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A randomized, double-blind, placebo-controlled clinical trial was conducted to investigate the efficacy of infliximab, abatacept, and cenicriviroc in treating patients hospitalized with COVID-19. The patient's clinical status was assessed daily on an 8-point ordinal scale. We evaluated the totality of evidence on the efficacy of the 3 immunomodulators by considering all possible changes in the clinical status of each patient over time. We demonstrated that infliximab accelerated improvement and reduced deterioration of clinical status when added to standard of care. There was also evidence for the benefit of abatacept. There was no evidence for the benefit of cenicriviroc., Competing Interests: Declaration of competing interest Lin: Nothing to report. Wang: Nothing to report. Anstrom: Research grants from Merck, Bayer, NIH, and Pfizer. LaVange: Nothing to report. Wen: Nothing to report. Bozzette: Employee of NIH. Powderly: Research grants from National Center for Advancing Translational Sciences; personal fees from Merck Laboratories., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Several antiretroviral therapy (ART) medications have been associated with increased cardiovascular risk, but less is known about the safety of modern ART. We sought to compare the risk of major adverse cardiac events (MACEs) among different ART regimens., Methods: Using insurance claims databases from 2008 to 2020, we identified adults aged <65 years who newly initiated ART. We compared non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens to protease inhibitors (PI)- and integrase inhibitors (INSTI)-based regimens. We used propensity score-weighted Kaplan-Meier functions to estimate the 6, 12, 18, 24, 36, and 48 months' risk and risk differences (RD) of MACE., Results: Among 37 935 ART initiators (median age, 40 years; 23% female; 26% Medicaid-insured), 45% started INSTI-, 16% PI-, and 39% NNRTI-based regimens. MACE occurred in 418 individuals (1.1%) within 48 months after ART initiation. Compared to NNRTI initiators, the risk of MACE was higher at 12 months (RD, 0.50; 95% CI, 0.14-0.99), 18 months (RD, 0.53; 95% CI, 0.11-1.06), and 24 months (RD, 0.62; 95% CI, 0.04-1.29) for PI initiators, and at 12 (RD, 0.20; 95% CI, 0.03-0.37) and 18 months (RD, 0.31; 95% CI, 0.06-0.54) for INSTI initiators; the precision of estimates was limited for longer duration of follow-up., Conclusions: Among ART initiators, PI-based and INSTI-based regimens were associated with higher short-term risk of MACE compared to NNRTI-based regimens. The pattern of association between INSTIs and PIs with excess risk of MACE was similar., Competing Interests: Potential conflicts of interest. J.A.O. reports receiving investigator-initiated funds from Janssen Scientific for work unrelated to this study. M.A.O. reports consulting fees from Pfizer for work unrelated to this study. A.M.B. reports receiving investigator-initiated funds from Merck. All other authors report no potential conflicts., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Importance: The pharmacokinetics of abatacept and the association between abatacept exposure and outcomes in patients with severe COVID-19 are unknown., Objective: To characterize abatacept pharmacokinetics, relate drug exposure with clinical outcomes, and evaluate the need for dosage adjustments., Design, Setting, and Participants: This study is a secondary analysis of data from the ACTIV-1 (Accelerating COVID-19 Therapeutic Interventions and Vaccines) Immune Modulator (IM) randomized clinical trial conducted between October 16, 2020, and December 31, 2021. The trial included hospitalized adults who received abatacept in addition to standard of care for treatment of COVID-19 pneumonia. Data analysis was performed between September 2022 and February 2024., Exposure: Single intravenous infusion of abatacept (10 mg/kg with a maximum dose of 1000 mg)., Main Outcomes and Measures: Mortality at day 28 was the primary outcome of interest, and time to recovery at day 28 was the secondary outcome. Drug exposure was assessed using the projected area under the serum concentration time curve over 28 days (AUC0-28). Logistic regression modeling was used to analyze the association between drug exposure and 28-day mortality, adjusted for age, sex, and disease severity. The association between time to recovery and abatacept exposure was examined using Fine-Gray modeling with death as a competing risk, and was adjusted for age, sex, and disease severity., Results: Of the 509 patients who received abatacept, 395 patients with 848 serum samples were included in the population pharmacokinetic analysis. Their median age was 55 (range, 19-89) years and most (250 [63.3%]) were men. Abatacept clearance increased with body weight and more severe disease activity at baseline. Drug exposure was higher in patients who survived vs those who died, with a median AUC0-28 of 21 428 (range, 8462-43 378) mg × h/L vs 18 262 (range, 9628-27 507) mg × h/L (P < .001). Controlling for age, sex, and disease severity, an increase of 5000 units in AUC0-28 was associated with lower odds of mortality at day 28 (OR, 0.52 [95% CI, 0.35-0.79]; P = .002). For an AUC0-28 of 19 400 mg × h/L or less, there was a higher probability of recovery at day 28 (hazard ratio, 2.63 [95% CI, 1.70-4.08] for every 5000-unit increase; P < .001). Controlling for age, sex, and disease severity, every 5000-unit increase in AUC0-28 was also associated with lower odds of a composite safety event at 28 days (OR, 0.46 [95% CI, 0.33-0.63]; P < .001). Using the dosing regimen studied in the ACTIV-1 IM trial, 121 of the 395 patients (30.6%) would not achieve an abatacept exposure of at least 19 400 mg × h/L, particularly at the extremes of body weight. Using a modified, higher-dose regimen, only 12 patients (3.0%) would not achieve the hypothesized target abatacept exposure., Conclusions and Relevance: In this study, patients who were hospitalized with severe COVID-19 and achieved higher projected abatacept exposure had reduced mortality and a higher probability of recovery with fewer safety events. However, abatacept clearance was high in this population, and the current abatacept dosing (10 mg/kg intravenously with a maximum of 1000 mg) may not achieve optimal exposure in all patients., Trial Registration: ClinicalTrials.gov Identifier: NCT04593940.

CD4 cell count at entry into human immunodeficiency virus (HIV) care is a useful indicator of success of multiple steps in HIV public health programming. We demonstrate that CD4 cell count at care initiation was stable in St Louis between 2017 and 2019 but declined in 2020. Missouri efforts in the Ending the HIV Epidemic plan should focus on rapidly identifying individuals with undiagnosed HIV infection., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Prior randomized clinical trials have reported benefit of fluvoxamine ≥200 mg/d vs placebo for patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)., Methods: This randomized, double-blind, placebo-controlled, fully remote multisite clinical trial evaluated whether fluvoxamine prevents clinical deterioration in higher-risk outpatients with acute coronavirus disease 2019 (COVID-19). Between December 2020 and May 2021, nonhospitalized US and Canadian participants with confirmed symptomatic infection received fluvoxamine (50 mg on day 1, 100 mg twice daily thereafter) or placebo for 15 days. The primary modified intent-to-treat (mITT) population included participants who started the intervention within 7 days of symptom onset with a baseline oxygen saturation ≥92%. The primary outcome was clinical deterioration within 15 days of randomization, defined as having both (1) shortness of breath (severity ≥4 on a 0-10 scale or requiring hospitalization) and (2) oxygen saturation <92% on room air or need for supplemental oxygen., Results: A total of 547 participants were randomized and met mITT criteria (n = 272 fluvoxamine, n = 275 placebo). The Data Safety Monitoring Board recommended stopping early for futility related to lower-than-predicted event rates and declining accrual concurrent with vaccine availability in the United States and Canada. Clinical deterioration occurred in 13 (4.8%) participants in the fluvoxamine group and 15 (5.5%) participants in the placebo group (absolute difference at day 15, 0.68%; 95% CI, -3.0% to 4.4%; log-rank P = .91)., Conclusions: This trial did not find fluvoxamine efficacious in preventing clinical deterioration in unvaccinated outpatients with symptomatic COVID-19. It was stopped early and underpowered due to low primary outcome rates., Clinical Trials Registration: ClinicalTrials.gov Identifier: NCT04668950., Competing Interests: Potential conflicts of interest. A.M.R. and E.J.L. are listed on a patent application that includes use of sigma-1 receptor agonists for treatment of COVID-19. C.F.Z. is on the Scientific Advisory Board of Sage Therapeutics and has stock in the company. Sage was not involved in any of this work. R.B.I. consulted for SeaGen, AbbVie, and Resverlogix and received research support through her institution from Novartis and Ascentage unrelated to this research. R.H. serves on a data safety and monitoring board for Astellas Pharmaceuticals unrelated to the current work. E.J.L. consulted for Prodeo, Merck, IngenioRx, Boehringer-Ingelheim, and Pritikin ICR and received research support through his institution from Janssen and PCORI. T.R.G. consulted for Pritikin ICR. J.T.R. has received funding for schizophrenia trials unrelated to this work. M.W.R. receives support from the NIH, but none of these grants are relevant to the current study. All other authors report no potential conflicts., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

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

Background: The dimorphic mycoses (DMs) of the United States-Histoplasma, Coccidioides, and Blastomyces-commonly known as endemic mycoses of North America (in addition to Paracoccidioides) are increasingly being diagnosed outside their historical areas of endemicity. Despite this trend, the maps outlining their geographic distributions have not been updated in more than half a century using a large, nationwide database containing individual-patient-level data., Methods: This was a retrospective analysis of >45 million Medicare fee-for-service beneficiaries from 1 January 2007 through 31 December 2016. Diagnoses of histoplasmosis, coccidioidomycosis, and blastomycosis were defined by International Classification of Diseases, Ninth/10th Revision, codes. The primary outcome was the incidence of histoplasmosis, coccidioidomycosis, and blastomycosis for each US county. Clinically meaningful thresholds for incidence were defined as 100 cases/100 000 person-years for histoplasmosis and coccidioidomycosis and 50 cases/100 000 person-years for blastomycosis., Results: There were 79 749 histoplasmosis, 37 726 coccidioidomycosis, and 6109 blastomycosis diagnoses in unique persons from 2007-2016 across 3143 US counties. Considering all US states plus Washington, DC, 94% (48/51) had ≥1 county above the clinically relevant threshold for histoplasmosis, 69% (35/51) for coccidioidomycosis, and 78% (40/51) for blastomycosis., Conclusions: Persons with histoplasmosis, coccidioidomycosis, and blastomycosis are diagnosed in significant numbers outside their historical geographic distributions established >50 years ago. Clinicians should consider DM diagnoses based on compatible clinical syndromes with less emphasis placed on patients' geographic exposure. Increased clinical suspicion leading to a subsequent increase in DM diagnostic testing would likely result in fewer missed diagnoses, fewer diagnostic delays, and improved patient outcomes., Competing Interests: Potential conflicts of interest. M. A. O. reports grants, consulting fees, and personal fees from Pfizer. W. G. P. reports grants and personal fees from Merck and Co and the National Institutes of Health (not directly related to this work) and personal fees from Gilead Sciences. A. S. reports grants from Astellas Global Development Pharma, Inc; grants from Scynexis; grants from Cidara; and grants and personal fees from Mayne Pharma. A. C.-R. reports grants or contracts from the Metabolic Skeletal Disorders Training Grant through the National Institute of Arthritis and Musculoskeletal and Skin Diseases (T32AR060719; funding for author PhD stipend 2020–2022 through the Washington University School of Medicine) and support for attending the Cold Spring Harbor Laboratory Mechanisms of Aging Meeting 2022 (Division of Bone and Mineral Diseases, Washington University in St Louis). M. P. reports consulting fees from Clinton Health Access Initiative (external consulting as web developer). All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

COVID-19 disproportionately affects persons with HIV (PWH) in worldwide locations with limited access to SARS-CoV-2 vaccines. PWH exhibit impaired immune responses to some, but not all, vaccines. Lymph node (LN) biopsies from PWH demonstrate abnormal LN structure, including dysregulated germinal center (GC) architecture. It is not clear whether LN dysregulation prevents PWH from mounting Ag-specific GC responses in the draining LN following vaccination. To address this issue, we longitudinally collected blood and draining LN fine needle aspiration samples before and after SARS-CoV-2 vaccination from a prospective, observational cohort of 11 PWH on antiretroviral therapy: 2 who received a two-dose mRNA vaccine series and 9 who received a single dose of the Ad26.COV2.S vaccine. Following vaccination, we observed spike-specific Abs, spike-specific B and T cells in the blood, and spike-specific GC B cell and T follicular helper cell responses in the LN of both mRNA vaccine recipients. We detected spike-specific Abs in the blood of all Ad26.COV2.S recipients, and one of six sampled Ad26.COV2.S recipients developed a detectable spike-specific GC B and T follicular helper cell response in the draining LN. Our data show that PWH can mount Ag-specific GC immune responses in the draining LN following SARS-CoV-2 vaccination. Due to the small and diverse nature of this cohort and the limited number of available controls, we are unable to elucidate all potential factors contributing to the infrequent vaccine-induced GC response observed in the Ad26.COV2.S recipients. Our preliminary findings suggest this is a necessary area of future research., (Copyright © 2023 by The American Association of Immunologists, Inc.)

Background: Integrase strand transfer inhibitors (INSTIs) are associated with weight gain in people with HIV (PWH). Less is known about the risk of other metabolic outcomes such as diabetes mellitus and hyperglycemia., Methods: IBM® MarketScan® databases for commercially and Medicaid-insured adults were used to identify PWH newly initiating antiretroviral therapy (ART). The primary outcome was a composite of new-onset diabetes mellitus/hyperglycemia in the 6 months following ART initiation and was identified using International Classification of Disease, Ninth revision, Clinical Modification (ICD-9-CM) and ICD-10-CM diagnosis and procedure codes and Current Procedural Terminology, 4th Edition (CPT-4) codes. To examine the relationship between INSTI use and the composite outcome, we estimated the risk using Cox proportional hazards models with calendar time-specific standardized mortality ratio weights., Results: Of 42 382 PWH who initiated ART between 1 July 2007 and 30 June 2018, 22 762 (54%) were treated with INSTI-based regimens. Mean age was 38 years, 74% were male, and 19% were Medicaid insured. PWH on INSTIs were 31% more likely to develop new-onset diabetes mellitus/hyperglycemia (hazard ratio [HR], 1.31; 95% confidence interval [CI], 1.15-1.48]) compared with those who initiated non-INSTI-based regimens. When examined individually, the highest risk was associated with elvitegravir (HR, 1.54; 95% CI, 1.32-1.97; P < .001) and the lowest risk with raltegravir (HR, 1.19; 95% CI, 1.03-1.37; P = .02)., Conclusions: INSTI use was associated with increased risk of new-onset diabetes mellitus/hyperglycemia in the 6 months following ART initiation., Competing Interests: Potential conflicts of interest . J. A. O. reports grants from Janssen. A. M. B. reports grants from Merck & Co. M. A. O. reports grants and personal fees from Pfizer. W. G. P. reports grants and personal fees from Merck & Co. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: This study quantifies the mortality attributable to Candida bloodstream infections (BSI) in the modern era of echinocandins., Methods: We conducted a retrospective cohort study of adult patients admitted to Barnes Jewish Hospital, a 1368-bed tertiary care academic hospital, in Saint Louis, Missouri, from 1 February 2012 to 30 April 2019. We identified 626 adult patients with Candida BSI that were frequency-matched with 6269 control patients that had similar Candida BSI risk-factors. The 90-day all-cause mortality attributable to Candida BSI was calculated using three methods-propensity score matching, matching by inverse weighting of propensity score, and stratified analysis by quintile., Results: The 90-day crude mortality was 42.4% (269 patients) for Candida BSI cases and 17.1% (1083 patients) for frequency-matched controls. Following propensity score-matching, the attributable risk difference for 90-day mortality was 28.4% with hazard ratio (HR) of 2.12 (95% confidence interval [CI], 1.98-2.25, P < .001). In the stratified analysis, the risk for mortality at 90 days was highest in patients in the lowest risk quintile to develop Candida BSI (hazard ratio [HR] 3.13 (95% CI, 2.33-4.19). Patients in this lowest risk quintile accounted for 81(61%) of the 130 untreated patients with Candida BSI. Sixty-nine percent of untreated patients (57/83) died versus 35% of (49/127) of treated patients (P < .001)., Conclusions: Patients with Candida BSI continue to experience high mortality. Mortality attributable to Candida BSI was more pronounced in patients at lowest risk to develop Candida BSI. A higher proportion of these low-risk patients went untreated, experienced higher mortality, and should be the target of aggressive interventions to ensure timely, effective treatment., Competing Interests: Potential conflicts of interest. M. O. reports grants and personal fees from Pfizer, grants from Merck and Sanofi. D. S. reports personal stock ownership in AbbVie, Inc. and Bristol-Myers Squibb. W. P. reports grants and personal fees from Merck and Co, personal fees from Gilead Sciences. A. S. reports grants from Astellas Global Development Pharma, Inc., grants and personal fees from Scynexis, grants from Cidara, grants from Mayne Pharma. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Fluconazole is recommended as first-line therapy for candidemia when risk of fluconazole resistance (fluc-R) is low. Lack of methods to estimate resistance risk results in extended use of echinocandins and prolonged hospitalization. This study aimed to develop a clinical predictive model to identify patients at low risk for fluc-R where initial or early step-down fluconazole would be appropriate., Methods: Retrospective analysis of hospitalized adult patients with positive blood culture for Candida spp from 2013 to 2019. Multivariable logistic regression model was performed to identify factors associated with fluc-R. Stepwise regression was performed on bootstrapped samples to test individual variable stability and estimate confidence intervals (CIs). We used receiver operating characteristic curves to assess performance across the probability spectrum., Results: We identified 539 adults with candidemia and 72 Candida isolates (13.4%) were fluc-R. Increased risk of fluc-R was associated with older age, prior bacterial bloodstream infection (odds ratio [OR], 2.02 [95% CI, 1.13-3.63]), myelodysplastic syndrome (OR, 3.09 [95% CI, 1.13-8.44]), receipt of azole therapy (OR, 5.42 [95% CI, 2.90-10.1]) within 1 year of index blood culture, and history of bone marrow or stem cell transplant (OR, 2.81 [95% CI, 1.41-5.63]). The model had good discrimination (optimism-corrected c-statistic 0.771), and all of the selected variables were stable. The prediction model had a negative predictive value of 95.7% for the selected sensitivity cutoff of 90.3%., Conclusions: This model is a potential tool for identifying patients at low risk for fluc-R candidemia to receive first-line or early step-down fluconazole., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Equity in vaccination coverage is a cornerstone for a successful public health response to COVID-19. To deepen understanding of the extent to which vaccination coverage compares with initial strategies for equitable vaccination, we explore primary vaccine series and booster rollout over time and by race/ethnicity, social vulnerability, and geography., Methods and Findings: We analyzed data from the Missouri Department of Health and Senior Services on all COVID-19 vaccinations administered across 7 counties in the St. Louis region and 4 counties in the Kansas City region. We compared rates of receiving the primary COVID-19 vaccine series and boosters relative to time, race/ethnicity, zip-code-level Social Vulnerability Index (SVI), vaccine location type, and COVID-19 disease burden. We adapted a well-established tool for measuring inequity-the Lorenz curve-to quantify inequities in COVID-19 vaccination relative to these key metrics. Between 15 December 2020 and 15 February 2022, 1,763,036 individuals completed the primary series and 872,324 received a booster. During early phases of the primary series rollout, Black and Hispanic individuals from high SVI zip codes were vaccinated at less than half the rate of White individuals from low SVI zip codes, but rates increased over time until they were higher than rates in White individuals after June 2021; Asian individuals maintained high levels of vaccination throughout. Increasing vaccination rates in Black and Hispanic communities corresponded with periods when more vaccinations were offered at small community-based sites such as pharmacies rather than larger health systems and mass vaccination sites. Using Lorenz curves, zip codes in the quartile with the lowest rates of primary series completion accounted for 19.3%, 18.1%, 10.8%, and 8.8% of vaccinations while representing 25% of the total population, cases, deaths, or population-level SVI, respectively. When tracking Gini coefficients, these disparities were greatest earlier during rollout, but improvements were slow and modest and vaccine disparities remained across all metrics even after 1 year. Patterns of disparities for boosters were similar but often of much greater magnitude during rollout in fall 2021. Study limitations include inherent limitations in the vaccine registry dataset such as missing and misclassified race/ethnicity and zip code variables and potential changes in zip code population sizes since census enumeration., Conclusions: Inequities in the initial COVID-19 vaccination and booster rollout in 2 large US metropolitan areas were apparent across racial/ethnic communities, across levels of social vulnerability, over time, and across types of vaccination administration sites. Disparities in receipt of the primary vaccine series attenuated over time during a period in which sites of vaccination administration diversified, but were recapitulated during booster rollout. These findings highlight how public health strategies from the outset must directly target these deeply embedded structural and systemic determinants of disparities and track equity metrics over time to avoid perpetuating inequities in healthcare access., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: EHG is a member of PLOS Medicine’s Editorial Board. All other authors have declared no competing interests.

Background: The true prevalence of COVID-19 is difficult to estimate due to the absence of random population-based testing. To estimate current and past COVID-19 infection prevalence in a large urban area, we conducted a population-based survey in St. Louis County, Missouri., Methods: The population-based survey of active infection (PCR) and seroprevalence (IgG antibodies) of adults (≥18 years) was conducted through random-digit dialing and targeted sampling of St. Louis County residents with oversampling of Black residents. Infection prevalence of residents was estimated using design-based and raking weighting., Results: Between August 17 and October 24, 2020, 1245 residents completed a survey and underwent PCR testing; 1073 residents completed a survey and underwent PCR and IgG testing or self-reported results. Weighted prevalence estimates of residents with active infection were 1.9% (95% CI, 0.4%-3.3%) and 5.6% were ever infected (95% CI, 3.3%-8.0%). Overall infection hospitalization and fatality ratios were 4.9% and 1.4%, respectively., Conclusions: Through October 2020, the percentage of residents that had ever been infected was relatively low. A markedly higher percentage of Black and other minorities compared to White residents were infected with COVID-19. The St. Louis region remained highly vulnerable to widespread infection in late 2020., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Coronavirus Disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has created a global pandemic infecting over 230 million people and costing millions of lives. Therapies to attenuate severe disease are desperately needed. Cenicriviroc (CVC), a C-C chemokine receptor type 5 (CCR5) and C-C chemokine receptor type 2 (CCR2) antagonist, an agent previously studied in advanced clinical trials for patients with HIV or nonalcoholic steatohepatitis (NASH), may have the potential to reduce respiratory and cardiovascular organ failures related to COVID-19. Inhibiting the CCR2 and CCR5 pathways could attenuate or prevent inflammation or fibrosis in both early and late stages of the disease and improve outcomes of COVID-19. Clinical trials using CVC either in addition to standard of care (SoC; e.g., dexamethasone) or in combination with other investigational agents in patients with COVID-19 are currently ongoing. These trials intend to leverage the anti-inflammatory actions of CVC for ameliorating the clinical course of COVID-19 and prevent complications. This article reviews the literature surrounding the CCR2 and CCR5 pathways, their proposed role in COVID-19, and the potential role of CVC to improve outcomes., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: TF received an unrestricted research grant from Allergan/AbbVie to support the Charité trial of CVC in COVID-19, institutional research funding from Allergan, BMS, Inventiva, Gilead, and consulting fees and honoraria for lectures from Allergan, Bayer, Gilead, BMS, Boehringer, Intercept, Ionis, Inventiva, Merz, Pfizer, Alnylam, NGM, CSL Behring, Novo Nordisk, Novartis, AbbVie, Falk, and Merz. WGP is the principal investigator in the ACTIV-1 clinical trial, he receives funding from the NIH unrelated to this work and has received grants and personal fees for Merck. FDC is an investigator in the ISPY COVID Clinical Trial, receives funding from the NIH unrelated to this work, is a consultant for Cytovale and on the Data Safety Board for Medpace. FGW, AO, PD are employees of AbbVie and may hold stock or options.

Background: Little is known about the relative harms of different antibiotic regimens prescribed to treat uncomplicated urinary tract infection (UTI). We sought to compare the risk of adverse events associated with commonly used oral antibiotic regimens for the outpatient treatment of uncomplicated UTI., Methods: Using data from the IBM® MarketScan® Commercial Database, we identified 1 169 033 otherwise healthy, nonpregnant women aged 18-44 years with uncomplicated UTI who initiated an oral antibiotic with activity against common uropathogens from 1 July 2006 to 30 September 2015. We used propensity score-weighted Kaplan-Meier methods and Cox proportional hazards regression models to estimate the association between antibiotic agent and adverse events., Results: Of 2 first-line agents, trimethoprim-sulfamethoxazole (vs nitrofurantoin) was associated with higher risk of several adverse drug events including hypersensitivity reaction (hazard ratio, 2.62; 95% confidence interval, 2.30-2.98), acute renal failure (2.56; 1.55-4.25), skin rash (2.42; 2.13-2.75), urticaria (1.37; 1.19-1.57), abdominal pain (1.14; 1.09-1.19), and nausea/vomiting (1.18; 1.10-1.28), but a similar risk of potential microbiome-related adverse events. Compared with nitrofurantoin, non-first-line agents were associated with higher risk of several adverse drug events and potential microbiome-related adverse events including non-Clostridium difficile diarrhea, C. difficile infection, vaginitis/vulvovaginal candidiasis, and pneumonia. Treatment duration modified the risk of potential microbiome-related adverse events., Conclusions: The risks of adverse drug events and potential microbiome-related events differ widely by antibiotic agent and duration. These findings underscore the utility of using real-world data to fill evidentiary gaps related to antibiotic safety., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Itraconazole is the preferred azole for histoplasmosis in the current Infectious Diseases Society of America guidelines. Voriconazole is increasingly used as treatment for histoplasmosis; it has in vitro activity against Histoplasma capsulatum and has shown success in case reports and small case series, but may have a lower barrier to resistance. No comparative studies have been published., Methods: We constructed a single-center, retrospective cohort of adult patients diagnosed with histoplasmosis from 2002 to 2017. Individual charts were reviewed to gather clinical information, including demographics, clinical features, immune status, treatments, and mortality. Patients were categorized based on the choice of azole and use as an initial treatment or as a step-down therapy from amphotericin B. Initial therapies with other azoles were excluded. Mortality was compared using a multivariable Cox proportional hazards with Heaviside function at 42 days., Results: We identified 261 cases of histoplasmosis from 2002 to 2017. After excluding patients not treated with itraconazole or voriconazole, 194 patients remained. Of these, 175 (90%) patients received itraconazole and 19 (10%) received voriconazole. There were no significant demographic differences between patient populations receiving either azole as their initial azole treatment. Death at 180 days occurred in 41 patients (23.4%) in the itraconazole group and 6 patients (31.6%) in the voriconazole group. Patients on voriconazole had a statistically significant increase in mortality during the first 42 days after initiation of treatment when compared to patients receiving itraconazole (hazard ratio, 4.30; 95% confidence interval, 1.3-13.9; P = .015), when controlled for other risk factors., Conclusions: Voriconazole in histoplasmosis was associated with increased mortality in the first 42 days when compared to itraconazole., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Clinical predictive models (CPM) serve to identify and categorize patients into risk categories to assist in treatment and intervention recommendations. Predictive accuracy and practicality of models varies depending on methods used for their development, and should be evaluated. The aim of this study was to summarize currently available CPM for invasive candidiasis, analyze their performance, and assess their suitability for use in clinical decision making. We identified studies that described the construction of a CPM for invasive candidiasis from PubMed/MEDLINE, EMBASE, SCOPUS, Web of Science, Cochrane Library databases, and Clinicaltrials.gov. Data extracted included: author, data source, study design, recruitment period, characteristics of study population, outcome types, predictor types, number of study participants and outcome events, modelling method, and list of predictors used in the final model. Calibration and discrimination in the derivative datasets were used to assess the performance of each model. Ten articles were identified in our search and included for full text review. Five models were developed using data from ICUs, and five models included all hospitalized patients. The findings of this review highlight the limitations of currently available models to predict invasive candidiasis, including lack of generalizability, difficulty in everyday clinical use, and overly optimistic performance. There are significant concerns regarding predictive performance and usability in every day practice of existing CPM to predict invasive candidiasis., (© The Author(s) 2021. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.)

Background: Disparities in coronavirus disease 2019 (COVID-19) testing-the pandemic's most critical but limited resource-may be an important but modifiable driver of COVID-19 inequities., Methods: We analyzed data from the Missouri State Department of Health and Senior Services on all COVID-19 tests conducted in the St Louis and Kansas City regions. We adapted a well-established tool for measuring inequity-the Lorenz curve-to compare COVID-19 testing rates per diagnosed case among Black and White populations., Results: Between 14/3/2020 and 15/9/2020, 606 725 and 328 204 COVID-19 tests were conducted in the St Louis and Kansas City regions, respectively. Over time, Black individuals consistently had approximately half the rate of testing per case than White individuals. In the early period (14/3/2020 to 15/6/2020), zip codes in the lowest quartile of testing rates accounted for only 12.1% and 8.8% of all tests in the St Louis and Kansas City regions, respectively, even though they accounted for 25% of all cases in each region. These zip codes had higher proportions of residents who were Black, without insurance, and with lower median incomes. These disparities were reduced but still persisted during later phases of the pandemic (16/6/2020 to 15/9/2020). Last, even within the same zip code, Black residents had lower rates of tests per case than White residents., Conclusions: Black populations had consistently lower COVID-19 testing rates per diagnosed case than White populations in 2 Missouri regions. Public health strategies should proactively focus on addressing equity gaps in COVID-19 testing to improve equity of the overall response., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)