Publications by authors named "Samuel Brown"

225 Publications

What Does "ARDS" Mean during the COVID-19 Pandemic?

Ann Am Thorac Soc 2021 Jul 21. Epub 2021 Jul 21.

Massachusetts General Hospital, Harvard School of Medicine,, 5Division of Pulmonary and Critical Care Medicine, Department of Medicine, Boston, Massachusetts, United States.

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http://dx.doi.org/10.1513/AnnalsATS.202105-534PSDOI Listing
July 2021

Effectiveness of SARS-CoV-2 mRNA Vaccines for Preventing Covid-19 Hospitalizations in the United States.

medRxiv 2021 Jul 8. Epub 2021 Jul 8.

Background: As SARS-CoV-2 vaccination coverage increases in the United States (US), there is a need to understand the real-world effectiveness against severe Covid-19 and among people at increased risk for poor outcomes.

Methods: In a multicenter case-control analysis of US adults hospitalized March 11 - May 5, 2021, we evaluated vaccine effectiveness to prevent Covid-19 hospitalizations by comparing odds of prior vaccination with an mRNA vaccine (Pfizer-BioNTech or Moderna) between cases hospitalized with Covid-19 and hospital-based controls who tested negative for SARS-CoV-2.

Results: Among 1210 participants, median age was 58 years, 22.8% were Black, 13.8% were Hispanic, and 20.6% had immunosuppression. SARS-CoV-2 lineage B.1.1.7 was most common variant (59.7% of sequenced viruses). Full vaccination (receipt of two vaccine doses ≥14 days before illness onset) had been received by 45/590 (7.6%) cases and 215/620 (34.7%) controls. Overall vaccine effectiveness was 86.9% (95% CI: 80.4 to 91.2%). Vaccine effectiveness was similar for Pfizer-BioNTech and Moderna vaccines, and highest in adults aged 18-49 years (97.3%; 95% CI: 78.9 to 99.7%). Among 45 patients with vaccine-breakthrough Covid hospitalizations, 44 (97.8%) were ≥50 years old and 20 (44.4%) had immunosuppression. Vaccine effectiveness was lower among patients with immunosuppression (59.2%; 95% CI: 11.9 to 81.1%) than without immunosuppression (91.3%; 95% CI: 85.5 to 94.7%).

Conclusion: During March-May 2021, SARS-CoV-2 mRNA vaccines were highly effective for preventing Covid-19 hospitalizations among US adults. SARS-CoV-2 vaccination was beneficial for patients with immunosuppression, but effectiveness was lower in the immunosuppressed population.
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http://dx.doi.org/10.1101/2021.07.08.21259776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282104PMC
July 2021

Humanizing the ICU Patient: A Qualitative Exploration of Behaviors Experienced by Patients, Caregivers, and ICU Staff.

Crit Care Explor 2021 Jun 15;3(6):e0463. Epub 2021 Jun 15.

Division of Pulmonary Critical Care and Sleep Medicine, Department of Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Health, Hempstead, NY.

Objectives: To understand how patients and family members experience dehumanizing or humanizing treatment when in the ICU.

Design: Qualitative study included web-based focus groups and open-ended surveys posted to ICU patient/family social media boards. Focus groups were audio recorded and transcribed. Social media responses were collected and organized by stakeholder group. Data underwent qualitative analysis.

Setting: Remote focus groups and online surveys.

Patients: ICU patient survivors, family members, and ICU teams.

Interventions: Not available.

Measurements And Main Results: Semi-structured questions and open-ended survey responses. We enrolled 40 patients/family members and 31 ICU team members. Focus groups and surveys revealed three primary themes orienting humanizing/dehumanizing ICU experiences: 1) communication, 2) outcomes, and 3) causes of dehumanization. Dehumanization occurred during "communication" exchanges when ICU team members talked "over" patients, made distressing remarks when patients were present, or failed to inform patients about ICU-related care. "Outcomes" of dehumanization were associated with patient loss of trust in the medical team, loss of motivation to participate in ICU recovery, feeling of distress, guilt, depression, and anxiety. Humanizing behaviors were associated with improved recovery, well-being, and trust. "Perceived causes" of dehumanizing behaviors were linked to patient, ICU team, and healthcare system factors.

Conclusions: Behaviors of ICU clinicians may cause patients and families to feel dehumanized when in the ICU. Negative behaviors are noticed by patients and families, possibly contributing to poor outcomes including mental health, recovery, and lack of trust in ICU teams. Supporting ICU clinicians may enable a more empathic environment and in turn more humanizing clinician-patient encounters.
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http://dx.doi.org/10.1097/CCE.0000000000000463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8208441PMC
June 2021

Republished: Case of relapsing sulfasalazine-induced hypersensitivity syndrome upon re-exposure.

Drug Ther Bull 2021 May 24. Epub 2021 May 24.

Internal Medicine, Roy J and Lucille A Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USA

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http://dx.doi.org/10.1136/dtb.2021.235803repDOI Listing
May 2021

The relationship between insurance and health outcomes of diabetes mellitus patients in Maryland: a retrospective archival record study.

BMC Health Serv Res 2021 May 24;21(1):495. Epub 2021 May 24.

Old Dominion University, 1 Old Dominion Way, Norfolk, VA, 23529, USA.

Background: Past studies examining the health outcomes of diabetes mellitus (DM) patients found that social determinants of health disparities were associated with variabilities in health outcomes. However, improving access to healthcare, such as health insurance, should mitigate negative health outcomes. The aim of the study was to explore the association between four types of health insurance, namely, Medicare Fee-For-Service (FFS), Medicare Managed Care (MC), Private FFS, and Private MC plans, and the health outcomes of DM patients, controlling for patients' social determinants of health.

Methods: This is a retrospective cross-sectional archival record study to explore the relationships between types of health insurance and health outcomes of DM patients who were at least 65 years old, or the elderly. Data was drawn from the 2012 Maryland Clinical Public Use Data and received an exempt status from our Institutional Review Board. Elderly Maryland residents with chronic DM were included in the study, resulting in a sample size of 43,519 individuals. Predictor variables were four types of insurance and health outcome variables were length of hospital stay (LOS), 30-day readmission, and end-stage renal disease (ESRD). Control variables included hospital characteristics, patient characteristics, and social determinants of health. Student's t-tests determined the statistical differences for the control variables between the types of insurance. Multiple hierarchical regression analysis was applied to test the association between insurance plans and LOS, while logistic regression analyses were applied to test the association between insurance plans with 30-day readmission and ESRD. Statistical significance was set at p < 0.05.

Results: t-test results indicated minimal statistical differences between the health statuses of patients enrolled in different insurance plans. After factoring out the control variables, regression analyses indicated that Medicare FFS patients had the worst outcome for LOS, 30-day readmission, and ESRD rates. Although patients on Medicare MC plans had lower LOS, 30-day readmission, and ESRD rates compared to those on Medicare FFS, patients enrolled in Private MC plans had the lowest odds of a 30-day readmission and patients enrolled in Private FFS had the lowest odds of an ESRD.

Conclusions: The data suggests that insurance plans were related to the health outcomes of elderly DM patients after considering their social determinants of health. Specifically, DM patients enrolled in managed care and private insurance plans had better health outcomes compared to those on Medicare FFS plans.
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http://dx.doi.org/10.1186/s12913-021-06534-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8146634PMC
May 2021

Response.

Chest 2021 Apr 6;159(4):1685-1686. Epub 2021 Apr 6.

Minneapolis Heart Institute Foundation, Minneapolis, MN.

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http://dx.doi.org/10.1016/j.chest.2020.11.055DOI Listing
April 2021

Influenza Vaccine Effectiveness for Prevention of Severe Influenza-Associated Illness among Adults in the United States, 2019-2020: A test-negative study.

Clin Infect Dis 2021 May 20. Epub 2021 May 20.

Vanderbilt University Medical Center, Nashville, Tennessee, USA.

Background: Influenza vaccine effectiveness (VE) against a spectrum of severe disease, including critical illness and death, remains poorly characterized.

Methods: We conducted a test-negative study in an intensive care unit (ICU) network at 10 United States hospitals to evaluate VE for preventing influenza-associated severe acute respiratory infection (SARI) during the 2019-2020 season, which was characterized by circulation of drifted A/H1N1 and B-lineage viruses. Cases were adults hospitalized in the ICU and a targeted number outside the ICU (to capture a spectrum of severity) with laboratory-confirmed influenza-associated SARI. Test-negative controls were frequency-matched based on hospital, timing of admission, and care location (ICU vs non-ICU). Estimates were adjusted for age, comorbidities, and other confounders.

Results: Among 638 patients, the median (interquartile) age was 57 (44-68) years; 286 (44.8%) patients were treated in the ICU and 42 (6.6%) died during hospitalization. Forty-five percent of cases and 61% of controls were vaccinated, which resulted in an overall VE of 32% (95% CI: 2 to 53%), including 28% (-9% to 52%) against influenza A, and 52% (13% to 74%) against influenza B. VE was higher in adults 18-49 years old (62%; 95% CI: 27% to 81%) than those 50-64 years old (20%, -48% to 57%) and ≥65 years old (-3%; 95% CI: -97% to 46%) (p=0.0789 for interaction). VE was significantly higher against influenza-associated death (80%, 95% CI: 4% to 96%) than non-fatal influenza illness.

Conclusions: During a season with drifted viruses, vaccination reduced severe influenza-associated illness among adults by 32%. VE was high among young adults.
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http://dx.doi.org/10.1093/cid/ciab462DOI Listing
May 2021

Modeling the impacts of clinical influenza testing on influenza vaccine effectiveness estimates.

J Infect Dis 2021 May 20. Epub 2021 May 20.

Influenza Division, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.

Background: Test-negative design studies for evaluating influenza vaccine effectiveness (VE) enroll patients with acute respiratory infection. Enrollment typically occurs before influenza status is determined, resulting in over-enrollment of influenza-negative patients. With availability of rapid and accurate molecular clinical testing, influenza status could be ascertained prior to enrollment, thus improving study efficiency. We estimate potential biases in VE when using clinical testing.

Methods: We simulate data assuming 60% vaccinated, 25% of those vaccinated are influenza positive, and VE of 50%. We show the effect on VE in five scenarios.

Results: VE is affected only when clinical testing preferentially targets patients based on both vaccination and influenza status. VE is overestimated by 10% if non-testing occurs in 39% of vaccinated influenza-positive patients and 24% of others; and if non-testing occurs in 8% of unvaccinated influenza-positive patients and 27% of others. VE is underestimated by 10% if non-testing occurs in 32% of unvaccinated influenza-negative patients and 18% of others.

Conclusions: Although differential clinical testing by vaccine receipt and influenza positivity may produce errors in estimated VE, bias in testing would have to be substantial and overall proportion of patients tested would have to be small to result in a meaningful difference in VE.
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http://dx.doi.org/10.1093/infdis/jiab273DOI Listing
May 2021

Forensic isoscapes based on intra-individual temporal variation of O and Pb/Pb in human teeth.

Forensic Sci Res 2020 Aug 28;6(1):42-52. Epub 2020 Aug 28.

Information Technology Services, Colorado College, Colorado Springs, CO, USA.

Isotopic signatures used in the georeferencing of human remains are largely fixed by spatially distinct geologic and environmental processes. However, location-dependent temporal changes in these isotope ratios should also be considered when determining an individual's provenance and/or trajectory. Distributions of the relevant isotopes can be impacted by predictable external factors such as climate change, delocalisation of food and water sources and changes in sources and uses of metals. Using Multi-Collector Inductively-Coupled Plasma Mass Spectrometer (MC-ICP-MS) analyses of Pb/Pb in tooth enamel and dentin from a population of 21 ± 1-year-old individuals born circa 1984 and isotope ratio mass spectrometry (IRMS) of O in their enamel, we examined the expected influence of some of these factors. The resulting adjustments to the geographic distribution of isotope ratios (isoscapes) found in tooth enamel and dentin may contain additional useful information for forensic identification, but the shifts in values can also impact the uncertainty and usefulness of identifications if they are not taken into account.KEY POINTSIsoscapes of Pb/Pb and O used for geolocation are not static.Within a few years, the enamel and dentin of a person may exhibit measurable differences in Pb/Pb even without changing locations.Changes in climatic patterns tied to rising temperatures are more significant than the direct effect of increasing temperature on O fixed in tooth bioapatite.Third molar (M3) enamel mineralisation includes material incorporated from before formal amelogenesis takes place.
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http://dx.doi.org/10.1080/20961790.2020.1795377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8112828PMC
August 2020

Adults Hospitalized With Coronavirus Disease 2019 (COVID-19)-United States, March-June and October-December 2020: Implications for the Potential Effects of COVID-19 Tier-1 Vaccination on Future Hospitalizations and Outcomes.

Clin Infect Dis 2021 07;73(Suppl 1):S32-S37

CDC COVID-19 Response Team, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.

Background: Because of the increased risk for severe coronavirus disease 2019 (COVID-19), the Advisory Committee on Immunization Practices (ACIP) initially prioritized COVID-19 vaccination for persons in long-term care facilities (LTCF), persons aged ≥65 years, and persons aged 16-64 years with high-risk medical conditions when there is limited vaccine supply. We compared characteristics and severe outcomes of hospitalized patients with COVID-19 in the United States between early and later in the pandemic categorized by groups at higher risk of severe COVID-19.

Methods: Observational study of sampled patients aged ≥18 years who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and admitted to one of 14 academic hospitals in the United States during March-June and October-December 2020. Demographic and clinical information were gathered from electronic health record data.

Results: Among 647 patients, 91% met ≥1 of the following risk factors for severe COVID-19 [91% March-June (n = 434); 90% October-December (n = 213)]; 19% were LTCF residents, 45% were aged ≥65-years, and 84% had ≥1 high-risk condition. The proportion of patients who resided in a LTCF declined significantly (25% vs 6%) from early to later pandemic periods. Compared with patients at lower risk for severe COVID-19, in-hospital mortality was higher among patients at high risk for severe COVID-19 (20% vs 7%); these differences were consistently observed between March-June and October-December.

Conclusions: Most adults hospitalized with COVID-19 were those recommended to be prioritized for vaccination based on risk for developing severe COVID-19. These findings highlight the continued urgency to vaccinate patients at high risk for severe COVID-19 and monitor vaccination impact on hospitalizations and outcomes.
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http://dx.doi.org/10.1093/cid/ciab319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8136001PMC
July 2021

What We Might Find If We Only Looked.

Chest 2021 May;159(5):1715-1716

Critical Care Echocardiography Service, Intermountain Medical Center, and the Division of Pulmonary and Critical Care Medicine, University of Utah, Salt Lake City, UT.

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http://dx.doi.org/10.1016/j.chest.2021.01.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097405PMC
May 2021

Effectiveness of Pfizer-BioNTech and Moderna Vaccines Against COVID-19 Among Hospitalized Adults Aged ≥65 Years - United States, January-March 2021.

MMWR Morb Mortal Wkly Rep 2021 May 7;70(18):674-679. Epub 2021 May 7.

Adults aged ≥65 years are at increased risk for severe outcomes from COVID-19 and were identified as a priority group to receive the first COVID-19 vaccines approved for use under an Emergency Use Authorization (EUA) in the United States (1-3). In an evaluation at 24 hospitals in 14 states,* the effectiveness of partial or full vaccination with Pfizer-BioNTech or Moderna vaccines against COVID-19-associated hospitalization was assessed among adults aged ≥65 years. Among 417 hospitalized adults aged ≥65 years (including 187 case-patients and 230 controls), the median age was 73 years, 48% were female, 73% were non-Hispanic White, 17% were non-Hispanic Black, 6% were Hispanic, and 4% lived in a long-term care facility. Adjusted vaccine effectiveness (VE) against COVID-19-associated hospitalization among adults aged ≥65 years was estimated to be 94% (95% confidence interval [CI] = 49%-99%) for full vaccination and 64% (95% CI = 28%-82%) for partial vaccination. These findings are consistent with efficacy determined from clinical trials in the subgroup of adults aged ≥65 years (4,5). This multisite U.S. evaluation under real-world conditions suggests that vaccination provided protection against COVID-19-associated hospitalization among adults aged ≥65 years. Vaccination is a critical tool for reducing severe COVID-19 in groups at high risk.
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http://dx.doi.org/10.15585/mmwr.mm7018e1DOI Listing
May 2021

Evaluation of potential COVID-19 recurrence in patients with late repeat positive SARS-CoV-2 testing.

PLoS One 2021 4;16(5):e0251214. Epub 2021 May 4.

Division of Pulmonary and Critical Care Medicine, Department of Medicine, Intermountain Healthcare, Salt Lake City, UT, United States of America.

Background: SARS-CoV-2 reinfection and reactivation has mostly been described in case reports. We therefore investigated the epidemiology of recurrent COVID-19 SARS-CoV-2.

Methods: Among patients testing positive for SARS-CoV-2 between March 11 and July 31, 2020 within an integrated healthcare system, we identified patients with a recurrent positive SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR) assay ≥60 days after an initial positive test. To assign an overall likelihood of COVID-19 recurrence, we combined quantitative data from initial and recurrent positive RT-PCR cycle thresholds-a value inversely correlated with viral RNA burden- with a clinical recurrence likelihood assigned based on independent, standardized case review by two physicians. "Probable" or "possible" recurrence by clinical assessment was confirmed as the final recurrence likelihood only if a cycle threshold value obtained ≥60 days after initial testing was lower than its preceding cycle threshold or if the patient had an interval negative RT-PCR.

Results: Among 23,176 patients testing positive for SARS-CoV-2, 1,301 (5.6%) had at least one additional SARS-CoV-2 RT-PCRs assay ≥60 days later. Of 122 testing positive, 114 had sufficient data for evaluation. The median interval to the recurrent positive RT-PCR was 85.5 (IQR 74-107) days. After combining clinical and RT-PCR cycle threshold data, four patients (3.5%) met criteria for probable COVID-19 recurrence. All four exhibited symptoms at recurrence and three required a higher level of medical care compared to their initial diagnosis. After including six additional patients (5.3%) with possible recurrence, recurrence incidence was 4.3 (95% CI 2.1-7.9) cases per 10,000 COVID-19 patients.

Conclusions: Only 0.04% of all COVID-19 patients in our health system experienced probable or possible recurrence; 90% of repeat positive SARS-CoV-2 RT-PCRs were not consistent with true recurrence. Our pragmatic approach combining clinical and quantitative RT-PCR data could aid assessment of COVID-19 reinfection or reactivation by clinicians and public health personnel.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0251214PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096096PMC
May 2021

Isolation and Molecular Characterization of the Romaine Lettuce Phylloplane Mycobiome.

J Fungi (Basel) 2021 Apr 7;7(4). Epub 2021 Apr 7.

Department of Botany and Plant Pathology, Purdue University, West Lafayette, IN 47907, USA.

Romaine lettuce () is an important staple of American agriculture. Unlike many vegetables, romaine lettuce is typically consumed raw. Phylloplane microbes occur naturally on plant leaves; consumption of uncooked leaves includes consumption of phylloplane microbes. Despite this fact, the microbes that naturally occur on produce such as romaine lettuce are for the most part uncharacterized. In this study, we conducted culture-based studies of the fungal romaine lettuce phylloplane community from organic and conventionally grown samples. In addition to an enumeration of all such microbes, we define and provide a discussion of the genera that form the "core" romaine lettuce mycobiome, which represent 85.5% of all obtained isolates: , , , , , , , , , and . We highlight the need for additional mycological expertise in that 23% of species in these core genera appear to be new to science and resolve some taxonomic issues we encountered during our work with new combinations for and . Finally, our work lays the ground for future studies that seek to understand the effect these communities may have on preventing or facilitating establishment of exogenous microbes, such as food spoilage microbes and plant or human pathogens.
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http://dx.doi.org/10.3390/jof7040277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8067711PMC
April 2021

Platelet MHC Class I Mediates CD8+ T Cell Suppression During Sepsis.

Blood 2021 Apr 25. Epub 2021 Apr 25.

Department of Medicine, Division of General Internal Medicine, University of Utah School of Medicine, Salt Lake City, United States.

Circulating platelets interact with leukocytes to modulate host immune and thrombotic responses. In sepsis, platelet-leukocyte interactions are increased, and have been associated with adverse clinical events, including increased platelet-T cell interactions. Sepsis is associated with reduced CD8+ T cell numbers and functional responses, but whether platelets regulate CD8+ T cell responses during sepsis remains unknown. In our current study, we systemically evaluated platelet antigen internalization and presentation through major histocompatibility complex class I (MHC-I) and their effects on antigen specific CD8+ T cells in sepsis in vivo and ex vivo. We discovered that both human and murine platelets internalize and proteolyze exogenous antigens, generating peptides that are loaded onto MHC-I. The expression of platelet MHC-I, but not platelet MHC-II, is significantly increased in human and murine platelets during sepsis and in human megakaryocytes stimulated with agonists generated systemically during sepsis (e.g., IFN-g and LPS). Upregulation of platelet MHC-I during sepsis increases antigen cross-presentation and interactions with CD8+ T cells in an antigen-specific manner. Using a platelet lineage specific MHC-I deficient mouse strain (B2mf/f--Pf4Cre), we demonstrate that platelet MHC-I regulates antigen-specific CD8+ T cell proliferation in vitro, as well as the number and functional responses of CD8+ T cells in vivo during sepsis. Loss of platelet MHC-I reduced sepsis-associated mortality in mice in an antigen specific setting. These data identify a new mechanism by which platelets, through MHC-I, process and cross-present antigens, engage antigen specific CD8+ T cells, and regulate CD8+ T cell number, functional responses, and outcomes during sepsis.
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http://dx.doi.org/10.1182/blood.2020008958DOI Listing
April 2021

Update in COVID-19 2020.

Am J Respir Crit Care Med 2021 06;203(12):1462-1471

Critical Care Medicine Department, NIH, Bethesda, Maryland.

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http://dx.doi.org/10.1164/rccm.202102-0415UPDOI Listing
June 2021

Beyond survival: identifying what matters to survivors of critical illness.

Crit Care 2021 04 6;25(1):129. Epub 2021 Apr 6.

Center for Humanizing Critical Care and Pulmonary Critical Care Medicine, Intermountain Medical Center, Murray, UT, 84107, USA.

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http://dx.doi.org/10.1186/s13054-021-03565-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025480PMC
April 2021

Effect of Early High-Dose Vitamin D3 Repletion on Cognitive Outcomes in Critically Ill Adults.

Chest 2021 Apr 2. Epub 2021 Apr 2.

Department of Emergency Medicine, Vanderbilt University Medical Center, TN.

Background: Long-term cognitive impairment frequently occurs after critical illness; no treatments are known to improve long-term cognition.

Research Question: Does a single high-dose (540,000 International Units) enteral treatment of vitamin D3 given shortly after hospital admission in critically ill patients who are vitamin D deficient improve long-term global cognition or executive function?

Study Design And Methods: This study evaluated long-term cognitive outcomes among patients enrolled in a multicenter, blinded, randomized clinical trial comparing vitamin D3 treatment vs placebo in critically ill adults with vitamin D deficiency. Global cognition was measured by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Executive function was measured with a composite score derived from three Delis-Kaplan Executive Function System subscales. Outcomes were assessed at a median of 443 days (interquartile range, 390-482 days) after randomization and were compared using multivariate proportional odds regression. Adjusted ORs of > 1.0 would indicate better outcomes in the vitamin D3 group compared with the placebo group.

Results: Ninety-five patients were enrolled, including 47 patients randomized to vitamin D3 treatment and 48 patients randomized to placebo. The adjusted median RBANS score at follow-up was 79.6 (95% CI, 73.0-84.0) in the vitamin D3 group and 82.1 (95% CI, 74.7-84.6) in the placebo group (adjusted OR, 0.83; 95% CI, 0.50-1.38). The adjusted median executive function composite scores were 8.1 (95% CI, 6.8-9.0) and 8.7 (95% CI, 7.4-9.3), respectively (adjusted OR, 0.72; 95% CI, 0.36-1.42).

Interpretation: In vitamin D-deficient, critically-ill adults, a large dose of enteral vitamin D3 did not improve long-term global cognition or executive function.

Trial Registry: ClinicalTrials.gov; No.: NCT03733418; URL: www.clinicaltrials.gov.
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http://dx.doi.org/10.1016/j.chest.2021.03.046DOI Listing
April 2021

Decreased Observance of Stroke in the Population Associated With COVID-19 Related Distancing Measures.

Neurohospitalist 2021 Apr 23;11(2):137-140. Epub 2020 Sep 23.

Intermountain Medical Center, Murray, UT, USA.

Stroke is a catastrophic medical disease with roughly 795,000 cases per year in the US. We strove to explore whether stroke admissions to a comprehensive stroke center in an area with moderately-low COVID-19 burden changed and if so, to better define the characteristics of the patients and their presentation. We performed a retrospective analysis of all patients with strokes admitted to Intermountain Medical Center. There was a 43% reduction in patients' presentations across all stroke types compared to average April patient volume over the prior 3 years. Likely this was due to a myriad of complex factors which we may retrospectively be able to more fully understand in the years to come.
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http://dx.doi.org/10.1177/1941874420961207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958674PMC
April 2021

ICU Bed Utilization During the Coronavirus Disease 2019 Pandemic in a Multistate Analysis-March to June 2020.

Crit Care Explor 2021 Mar 12;3(3):e0361. Epub 2021 Mar 12.

University of Colorado School of Medicine, Aurora, CO.

Objectives: Given finite ICU bed capacity, knowledge of ICU bed utilization during the coronavirus disease 2019 pandemic is critical to ensure future strategies for resource allocation and utilization. We sought to examine ICU census trends in relation to ICU bed capacity during the rapid increase in severe coronavirus disease 2019 cases early during the pandemic.

Design: Observational cohort study.

Setting: Thirteen geographically dispersed academic medical centers in the United States.

Patients/subjects: We obtained daily ICU censuses from March 26 to June 30, 2020, as well as prepandemic ICU bed capacities. The primary outcome was daily census of ICU patients stratified by coronavirus disease 2019 and mechanical ventilation status in relation to ICU capacity.

Interventions: None.

Measurements And Main Results: Prepandemic overall ICU capacity ranged from 62 to 225 beds (median 109). During the study period, the median daily coronavirus disease 2019 ICU census per hospital ranged from 1 to 84 patients, and the daily ICU census exceeded overall ICU capacity for at least 1 day at five institutions. The number of critically ill patients exceeded ICU capacity for a median (interquartile range) of 17 (12-50) of 97 days at these five sites. All 13 institutions experienced decreases in their noncoronavirus disease ICU population, whereas local coronavirus disease 2019 cases increased. Coronavirus disease 2019 patients reached their greatest proportion of ICU capacity on April 12, 2020, when they accounted for 44% of ICU patients across all participating hospitals. Maximum ICU census ranged from 52% to 289% of overall ICU capacity, with three sites less than 80%, four sites 80-100%, five sites 100-128%, and one site 289%.

Conclusions: From March to June 2020, the coronavirus disease 2019 pandemic led to ICU censuses greater than ICU bed capacity at fives of 13 institutions evaluated. These findings demonstrate the short-term adaptability of U.S. healthcare institutions in redirecting limited resources to accommodate a public health emergency.
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http://dx.doi.org/10.1097/CCE.0000000000000361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994039PMC
March 2021

Effect of Vitamin C, Thiamine, and Hydrocortisone on Ventilator- and Vasopressor-Free Days in Patients With Sepsis: The VICTAS Randomized Clinical Trial.

JAMA 2021 02;325(8):742-750

Department of Emergency Medicine, Johns Hopkins University, Baltimore, Maryland.

Importance: Sepsis is a common syndrome with substantial morbidity and mortality. A combination of vitamin C, thiamine, and corticosteroids has been proposed as a potential treatment for patients with sepsis.

Objective: To determine whether a combination of vitamin C, thiamine, and hydrocortisone every 6 hours increases ventilator- and vasopressor-free days compared with placebo in patients with sepsis.

Design, Setting, And Participants: Multicenter, randomized, double-blind, adaptive-sample-size, placebo-controlled trial conducted in adult patients with sepsis-induced respiratory and/or cardiovascular dysfunction. Participants were enrolled in the emergency departments or intensive care units at 43 hospitals in the United States between August 2018 and July 2019. After enrollment of 501 participants, funding was withheld, leading to an administrative termination of the trial. All study-related follow-up was completed by January 2020.

Interventions: Participants were randomized to receive intravenous vitamin C (1.5 g), thiamine (100 mg), and hydrocortisone (50 mg) every 6 hours (n = 252) or matching placebo (n = 249) for 96 hours or until discharge from the intensive care unit or death. Participants could be treated with open-label corticosteroids by the clinical team, with study hydrocortisone or matching placebo withheld if the total daily dose was greater or equal to the equivalent of 200 mg of hydrocortisone.

Main Outcomes And Measures: The primary outcome was the number of consecutive ventilator- and vasopressor-free days in the first 30 days following the day of randomization. The key secondary outcome was 30-day mortality.

Results: Among 501 participants randomized (median age, 62 [interquartile range {IQR}, 50-70] years; 46% female; 30% Black; median Acute Physiology and Chronic Health Evaluation II score, 27 [IQR, 20.8-33.0]; median Sequential Organ Failure Assessment score, 9 [IQR, 7-12]), all completed the trial. Open-label corticosteroids were prescribed to 33% and 32% of the intervention and control groups, respectively. Ventilator- and vasopressor-free days were a median of 25 days (IQR, 0-29 days) in the intervention group and 26 days (IQR, 0-28 days) in the placebo group, with a median difference of -1 day (95% CI, -4 to 2 days; P = .85). Thirty-day mortality was 22% in the intervention group and 24% in the placebo group.

Conclusions And Relevance: Among critically ill patients with sepsis, treatment with vitamin C, thiamine, and hydrocortisone, compared with placebo, did not significantly increase ventilator- and vasopressor-free days within 30 days. However, the trial was terminated early for administrative reasons and may have been underpowered to detect a clinically important difference.

Trial Registration: ClinicalTrials.gov Identifier: NCT03509350.
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http://dx.doi.org/10.1001/jama.2020.24505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903252PMC
February 2021

Long-Term Implications of Abnormal Left Ventricular Strain During Sepsis.

Crit Care Med 2021 04;49(4):e444-e453

Division of Pulmonary, Department of Medicine, Intermountain Medical Center, Salt Lake City, UT.

Objectives: Septic cardiomyopathy develops frequently in patients with sepsis and likely increases short-term mortality. However, whether septic cardiomyopathy is associated with long-term outcomes after sepsis is unknown. We investigated whether septic patients with septic cardiomyopathy have worse long-term outcomes than septic patients without septic cardiomyopathy.

Design: Retrospective cohort study.

Setting: Adult ICU.

Patients: Adult ICU patients with sepsis.

Interventions: None.

Measurements And Main Results: Left ventricular global longitudinal systolic strain was our primary measure of septic cardiomyopathy. We employed a suite of multivariable survival analyses to explore linear and nonlinear associations between left ventricular global longitudinal systolic strain and major adverse cardiovascular events, which included death, stroke, and myocardial infarction. Our primary outcome was major adverse cardiovascular event through 24 months after ICU discharge. Among 290 study patients, median left ventricular global longitudinal systolic strain was -16.8% (interquartile range, -20.4% to -12.6%), and 38.3% of patients (n = 111) experienced a major adverse cardiovascular event within 24 months after discharge. On our primary, linear analysis, there was a trend (p = 0.08) toward association between left ventricular global longitudinal systolic strain and major adverse cardiovascular event (odds ratio, 1.03; CI, < 1 to 1.07). On our nonlinear analysis, the association was highly significant (p < 0.001) with both high and low left ventricular global longitudinal systolic strain associated with major adverse cardiovascular event among patients with pre-existing cardiac disease. This association was pronounced among patients who were younger (age < 65 yr) and had Charlson Comorbidity Index greater than 5.

Conclusions: Among patients with sepsis and pre-existing cardiac disease who survived to ICU discharge, left ventricular global longitudinal systolic strain demonstrated a U-shaped association with cardiovascular outcomes through 24 months. The relationship was especially strong among younger patients with more comorbidities. These observations are likely of use to design of future trials.
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http://dx.doi.org/10.1097/CCM.0000000000004886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996634PMC
April 2021

Response to: towards the rational utilization of SARS-CoV-2 serological tests in clinical practice.

Clin Chem Lab Med 2021 05 11;59(6):e227-e229. Epub 2021 Jan 11.

Biochemistry Department, Western Sussex Hospitals NHS Foundation Trust, Worthing, West Sussex, UK.

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http://dx.doi.org/10.1515/cclm-2020-1762DOI Listing
May 2021

Symptoms and recovery among adult outpatients with and without COVID-19 at 11 healthcare facilities-July 2020, United States.

Influenza Other Respir Viruses 2021 05 6;15(3):345-351. Epub 2021 Jan 6.

CDC COVID-19 Response Team, Centers for Disease Control and Prevention (CDC), Atlanta, GA, USA.

Background: Symptoms of mild COVID-19 illness are non-specific and may persist for prolonged periods. Effects on quality of life of persistent poor physical or mental health associated with COVID-19 are not well understood.

Methods: Adults aged ≥18 years with laboratory-confirmed COVID-19 and matched control patients who tested negative for SARS-CoV-2 infection at outpatient facilities associated with 11 medical centers in the United States were interviewed to assess symptoms, illness duration, and health-related quality of life. Duration of symptoms, health-related quality of life measures, and days of poor physical health by symptoms experienced during illness were compared between case patients and controls using Wilcoxon rank-sum tests. Symptoms associated with COVID-19 case status were evaluated by multivariable logistic regression.

Results: Among 320 participants included, 157 were COVID-19 cases and 163 were SARS-CoV-2 negative controls. Loss of taste or smell was reported by 63% of cases and 6% of controls and was strongly associated with COVID-19 in logistic regression models (adjusted odds ratio [aOR] = 32.4; 95% confidence interval [CI], 12.6-83.1). COVID-19 cases were more likely than controls to have experienced fever, body aches, weakness, or fatigue during illness, and to report ≥1 persistent symptom more than 14 days after symptom onset (50% vs 32%, P < .001). Cases reported significantly more days of poor physical health during the past 14 days than controls (P < .01).

Conclusions: Differentiating COVID-19 from other acute illnesses will require widespread diagnostic testing, especially during influenza seasons. Persistent COVID-19-related symptoms may negatively affect quality of life, even among those initially presenting with mild illness.
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http://dx.doi.org/10.1111/irv.12832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8051737PMC
May 2021

A Neutralizing Monoclonal Antibody for Hospitalized Patients with Covid-19.

N Engl J Med 2021 03 22;384(10):905-914. Epub 2020 Dec 22.

From the CHIP Center of Excellence for Health, Immunity, and Infections (J.D.L., D.D.M.), and the Department of Infectious Diseases (J.D.L., D.D.M., J.-U.J.), Rigshospitalet, Copenhagen, the Department of Infectious Diseases, Copenhagen University Hospital, Amager and Hvidovre (T.B.), the Department of Internal Medicine, Respiratory Medicine Section, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup (J.-U.J.), the Department of Infectious Diseases, Odense University Hospital, Odense (I.S.J.), and the Department of Infectious Diseases, Aarhus University Hospital, Skejby (L.Ø.) - all in Denmark; the School of Statistics (B.G.) and the Division of Biostatistics, School of Public Health (T.A.M., C.R., S.S., D.W., J.D.N.), University of Minnesota, Hennepin Healthcare Research Institute (J.V.B.), and the University of Minnesota (J.V.B.), Minneapolis; the Divisions of Pulmonary, Allergy, and Critical Care Medicine (C.E.B.) and Infectious Disease (T.L.H.), Department of Medicine, Duke University, Durham, and the Department of Internal Medicine, Section on Pulmonary, Critical Care, Allergy, and Immunology, Wake Forest School of Medicine, Winston-Salem (D.C.F.) - both in North Carolina; the Center for Advanced Heart and Lung Disease (R.L.G.) and the Division of Infectious Diseases (U.S.), Baylor University Medical Center, and the Department of Internal Medicine, UT Southwestern Medical Center (M.K.J.), Dallas; the Division of Pulmonary and Critical Care Medicine, Intermountain Medical Center, Murray (S.M.B.), and the Department of Internal Medicine, University of Utah (S.M.B., E.S.H.) and Intermountain Healthcare (K.U.K.), Salt Lake City - both in Utah; the Department of Emergency Medicine, Vanderbilt University Medical Center, Nashville (W.H.S.); the Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles (M.E.B.), the Department of Medicine and Anesthesia and the Cardiovascular Research Institute, University of California, San Francisco, San Francisco (M.A.M.), and Gilead Sciences, Foster City (H.C.) - all in California; the Division of Cardiothoracic Surgery, Emory University School of Medicine, Atlanta (B.G.L.); Denver Public Health, Denver Health and Hospital Authority, Denver (E.M.G.), and the Department of Emergency Medicine, University of Colorado School of Medicine, Aurora (A.A.G.); the Department of Infectious Diseases, Henry Ford Hospital, Detroit (N.M.); the Kirby Institute, University of New South Wales (C.C.C., M.N.P.), and St. Vincent's Hospital (M.N.P.), Sydney; the Department of Veterans Affairs (V.J.D.), the Veterans Affairs Medical Center (V.L.K.), and George Washington University School of Medicine and Health Sciences (V.L.K.), Washington, DC; the Medical Research Council Clinical Trials Unit at UCL (A.G., A.G.B., M.K.B.P.), the Institute of Clinical Trials and Methodology (M.K.B.P.), and the Institute for Global Health (A.N.P.), University College London, and Guy's and St. Thomas' NHS Foundation Trust (A.G.), London; the National Institute of Allergy and Infectious Diseases, Bethesda (E.S.H., H.C.L.), and Leidos Biomedical Research, Frederick (R.L.D., M.T.) - both in Maryland; the Infectious Diseases Department and IrsiCaixa AIDS Research Institute, Hospital Universitari Germans Trias i Pujol, Badalona, Spain (R.P.); Eli Lilly, Indianapolis (P.K.); the Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York (A.C.G.); and the Division of Pulmonary and Critical Care, Department of Medicine, Massachusetts General Hospital, and Harvard Medical School, Boston (B.T.T.).

Background: LY-CoV555, a neutralizing monoclonal antibody, has been associated with a decrease in viral load and the frequency of hospitalizations or emergency department visits among outpatients with coronavirus disease 2019 (Covid-19). Data are needed on the effect of this antibody in patients who are hospitalized with Covid-19.

Methods: In this platform trial of therapeutic agents, we randomly assigned hospitalized patients who had Covid-19 without end-organ failure in a 1:1 ratio to receive either LY-CoV555 or matching placebo. In addition, all the patients received high-quality supportive care as background therapy, including the antiviral drug remdesivir and, when indicated, supplemental oxygen and glucocorticoids. LY-CoV555 (at a dose of 7000 mg) or placebo was administered as a single intravenous infusion over a 1-hour period. The primary outcome was a sustained recovery during a 90-day period, as assessed in a time-to-event analysis. An interim futility assessment was performed on the basis of a seven-category ordinal scale for pulmonary function on day 5.

Results: On October 26, 2020, the data and safety monitoring board recommended stopping enrollment for futility after 314 patients (163 in the LY-CoV555 group and 151 in the placebo group) had undergone randomization and infusion. The median interval since the onset of symptoms was 7 days (interquartile range, 5 to 9). At day 5, a total of 81 patients (50%) in the LY-CoV555 group and 81 (54%) in the placebo group were in one of the two most favorable categories of the pulmonary outcome. Across the seven categories, the odds ratio of being in a more favorable category in the LY-CoV555 group than in the placebo group was 0.85 (95% confidence interval [CI], 0.56 to 1.29; P = 0.45). The percentage of patients with the primary safety outcome (a composite of death, serious adverse events, or clinical grade 3 or 4 adverse events through day 5) was similar in the LY-CoV555 group and the placebo group (19% and 14%, respectively; odds ratio, 1.56; 95% CI, 0.78 to 3.10; P = 0.20). The rate ratio for a sustained recovery was 1.06 (95% CI, 0.77 to 1.47).

Conclusions: Monoclonal antibody LY-CoV555, when coadministered with remdesivir, did not demonstrate efficacy among hospitalized patients who had Covid-19 without end-organ failure. (Funded by Operation Warp Speed and others; TICO ClinicalTrials.gov number, NCT04501978.).
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http://dx.doi.org/10.1056/NEJMoa2033130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781100PMC
March 2021

Decline in SARS-CoV-2 Antibodies After Mild Infection Among Frontline Health Care Personnel in a Multistate Hospital Network - 12 States, April-August 2020.

MMWR Morb Mortal Wkly Rep 2020 Nov 27;69(47):1762-1766. Epub 2020 Nov 27.

Most persons infected with SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), develop virus-specific antibodies within several weeks, but antibody titers might decline over time. Understanding the timeline of antibody decline is important for interpreting SARS-CoV-2 serology results. Serum specimens were collected from a convenience sample of frontline health care personnel at 13 hospitals and tested for antibodies to SARS-CoV-2 during April 3-June 19, 2020, and again approximately 60 days later to assess this timeline. The percentage of participants who experienced seroreversion, defined as an antibody signal-to-threshold ratio >1.0 at baseline and <1.0 at the follow-up visit, was assessed. Overall, 194 (6.0%) of 3,248 participants had detectable antibodies to SARS-CoV-2 at baseline (1). Upon repeat testing approximately 60 days later (range = 50-91 days), 146 (93.6%) of 156 participants experienced a decline in antibody response indicated by a lower signal-to-threshold ratio at the follow-up visit, compared with the baseline visit, and 44 (28.2%) experienced seroreversion. Participants with higher initial antibody responses were more likely to have antibodies detected at the follow-up test than were those who had a lower initial antibody response. Whether decay in these antibodies increases risk for reinfection and disease remains unanswered. However, these results suggest that serology testing at a single time point is likely to underestimate the number of persons with previous SARS-CoV-2 infection, and a negative serologic test result might not reliably exclude prior infection.
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http://dx.doi.org/10.15585/mmwr.mm6947a2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727600PMC
November 2020

At the X-Roads of Sex and Genetics in Pulmonary Arterial Hypertension.

Genes (Basel) 2020 11 20;11(11). Epub 2020 Nov 20.

Division of Pulmonary, Critical Care and Occupational Medicine, University of Utah, Salt Lake City, UT 84132, USA.

Group 1 pulmonary hypertension (pulmonary arterial hypertension; PAH) is a rare disease characterized by remodeling of the small pulmonary arteries leading to progressive elevation of pulmonary vascular resistance, ultimately leading to right ventricular failure and death. Deleterious mutations in the serine-threonine receptor bone morphogenetic protein receptor 2 (; a central mediator of bone morphogenetic protein (BMP) signaling) and female sex are known risk factors for the development of PAH in humans. In this narrative review, we explore the complex interplay between the BMP and estrogen signaling pathways, and the potentially synergistic mechanisms by which these signaling cascades increase the risk of developing PAH. A comprehensive understanding of these tangled pathways may reveal therapeutic targets to prevent or slow the progression of PAH.
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http://dx.doi.org/10.3390/genes11111371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699559PMC
November 2020

Design and implementation of the multi-arm, multi-stage Therapeutics for Inpatients with COVID-19 (TICO) platform master protocol: An Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) initiative.

medRxiv 2020 Nov 12. Epub 2020 Nov 12.

CHIP Centre of Excellence for Health, Immunity, and Infections, Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark.

Background: The SARS-CoV-2 pandemic is a public health emergency. Safe and effective therapies are urgently needed.

Methods: Therapeutics for Inpatients with COVID-19 (TICO), is a global multi-arm, multi-stage (MAMS) platform master protocol, which facilitates the rapid evaluation of the safety and efficacy of candidate anti-viral therapeutic agents for adults hospitalized with COVID-19. The protocol design allows multiple therapeutic agents to be evaluated in an efficient and scientifically rigorous manner, with efficiencies delivered by the MAMS design, and began by studying neutralizing monoclonal antibodies. TICO employs an agile and robust approach to futility and safety evaluation at 300 patients enrolled (Stage 1), with subsequent expansion to full sample size and an expanded target population (Stage 2) if the agent shows an acceptable safety profile and evidence of efficacy. Two ordinal outcomes applied early (Day 5) determine the efficacy signals of the investigational agents(s) and progression to Stage 2. These ordinal outcomes assess both respiratory and other organ failure events, recognizing the broad range of COVID-19 morbidity. In Stage 2, overall efficacy is assessed using the primary outcome of 'time to sustained recovery' assessed over 90 days. This approach to early futility assessment using an early intermediate outcome and a primary endpoint out to 90 days allows the study team to make rapid decisions on safety and potential efficacy of novel agents while ultimately focusing on patient-centered, longer-term outcomes. The implementation of TICO across a global network allows for continued enrollment despite variations in geographic epidemiology.

Study Status: The TICO master protocol moved from conception to first patient enrolled in approximately 9 weeks, a testament to the expedited regulatory and ethics review, coupled with flexible and responsive study operations. The first agent to be tested using this protocol, LY-CoV-555, enrolled N=326 participants before undergoing Stage 1 futility and safety assessment. Two additional agents will enter the study in November 2020, with other agents planned.

Conclusion: The TICO MAMS platform trial has been implemented efficiently across a global network of sites and several trial networks. It will generate results rapidly for multiple novel neutralizing monoclonal antibodies and other therapeutics agents.
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http://dx.doi.org/10.1101/2020.11.08.20227876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675662PMC
November 2020

Hydroxychloroquine vs. Azithromycin for Hospitalized Patients with COVID-19 (HAHPS): Results of a Randomized, Active Comparator Trial.

Ann Am Thorac Soc 2020 Nov 9. Epub 2020 Nov 9.

University of Utah School of Medicine, 12348, Study Design and Biostatistics Center and Division of Epidemiology, Salt Lake City, Utah, United States.

Rationale: The COVID-19 pandemic struck an immunologically naïve, globally interconnected population. In the face of a new infectious agent causing acute respiratory failure for which there were no known effective therapies, rapid, often pragmatic trials were necessary to evaluate potential treatments, frequently starting with medications that are already marketed for other indications. Early in the pandemic, hydroxychloroquine and azithromycin were two such candidates.

Objective: Assess the relative efficacy of hydroxychloroquine and azithromycin among hospitalized patients with COVID-19.

Methods: We performed a randomized clinical trial of hydroxychloroquine vs. azithromycin among hospitalized patients with COVID-19. Treatment was 5 days of study medication. The primary endpoint was the COVID Ordinal Outcomes scale at day 14. Secondary endpoints included hospital-, ICU-, and ventilator-free days at day 28. The trial was stopped early after enrollment of 85 patients when a separate clinical trial concluded that a clinically important effect of hydroxychloroquine over placebo was definitively excluded. Comparisons were made a priori using a proportional odds model from a Bayesian perspective.

Results: We enrolled 85 patients at 13 hospitals over 11 weeks. Adherence to study medication was high. The estimated odds ratio for less favorable status on the ordinal scale for hydroxychloroquine vs. azithromycin from the primary analysis was 1.07, with a 95% credible interval from 0.63 to 1.83 with a posterior probability of 60% that hydroxychloroquine was worse than azithryomycin. Secondary outcomes displayed a similar, slight preference for azithromycin over hydroxychloroquine. QTc prolongation was rare and did not differ between groups. The twenty safety outcomes were similar between arms with the possible exception of post-randomization onset acute kidney injury, which was more common with hydroxychloroquine (15% vs. 0%). Patients in the hydroxychloroquine arm received remdesivir more often than in the azithromycin arm (19% vs. 2%). There was no apparent association between remdesivir use and acute kidney injury.

Conclusions: While early termination limits the precision of our results, we found no suggestion of substantial efficacy for hydroxychloroquine over azithromycin. Acute kidney injury may be more common with hydroxychloroquine than azithromycin, although this may be due to the play of chance. Differential use of remdesivir may have biased our results in favor of hydroxychloroquine. Our results are consistent with conclusions from other trials that hydroxychloroquine cannot be recommended for inpatients with COVID-19; azithromycin may merit additional investigation.

Clinical Trial Registration: This trial was prospectively registered (NCT04329832) before enrollment of the first patient.
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http://dx.doi.org/10.1513/AnnalsATS.202008-940OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009003PMC
November 2020

Effect of Hydroxychloroquine on Clinical Status at 14 Days in Hospitalized Patients With COVID-19: A Randomized Clinical Trial.

JAMA 2020 12;324(21):2165-2176

Department of Emergency Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.

Importance: Data on the efficacy of hydroxychloroquine for the treatment of coronavirus disease 2019 (COVID-19) are needed.

Objective: To determine whether hydroxychloroquine is an efficacious treatment for adults hospitalized with COVID-19.

Design, Setting, And Participants: This was a multicenter, blinded, placebo-controlled randomized trial conducted at 34 hospitals in the US. Adults hospitalized with respiratory symptoms from severe acute respiratory syndrome coronavirus 2 infection were enrolled between April 2 and June 19, 2020, with the last outcome assessment on July 17, 2020. The planned sample size was 510 patients, with interim analyses planned after every 102 patients were enrolled. The trial was stopped at the fourth interim analysis for futility with a sample size of 479 patients.

Interventions: Patients were randomly assigned to hydroxychloroquine (400 mg twice daily for 2 doses, then 200 mg twice daily for 8 doses) (n = 242) or placebo (n = 237).

Main Outcomes And Measures: The primary outcome was clinical status 14 days after randomization as assessed with a 7-category ordinal scale ranging from 1 (death) to 7 (discharged from the hospital and able to perform normal activities). The primary outcome was analyzed with a multivariable proportional odds model, with an adjusted odds ratio (aOR) greater than 1.0 indicating more favorable outcomes with hydroxychloroquine than placebo. The trial included 12 secondary outcomes, including 28-day mortality.

Results: Among 479 patients who were randomized (median age, 57 years; 44.3% female; 37.2% Hispanic/Latinx; 23.4% Black; 20.1% in the intensive care unit; 46.8% receiving supplemental oxygen without positive pressure; 11.5% receiving noninvasive ventilation or nasal high-flow oxygen; and 6.7% receiving invasive mechanical ventilation or extracorporeal membrane oxygenation), 433 (90.4%) completed the primary outcome assessment at 14 days and the remainder had clinical status imputed. The median duration of symptoms prior to randomization was 5 days (interquartile range [IQR], 3 to 7 days). Clinical status on the ordinal outcome scale at 14 days did not significantly differ between the hydroxychloroquine and placebo groups (median [IQR] score, 6 [4-7] vs 6 [4-7]; aOR, 1.02 [95% CI, 0.73 to 1.42]). None of the 12 secondary outcomes were significantly different between groups. At 28 days after randomization, 25 of 241 patients (10.4%) in the hydroxychloroquine group and 25 of 236 (10.6%) in the placebo group had died (absolute difference, -0.2% [95% CI, -5.7% to 5.3%]; aOR, 1.07 [95% CI, 0.54 to 2.09]).

Conclusions And Relevance: Among adults hospitalized with respiratory illness from COVID-19, treatment with hydroxychloroquine, compared with placebo, did not significantly improve clinical status at day 14. These findings do not support the use of hydroxychloroquine for treatment of COVID-19 among hospitalized adults.

Trial Registration: ClinicalTrials.gov: NCT04332991.
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http://dx.doi.org/10.1001/jama.2020.22240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653542PMC
December 2020