departments to facilitate outreach strategies.Item Open Access An atlas connecting shared genetic architecture of human diseases and molecular phenotypes provides insight into COVID-19 susceptibility.(Genome medicine, 2021-05) Wang, Liuyang; Balmat, Thomas J; Antonia, Alejandro L; Constantine, Florica J; Henao, Ricardo; Burke, Thomas W; Ingham, Andy; McClain, Micah T; Tsalik, Ephraim L; Ko, Emily R; Ginsburg, Geoffrey S; DeLong, Mark R; Shen, Xiling; Woods, Christopher W; Hauser, Elizabeth R; Ko, Dennis CBackground
While genome-wide associations studies (GWAS) have successfully elucidated the genetic architecture of complex human traits and diseases, understanding mechanisms that lead from genetic variation to pathophysiology remains an important challenge. Methods are needed to systematically bridge this crucial gap to facilitate experimental testing of hypotheses and translation to clinical utility.Results
Here, we leveraged cross-phenotype associations to identify traits with shared genetic architecture, using linkage disequilibrium (LD) information to accurately capture shared SNPs by proxy, and calculate significance of enrichment. This shared genetic architecture was examined across differing biological scales through incorporating data from catalogs of clinical, cellular, and molecular GWAS. We have created an interactive web database (interactive Cross-Phenotype Analysis of GWAS database (iCPAGdb)) to facilitate exploration and allow rapid analysis of user-uploaded GWAS summary statistics. This database revealed well-known relationships among phenotypes, as well as the generation of novel hypotheses to explain the pathophysiology of common diseases. Application of iCPAGdb to a recent GWAS of severe COVID-19 demonstrated unexpected overlap of GWAS signals between COVID-19 and human diseases, including with idiopathic pulmonary fibrosis driven by the DPP9 locus. Transcriptomics from peripheral blood of COVID-19 patients demonstrated that DPP9 was induced in SARS-CoV-2 compared to healthy controls or those with bacterial infection. Further investigation of cross-phenotype SNPs associated with both severe COVID-19 and other human traits demonstrated colocalization of the GWAS signal at the ABO locus with plasma protein levels of a reported receptor of SARS-CoV-2, CD209 (DC-SIGN). This finding points to a possible mechanism whereby glycosylation of CD209 by ABO may regulate COVID-19 disease severity.Conclusions
Thus, connecting genetically related traits across phenotypic scales links human diseases to molecular and cellular measurements that can reveal mechanisms and lead to novel biomarkers and therapeutic approaches. The iCPAGdb web portal is accessible at http://cpag.oit.duke.edu and the software code at https://github.com/tbalmat/iCPAGdb .Item Open Access An enhanced isothermal amplification assay for viral detection.(Nature communications, 2020-11) Qian, Jason; Boswell, Sarah A; Chidley, Christopher; Lu, Zhi-Xiang; Pettit, Mary E; Gaudio, Benjamin L; Fajnzylber, Jesse M; Ingram, Ryan T; Ward, Rebecca H; Li, Jonathan Z; Springer, MichaelRapid, inexpensive, robust diagnostics are essential to control the spread of infectious diseases. Current state of the art diagnostics are highly sensitive and specific, but slow, and require expensive equipment. Here we report the development of a molecular diagnostic test for SARS-CoV-2 based on an enhanced recombinase polymerase amplification (eRPA) reaction. eRPA has a detection limit on patient samples down to 5 viral copies, requires minimal instrumentation, and is highly scalable and inexpensive. eRPA does not cross-react with other common coronaviruses, does not require RNA purification, and takes ~45 min from sample collection to results. eRPA represents a first step toward at-home SARS-CoV-2 detection and can be adapted to future viruses within days of genomic sequence availability.Item Open Access An update on the progress of galidesivir (BCX4430), a broad-spectrum antiviral.(Antiviral research, 2021-09-20) Julander, Justin G; Demarest, James F; Taylor, Ray; Gowen, Brian B; Walling, Dennis M; Mathis, Amanda; Babu, YSGalidesivir (BCX4430) is an adenosine nucleoside analog that is broadly active in cell culture against several RNA viruses of various families. This activity has also been shown in animal models of viral disease associated with Ebola, Marburg, yellow fever, Zika, and Rift Valley fever viruses. In many cases, the compound is more efficacious in animal models than cell culture activity would predict. Based on favorable data from in vivo animal studies, galidesivir has recently undergone evaluation in several phase I clinical trials, including against severe acute respiratory syndrome coronavirus 2, and as a medical countermeasure for the treatment of Marburg virus disease.Item Open Access Assessment of an Online Tool to Simulate the Effect of Pooled Testing for SARS-CoV-2 Detection in Asymptomatic and Symptomatic Populations.(JAMA network open, 2020-12) Polage, Christopher R; Lee, Mark J; Hubbard, Christopher; Rehder, Catherine; Cardona, Diana; Denny, Thomas; Datto, Michael BItem Open Access Bilateral anterior and intermediate uveitis in SARS-CoV-2 associated multisystem inflammatory syndrome in a pediatric patient.(Pediatric rheumatology online journal, 2022-07) Shantha, Jessica; Reddy, Amit K; Sura, Amol; Tsang, Adrian; Moussa, Kareem; Acharya, Nisha; Gonzales, John; Doan, ThuyPurpose
To report a case of bilateral anterior intermediate uveitis after recovery from SARS-CoV-2 associated multisystem inflammatory syndrome in children (MIS-C).Case report
A 9-year-old male presented with bilateral anterior intermediate uveitis with fluorescein angiography (FA) leakage of the disc and peripheral vasculature 1 month after recovery from MIS-C. He was treated with difluprednate 0.05% in both eyes with resolution of FA leakage, but our patient has required an extended treatment of topical therapy and the need long term immunosuppression.Conclusions
This is a case of uveitis presenting after recent MIS-C related to SARS-CoV-2. Ongoing follow up and monitoring is required, and it is important for the ophthalmologist and rheumatologist to be aware of this rare complication during the current COVID-19 pandemic.Item Open Access Brequinar and dipyridamole in combination exhibits synergistic antiviral activity against SARS-CoV-2 in vitro: Rationale for a host-acting antiviral treatment strategy for COVID-19.(Antiviral research, 2022-10) Demarest, James F; Kienle, Maryline; Boytz, RuthMabel; Ayres, Mary; Kim, Eun Jung; Patten, JJ; Chung, Donghoon; Gandhi, Varsha; Davey, Robert A; Sykes, David B; Shohdy, Nadim; Pottage, John C; Kumar, Vikram SThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19) and the associated global pandemic resulting in >400 million infections worldwide and several million deaths. The continued evolution of SARS-CoV-2 to potentially evade vaccines and monoclonal antibody (mAb)-based therapies and the limited number of authorized small-molecule antivirals necessitates the need for development of new drug treatments. There remains an unmet medical need for effective and convenient treatment options for SARS-CoV-2 infection. SARS-CoV-2 is an RNA virus that depends on host intracellular ribonucleotide pools for its replication. Dihydroorotate dehydrogenase (DHODH) is a ubiquitous host enzyme that is required for de novo pyrimidine synthesis. The inhibition of DHODH leads to a depletion of intracellular pyrimidines, thereby impacting viral replication in vitro. Brequinar (BRQ) is an orally available, selective, and potent low nanomolar inhibitor of human DHODH that has been shown to exhibit broad spectrum inhibition of RNA virus replication. However, host cell nucleotide salvage pathways can maintain intracellular pyrimidine levels and compensate for BRQ-mediated DHODH inhibition. In this report, we show that the combination of BRQ and the salvage pathway inhibitor dipyridamole (DPY) exhibits strong synergistic antiviral activity in vitro against SARS-CoV-2 by enhanced depletion of the cellular pyrimidine nucleotide pool. The combination of BRQ and DPY showed antiviral activity against the prototype SARS-CoV-2 as well as the Beta (B.1.351) and Delta (B.1.617.2) variants. These data support the continued evaluation of the combination of BRQ and DPY as a broad-spectrum, host-acting antiviral strategy to treat SARS-CoV-2 and potentially other RNA virus infections.Item Open Access Caring for Caregivers During COVID-19.(Journal of the American Geriatrics Society, 2020-10) Dang, Stuti; Penney, Lauren S; Trivedi, Ranak; Noel, Polly H; Pugh, Mary Jo; Finley, Erin; Pugh, Jacqueline A; Van Houtven, Courtney H; Leykum, LuciItem Open Access Cell-based therapy to reduce mortality from COVID-19: Systematic review and meta-analysis of human studies on acute respiratory distress syndrome.(Stem cells translational medicine, 2020-09) Qu, Wenchun; Wang, Zhen; Hare, Joshua M; Bu, Guojun; Mallea, Jorge M; Pascual, Jorge M; Caplan, Arnold I; Kurtzberg, Joanne; Zubair, Abba C; Kubrova, Eva; Engelberg-Cook, Erica; Nayfeh, Tarek; Shah, Vishal P; Hill, James C; Wolf, Michael E; Prokop, Larry J; Murad, M Hassan; Sanfilippo, Fred PSevere cases of COVID-19 infection, often leading to death, have been associated with variants of acute respiratory distress syndrome (ARDS). Cell therapy with mesenchymal stromal cells (MSCs) is a potential treatment for COVID-19 ARDS based on preclinical and clinical studies supporting the concept that MSCs modulate the inflammatory and remodeling processes and restore alveolo-capillary barriers. The authors performed a systematic literature review and random-effects meta-analysis to determine the potential value of MSC therapy for treating COVID-19-infected patients with ARDS. Publications in all languages from 1990 to March 31, 2020 were reviewed, yielding 2691 studies, of which nine were included. MSCs were intravenously or intratracheally administered in 117 participants, who were followed for 14 days to 5 years. All MSCs were allogeneic from bone marrow, umbilical cord, menstrual blood, adipose tissue, or unreported sources. Combined mortality showed a favorable trend but did not reach statistical significance. No related serious adverse events were reported and mild adverse events resolved spontaneously. A trend was found of improved radiographic findings, pulmonary function (lung compliance, tidal volumes, PaO2 /FiO2 ratio, alveolo-capillary injury), and inflammatory biomarker levels. No comparisons were made between MSCs of different sources.Item Open Access Challenges of COVID-19 Case Forecasting in the US, 2020-2021.(PLoS computational biology, 2024-05) Lopez, Velma K; Cramer, Estee Y; Pagano, Robert; Drake, John M; O'Dea, Eamon B; Adee, Madeline; Ayer, Turgay; Chhatwal, Jagpreet; Dalgic, Ozden O; Ladd, Mary A; Linas, Benjamin P; Mueller, Peter P; Xiao, Jade; Bracher, Johannes; Castro Rivadeneira, Alvaro J; Gerding, Aaron; Gneiting, Tilmann; Huang, Yuxin; Jayawardena, Dasuni; Kanji, Abdul H; Le, Khoa; Mühlemann, Anja; Niemi, Jarad; Ray, Evan L; Stark, Ariane; Wang, Yijin; Wattanachit, Nutcha; Zorn, Martha W; Pei, Sen; Shaman, Jeffrey; Yamana, Teresa K; Tarasewicz, Samuel R; Wilson, Daniel J; Baccam, Sid; Gurung, Heidi; Stage, Steve; Suchoski, Brad; Gao, Lei; Gu, Zhiling; Kim, Myungjin; Li, Xinyi; Wang, Guannan; Wang, Lily; Wang, Yueying; Yu, Shan; Gardner, Lauren; Jindal, Sonia; Marshall, Maximilian; Nixon, Kristen; Dent, Juan; Hill, Alison L; Kaminsky, Joshua; Lee, Elizabeth C; Lemaitre, Joseph C; Lessler, Justin; Smith, Claire P; Truelove, Shaun; Kinsey, Matt; Mullany, Luke C; Rainwater-Lovett, Kaitlin; Shin, Lauren; Tallaksen, Katharine; Wilson, Shelby; Karlen, Dean; Castro, Lauren; Fairchild, Geoffrey; Michaud, Isaac; Osthus, Dave; Bian, Jiang; Cao, Wei; Gao, Zhifeng; Lavista Ferres, Juan; Li, Chaozhuo; Liu, Tie-Yan; Xie, Xing; Zhang, Shun; Zheng, Shun; Chinazzi, Matteo; Davis, Jessica T; Mu, Kunpeng; Pastore Y Piontti, Ana; Vespignani, Alessandro; Xiong, Xinyue; Walraven, Robert; Chen, Jinghui; Gu, Quanquan; Wang, Lingxiao; Xu, Pan; Zhang, Weitong; Zou, Difan; Gibson, Graham Casey; Sheldon, Daniel; Srivastava, Ajitesh; Adiga, Aniruddha; Hurt, Benjamin; Kaur, Gursharn; Lewis, Bryan; Marathe, Madhav; Peddireddy, Akhil Sai; Porebski, Przemyslaw; Venkatramanan, Srinivasan; Wang, Lijing; Prasad, Pragati V; Walker, Jo W; Webber, Alexander E; Slayton, Rachel B; Biggerstaff, Matthew; Reich, Nicholas G; Johansson, Michael ADuring the COVID-19 pandemic, forecasting COVID-19 trends to support planning and response was a priority for scientists and decision makers alike. In the United States, COVID-19 forecasting was coordinated by a large group of universities, companies, and government entities led by the Centers for Disease Control and Prevention and the US COVID-19 Forecast Hub (https://covid19forecasthub.org). We evaluated approximately 9.7 million forecasts of weekly state-level COVID-19 cases for predictions 1-4 weeks into the future submitted by 24 teams from August 2020 to December 2021. We assessed coverage of central prediction intervals and weighted interval scores (WIS), adjusting for missing forecasts relative to a baseline forecast, and used a Gaussian generalized estimating equation (GEE) model to evaluate differences in skill across epidemic phases that were defined by the effective reproduction number. Overall, we found high variation in skill across individual models, with ensemble-based forecasts outperforming other approaches. Forecast skill relative to the baseline was generally higher for larger jurisdictions (e.g., states compared to counties). Over time, forecasts generally performed worst in periods of rapid changes in reported cases (either in increasing or decreasing epidemic phases) with 95% prediction interval coverage dropping below 50% during the growth phases of the winter 2020, Delta, and Omicron waves. Ideally, case forecasts could serve as a leading indicator of changes in transmission dynamics. However, while most COVID-19 case forecasts outperformed a naïve baseline model, even the most accurate case forecasts were unreliable in key phases. Further research could improve forecasts of leading indicators, like COVID-19 cases, by leveraging additional real-time data, addressing performance across phases, improving the characterization of forecast confidence, and ensuring that forecasts were coherent across spatial scales. In the meantime, it is critical for forecast users to appreciate current limitations and use a broad set of indicators to inform pandemic-related decision making.Item Open Access Changing trends in mortality among solid organ transplant recipients hospitalized for COVID-19 during the course of the pandemic.(American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons, 2022-01) Heldman, Madeleine R; Kates, Olivia S; Safa, Kassem; Kotton, Camille N; Georgia, Sarah J; Steinbrink, Julie M; Alexander, Barbara D; Hemmersbach-Miller, Marion; Blumberg, Emily A; Multani, Ashrit; Haydel, Brandy; La Hoz, Ricardo M; Moni, Lisset; Condor, Yesabeli; Flores, Sandra; Munoz, Carlos G; Guitierrez, Juan; Diaz, Esther I; Diaz, Daniela; Vianna, Rodrigo; Guerra, Giselle; Loebe, Matthias; Rakita, Robert M; Malinis, Maricar; Azar, Marwan M; Hemmige, Vagish; McCort, Margaret E; Chaudhry, Zohra S; Singh, Pooja P; Hughes Kramer, Kailey; Velioglu, Arzu; Yabu, Julie M; Morillis, Jose A; Mehta, Sapna A; Tanna, Sajal D; Ison, Michael G; Derenge, Ariella C; van Duin, David; Maximin, Adrienne; Gilbert, Carlene; Goldman, Jason D; Lease, Erika D; Fisher, Cynthia E; Limaye, Ajit P; UW COVID-19 SOT Study TeamMortality among patients hospitalized for COVID-19 has declined over the course of the pandemic. Mortality trends specifically in solid organ transplant recipients (SOTR) are unknown. Using data from a multicenter registry of SOTR hospitalized for COVID-19, we compared 28-day mortality between early 2020 (March 1, 2020-June 19, 2020) and late 2020 (June 20, 2020-December 31, 2020). Multivariable logistic regression was used to assess comorbidity-adjusted mortality. Time period of diagnosis was available for 1435/1616 (88.8%) SOTR and 971/1435 (67.7%) were hospitalized: 571/753 (75.8%) in early 2020 and 402/682 (58.9%) in late 2020 (p < .001). Crude 28-day mortality decreased between the early and late periods (112/571 [19.6%] vs. 55/402 [13.7%]) and remained lower in the late period even after adjusting for baseline comorbidities (aOR 0.67, 95% CI 0.46-0.98, p = .016). Between the early and late periods, the use of corticosteroids (≥6 mg dexamethasone/day) and remdesivir increased (62/571 [10.9%] vs. 243/402 [61.5%], p < .001 and 50/571 [8.8%] vs. 213/402 [52.2%], p < .001, respectively), and the use of hydroxychloroquine and IL-6/IL-6 receptor inhibitor decreased (329/571 [60.0%] vs. 4/492 [1.0%], p < .001 and 73/571 [12.8%] vs. 5/402 [1.2%], p < .001, respectively). Mortality among SOTR hospitalized for COVID-19 declined between early and late 2020, consistent with trends reported in the general population. The mechanism(s) underlying improved survival require further study.Item Open Access Chronic lung diseases are associated with gene expression programs favoring SARS-CoV-2 entry and severity.(Nature communications, 2021-07) Bui, Linh T; Winters, Nichelle I; Chung, Mei-I; Joseph, Chitra; Gutierrez, Austin J; Habermann, Arun C; Adams, Taylor S; Schupp, Jonas C; Poli, Sergio; Peter, Lance M; Taylor, Chase J; Blackburn, Jessica B; Richmond, Bradley W; Nicholson, Andrew G; Rassl, Doris; Wallace, William A; Rosas, Ivan O; Jenkins, R Gisli; Kaminski, Naftali; Kropski, Jonathan A; Banovich, Nicholas E; Human Cell Atlas Lung Biological NetworkPatients with chronic lung disease (CLD) have an increased risk for severe coronavirus disease-19 (COVID-19) and poor outcomes. Here, we analyze the transcriptomes of 611,398 single cells isolated from healthy and CLD lungs to identify molecular characteristics of lung cells that may account for worse COVID-19 outcomes in patients with chronic lung diseases. We observe a similar cellular distribution and relative expression of SARS-CoV-2 entry factors in control and CLD lungs. CLD AT2 cells express higher levels of genes linked directly to the efficiency of viral replication and the innate immune response. Additionally, we identify basal differences in inflammatory gene expression programs that highlight how CLD alters the inflammatory microenvironment encountered upon viral exposure to the peripheral lung. Our study indicates that CLD is accompanied by changes in cell-type-specific gene expression programs that prime the lung epithelium for and influence the innate and adaptive immune responses to SARS-CoV-2 infection.