Design of VA CoronavirUs Research and Efficacy Studies-1 (VA CURES-1): A double-blind, randomized placebo-controlled trial of COVID-19 convalescent plasma in hospitalized patients with early respiratory compromise.

Background: Effective therapeutics for severe acute respiratory syndrome CoronaVirus-2 (SARS-CoV-2) infection are evolving. Under Emergency Use Authorization, COVID-19 convalescent plasma (CCP) was widely used in individuals hospitalized for COVID-19, but few randomized controlled trials supported its efficacy to limit respiratory failure or death. Methods: VA CoronavirUs Research and Efficacy Studies-1 (VA CURES-1) was a double-blind, multi-site, placebo-controlled, randomized clinical trial evaluating the efficacy and safety of CCP with conventional therapy in hospitalized Veterans with SARS-CoV-2 infection and early respiratory compromise (requirement for oxygen). Participants (planned sample size 702) were randomized 1:1 to receive CCP with high titer neutralizing activity or 0.9% saline, stratified by site and age (≥65 versus <65 years old). Participants were followed daily during initial hospitalization and at Days 15, 22 and 28. Outcomes: The composite primary outcome was acute hypoxemic respiratory failure or all-cause death by Day 28. Secondary outcomes by day 28 included time-to-recovery, clinical severity, mortality, rehospitalization for COVID-19, and adverse events. Serial respiratory and blood samples were collected for safety, virologic and immunologic analyses and future studies. Key variables in predicting the success of CURES-1 were: (1) enrollment early in the course of severe infection; (2) use of plasma with high neutralizing activity; (3) reliance on unambiguous, clinically meaningful outcomes. CURES-1 was terminated for futility due to perceived inability to enroll in the lull between the Alpha and Delta waves of the SARS CoV-2 epidemic. Conclusions: VA CURES-1 was a large multi-site trial designed to provide conclusive information about the efficacy of CCP in well-characterized patients at risk for progression of COVID-19. It utilized a rigorous study design with relevant initial timing, quality of product and outcomes. Trial registration: ClinicalTrials.gov Identifier: NCT04539275.

Left Atrial Mechanics and Diastolic Function Among People Living With Human Immunodeficiency Virus (from the Veterans Aging Cohort Study).

Human immunodeficiency virus (HIV) infection is associated with subclinical cardiomyopathy, diastolic dysfunction, and increased risk of cardiovascular death. However, the relationship between left atrial (LA) mechanics and left ventricular (LV) diastolic function has not been evaluated in people living with HIV (PLWH) relative to HIV-uninfected (HIV-) controls. This is a multicenter, cross-sectional cohort analysis using the HIV Cardiovascular Disease substudy of the Veterans Aging Cohort Study database, which aimed to examine a cohort of PLWH and HIV- veterans without known cardiovascular disease. A total of 277 subjects (180 PLWH, 97 HIV-) with echocardiograms were identified. LV and LA phasic strain were derived and diastolic function was evaluated. Relationship between LA strain, LV strain, and the degree of diastolic dysfunction were assessed using analysis of variance and ordinal logistic regression with propensity weighting. In the PLWH cohort, 91.7% were on antiretroviral therapy and 86.1% had HIV viral loads <500 copies/ml. The mean (± SD) duration of infection was 9.7 ± 4.9 years. Relative to HIV- veterans, PLWH did not differ in LA mechanics and proportion of diastolic dysfunction (p = 0.31). Using logistic regression with propensity weighting, we found no association between HIV status and degree of diastolic dysfunction. In both cohorts, LA reservoir strain and LA conduit strain were inversely and independently associated with the degree of diastolic dysfunction. Compared with HIV- veterans, PLWH who are primarily virally suppressed and antiretroviral-treated did not differ in LA strain or LV diastolic dysfunction. If confirmed in other cohorts, HIV viral suppression may curtail adverse alterations in cardiac structure and function.

Combining Charlson comorbidity and VACS indices improves prognostic accuracy for all-cause mortality for patients with and without HIV in the Veterans Health Administration.

Introduction: As people age with HIV (PWH), many comorbid diseases are more common than among age matched comparators without HIV (PWoH). While the Veterans Aging Cohort (VACS) Index 2.0 accurately predicts mortality in PWH using age and clinical biomarkers, the only included comorbidity is hepatitis C. We asked whether adding comorbid disease groupings from the Charlson Comorbidity Index (CCI) improves the accuracy of VACS Index. Methods: To maximize our ability to model mortality among older age groups, we began with PWoH in Veterans Health Administration (VA) from 2007-2017, divided into development and validation samples. Baseline predictors included age, and components of CCI and VACS Index (excluding CD4 count and HIV RNA). Patients were followed until December 31, 2021. We used Cox models to develop the VACS-CCI score and estimated mortality using a parametric (gamma) survival model. We compared accuracy using C-statistics and calibration curves in validation overall and within subgroups (gender, age

Influence of Cancer on COVID-19 Incidence, Outcomes, and Vaccine Effectiveness: A Prospective Cohort Study of U.S. Veterans.

PURPOSE: Coronavirus disease 2019 (COVID-19) has been a constant health threat since its emergence. Amongst risk factors proposed, a diagnosis of cancer has been worrisome. We report the impact of cancer and other risk factors in US Veterans receiving care at Veterans Administration (VA) Hospitals, their adjusted odds ratio (aOR) for infection and death, and report on the impact of vaccines on the incidence and severity of COVID-19 infections in Veterans without/with cancer. METHODS: We conducted a cohort study of US Veterans without/with cancer by mining VA COVID-19 Shared Data Resource (CSDR) data using the VA Informatics and Computing Infrastructure (VINCI). Our observation period includes index dates from 14DEC2020 to 25JAN2022, encompassing both the delta and omicron waves in the US. RESULTS: We identified 915,928 Veterans, 24% of whom were African Americans who had undergone COVID testing-688,541 were and 227,387 were not vaccinated. 157,072 had a cancer diagnosis in the preceding two years. Age emerged as the major risk factor, with gender, BMI, and (Elixhauser) comorbidity contributing less. Among veterans with solid tumors other than lung cancer, risks of infection and death within 60 days were comparable to Veterans without cancer. However, those with hematologic malignancies fared worse. Vaccination was highly effective across all cancer cohorts; the respective rates of infection and death after infection were 8% and 5% among the vaccinated compared to 47% and 10% in the unvaccinated. Amongst vaccinated, increased risk of infection was noted in both, Veterans with hematologic malignancy treated with chemotherapy (HR, 2.993, P < 0.0001) or targeted therapies (HR, 1.781, P < 0.0001), and in solid tumors treated with either chemotherapy (HR 2.328, 95%CI 2.075-2.611, P < 0.0001) or targeted therapies (HR 1.328, P < 0.0001) when compared to those not on treatment. CONCLUSIONS: Risk for COVID-19 infection and death from infection vary based on cancer type and therapies administered. Importantly and encouragingly, the duration of protection from infection following vaccination in Veterans with a diagnosis of cancer was remarkably like those without a cancer diagnosis. Veterans with hematologic malignancies are especially vulnerable, with lower vaccine effectiveness (VE).

Risk Factors for Acute Gastroenteritis Among Patients Hospitalized in 5 Veterans Affairs Medical Centers, 2016-2019.

Background: In the United States, ∼179 million acute gastroenteritis (AGE) episodes occur annually. We aimed to identify risk factors for all-cause AGE, norovirus-associated vs non-norovirus AGE, and severe vs mild/moderate AGE among hospitalized adults. Methods: We enrolled 1029 AGE cases and 624 non-AGE controls from December 1, 2016, to November 30, 2019, at 5 Veterans Affairs Medical Centers. Patient interviews and medical chart abstractions were conducted, and participant stool samples were tested using the BioFire Gastrointestinal Panel. Severe AGE was defined as a modified Vesikari score of ≥11. Multivariate logistic regression was performed to assess associations between potential risk factors and outcomes; univariate analysis was conducted for norovirus-associated AGE due to limited sample size. Results: Among 1029 AGE cases, 551 (54%) had severe AGE and 44 (4%) were norovirus positive. Risk factors for all-cause AGE included immunosuppressive therapy (adjusted odds ratio [aOR], 5.6; 95% CI, 2.7-11.7), HIV infection (aOR, 3.9; 95% CI, 1.8-8.5), severe renal disease (aOR, 3.1; 95% CI, 1.8-5.2), and household contact with a person with AGE (aOR, 2.9; 95% CI, 1.3-6.7). Household (OR, 4.4; 95% CI, 1.6-12.0) and non-household contact (OR, 5.0; 95% CI, 2.2-11.5) with AGE was associated with norovirus-associated AGE. Norovirus positivity (aOR, 3.4; 95% CI, 1.3-8.8) was significantly associated with severe AGE. Conclusions: Patients with immunosuppressive therapy, HIV, and severe renal disease should be monitored for AGE and may benefit from targeted public health messaging regarding AGE prevention. These results may also direct future public health interventions, such as norovirus vaccines, to specific high-risk populations.

Effectiveness of mRNA COVID-19 vaccines against Omicron and Delta variants in a matched test-negative case-control study among US veterans.

OBJECTIVE: To estimate the effectiveness of messenger RNA (mRNA) booster doses during the period of Delta and Omicron variant dominance. DESIGN: We conducted a matched test-negative case-control study to estimate the vaccine effectiveness (VE) of three and two doses of mRNA vaccines against infection (regardless of symptoms) and against COVID-19-related hospitalisation and death. SETTING: Veterans Health Administration. PARTICIPANTS: We used electronic health record data from 114 640 veterans who had a SARS-CoV-2 test during November 2021-January 2022. Patients were largely 65 years or older (52%), male (88%) and non-Hispanic white (59%). MAIN OUTCOME MEASURES: First positive result for a SARS-CoV-2 PCR or antigen test. RESULTS: Against infection, booster doses had higher estimated VE (64%, 95% CI 63 to 65) than two-dose vaccination (12%, 95% CI 10 to 15) during the Omicron period. For the Delta period, the VE against infection was 90% (95% CI 88 to 92) among boosted vaccinees, higher than the VE among two-dose vaccinees (54%, 95% CI 50 to 57). Against hospitalisation, booster dose VE was 89% (95% CI 88 to 91) during Omicron and 94% (95% CI 90 to 96) during Delta; two-dose VE was 63% (95% CI 58 to 67) during Omicron and 75% (95% CI 69 to 80) during Delta. Against death, the VE with a booster dose was 94% (95% CI 90 to 96) during Omicron and 96% (95% CI 87 to 99) during Delta. CONCLUSIONS: Among an older, mostly male, population with comorbidities, we found that an mRNA vaccine booster was highly effective against infection, hospitalisation and death. Although the effectiveness of booster vaccination against infection was moderately higher against Delta than against the Omicron SARS-CoV-2 variant, effectiveness against severe disease and death was similarly high against both variants.

Association of Secretor Status and Recent Norovirus Infection With Gut Microbiome Diversity Metrics in a Veterans Affairs Population.

Norovirus infection causing acute gastroenteritis could lead to adverse effects on the gut microbiome. We assessed the association of microbiome diversity with norovirus infection and secretor status in patients from Veterans Affairs medical centers. Alpha diversity metrics were lower among patients with acute gastroenteritis but were similar for other comparisons.

Designing and implementing methodology for double-blind, placebo-controlled clinical trials using blood products within the Department of Veterans Affairs.

BACKGROUND: Success in conducting clinical trials during the coronavirus disease of 2019 pandemic requires the ability to innovate and adapt. There are well-established procedures for the blinding of investigational agents, especially medications, in placebo-controlled randomized clinical trials within the Veterans Health Administration. However, these procedures, managed by research pharmacists, may not apply to investigational agents that are not exclusively managed by pharmacy, such as blood products, including coronavirus disease of 2019 convalescent plasma (plasma). In the absence of established blinding procedures, such studies require special design considerations to minimize uncertainty or bias. METHODS: We describe the processes and procedures developed for blinding of plasma in "Veterans Affairs CoronavirUs Research and Efficacy Studies-1" as a prototypical study using this class of investigational therapeutic agents. Veterans Affairs CoronavirUs Research and Efficacy Studies-1 is an ongoing multicenter randomized clinical trial testing the efficacy of plasma added to conventional therapy for severe acute respiratory syndrome coronavirus-2 infection. RESULTS: We report the design of procedures to supply investigational blood products or 0.9% normal saline (saline) control while ensuring the integrity of the blind. Key aspects include workflow considerations, physical blinding strategies, and methods for engaging stakeholders. These procedures leverage the well-established Veterans Affairs research pharmacist's research infrastructure, and Blood Bank Services, which is responsible for blood-based investigational products. CONCLUSION: By describing the methods used to deliver blood products in a blinded manner in Veterans Affairs CoronavirUs Research and Efficacy Studies-1, we strive both to educate and to increase awareness to improve the implementation of these biological therapeutics for future, high-quality research studies.

Inhibiting Mycobacterium abscessus Cell Wall Synthesis: Using a Novel Diazabicyclooctane ß-Lactamase Inhibitor To Augment ß-Lactam Action.

Mycobacterium abscessus (Mab) infections are a growing menace to the health of many patients, especially those suffering from structural lung disease and cystic fibrosis. With multidrug resistance a common feature and a growing understanding of peptidoglycan synthesis in Mab, it is advantageous to identify potent ß-lactam and ß-lactamase inhibitor combinations that can effectively disrupt cell wall synthesis. To improve existing therapeutic regimens to address serious Mab infections, we evaluated the ability of durlobactam (DUR), a novel diazobicyclooctane ß-lactamase inhibitor to restore in vitro susceptibilities in combination with ß-lactams and provide a biochemical rationale for the activity of this compound. In cell-based assays, susceptibility of Mab subsp. abscessus isolates to amoxicillin (AMOX), imipenem (IMI), and cefuroxime (CXM) was significantly enhanced with the addition of DUR. The triple drug combinations of CXM-DUR-AMOX and IMI-DUR-AMOX were most potent, with MIC ranges of ≤0.06 to 1 µg/mL and an MIC50/MIC90 of ≤0.06/0.25 µg/mL, respectively. We propose a model by which this enhancement may occur, DUR potently inhibited the ß-lactamase BlaMab with a relative Michaelis constant (Ki app) of 4 × 10-3 ± 0.8 × 10-3 µM and acylation rate (k2/K) of 1 × 107 M-1 s-1. Timed mass spectrometry captured stable formation of carbamoyl-enzyme complexes between DUR and LdtMab2-4 and Mab d,d-carboxypeptidase, potentially contributing to the intrinsic activity of DUR. Molecular modeling showed unique and favorable interactions of DUR as a BlaMab inhibitor. Similarly, modeling showed how DUR might form stable Michaelis-Menten complexes with LdtMab2-4 and Mab d,d-carboxypeptidase. The ability of DUR combined with amoxicillin or cefuroxime and imipenem to inactivate multiple targets such as d,d-carboxypeptidase and LdtMab2,4 supports new therapeutic approaches using ß-lactams in eradicating Mab. IMPORTANCE Durlobactam (DUR) is a potent inhibitor of BlaMab and provides protection of amoxicillin and imipenem against hydrolysis. DUR has intrinsic activity and forms stable acyl-enzyme complexes with LdtMab2 and LdtMab4. The ability of DUR to protect amoxicillin and imipenem against BlaMab and its intrinsic activity along with the dual ß-lactam target redundancy can explain the rationale behind the potent activity of this combination.

Prostate Cancer Screening and Incidence among Aging Persons Living with HIV.

PURPOSE: The risk of prostate cancer among persons living with human immunodeficiency virus (PWH) is not well understood and may be obscured by different opportunities for detection. MATERIALS AND METHODS: We identified 123,472 (37,819 PWH and 85,653 comparators) men enrolled in the Veterans Aging Cohort Study, a prospective national cohort of PWH and demographically matched, uninfected comparators in 2000-2015. We calculated rates of prostate specific antigen (PSA) testing by human immunodeficiency virus (HIV) status and fit multivariable Poisson models comparing the rates of PSA testing, prostate biopsy, and cancer incidence. RESULTS: The mean age at enrollment was 52 years. Rates of PSA testing were lower in PWH versus uninfected comparators (0.58 versus 0.63 tests per person-year). Adjusted rates of PSA screening and prostate biopsy were lower among PWH (incidence rate ratio [IRR] 0.87, 95% CI 0.75-0.84 and IRR 0.79 95% CI 0.74-0.83, respectively). The crude IRR for prostate cancer was lower in PWH versus controls (IRR 0.90, 95% CI 0.83-0.97). However, in a multivariable model adjusting for PSA testing, cancer incidence was similar by HIV status (IRR=0.93, 95% CI 0.86-1.01, p=0.08). Among patients who received a prostate biopsy, incidence of prostate cancer did not differ significantly by HIV status (IRR 1.06, 95% CI 0.98-1.15, p=0.15). Among incident cancers, there were significant differences in the distributions of Gleason grade (p=0.05), but not cancer stage (p=0.14) by HIV status. CONCLUSIONS: When accounting for less PSA testing among PWH, the incidence of prostate cancer was similar by HIV status. These findings suggest that less screening contributed to lower observed incidence of prostate cancer in PWH.

The US Department of Veterans Affairs Science and Health Initiative to Combat Infectious and Emerging Life-Threatening Diseases (VA SHIELD): A Biorepository Addressing National Health Threats.

Background: The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has demonstrated the need to share data and biospecimens broadly to optimize clinical outcomes for US military Veterans. Methods: In response, the Veterans Health Administration established VA SHIELD (Science and Health Initiative to Combat Infectious and Emerging Life-threatening Diseases), a comprehensive biorepository of specimens and clinical data from affected Veterans to advance research and public health surveillance and to improve diagnostic and therapeutic capabilities. Results: VA SHIELD now comprises 12 sites collecting de-identified biospecimens from US Veterans affected by SARS-CoV-2. In addition, 2 biorepository sites, a data processing center, and a coordinating center have been established under the direction of the Veterans Affairs Office of Research and Development. Phase 1 of VA SHIELD comprises 34 157 samples. Of these, 83.8% had positive tests for SARS-CoV-2, with the remainder serving as contemporaneous controls. The samples include nasopharyngeal swabs (57.9%), plasma (27.9%), and sera (12.5%). The associated clinical and demographic information available permits the evaluation of biological data in the context of patient demographics, clinical experience and management, vaccinations, and comorbidities. Conclusions: VA SHIELD is representative of US national diversity with a significant potential to impact national healthcare. VA SHIELD will support future projects designed to better understand SARS-CoV-2 and other emergent healthcare crises. To the extent possible, VA SHIELD will facilitate the discovery of diagnostics and therapeutics intended to diminish COVID-19 morbidity and mortality and to reduce the impact of new emerging threats to the health of US Veterans and populations worldwide.

Using the biomarker cotinine and survey self-report to validate smoking data from United States Veterans Health Administration electronic health records.

Objective: Tobacco use/smoking for epidemiologic studies is often derived from electronic health record (EHR) data, which may be inaccurate. We previously compared smoking from the United States Veterans Health Administration (VHA) EHR clinical reminder data with survey data and found excellent agreement. However, the smoking clinical reminder items changed October 1, 2018. We sought to use the biomarker salivary cotinine (cotinine ≥30) to validate current smoking from multiple sources. Materials and Methods: We included 323 Veterans Aging Cohort Study participants with cotinine, clinical reminder, and self-administered survey smoking data from October 1, 2018 to September 30, 2019. We included International Classification of Disease (ICD)-10 codes F17.21 and Z72.0. Operating characteristics and kappa statistics were calculated. Results: Participants were mostly male (96%), African American (75%) and mean age was 63 years. Of those identified as currently smoking based on cotinine, 86%, 85%, and 51% were identified as currently smoking based on clinical reminder, survey, and ICD-10 codes, respectively. Of those identified as not currently smoking based on cotinine, 95%, 97%, and 97% were identified as not currently smoking based on clinical reminder, survey, and ICD-10 codes. Agreement with cotinine was substantial for clinical reminder (kappa = .81) and survey (kappa = .83), but only moderate for ICD-10 (kappa = .50). Discussion: To determine current smoking, clinical reminder, and survey agreed well with cotinine, whereas ICD-10 codes did not. Clinical reminders could be used in other health systems to capture more accurate smoking information. Conclusions: Clinical reminders are an excellent source for self-reported smoking status and are readily available in the VHA EHR.

Comparative Effectiveness and Antibody Responses to Moderna and Pfizer-BioNTech COVID-19 Vaccines among Hospitalized Veterans - Five Veterans Affairs Medical Centers, United States, February 1-September 30, 2021.

The mRNA COVID-19 vaccines (Moderna and Pfizer-BioNTech) provide strong protection against severe COVID-19, including hospitalization, for at least several months after receipt of the second dose (1,2). However, studies examining immune responses and differences in protection against COVID-19-associated hospitalization in real-world settings, including by vaccine product, are limited. To understand how vaccine effectiveness (VE) might change with time, CDC and collaborators assessed the comparative effectiveness of Moderna and Pfizer-BioNTech vaccines in preventing COVID-19-associated hospitalization at two periods (14-119 days and ≥120 days) after receipt of the second vaccine dose among 1,896 U.S. veterans at five Veterans Affairs medical centers (VAMCs) during February 1-September 30, 2021. Among 234 U.S. veterans fully vaccinated with an mRNA COVID-19 vaccine and without evidence of current or prior SARS-CoV-2 infection, serum antibody levels (anti-spike immunoglobulin G [IgG] and anti-receptor binding domain [RBD] IgG) to SARS-CoV-2 were also compared. Adjusted VE 14-119 days following second Moderna vaccine dose was 89.6% (95% CI = 80.1%-94.5%) and after the second Pfizer-BioNTech dose was 86.0% (95% CI = 77.6%-91.3%); at ≥120 days VE was 86.1% (95% CI = 77.7%-91.3%) for Moderna and 75.1% (95% CI = 64.6%-82.4%) for Pfizer-BioNTech. Antibody levels were significantly higher among Moderna recipients than Pfizer-BioNTech recipients across all age groups and periods since vaccination; however, antibody levels among recipients of both products declined between 14-119 days and ≥120 days. These findings from a cohort of older, hospitalized veterans with high prevalences of underlying conditions suggest the importance of booster doses to help maintain long-term protection against severe COVID-19.†.

Adapting the Surveillance Platform for Enteric and Respiratory Infectious Organisms at United States Veterans Affairs Medical Centers (SUPERNOVA) for COVID-19 Among Hospitalized Adults: Surveillance Protocol.

Introduction: Early in the COVID-19 pandemic, the Centers for Disease Control and Prevention (CDC) rapidly initiated COVID-19 surveillance by leveraging existing hospital networks to assess disease burden among hospitalized inpatients and inform prevention efforts. Materials and Methods: The Surveillance Platform for Enteric and Respiratory Infectious Organisms at Veterans Affairs Medical Centers (SUPERNOVA) is a network of five United States Veterans Affairs Medical Centers which serves nearly 400,000 Veterans annually and conducts laboratory-based passive and active monitoring for pathogens associated with acute gastroenteritis and acute respiratory illness among hospitalized Veterans. This paper presents surveillance methods for adapting the SUPERNOVA surveillance platform to prospectively evaluate COVID-19 epidemiology during a public health emergency, including detecting, characterizing, and monitoring patients with and without COVID-19 beginning in March 2020. To allow for case-control analyses, patients with COVID-19 and patients with non-COVID-19 acute respiratory illness were included. Results: SUPERNOVA included 1,235 participants with COVID-19 and 707 participants with other acute respiratory illnesses hospitalized during February through December 2020. Most participants were male (93.1%), with a median age of 70 years, and 45.8% non-Hispanic Black and 32.6% non-Hispanic White. Among those with COVID-19, 28.2% were transferred to an intensive care unit, 9.4% received invasive mechanical ventilation, and 13.9% died. Compared with controls, after adjusting for age, sex, and race/ethnicity, COVID-19 case-patients had significantly higher risk of mortality, respiratory failure, and invasive mechanical ventilation, and longer hospital stays. Discussion: Strengths of the SUPERNOVA platform for COVID-19 surveillance include the ability to collect and integrate multiple types of data, including clinical and illness outcome information, and SARS-CoV-2 laboratory test results from respiratory and serum specimens. Analysis of data from this platform also enables formal comparisons of participants with and without COVID-19. Surveillance data collected during a public health emergency from this key U.S. population of Veterans will be useful for epidemiologic investigations of COVID-19 spectrum of disease, underlying medical conditions, virus variants, and vaccine effectiveness, according to public health priorities and needs.

Effectiveness of COVID-19 mRNA Vaccines Against COVID-19-Associated Hospitalization - Five Veterans Affairs Medical Centers, United States, February 1-August 6, 2021.

COVID-19 mRNA vaccines (Pfizer-BioNTech and Moderna) have been shown to be highly protective against COVID-19-associated hospitalizations (1-3). Data are limited on the level of protection against hospitalization among disproportionately affected populations in the United States, particularly during periods in which the B.1.617.2 (Delta) variant of SARS-CoV-2, the virus that causes COVID-19, predominates (2). U.S. veterans are older, more racially diverse, and have higher prevalences of underlying medical conditions than persons in the general U.S. population (2,4). CDC assessed the effectiveness of mRNA vaccines against COVID-19-associated hospitalization among 1,175 U.S. veterans aged ≥18 years hospitalized at five Veterans Affairs Medical Centers (VAMCs) during February 1-August 6, 2021. Among these hospitalized persons, 1,093 (93.0%) were men, the median age was 68 years, 574 (48.9%) were non-Hispanic Black (Black), 475 were non-Hispanic White (White), and 522 (44.4%) had a Charlson comorbidity index score of ≥3 (5). Overall adjusted vaccine effectiveness against COVID-19-associated hospitalization was 86.8% (95% confidence interval [CI] = 80.4%-91.1%) and was similar before (February 1-June 30) and during (July 1-August 6) SARS-CoV-2 Delta variant predominance (84.1% versus 89.3%, respectively). Vaccine effectiveness was 79.8% (95% CI = 67.7%-87.4%) among adults aged ≥65 years and 95.1% (95% CI = 89.1%-97.8%) among those aged 18-64 years. COVID-19 mRNA vaccines are highly effective in preventing COVID-19-associated hospitalization in this older, racially diverse population of predominately male U.S. veterans. Additional evaluations of vaccine effectiveness among various age groups are warranted. To prevent COVID-19-related hospitalizations, all eligible persons should receive COVID-19 vaccination.

Risks of Opportunistic Infections in People With Human Immunodeficiency Virus With Cancers Treated With Chemotherapy.

BACKGROUND: We ascertained incidence of opportunistic infections (OIs) in people with human immunodeficiency virus (PWH) with cancer undergoing chemotherapy with non-human immunodeficiency virus (HIV) comparators. METHODS: We identified 2106 PWH and 2981 uninfected Veterans with cancer who received at least 1 dose of chemotherapy between 1996 and 2017 from the Veterans Aging Cohort Study. We ascertained incident OIs within 6 months of chemotherapy amongst zoster, cytomegalovirus, tuberculosis, Candida esophagitis, Pneumocystis jirovecii pneumonia (PCP), toxoplasmosis, Cryptococcosis, atypical Mycobacterium infection, Salmonella bacteremia, histoplasmosis, coccidioidomycosis, or progressive multifocal leukoencephalopathy. We used Poisson methods to calculate OI incidence rates by HIV status, stratifying for hematological and nonhematological tumors. We compared OI rates by HIV status, using inverse probability weights of HIV status, further adjusting for PCP prophylaxis. RESULTS: We confirmed 106 OIs in 101 persons. Adjusted OI incidence rate ratios (IRRs) indicated higher risk in PWH for all cancers (IRR, 4.8; 95% confidence interval [CI], 2.8-8.2), hematological cancers (IRR, 8.2; 95% CI, 2.4-27.3), and nonhematological cancers (IRR, 3.9; 95% CI, 2.1-7.2). Incidence rate ratios were not significantly higher in those with CD4 >200 cells/mm3 and viral load <500 copies/mL (IRR, 1.8; 95% CI, 0.9-3.2). All PCP cases (n = 11) occurred in PWH, with 2 microbiologically unconfirmed cases among 1467 PWH with nonhematological cancers, no PCP prophylaxis, and CD4 counts >200/mm3. CONCLUSIONS: Veterans with HIV undergoing chemotherapy had higher rates of OIs than uninfected Veterans, particularly those with hematological cancers, but not in PWH with HIV controlled disease. Our study does not support systematic PCP prophylaxis in solid tumors in PWH with HIV controlled disease.

"One-Two Punch": Synergistic ß-Lactam Combinations for Mycobacterium abscessus and Target Redundancy in the Inhibition of Peptidoglycan Synthesis Enzymes.

Mycobacterium abscessus subsp. abscessus is one of the most difficult pathogens to treat and its incidence in disease is increasing. Dual ß-lactam combinations act synergistically in vitro but are not widely employed in practice. A recent study shows that a combination of imipenem and ceftaroline significantly lowers the minimum inhibitory concentration of clinical isolates, despite both drugs targeting the same peptidoglycan synthesis enzymes. The underlying mechanism of this effect provides a basis for further investigations of dual ß-lactam combinations in the treatment of M. abscessus subsp. abscessus, eventually leading to a clinical trial. Furthermore, dual ß-lactam strategies may be explored for other difficult mycobacterial infections.

Comparison of a mycobacterial phage assay to detect viable Mycobacterium avium subspecies paratuberculosis with standard diagnostic modalities in cattle with naturally infected Johne disease.

BACKGROUND: Mycobacterium avium subspecies paratuberculosis (MAP), the cause of Johne disease, is a slow growing mycobacterium. Viable MAP detection is difficult, inconstant and time-consuming. The purpose of this study was to compare a rapid phage/qPCR assay performed on peripheral blood mononuclear cells (PBMCs) with three standard methods of MAP detection: fecal MAP PCR; plasma antigen-specific IFN-γ & serum MAP ELISA hypothesizing that, if sensitive and specific, Johne animals would be positive and Control animals negative. We studied a well characterized herd of Holstein cattle that were naturally infected with MAP and their Controls. RESULTS: With phage/qPCR 72% (23/32) of Johne and 35% (6/17) of Controls were MAP positive. With fecal PCR 75% (24/32) of Johne and 0% (0/17) of Controls were MAP positive. With plasma antigen-specific IFN-γ 69% (22/32) of Johne and 12% (2/17) of Controls were MAP positive. With serum MAP ELISA, 31% (10/32) of Johne and 0% (0/17) of Controls were MAP positive. When phage / qPCR and fecal PCR results were combined, 100% (32/32) Johne and 35% (6/17) of Control animals were MAP positive. Younger Control animals (1-3 years) had significantly fewer plaques (25 ± 17 SEM) than older Controls (4-12 years) (309 ± 134 p = 0.04). The same trend was not observed in the Johne animals (p = 0.19). CONCLUSIONS: In contrast to our hypothesis, using the phage/qPCR assay we find that viable circulating MAP can rapidly be detected from the blood of animals infected with, as well as those in the Control group evidently colonized by MAP. These data indicate that the presence of viable MAP in blood does not necessarily signify that an animal must of necessity be demonstrably ill or be MAP positive by standard diagnostic methods.

Incidence, Etiology, and Severity of Acute Gastroenteritis Among Prospectively Enrolled Patients in 4 Veterans Affairs Hospitals and Outpatient Centers, 2016-2018.

BACKGROUND: Acute gastroenteritis (AGE) burden, etiology, and severity in adults is not well characterized. We implemented a multisite AGE surveillance platform in 4 Veterans Affairs Medical Centers (Atlanta, Georgia; Bronx, New York; Houston, Texas; and Los Angeles, California), collectively serving >320 000 patients annually. METHODS: From 1 July 2016 to 30 June 2018, we actively identified inpatient AGE case patients and non-AGE inpatient controls through prospective screening of admitted patients and passively identified outpatients with AGE through stool samples submitted for clinical diagnostics. We abstracted medical charts and tested stool samples for 22 pathogens by means of multiplex gastrointestinal polymerase chain reaction panel followed by genotyping of norovirus- and rotavirus-positive samples. We determined pathogen-specific prevalence, incidence, and modified Vesikari severity scores. RESULTS: We enrolled 724 inpatients with AGE, 394 non-AGE inpatient controls, and 506 outpatients with AGE. Clostridioides difficile and norovirus were most frequently detected among inpatients (for AGE case patients vs controls: C. difficile, 18.8% vs 8.4%; norovirus, 5.1% vs 1.5%; P < .01 for both) and outpatients (norovirus, 10.7%; C. difficile, 10.5%). The incidence per 100 000 population was highest among outpatients (AGE, 2715; C. difficile, 285; norovirus, 291) and inpatients ≥65 years old (AGE, 459; C. difficile, 91; norovirus, 26). Clinical severity scores were highest for inpatient norovirus, rotavirus, and Shigella/enteroinvasive Escherichia coli cases. Overall, 12% of inpatients with AGE had intensive care unit stays, and 2% died; 3 deaths were associated with C. difficile and 1 with norovirus. C. difficile and norovirus were detected year-round with a fall/winter predominance. CONCLUSIONS: C. difficile and norovirus were leading AGE pathogens in outpatient and hospitalized US veterans, resulting in severe disease. Clinicians should remain vigilant for bacterial and viral causes of AGE year-round.

Statin exposure and risk of cancer in people with and without HIV infection.

OBJECTIVE: To determine whether statin exposure is associated with decreased cancer and mortality risk among persons with HIV (PWH) and uninfected persons. Statins appear to have immunomodulatory and anti-inflammatory effects and may reduce cancer risk, particularly among PWH as they experience chronic inflammation and immune activation. DESIGN: Propensity score-matched cohort of statin-exposed and unexposed patients from 2002 to 2017 in the Veterans Aging Cohort Study (VACS), a large cohort with cancer registry linkage and detailed pharmacy data. METHODS: We calculated Cox regression hazard ratios (HRs) and 95% confidence intervals (CI) associated with statin use for all cancers, microbial cancers (associated with bacterial or oncovirus coinfection), nonmicrobial cancers, and mortality. RESULTS: :The propensity score-matched sample (N = 47 940) included 23 970 statin initiators (31% PWH). Incident cancers were diagnosed in 1160 PWH and 2116 uninfected patients. Death was reported in 1667 (7.0%) statin-exposed, and 2215 (9.2%) unexposed patients. Statin use was associated with 24% decreased risk of microbial-associated cancers (hazard ratio 0.76; 95% CI 0.69-0.85), but was not associated with nonmicrobial cancer risk (hazard ratio 1.00; 95% CI 0.92-1.09). Statin use was associated with 33% lower risk of death overall (hazard ratio 0.67; 95% CI 0.63-0.72). Results were similar in analyses stratified by HIV status, except for non-Hodgkin lymphoma where statin use was associated with reduced risk (hazard ratio 0.56; 95% CI 0.38-0.83) for PWH, but not for uninfected (P interaction = 0.012). CONCLUSION: In both PWH and uninfected, statin exposure was associated with lower risk of microbial, but not nonmicrobial cancer incidence, and with decreased mortality.