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Kirsha S Gordon,1,2 Eugenia Buta,3 Mandi L Pratt-Chapman,4 Cynthia A Brandt,1,3,5 Ralitza Gueorguieva,3 Allison R Warren,6,7 T Elizabeth Workman,8,9 Qing Zeng-Treitler,8,9 Joseph L Goulet1,5 1Research, VA Connecticut Healthcare System, West Haven, CT, USA; 2General Internal Medicine, Yale School of Medicine, New Haven, CT, USA; 3Department of Biostatistics, Yale School of Public Health, New Haven, CT, USA; 4Department of Medicine and The George Washington Cancer Center, School of Medicine and Health Sciences, The George Washington University, Washington, DC, USA; 5Department of Emergency Medicine, Yale School of Medicine, New Haven, CT, USA; 6Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA; 7Pain Research, Informatics, Multi-Morbidities, and Education Center, VA Connecticut Healthcare System, West Haven, CT, USA; 8Biomedical Informatics Center, School of Medicine and Health Sciences, The George Washington University, Washington, DC, USA; 9Research, Washington VA Medical Center, Washington, DC, USACorrespondence: Kirsha S Gordon, VA Connecticut Healthcare System, Bldg. 35A, 950 Campbell Avenue, West Haven, CT, 06516, USA, Tel +1 203-932-5711, Email kirsha.gordon2@va.govBackground: Pain assessment is performed in many healthcare systems, such as the Veterans Health Administration, but prior studies have not assessed whether pain screening varies in sexual and gender minority populations that include individuals who identify as lesbian, gay, bisexual, and/or transgender (LGBT).Objective: The purpose of this study was to evaluate pain screening and reported pain of LGBT Veterans compared to non-LGBT Veterans.Methods: Using a retrospective cross-sectional cohort, data from the Corporate Data Warehouse, a national repository with clinical/administrative data, were analyzed. Veterans were classified as LGBT using natural language processing. We used a robust Poisson model to examine the association between LGBT status and binary outcomes of pain screening, any pain, and persistent pain within one year of entry in the cohort. All models were adjusted for demographics, mental health, substance use, musculoskeletal disorder(s), and number of clinic visits.Results: There were 1,149,486 Veterans (218,154 (19%) classified as LGBT) in our study. Among LGBT Veterans, 94% were screened for pain compared to 89% among those not classified as LGBT (non-LGBT) Veterans. In adjusted models, LGBT Veterans’ probability of being screened for pain compared to non-LGBT Veterans was 2.5% higher (95% CI 2.3%, 2.6%); risk of any pain was 2.1% lower (95% CI 1.6%, 2.6%); and there was no significant difference between LGBT and non-LGBT Veterans in persistent pain (RR = 1.00, 95% CI (0.99, 1.01), p = 0.88).Conclusions: In a nationwide sample, LGBT Veterans were more likely to be screened for pain but had lower self-reported pain scores, though adjusted differences were small. It was notable that transgender and Black Veterans reported the greatest pain. Reasons for these findings require further investigation.Keywords: LGBT, pain, screening, persistent pain, Veterans

OBJECTIVES:Community viral load (CVL) estimates vary based on analytic methods. We extended the CVL concept and used data from the Veterans Health Administration (VA) to determine trends in the health care system viral load (HSVL) and its sensitivity to varying definitions of the clinical population and assumptions regarding missing data. METHODS:We included HIV-infected patients in the Veterans Aging Cohort Study, 2000-2010, with at least one documented CD4 count, HIV-1 RNA or antiretroviral prescription (n = 37 318). We created 6-month intervals including patients with at least one visit in the past 2 years. We assessed temporal trends in clinical population size, patient clinical status and mean HSVL and explored the impact of varying definitions of the clinical population and assumptions about missing viral load. RESULTS:The clinical population size varied by definition, increasing from 16 000-19 000 patients in 2000 to 23 000-26 000 in 2010. The proportion of patients with suppressed HIV-1 RNA increased over time. Over 20% of patients had no viral load measured in a given interval or the past 2 years. Among patients with a current HIV-1 RNA, mean HSVL decreased from 97 800 HIV-1 RNA copies/mL in 2000 to 2000 copies/mL in 2010. When current HIV-1 RNA data were unavailable and the HSVL was recalculated using the last available HIV-1 RNA, HSVL decreased from 322 300 to 9900 copies/mL. HSVL was underestimated when using only current data in each interval. CONCLUSIONS:The CVL concept can be applied to a health care system, providing a measure of health care quality. Like CVL, HSVL estimates depend on definitions of the clinical population and assumptions about missing data.

OBJECTIVES:Community viral load (CVL) estimates vary based on analytic methods. We extended the CVL concept and used data from the Veterans Health Administration (VA) to determine trends in the health care system viral load (HSVL) and its sensitivity to varying definitions of the clinical population and assumptions regarding missing data. METHODS:We included HIV-infected patients in the Veterans Aging Cohort Study, 2000-2010, with at least one documented CD4 count, HIV-1 RNA or antiretroviral prescription (n = 37 318). We created 6-month intervals including patients with at least one visit in the past 2 years. We assessed temporal trends in clinical population size, patient clinical status and mean HSVL and explored the impact of varying definitions of the clinical population and assumptions about missing viral load. RESULTS:The clinical population size varied by definition, increasing from 16 000-19 000 patients in 2000 to 23 000-26 000 in 2010. The proportion of patients with suppressed HIV-1 RNA increased over time. Over 20% of patients had no viral load measured in a given interval or the past 2 years. Among patients with a current HIV-1 RNA, mean HSVL decreased from 97 800 HIV-1 RNA copies/mL in 2000 to 2000 copies/mL in 2010. When current HIV-1 RNA data were unavailable and the HSVL was recalculated using the last available HIV-1 RNA, HSVL decreased from 322 300 to 9900 copies/mL. HSVL was underestimated when using only current data in each interval. CONCLUSIONS:The CVL concept can be applied to a health care system, providing a measure of health care quality. Like CVL, HSVL estimates depend on definitions of the clinical population and assumptions about missing data.

Importance: Hepatocellular carcinoma (HCC) is typically detected only at advanced stages when treatment options are limited. Most of the current HCC risk models focus on patients with viral hepatitis or diagnosed cirrhosis or require variables not routinely available in clinical care., Objective: To identify modifiable HCC risk factors in the general population and to develop a risk score to inform HCC screening and risk-factor modification interventions for high-risk individuals without viral hepatitis or decompensated cirrhosis., Design, Setting, and Participants: This cohort study analyzed demographic, clinical, laboratory, and diagnostic data from the US Department of Veterans Affairs (VA) electronic health records. Data were divided into development and validation samples. Veterans aged 30 to 95 years were included, and those with hepatitis B or C virus infection, hepatic decompensation, or prevalent HCC were excluded. Patients were followed up until the occurrence of HCC diagnosis, death, or December 31, 2021. A Cox proportional hazards regression model for 10-year risk of HCC was developed and used to create an HCC risk score, and performance in development and validation samples and in patient subgroups was evaluated. One outpatient visit date per person at least 18 months after VA entry, between October 1, 2007, and March 31, 2020, was randomly selected and used as the index date for the start of follow-up. Analyses were performed from March 2023 to May 2024., Exposures: Age, sex, race and ethnicity, body mass index, liver fibrosis (detected with Fibrosis-4 Index [FIB-4]), diabetes status, smoking status, and alcohol use., Main Outcomes and Measures: First HCC diagnosis during follow-up. This information was ascertained from VA national cancer registry topography and histology codes and from International Classification of Diseases, Ninth Revision and International Statistical Classification of Diseases, Tenth Revision, Clinical Modification diagnosis codes for the inpatient or outpatient visits., Results: This study of 6 509 288 veterans included 6 048 917 males (92.9%), with a median (IQR) age of 65 (54-74) years, who identified as being of Hispanic (5.3%), non-Hispanic Black (15.0%), non-Hispanic White (68.9%), or other (4.6%) race and ethnicity. Overall, 15 142 patients (0.2%) developed HCC, 69.5% of whom had FIB-4 of 3.25 or lower at baseline. While FIB-4 was the most important variable, age, sex, race and ethnicity, body mass index, diabetes, smoking, and alcohol use were also informative. Discrimination in the development sample was better than FIB-4 alone (C statistic, 0.83 [95% CI, 0.82-0.85] vs 0.79 [95% CI, 0.77-0.80]). The HCC risk score performed consistently well in the validation sample and in all subgroups. A FIB-4 threshold of 3.25 would screen 5.0% of the cohort at a cost of 28 false-positives for every true-positive; a model risk score of 58 would screen 4.7% of the cohort at a cost of 23 false-positives for every true-positive., Conclusions and Relevance: Results of this study suggest that a multivariable risk score that uses routinely available clinical data outperforms FIB-4 alone in identifying patients at risk of HCC who do not have viral hepatitis or hepatic decompensation at baseline.

Treatment of opioid use disorder (OUD) with buprenorphine improves outcomes and mortality among people with HIV (PWH). However, engagement is low and is influenced by comorbidities. We examined the impact of patterns of co-occurring pain, substance use disorders (SUDs), and mental health diagnoses on buprenorphine initiation and retention in PWH. The Veterans Aging Cohort Study contained 7,875 patients (2,702 PWH and 5,173 without HIV) with new OUD clinical encounters (2008-2017). Buprenorphine initiation and retention were derived from prescription data. We identified patterns of co-occurring diagnoses (via ICD codes) and assessed the effects of class membership on both outcomes using latent class analysis and regression analyses. The mean age of patients was 55, 98% were male, 58% Black, 8% Hispanic, and only 8% initiated buprenorphine within 12 months of OUD diagnosis. Four classes of co-occurring diagnoses were identified: "Few Co-occurring Diagnoses" (42.3%); "Multiple Pain Conditions" (21.3%); "Pain + SUD" (18.4%) and "Pain + SUD + Mental Health" (18.0%). Patients in the "Pain + SUD" class and "Pain + SUD + Mental Health" class were significantly less likely to initiate buprenorphine and had 59% and 45% lower odds, respectively, of initiating buprenorphine compared with patients in the "Few Co-occurring Diagnoses" class; this effect did not vary by HIV status. Buprenorphine retention was not significantly associated with HIV status or class membership. However, Black Veterans were less likely to initiate or be retained in buprenorphine treatment. Higher comorbidity burden was negatively associated with buprenorphine initiation but not with retention. More research is warranted to determine other factors that may influence treatment retention., (© 2024. The Author(s).)

Background: Alcohol withdrawal is a common reason for admission to acute care hospitals. Prescription of medications for alcohol-use disorder (AUD) and close outpatient follow-up are commonly recommended, but few studies report their effects on postdischarge outcomes., Objectives: The objective of this study is to evaluate the effects of medications for AUD and follow-up appointments on readmission and abstinence., Methods: This retrospective cohort study evaluated veterans admitted for alcohol withdrawal to medical services at 19 Veteran Health Administration hospitals between October 1, 2018 and September 30, 2019. Factors associated with all-cause 30-day readmission and 6-month abstinence were examined using logistic regression., Results: Of the 594 patients included in this study, 296 (50.7%) were prescribed medications for AUD at discharge and 459 (78.5%) were discharged with follow-up appointments, including 251 (42.8%) with a substance-use clinic appointment, 191 (32.9%) with a substance-use program appointment, and 73 (12.5%) discharged to a residential program. All-cause 30-day readmission occurred for 150 patients (25.5%) and 103 (17.8%) remained abstinent at 6 months. Medications for AUD and outpatient discharge appointments were not associated with readmission or abstinence. Discharge to residential treatment program was associated with reduced 30-day readmission (adjusted odds ratio [AOR]: 0.39, 95% confidence interval [95% CI]: 0.18-0.82) and improved abstinence (AOR: 2.50, 95% CI: 1.33-4.73)., Conclusions: Readmission and return to heavy drinking are common for patients discharged for alcohol withdrawal. Medications for AUD were not associated with improved outcomes. The only intervention at the time of discharge that improved outcomes was discharge to residential treatment program, which was associated with decreased readmission and improved abstinence., (Published 2024. This article is a US Government work and is in the public domain in the USA.)

Objectives: Few studies describe contemporary alcohol withdrawal management in hospitalized settings or review current practices considering the guidelines by the American Society of Addiction Medicine (ASAM)., Methods: We conducted a retrospective cohort study of patients hospitalized with alcohol withdrawal on medical or surgical wards in 19 Veteran Health Administration (VHA) hospitals between October 1, 2018, and September 30, 2019. Demographic and comorbidity data were obtained from the Veteran Health Administration Corporate Data Warehouse. Inpatient management and hospital outcomes were obtained by chart review. Factors associated with treatment duration and complicated withdrawal were examined., Results: Of the 594 patients included in this study, 51% were managed with symptom-triggered therapy alone, 26% with fixed dose plus symptom-triggered therapy, 10% with front loading regimens plus symptom-triggered therapy, and 3% with fixed dose alone. The most common medication given was lorazepam (87%) followed by chlordiazepoxide (33%), diazepam (14%), and phenobarbital (6%). Symptom-triggered therapy alone (relative risk [RR], 0.68; 95% confidence interval [CI], 0.57-0.80) and front loading with symptom-triggered therapy (RR, 0.75; 95% CI, 0.62-0.92) were associated with reduced treatment duration. Lorazepam (RR, 1.20; 95% CI, 1.02-1.41) and phenobarbital (RR, 1.28; 95% CI, 1.06-1.54) were associated with increased treatment duration. Lorazepam (adjusted odds ratio, 4.30; 95% CI, 1.05-17.63) and phenobarbital (adjusted odds ratio, 6.51; 95% CI, 2.08-20.40) were also associated with complicated withdrawal., Conclusions: Overall, our results support guidelines by the ASAM to manage patients with long-acting benzodiazepines using symptom-triggered therapy. Health care systems that are using shorter acting benzodiazepines and fixed-dose regimens should consider updating alcohol withdrawal management pathways to follow ASAM recommendations., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “work of the United States Government” for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.)

Background: The role of potentially inappropriate medications (PIMs) in mortality has been studied among those 65 years or older. While middle-aged individuals are believed to be less susceptible to the harms of polypharmacy, PIMs have not been as carefully studied in this group., Objective: To estimate PIM-associated risk of mortality and evaluate the extent PIMs explain associations between polypharmacy and mortality in middle-aged patients, overall and by sex and race/ethnicity., Design: Observational cohort study., Setting: Department of Veterans Affairs (VA), the largest integrated healthcare system in the US., Participants: Patients aged 41 to 64 who received a chronic medication (continuous use of ≥ 90 days) between October 1, 2008, and September 30, 2017., Measurement: Patients were followed for 5 years until death or end of study period (September 30, 2019). Time-updated polypharmacy and hyperpolypharmacy were defined as 5-9 and ≥ 10 chronic medications, respectively. PIMs were identified using the Beers criteria (2015) and were time-updated. Cox models were adjusted for demographic, behavioral, and clinical characteristics., Results: Of 733,728 patients, 676,935 (92.3%) were men, 479,377 (65.3%) were White, and 156,092 (21.3%) were Black. By the end of follow-up, 104,361 (14.2%) patients had polypharmacy, 15,485 (2.1%) had hyperpolypharmacy, and 129,992 (17.7%) were dispensed ≥ 1 PIM. PIMs were independently associated with mortality (HR 1.11, 95% CI 1.04-1.18). PIMs also modestly attenuated risk of mortality associated with polypharmacy (HR 1.07, 95% CI 1.03-1.11 before versus HR 1.05, 95% CI 1.01-1.09 after) and hyperpolypharmacy (HR 1.18, 95% CI 1.09-1.28 before versus HR 1.12, 95% CI 1.03-1.22 after). Patterns varied when stratified by sex and race/ethnicity., Limitations: The predominantly male VA patient population may not represent the general population., Conclusion: PIMs were independently associated with increased mortality, and partially explained polypharmacy-associated mortality in middle-aged people. Other mechanisms of injury from polypharmacy should also be studied., (© 2024. The Author(s), under exclusive licence to Society of General Internal Medicine.)

Opioid prescribing remains common despite known overdose-related harms. Less is known about links to nonoverdose morbidity. We determined the association between prescribed opioid receipt with incident cardiovascular disease (CVD) using data from the Veterans Aging Cohort Study, a national prospective cohort of Veterans with/without Human Immunodeficiency Virus (HIV) receiving Veterans Health Administration care. Selected participants had no/minimal prior exposure to prescription opioids, no opioid use disorder, and no severe illness 1 year after the study start date (baseline period). We ascertained prescription opioid exposure over 3 years after the baseline period using outpatient pharmacy fill/refill data. Incident CVD ascertainment began at the end of the prescribed opioid exposure ascertainment period until the first incident CVD event, death, or September 30, 2015. We used adjusted Cox proportional hazards regression models with matching weights using propensity scores for opioid receipt to estimate CVD risk. Among 49,077 patients, 30% received opioids; the median age was 49 years, 97% were male, 49% were Black, and 47% were currently smoking. Prevalence of hypertension, diabetes, current smoking, alcohol and cocaine use disorder, and depression was higher in patients receiving opioids versus those not but were well-balanced by matching weights. Unadjusted CVD incidence rates per 1,000-person-years were higher among those receiving opioids versus those not: 17.4 (95% confidence interval [CI], 16.5-18.3) versus 14.7 (95% CI, 14.2-15.3). In adjusted analyses, those receiving opioids versus those not had an increased hazard of incident CVD (adjusted hazard ratio 1.16 [95% CI, 1.08-1.24]). Prescribed opioids were associated with increased CVD incidence, making opioids a potential modifiable CVD risk factor. PERSPECTIVE: In a propensity score weighted analysis of Veterans Administration data, prescribed opioids compared to no opioids were associated with an increased hazard of incident CVD. Higher opioid doses compared with lower doses were associated with increased hazard of incident CVD. Opioids are a potentially modifiable CVD risk factor., (Published by Elsevier Inc.)

Background: Opioids may play a part in the development of atrial fibrillation (AF). Understanding the relationship between opioid exposure and AF can help providers better assess the risk and benefits of prescribing opioids., Objective: To assess the incidence of AF as a function of prescribed opioids and opioid type., Design: We performed unadjusted and adjusted time-updated Cox regressions to assess the association between opioid exposure and incident AF., Participants: The national study sample was comprised of Veterans enrolled in the Veterans Health Administration (VHA) who served in support of post-9/11 operations., Main Measures: The main predictor of interest was prescription opioid exposure, which was treated as a time-dependent variable. The first was any opioid exposure (yes/no). Secondary was opioid type. The outcome, incident AF, was identified through ICD-9-CM diagnostic codes at any primary care visit after the baseline period., Key Results: A total of 609,763 veterans (mean age: 34 years and 13.24% female) were included in our study. Median follow-up time was 4.8 years. Within this cohort, 124,395 veterans (20.40%) were prescribed an opioid. A total of 1,455 Veterans (0.24%) were diagnosed with AF. In adjusted time-updated Cox regressions, the risk of incident AF was higher in the veterans prescribed opioids (hazard ratio [HR]: 1.47; 95% confidence interval [CI]: 1.38-1.57). In adjusted time-updated Cox regressions, both immunomodulating and nonimmunomodulating opioid type was associated with increased risk of incident AF (HR: 1.40; 95% CI: 1.25-1.57 and HR: 1.49; 95% CI: 1.39-1.60), compared to no opioid use, respectively., Conclusions: Our findings suggest opioid prescription may be a modifiable risk factor for the development of AF., (Copyright © 2023. Published by Elsevier Inc.)

CAR-T therapy is a promising, novel treatment modality for B-cell malignancies and yet many patients relapse through a variety of means, including loss of CAR-T cells and antigen escape. To investigate leukemia-intrinsic CAR-T resistance mechanisms, we performed genome-wide CRISPR-Cas9 loss-of-function screens in an immunocompetent murine model of B-cell acute lymphoblastic leukemia (B-ALL) utilizing a modular guide RNA library. We identified IFNγR/JAK/STAT signaling and components of antigen processing and presentation pathway as key mediators of resistance to CAR-T therapy in vivo; intriguingly, loss of this pathway yielded the opposite effect in vitro (sensitized leukemia to CAR-T cells). Transcriptional characterization of this model demonstrated upregulation of these pathways in tumors relapsed after CAR-T treatment, and functional studies showed a surprising role for natural killer (NK) cells in engaging this resistance program. Finally, examination of data from B-ALL patients treated with CAR-T revealed an association between poor outcomes and increased expression of JAK/STAT and MHC-I in leukemia cells. Overall, our data identify an unexpected mechanism of resistance to CAR-T therapy in which tumor cell interaction with the in vivo tumor microenvironment, including NK cells, induces expression of an adaptive, therapy-induced, T-cell resistance program in tumor cells., (© 2023. The Author(s).)

Objective: The Graded Chronic Pain Scale (GCPS) is frequently used in pain research and treatment to classify mild, bothersome, and high impact chronic pain. This study's objective was to validate the revised version of the GCPS (GCPS-R) in a US Veterans Affairs (VA) healthcare sample to support its use in this high-risk population., Methods: Data were collected from Veterans (n = 794) via self-report (GCPS-R and relevant health questionnaires) and electronic health record extraction (demographics and opioid prescriptions). Logistic regression, adjusting for age and gender, was used to test for differences in health indicators by pain grade. Adjusted odds ratio (AOR) with 95% confidence intervals (CIs) were reported with CIs not including an AOR of 1 indicating that the difference exceeded chance., Results: In this population, the prevalence of chronic pain (pain present most or every day, prior 3 months) was 49.3%: 7.1% with mild chronic pain (mild pain intensity and lower interference with activities); 23.3% bothersome chronic pain (moderate to severe pain intensity with lower interference); and 21.1% high impact chronic pain (higher interference). Results of this study mirrored findings in the non-VA validation study; differences between bothersome and high impact were consistent for activity limitations and present but not fully consistent for psychological variables. Those with bothersome chronic pain or high impact chronic pain were more likely to receive long-term opioid therapy compared to those with no/mild chronic pain., Conclusions: Findings highlight categorical differences captured with the GCPS-R, and convergent validity supports use of the GCPS-R in US Veterans., (© The Author(s) 2023. Published by Oxford University Press on behalf of the American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Bothersome symptoms potentially related to drinking are commonly reported by people with and without HIV (PWH/PWoH). However, the relationship between bothersome symptoms and level of alcohol use is often not appreciated by patients or providers. Therefore, among persons reporting prior-year alcohol use, we assessed whether alcohol use level (AUDIT-C score), HIV status, and demographic covariates influenced the likelihood of the patient reporting a bothersome symptom. We used the Veterans Aging Cohort Study (VACS) surveys (2002-2018), including a validated symptoms index. Among 3679 PWH and 3830 PWoH currently drinking alcohol, the most commonly reported symptoms were muscle/joint pain (52%), sleep disturbance (51%), and fatigue (50%). Level of alcohol use was independently associated with 18 of 20 bothersome symptoms, including seven symptoms more common among PWH. Results can help inform PWH/PWoH who drink alcohol about the strong relationship between level of alcohol use and bothersome symptoms, potentially motivating reduced use., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: People aging with and without HIV (PWH and PWoH) want to avoid neurocognitive dysfunction, especially delirium. Continued use of alcohol in conjunction with neurocognitively active medications (NCAMs) may be a largely underappreciated cause, especially for PWH who experience polypharmacy a decade earlier than PWoH. We compare absolute and relative risk of delirium among PWH and PWoH by age, level of alcohol use, and exposure to NCAMs., Methods: Using the VACS cohort, we compare absolute and relative risk of inpatient delirium among PWH and PWoH by age, level of alcohol use, and exposure to NCAMs between 2007 and 2019. We matched each case based on age, race/ethnicity, sex, HIV, baseline year, and observation time with up to 5 controls. The case/control date was defined as date of admission for cases and the date corresponding to the same length of time on study for controls. Level of alcohol use was defined using Alcohol Use Disorder Identification Test-Consumption (AUDIT-C). Medication exposure was measured from 45 to 3 days prior to index date; medications were classified as anticholinergic NCAM, non-anticholinergic NCAM, or non NCAM and counts generated. We used logistic regression to determine odds ratios (ORs) for delirium associated with medication counts stratified by HIV status and adjusted for demographics, severity of illness, and related diagnoses., Results: PWH experienced a higher incidence of delirium (5.6, [95% CI 5.3-5.9/1000 PY]) than PWoH (5.0, [95% CI 4.8-5.1/1000 PY]). In multivariable analysis, anticholinergic and non-anticholinergic NCAM counts and level of alcohol use demonstrated strong independent dose-response associations with delirium., Conclusions: Decreasing alcohol use and limiting the use of neurocognitively active medications may help decrease excess rates of delirium, especially among PWH., (© 2023 The American Geriatrics Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Background: People with human immunodeficiency virus (HIV) (PWH) may be at increased risk for severe coronavirus disease 2019 (COVID-19) outcomes. We examined HIV status and COVID-19 severity, and whether tenofovir, used by PWH for HIV treatment and people without HIV (PWoH) for HIV prevention, was associated with protection., Methods: Within 6 cohorts of PWH and PWoH in the United States, we compared the 90-day risk of any hospitalization, COVID-19 hospitalization, and mechanical ventilation or death by HIV status and by prior exposure to tenofovir, among those with severe acute respiratory syndrome coronavirus 2 infection between 1 March and 30 November 2020. Adjusted risk ratios (aRRs) were estimated by targeted maximum likelihood estimation, with adjustment for demographics, cohort, smoking, body mass index, Charlson comorbidity index, calendar period of first infection, and CD4 cell counts and HIV RNA levels (in PWH only)., Results: Among PWH (n = 1785), 15% were hospitalized for COVID-19 and 5% received mechanical ventilation or died, compared with 6% and 2%, respectively, for PWoH (n = 189 351). Outcome prevalence was lower for PWH and PWoH with prior tenofovir use. In adjusted analyses, PWH were at increased risk compared with PWoH for any hospitalization (aRR, 1.31 [95% confidence interval, 1.20-1.44]), COVID-19 hospitalizations (1.29 [1.15-1.45]), and mechanical ventilation or death (1.51 [1.19-1.92]). Prior tenofovir use was associated with reduced hospitalizations among PWH (aRR, 0.85 [95% confidence interval, .73-.99]) and PWoH (0.71 [.62-.81])., Conclusions: Before COVID-19 vaccine availability, PWH were at greater risk for severe outcomes than PWoH. Tenofovir was associated with a significant reduction in clinical events for both PWH and PWoH., Competing Interests: Potential conflicts of interest. V. C. M. has received investigator-initiated research grants (to the institution) and consultation fees, both unrelated to the current work, from Eli Lilly, Bayer, Gilead Sciences, and ViiV; research grants from the NIH, the Centers for Disease Control and Prevention, and the Department of Veterans Affairs; payment or honoraria for speaking from Medscape/WebMD/ViiV; and writing honoraria from Integritas and Lilly. V. C. M. also reports participation on a data and safety monitoring board study section for the NIH. K. N. A. has received investigator-initiated research grants from the NIH (to the institution) and consultation fees (both unrelated to the current work) from the All of Us Research Program (NIH; payment to the author), TrioHealth (payment to the author as advisory board member), and Kennedy Dundas; K. N. A. also reports royalties or licenses from Coursera as the director of a 5-course specialization (payment to the author and institution). K. A. G. has received consulting fees, unrelated to the current work, from Teach for America, the Aspen Institute, and UptoDate. K. A. G. also reports grants to the institution from Octapharma, the US Department of Defense's Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense, the National Institute of Allergy and Infectious Diseases, NIH (grant 3R01AI152078-01S1), the NIH National Center for Advancing Translational Sciences (grants U24TR001609-S3 and UL1TR00309), the Mental Wellness Foundation, HealthNetwork Foundation, Bloomberg Philanthropies, Moriah Fund, the Shear Family Foundation, the State of Maryland, and the Defense Health Agency (grant W911QY2090012); royalties or licenses to the author from UpToDate; consulting fees to the author from Spark Healthcare, Aspen Institute, and Teach for America; and unpaid consultation to Pfizer for Scientific Advisory Board. R. L. reports grants or contracts paid to the institution from University of Calgary. 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) 2023. 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.)

Objectives: We performed a systematic review and meta-analysis to estimate the effect of early active empirical antibiotics for MRSA on mortality, both in patients admitted with MRSA infections and in patients admitted with common infectious syndromes, for whom the causative pathogen may not have been MRSA., Methods: A systematic literature search was conducted using Embase, MEDLINE, PubMed, Web of Science, Cochrane, Scopus and Google Scholar from the earliest entry through to 26 April 2022. We included studies of patients hospitalized with culture-proven MRSA infections that compared mortality rates depending on whether patients received active empirical antibiotics. The primary outcome was the adjusted OR for mortality with early active empirical antibiotics. After performing random-effects meta-analysis, we estimated the absolute risk reduction in mortality with initial empirical MRSA coverage for common infectious syndromes based on the prevalence of MRSA and baseline mortality rate for each syndrome, as reported in the medical literature., Results: Of an initial 2136 unique manuscripts, 37 studies (11 661 participants) met our inclusion criteria. Fifteen studies (6066 participants) reported adjusted OR of mortality. The pooled adjusted OR for mortality was 0.64 (95% CI, 0.48-0.84), favouring active empirical antibiotics. The estimated absolute mortality benefit was 0% for patients with pneumonia, 0.1% (95% CI, 0.04-0.2) for non-critically ill patients with soft tissue infections, 0.04% (95% CI, 0.01-0.05) for non-critically ill patients with urinary tract infections, 0.6% (95% CI, 0.2-1.0) for patients with septic shock, and 1.0% (95% CI, 0.3-1.4) for patients with catheter-related infections admitted to ICUs., Conclusions: For the three most common infections in the hospital, the absolute benefit on mortality of empirical antibiotics against MRSA is 0.1% or less. Meaningful benefit of empirical antimicrobials against MRSA is limited to patients with approximately 30% mortality and 10% prevalence of MRSA. Avoiding empirical antibiotics against MRSA for low-risk infections would substantially reduce the use of anti-MRSA therapy., (Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy 2023.)

Background: Collection of accurate Hispanic ethnicity data is critical to evaluate disparities in health and health care. However, this information is often inconsistently recorded in electronic health record (EHR) data., Objective: To enhance capture of Hispanic ethnicity in the Veterans Affairs EHR and compare relative disparities in health and health care., Methods: We first developed an algorithm based on surname and country of birth. We then determined sensitivity and specificity using self-reported ethnicity from the 2012 Veterans Aging Cohort Study survey as the reference standard and compared this to the research triangle institute race variable from the Medicare administrative data. Finally, we compared demographic characteristics and age-adjusted and sex-adjusted prevalence of conditions in Hispanic patients among different identification methods in the Veterans Affairs EHR 2018-2019., Results: Our algorithm yielded higher sensitivity than either EHR-recorded ethnicity or the research triangle institute race variable. In 2018-2019, Hispanic patients identified by the algorithm were more likely to be older, had a race other than White, and foreign born. The prevalence of conditions was similar between EHR and algorithm ethnicity. Hispanic patients had higher prevalence of diabetes, gastric cancer, chronic liver disease, hepatocellular carcinoma, and human immunodeficiency virus than non-Hispanic White patients. Our approach evidenced significant differences in burden of disease among Hispanic subgroups by nativity status and country of birth., Conclusions: We developed and validated an algorithm to supplement Hispanic ethnicity information using clinical data in the largest integrated US health care system. Our approach enabled clearer understanding of demographic characteristics and burden of disease in the Hispanic Veteran population., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Disclosure of sexual orientation and gender identity correlates with better outcomes, yet data may not be available in structured fields in electronic health record data. To gain greater insight into the care of sexual and gender-diverse patients in the Veterans Health Administration (VHA), we examined the documentation patterns of sexual orientation and gender identity through extraction and analyses of data contained in unstructured electronic health record clinical notes., Methods: Salient terms were identified through authoritative vocabularies, the research team's expertise, and frequencies, and the use of consistency in VHA clinical notes. Term frequencies were extracted from VHA clinical notes recorded from 2000 to 2018. Temporal analyses assessed usage changes in normalized frequencies as compared with nonclinical use, relative growth rates, and geographic variations., Results: Over time most terms increased in use, similar to Google ngram data, especially after the repeal of the "Don't Ask Don't Tell" military policy in 2010. For most terms, the usage adoption consistency also increased by the study's end. Aggregated use of all terms increased throughout the United States., Conclusion: Term usage trends may provide a view of evolving care in a temporal continuum of changing policy. These findings may be useful for policies and interventions geared toward sexual and gender-diverse individuals. Despite the lack of structured data, the documentation of sexual orientation and gender identity terms is increasing in clinical notes., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Morning report is a core educational activity in internal medicine resident education. Attending physicians regularly participate in morning report and influence the learning environment, though no previous study has described the contribution of attending physicians to this conference. This study aims to describe attending comments at internal medicine morning reports., Methods: We conducted a prospective, observational study of morning reports conducted at 13 internal medicine residency programs between September 1, 2020, and March 30, 2021. Each attending comment was described including its duration, whether the comment was teaching or non-teaching, teaching topic, and field of practice of the commenter. We also recorded morning report-related variables including number of learners, report format, program director participation, and whether report was scripted (facilitator has advance knowledge of the case). A regression model was developed to describe variables associated with the number of attending comments per report., Results: There were 2,344 attending comments during 250 conferences. The median number of attendings present was 3 (IQR, 2-5). The number of comments per report ranged across different sites from 3.9 to 16.8 with a mean of 9.4 comments/report (SD, 7.4). 66% of comments were shorter than one minute in duration and 73% were categorized as teaching by observers. The most common subjects of teaching comments were differential diagnosis, management, and testing. Report duration, number of general internists, unscripted reports, and in-person format were associated with significantly increased number of attending comments., Conclusions: Attending comments in morning report were generally brief, focused on clinical teaching, and covered a wide range of topics. There were substantial differences between programs in terms of the number of comments and their duration which likely affects the local learning environment. Morning report stakeholders that are interested in increasing attending involvement in morning report should consider employing in-person and unscripted reports. Additional studies are needed to explore best practice models of attending participation in morning report., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Purpose: We describe pain intensity and opioid prescription jointly over time in Veterans with back pain to better understand their relationship., Methods: We performed a retrospective cohort study on electronic health record data from 117 126 Veterans (mean age 49.2 years) diagnosed with back pain in 2015. We used latent class growth analysis to jointly model pain intensity (0-10 scores) and opioid prescriptions over 2 years to identify classes of individuals similar in their trajectory of pain and opioid over time. Multivariable multinomial logit models assessed sociodemographic and clinical predictors of class membership., Results: We identified six trajectory classes: a "no pain/no opioid" class (22.2%), a "mild pain/no opioid" class (45.0%), a "moderate pain/no opioid" class (24.6%), a "moderate, decreasing pain/decreasing opioid" class (3.3%), a "moderate pain/high opioid" class (2.6%), and a "moderate, increasing pain/increasing opioid" class (2.3%). Among those in moderate pain classes, being white (vs. non-white) and older were associated with higher odds of being prescribed opioids. Veterans with mental health diagnoses had increased odds of being in the painful classes versus "no pain/no opioid" class., Conclusion: We found distinct patterns in the long-term joint course of pain and opioid prescription in Veterans with back pain. Understanding these patterns and associated predictors may help with development of targeted interventions for patients with back pain., (© 2022 John Wiley & Sons Ltd. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Background: Racial/ethnic disparities during the first six months of the COVID-19 pandemic led to differences in COVID-19 testing and adverse outcomes. We examine differences in testing and adverse outcomes by race/ethnicity and sex across a geographically diverse and system-based COVID-19 cohort collaboration., Methods: Observational study among adults (≥18 years) within six US cohorts from March 1, 2020 to August 31, 2020 using data from electronic health record and patient reporting. Race/ethnicity and sex as risk factors were primary exposures, with health system type (integrated health system, academic health system, or interval cohort) as secondary. Proportions measured SARS-CoV-2 testing and positivity; attributed hospitalization and death related to COVID-19. Relative risk ratios (RR) with 95% confidence intervals quantified associations between exposures and main outcomes., Results: 5,958,908 patients were included. Hispanic patients had the highest proportions of SARS-CoV-2 testing (16%) and positivity (18%), while Asian/Pacific Islander patients had the lowest portions tested (11%) and White patients had the lowest positivity rates (5%). Men had a lower likelihood of testing (RR = 0.90 [0.89-0.90]) and a higher positivity risk (RR = 1.16 [1.14-1.18]) compared to women. Black patients were more likely to have COVID-19-related hospitalizations (RR = 1.36 [1.28-1.44]) and death (RR = 1.17 [1.03-1.32]) compared with White patients. Men were more likely to be hospitalized (RR = 1.30 [1.16-1.22]) or die (RR = 1.70 [1.53-1.89]) compared to women. These racial/ethnic and sex differences were reflected in both health system types., Conclusions: This study supports evidence of disparities by race/ethnicity and sex during the COVID-19 pandemic that persisted even in healthcare settings with reduced barriers to accessing care. Further research is needed to understand and prevent the drivers that resulted in higher burdens of morbidity among certain Black patients and men., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Helping people with HIV (PWH) and without HIV (PWoH) understand the relationship between physical symptoms and alcohol use might help motivate them to decrease use. In surveys collected in the Veterans Aging Cohort Study from 2002 to 2018, PWH and PWoH were asked about 20 common symptoms and whether they thought any were caused by alcohol use. Analyses were restricted to current alcohol users (AUDIT-C > 0). We applied generalized estimating equations. The outcome was having any Symptoms Attributed to Alcohol use (SxAA). Primary independent variables were each of the 20 symptoms and HIV status. Compared to PWoH, PWH had increased odds of SxAA (OR 1.54; 95% CI 1.27, 1.88). Increased AUDIT-C score was also associated with SxAA (OR 1.32; 95% CI 1.28, 1.36), as were trouble remembering, anxiety, and weight loss/wasting. Evidence that specific symptoms are attributed to alcohol use may help motive people with and without HIV decrease their alcohol use., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: Medical intensive care unit (MICU) admissions have been declining in people with HIV infection (PWH), but frequency of outpatient polypharmacy (prescription of ≥5 chronic medications) has increased. Among those hospitalized, we examined whether outpatient polypharmacy is associated with subsequent 1-year MICU admission or 10-year all-cause mortality, and if the association varies by HIV status., Design: Retrospective cohort study., Methods: Using a national electronic health record cohort of Veterans in care, we ascertained outpatient polypharmacy during fiscal year (FY) 2009 and followed patients for 1-year MICU admission and 10-year mortality. We assessed associations of any polypharmacy (yes/no and categorized ≤4, 5-7, 8-9, and ≥10 medications) with 1-year MICU admission and 10-year mortality using logistic and Cox regressions, respectively, adjusted for demographics, HIV status, substance use, and severity of illness., Results: Among 9898 patients (1811 PWH) hospitalized in FY2010, prior outpatient polypharmacy was common (51%). Within 1 year, 1532 (15%) had a MICU admission and within 10 years, 4585 (46%) died. Polypharmacy was associated with increased odds of 1-year MICU admission, in both unadjusted (odds ratio (OR) 1.36 95% CI: (1.22, 1.52)) and adjusted models, aOR (95% CI) = 1.28 (1.14, 1.43) and with 10-year mortality in unadjusted, hazard ratio (HR) (95% CI) = 1.40 (1.32, 1.48), and adjusted models, HR (95% CI) = 1.26 (1.19, 1.34). Increasing levels of polypharmacy demonstrated a dose-response with both outcomes and by HIV status, with a stronger association among PWH., Conclusions: Among hospitalized patients, prior outpatient polypharmacy was associated with 1-year MICU admission and 10-year all-cause mortality after adjusting for severity of illness in PWH and PWoH., Competing Interests: The authors have declared that no competing interests exist.

Importance: Understanding the severity of postvaccination SARS-CoV-2 (ie, COVID-19) breakthrough illness among people with HIV (PWH) can inform vaccine guidelines and risk-reduction recommendations., Objective: To estimate the rate and risk of severe breakthrough illness among vaccinated PWH and people without HIV (PWoH) who experience a breakthrough infection., Design, Setting, and Participants: In this cohort study, the Corona-Infectious-Virus Epidemiology Team (CIVET-II) collaboration included adults (aged ≥18 years) with HIV who were receiving care and were fully vaccinated by June 30, 2021, along with PWoH matched according to date fully vaccinated, age group, race, ethnicity, and sex from 4 US integrated health systems and academic centers. Those with postvaccination COVID-19 breakthrough before December 31, 2021, were eligible., Exposures: HIV infection., Main Outcomes and Measures: The main outcome was severe COVID-19 breakthrough illness, defined as hospitalization within 28 days after a breakthrough SARS-CoV-2 infection with a primary or secondary COVID-19 discharge diagnosis. Discrete time proportional hazards models estimated adjusted hazard ratios (aHRs) and 95% CIs of severe breakthrough illness within 28 days of breakthrough COVID-19 by HIV status adjusting for demographic variables, COVID-19 vaccine type, and clinical factors. The proportion of patients who received mechanical ventilation or died was compared by HIV status., Results: Among 3649 patients with breakthrough COVID-19 (1241 PWH and 2408 PWoH), most were aged 55 years or older (2182 patients [59.8%]) and male (3244 patients [88.9%]). The cumulative incidence of severe illness in the first 28 days was low and comparable between PWoH and PWH (7.3% vs 6.7%; risk difference, -0.67%; 95% CI, -2.58% to 1.23%). The risk of severe breakthrough illness was 59% higher in PWH with CD4 cell counts less than 350 cells/μL compared with PWoH (aHR, 1.59; 95% CI, 0.99 to 2.46; P = .049). In multivariable analyses among PWH, being female, older, having a cancer diagnosis, and lower CD4 cell count were associated with increased risk of severe breakthrough illness, whereas previous COVID-19 was associated with reduced risk. Among 249 hospitalized patients, 24 (9.6%) were mechanically ventilated and 20 (8.0%) died, with no difference by HIV status., Conclusions and Relevance: In this cohort study, the risk of severe COVID-19 breakthrough illness within 28 days of a breakthrough infection was low among vaccinated PWH and PWoH. PWH with moderate or severe immune suppression had a higher risk of severe breakthrough infection and should be included in groups prioritized for additional vaccine doses and risk-reduction strategies.

Background: Potentially inappropriate medications (PIMs) are medications contra-indicated in particular circumstances. We sought to characterize PIMs by level of polypharmacy by age, sex, and race/ethnicity., Methods: We performed a cross-sectional drug dispensing study using electronic health records available through the US Department of Veterans Affairs. We extracted pharmacy fill and refill records during fiscal year 2016 (i.e., October 1, 2015-September 30, 2016) for all patients aged 49-70 who accessed care in the preceding fiscal year. PIMs were defined by the combined Beers and Laroche (henceforth Beers Laroche) criteria used for older patients and the PROMPT criteria used for middle-aged., Results: In the 1 499 586 patients aged 49-64, PIMs prevalence by PROMPT in patients with 0-4, 5-9, and ≥10 medications was 14.0%, 62.2%, and 86.1%, respectively, and by Beers Laroche was 14.3%, 63.4%, and 85.7%, respectively. In the 1 249 119 patients aged 65-70, PIMs prevalence by Beers Laroche was 14.8%, 59.9%, and 83.3%, and by PROMPT was 13.9%, 57.4%, and 82.0%, respectively. Meaningful differences in prevalence were shown by sex and race/ethnicity according to both set of criteria (e.g. PROMPT in patients with 5-9 medications: 66.1% women vs. 59.3% men; standardized-mean-differences [SMD] = 0.14; 61.7% of White vs. 54.5% of non-White; SMD = 0.15). The most common PIMs were digestive, analgesic, antidiabetic, and psychotropic medications., Conclusion: Prevalence of PIMs was high and increased with polypharmacy. Beers Laroche and PROMPT provided similar estimations inside and outside their target age, suggesting that PIMs are common among those with polypharmacy regardless of age., (© 2022 John Wiley & Sons Ltd.)

Gabapentin is commonly prescribed for chronic pain, including to patients with HIV (PWH). There is growing concern regarding gabapentin's potential for harm, particularly in combination with opioids. Among PWH, we examined factors associated with higher doses of gabapentin receipt and determined if receipt varied by opioid use. We examined data from the Veterans Aging Cohort Study, a national prospective cohort including PWH, from 2002 through 2017. Covariates included prescribed opioid dose, self-reported past year opioid use, and other sociodemographic and clinical variables. We used multinomial logistic regression to determine independent predictors of gabapentin receipt. Among 3,702 PWH, 902 (24%) received any gabapentin during the study period at a mean daily dose of 1,469 mg. In the multinomial model, high-dose gabapentin receipt was associated with high-dose benzodiazepine receipt (adjusted odds ratio [aOR], 95% confidence interval [CI]= 1.53, [1.03-2.27]), pain interference (1.65 [1.39-1.95]), and hand or foot pain (1.81, [1.45-2.26]). High-dose gabapentin receipt was associated with prescribed high-dose opioids receipt (2.66 [1.95-3.62]) but not self-reported opioid use (1.03 [0.89-1.21]). PWH prescribed gabapentin at higher doses are more likely to receive high-dose opioids and high-dose benzodiazepines, raising safety concerns.

Background: It is not definitively known if persons with HIV (PWH) are more likely to be SARS-CoV-2 tested or test positive than persons without HIV (PWoH). We describe SARS-CoV-2 testing and positivity in 6 large geographically and demographically diverse cohorts of PWH and PWoH in the United States., Setting: The Corona Infectious Virus Epidemiology Team comprises 5 clinical cohorts within a health system (Kaiser Permanente Northern California, Oakland, CA; Kaiser Permanente Mid-Atlantic States, Rockville, MD; University of North Carolina Health, Chapel Hill, NC; Vanderbilt University Medical Center, Nashville, TN; and Veterans Aging Cohort Study) and 1 interval cohort (Multicenter AIDS Cohort Study/Women's Interagency HIV Study Combined Cohort Study)., Methods: We calculated the proportion of patients SARS-CoV-2 tested and the test positivity proportion by HIV status from March 1 to December 31, 2020., Results: The cohorts ranged in size from 1675 to 31,304 PWH and 1430 to 3,742,604 PWoH. The proportion of PWH who were tested for SARS-CoV-2 (19.6%-40.5% across sites) was significantly higher than PWoH (14.8%-29.4%) in the clinical cohorts. However, among those tested, the proportion of patients with positive SARS-CoV-2 tests was comparable by HIV status; the difference in proportion of SARS-CoV-2 positivity ranged from 4.7% lower to 1.4% higher., Conclusions: Although PWH had higher testing proportions compared with PWoH, we did not find evidence of increased positivity in 6 large, diverse populations across the United States. Ongoing monitoring of testing, positivity, and COVID-19-related outcomes in PWH are needed, given availability, response, and durability of COVID-19 vaccines; emergence of SARS-CoV-2 variants; and latest therapeutic options., Competing Interests: M. J. Silverberg has received research funding from Gilead Sciences, Inc. The remaining authors have no conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

The immunostimulatory intracellular domains (ICDs) of chimaeric antigen receptors (CARs) are essential for converting antigen recognition into antitumoural function. Although there are many possible combinations of ICDs, almost all current CARs rely on combinations of CD3𝛇, CD28 and 4-1BB. Here we show that a barcoded library of 700,000 unique CD19-specific CARs with diverse ICDs cloned into lentiviral vectors and transduced into Jurkat T cells can be screened at high throughput via cell sorting and next-generation sequencing to optimize CAR signalling for antitumoural functions. By using this screening approach, we identified CARs with new ICD combinations that, compared with clinically available CARs, endowed human primary T cells with comparable tumour control in mice and with improved proliferation, persistence, exhaustion and cytotoxicity after tumour rechallenge in vitro. The screening strategy can be adapted to other disease models, cell types and selection conditions, and could be used to improve adoptive cell therapies and to expand their utility to new disease indications., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

While immune checkpoint blockade results in durable responses for some patients, many others have not experienced such benefits. These treatments rely upon reinvigorating specific T cell-antigen interactions. However, it is often unknown what antigens are being recognized by T cells or how to potently induce antigen-specific responses in a broadly applicable manner. Here, we characterized the CD8 + T cell response to a murine model of melanoma following combination immunotherapy to determine the basis of tumor recognition. Sequencing of tumor-infiltrating T cells revealed a repertoire of highly homologous TCR sequences that were particularly expanded in treated mice and which recognized an antigen from an endogenous retrovirus. While vaccination against this peptide failed to raise a protective T cell response in vivo , engineered antigen mimotopes induced a significant expansion of CD8 + T cells cross-reactive to the original antigen. Vaccination with mimotopes resulted in killing of antigen-loaded cells in vivo yet showed modest survival benefit in a prophylactic vaccine paradigm. Together, this work demonstrates the identification of a dominant tumor-associated antigen and generation of mimotopes which can induce robust functional T cell responses that are cross-reactive to the endogenous antigen across multiple individuals., Competing Interests: BG is currently an employee of Repertoire Immune Medicines. MB is a co-founder, equity holder, and advisor of Kelonia Therapeutics and Abata Therapeutics, an equity holder in 3T Biosciences, and an inventor on patents related to yeast display approaches licensed to 3T Biosciences. DI is a co-founder, SAB member, and equity holder in Elicio Therapeutics, and is an inventor on patents licensed to Elicio Therapeutics related to the amphiphile-vaccine technology. JL has interests in Honeycomb Biotechnologies, and is an inventor on patents related to the SeqWell technology. MB, DI, and JL’s interests are reviewed and managed under MIT’s policies for potential conflicts of interest. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Grace, Backlund, Morgan, Kang, Singh, Huisman, Rappazzo, Moynihan, Maiorino, Dobson, Kyung, Gordon, Holec, Mbah, Garafola, Wu, Love, Wittrup, Irvine and Birnbaum.)

Human Immunodeficiency Virus (HIV) infection remains prevalent among the marginalized and drug using population in the United States. Testing for HIV is an important and cost-effective way to reduce HIV prevalence. Our objective was to determine if there is a difference in the number of HIV testing by injection status among users of illicit drugs and if a person's social network characteristics is a contributing factor. Using a cross-sectional design and negative binomial regression models, we assessed HIV testing behavior of people who use non-injected drugs (PWND) compared to people who use injected drugs (PWID). In an analytic sample of 539 participants, PWND tested for HIV 19% less compared to PWID, PR (95% CI) = 0.81 (0.66, 0.98), p  = 0.03. Other contributing factors of testing were education, condomless sex, STIs, heroin use, and participant's sex network. The interaction term between PWND and emotional support in relation to HIV testing was significant, 1.33 (1.03, 1.69), p =0.03. These findings suggest HIV testing behavior differed by injection status, and this relationship may be dependent on emotional support. To exert a greater impact on the HIV epidemic, interventions and policies encouraging HIV testing in PWND, an understudied at-risk sub-population, are warranted.

Importance: Recommendations for additional doses of COVID-19 vaccines for people with HIV (PWH) are restricted to those with advanced disease or unsuppressed HIV viral load. Understanding SARS-CoV-2 infection risk after vaccination among PWH is essential for informing vaccination guidelines., Objective: To estimate the rate and risk of breakthrough infections among fully vaccinated PWH and people without HIV (PWoH) in the United States., Design, Setting, and Participants: This cohort study used the Corona-Infectious-Virus Epidemiology Team (CIVET)-II (of the North American AIDS Cohort Collaboration on Research and Design [NA-ACCORD], which is part of the International Epidemiology Databases to Evaluate AIDS [IeDEA]), collaboration of 4 prospective, electronic health record-based cohorts from integrated health systems and academic health centers. Adult PWH who were fully vaccinated prior to June 30, 2021, were matched with PWoH on date of full vaccination, age, race and ethnicity, and sex and followed up through December 31, 2021., Exposures: HIV infection., Main Outcomes and Measures: COVID-19 breakthrough infections, defined as laboratory evidence of SARS-CoV-2 infection or COVID-19 diagnosis after a patient was fully vaccinated., Results: Among 113 994 patients (33 029 PWH and 80 965 PWoH), most were 55 years or older (80 017 [70%]) and male (104 967 [92%]); 47 098 (41%) were non-Hispanic Black, and 43 218 (38%) were non-Hispanic White. The rate of breakthrough infections was higher in PWH vs PWoH (55 [95% CI, 52-58] cases per 1000 person-years vs 43 [95% CI, 42-45] cases per 1000 person-years). Cumulative incidence of breakthroughs 9 months after full vaccination was low (3.8% [95% CI, 3.7%-3.9%]), albeit higher in PWH vs PWoH (4.4% vs 3.5%; log-rank P < .001; risk difference, 0.9% [95% CI, 0.6%-1.2%]) and within each vaccine type. Breakthrough infection risk was 28% higher in PWH vs PWoH (adjusted hazard ratio, 1.28 [95% CI, 1.19-1.37]). Among PWH, younger age (<45 y vs 45-54 y), history of COVID-19, and not receiving an additional dose (aHR, 0.71 [95% CI, 0.58-0.88]) were associated with increased risk of breakthrough infections. There was no association of breakthrough with HIV viral load suppression, but high CD4 count (ie, ≥500 cells/mm3) was associated with fewer breakthroughs among PWH., Conclusions and Relevance: In this study, COVID-19 vaccination, especially with an additional dose, was effective against infection with SARS-CoV-2 strains circulating through December 31, 2021. PWH had an increased risk of breakthrough infections compared with PWoH. Expansion of recommendations for additional vaccine doses to all PWH should be considered.

Background: The association between cannabis use and HIV-1 RNA (viral load) among people with HIV (PWH) engaged in care is unclear. Methods: We used data collected from 2002 to 2018 on PWH receiving antiretroviral therapy (ART) enrolled in the Veterans Aging Cohort Study. Generalized estimating equations were used to estimate associations between self-reported past-year cannabis use and detectable viral load (≥500 copies/mL), with and without adjustment for demographics, other substance use, and adherence. Results: Among 2515 participants, 97% were male, 66% were Black, the mean age was 50 years, and 33% had detectable HIV viral load at the first study visit. In unadjusted analyses, PWH with any past-year cannabis use had 21% higher odds of a detectable viral load than those with no past-year use (OR = 1.21; 95% CI, 1.07-1.37). However, there was no significant association between cannabis use and viral load after adjustment. Conclusions: Among PWH engaged in care and receiving ART, cannabis use is associated with decreased adherence in unadjusted analyses but does not appear to directly impact viral control. Future studies are needed to understand other potential risks and benefits of cannabis use among PWH.

Background: Heavy episodic drinking (HED) is a risk factor for opioid-related overdose and negatively impacts HIV disease progression. Among a national cohort of patients with HIV (PWH), we examined sociodemographic and clinical correlates of concomitant HED and self-reported opioid use., Methods: We used data collected from 2002 through 2018 from the Veterans Aging Cohort Study, a prospective cohort including PWH in care at eight US Veterans Health Administration sites. HED was defined as consuming six or more drinks at least once in the year prior to survey collection. We examined the relationship between HED and self-reported opioid use and created a 4-level composite variable of HED and opioid use. We used multinomial logistic regression to estimate odds of reporting concomitant HED and self-reported opioid use., Results: Among 3702 PWH, 1458 (39.4%) reported HED during the study period and 350 (9.5%) reported opioid use. In the multinomial model, compared to reporting neither HED nor opioid use, lifetime housing instability (adjusted odds ratio [aOR] 1.54, 95% confidence interval [CI] 1.01 to 2.35), Veterans Aging Cohort Study Index 2.0 (a measure of disease severity; aOR 1.14, 95% CI 1.02 to 1.28), depressive symptoms (aOR 2.27, 95% CI 1.42 to 3.62), past-year cigarette smoking (aOR 3.06, 95% CI 1.53 to 6.14), cannabis use (aOR 1.69, 95% CI 1.09 to 2.62), and cocaine/stimulant use (aOR 11.54, 95% CI 7.40 to 17.99) were independently associated with greater odds of concomitant HED and self-reported opioid use. Compared to having attended no college, having some college or more (aOR 0.39, 95% CI 0.26 to 0.59) was associated with lower odds of concomitant HED and self-reported opioid use., Conclusions: Among PWH, concomitant HED and self-reported opioid use are more common among individuals with depressive symptoms and substance use, structural vulnerabilities, and greater illness severity. Efforts to minimize opioid-related risk should address high-risk drinking as a modifiable risk factor for harm among these groups., (© 2022 by the Research Society on Alcoholism.)

Although opioid agonist therapy (OAT) is associated with positive health outcomes, including improved HIV management, long-term retention in OAT remains low among patients with opioid use disorder (OUD). Using data from the Veterans Aging Cohort Study (VACS), we identify variables independently associated with OAT retention overall and by HIV status. Among 7,334 patients with OUD, 13.7% initiated OAT, and 27.8% were retained 12-months later. Likelihood of initiation and retention did not vary by HIV status. Variables associated with improved likelihood of retention included receiving buprenorphine (relative to methadone), receiving both buprenorphine and methadone at some point over the 12-month period, or diagnosis of HCV. History of homelessness was associated with a lower likelihood of retention. Predictors of retention were largely distinct between patients with HIV and patients without HIV. Findings highlight the need for clinical, systems, and research initiatives to better understand and improve OAT retention., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

The timeline followback (TLFB) takes more resources to collect than the Alcohol Use Disorder Identification Test (AUDIT-C). We assessed agreement of TLFB and AUDIT-C with the biomarker phosphatidylethanol (PEth) and compared changes in TLFB and PEth among persons with HIV (PWH) using secondary data from randomized trials. We calculated operating characteristics and agreement between TLFB (> 1 and > 2 average drinks/day), AUDIT-C ≥ 4 and PEth ≥ 20 among 275 men with HIV. Median age was 57 years, 80% were African-American; and 17% white. Sixty-eight percent had PEth ≥ 20, 46% reported > 2 average drinks/day on TLFB, 61% reported > 1 average drinks/day on TLFB, and 72% had an AUDIT-C ≥ 4. Relative to PEth, sensitivity for AUDIT-C ≥ 4 was 84% (kappa = 0.36), and for TLFB > 1 average drink/day was 76% (kappa = 0.44). Change in alcohol use appeared greater using TLFB measures than PEth. Strategies to robustly assess alcohol use in PWH may require both self-report and biomarkers., (© 2021. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background and Aims: The Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) questionnaire screens for harmful drinking using a 12-month timeframe. A score of 0 is assigned to individuals who report abstaining from alcohol in the past year. However, many middle-age individuals reporting current abstinence are former drinkers (FDs). Because FDs may be more genetically prone to harmful alcohol use than lifelong abstainers (LAs) and are often combined with LAs, we evaluated the impact of differentiating them on the identification of genetic association., Design and Setting: The United Kingdom Biobank (UKBB) includes AUDIT-C and alcohol drinker status., Participants: 131 510 Europeans, including 5135 FDs., Measurements: We compared three genome-wide association (GWAS) analyses to explore the effects of removing FDs: the full AUDIT-C data, AUDIT-C data without FDs, and data from a random sample numerically matched to the data without FDs. Because prior studies show a consistent association of the ADH1B polymorphism rs1229984 with both alcohol consumption and alcohol use disorder, we compared allele frequencies for rs1229984 stratified by AUDIT-C value and FD versus LA status. Additionally, we calculated polygenic risk scores (PRS) of related diseases., Findings: The rs1229984 allele frequencies among FDs were numerically comparable to those with high AUDIT-C scores and very different from those of LAs. Removing FDs from GWAS yielded a stronger association with rs1229984 (P value after removal: 1.9 × 10 -70 vs 1.7 × 10 -65 and 2.5 × 10 -62 ), more statistically significant single nucleotide polymorphisms (SNPs) (after removal: 11 vs 9 and 8), and genomic loci (after removal: 11 vs 9 and 7). Additional independent SNPs were identified after removal of FDs: rs2817866 (PTGER3), rs7105867 (ANO3), and rs17601612 (DRD2). For PRS of alcohol use disorder and major depressive disorder, there are statistically significant differences between FDs and LAs., Conclusions: Differentiating between former drinkers and lifelong abstainers can improve Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) genome-wide association results., (Published 2021. This article is a U.S. Government work and is in the public domain in the USA.)

Background: Polypharmacy, defined as use of five or more medications concurrently, is associated with adverse health outcomes and people ageing with HIV might be at greater risk than similar uninfected individuals. We aimed to determine whether known pairwise drug interactions (KPDIs) were associated with risk of admission to hospital (hereafter referred to as hospitalisation) and medication count among people ageing with and without HIV after accounting for physiological frailty., Methods: In this observational study, we collected individual-level data for participants of the Veterans Aging Cohort Study (VACS) with HIV on antiretroviral therapy (ART) and with supressed HIV-1 RNA and people without HIV who were receiving at least one prescription medication, based on active medications in the 2009 fiscal year (ie, Oct 1, 2008, to Sept 30, 2009). We identified KPDIs among these patients by linking prescription fill and refill data with data from DrugBank (version 5.0.11). We collected data on all-cause mortality and hospitalisations between Oct 1, 2009, and March 31, 2019. We compared KPDI counts using random selection and actual patterns of use across medication counts from two to 12. We created a weighted KPDI Index on the basis of the average association of each KPDI with mortality among people ageing without HIV and used nested Cox models stratified by HIV status to estimate the association between medication count and hospitalisation, with incremental adjustments for demographics, physiological frailty, and KPDI Index., Findings: We collected data for 9186 people ageing with HIV and 37 930 individuals without HIV. 45 913 (97·4%) of 47 116 patients were men and the sample was predominantly aged 50-64 years (30 413 [64·6%]). Compared with a random sample of medications, real-world pattern of medication counts and combinations were associated with five-to-six times more KPDIs (eg, for a combination of six medications, KPDI count was 1·09 in the random sample, 5·49 in the HIV-negative population, and 7·13 in the HIV-positive population). For each additional observed medication, people ageing with HIV had approximately 2·94 additional KPDIs and comparators had approximately 2·67 additional KPDIs. Adjustment for demographics, physiological frailty, and KPDI Index reduced the association between medication count and risk of hospitalisation for people ageing with HIV (hazard ratio 1·08 [95% CI 1·07-1·09] reduced to 1·06 [1·05-1·07]) and those without HIV (1·08 [1·07-1·08] reduced to 1·04 [1·03-1·05])., Interpretation: For each additional medication, people ageing with HIV have more drug-drug interactions than those without HIV. Adjusting for known non-ART drug-drug interactions, each additional non-ART medication confers excess risk of hospitalisation for people ageing with HIV. Randomised trials will be needed to determine whether reducing these interactions improves outcomes., Funding: National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism, Department of Veterans Affairs Health Services Research & Development, and Office of Research and Development.

Longitudinal analyses of opioid use and overall disease severity among people with HIV (PWH) are lacking. We used joint-trajectory and Cox proportional hazard modeling to examine the relationship between self-reported opioid use and the Veterans Aging Cohort Study (VACS) Index 2.0, a validated measure of disease severity and mortality, among PWH engaged in care. Using data from 2002 and 2018, trajectory modeling classified 20% of 3658 PWH in low (i.e., lower risk of mortality), 40% in moderate, 28% in high, and 12% in extremely high VACS Index trajectories. Compared to those with moderate VACS Index trajectory, PWH with an extremely high trajectory were more likely to have high, then de-escalating opioid use (adjusted odds ratio [AOR], 95% confidence interval [CI] 5·17 [3·19-8·37]) versus stable, infrequent use. PWH who report high frequency opioid use have increased disease severity and mortality risk over time, even when frequency of opioid use de-escalates., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Cardiovascular implantable electronic device (CIED) has helped with advanced technological improvement in the cardiac field and has been a long-term alternative to medical management. There are different forms of CIEDs such as pacemakers, implantable cardioverter-defibrillators, and cardiac resynchronization therapy. These devices are efficient in establishing near-normal hemodynamics and circulation that ultimately aid physicians to improve the quality of life for their patients. However, there are risk factors that can result in postoperative complications, including infection, lead and pulse generator complications, heart complications, medication-related complications, and psychosocial complications. To ensure optimal outcome of CIED placement, preprocedural measures need to be in place such as matching the right candidate and using appropriate devices. This review aims to highlight the surgical techniques for CIEDs, the associated postoperative complications, and long-term health effects., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Richardson et al.)

Objective: Pain is one of the most significant causes of morbidity and disability worldwide. The efficacy of several nonpharmacological approaches for pain management has been established, but significant gaps exist between this evidence and their limited availability and use in routine clinical practice. Questions remain about their effectiveness and how best to integrate them in usual care to optimize patient-centered outcomes. Pragmatic clinical trials (PCTs) may help address this gap. Informed by the Pragmatic Explanatory Continuum Indicator Summary (PRECIS-2), we sought to describe the key features of optimized PCTs of nonpharmacological approaches for the management of pain and common co-occurring conditions., Methods: To accomplish this objective, we searched the published literature on PCTs of nonpharmacological pain management approaches from 2010-2019 and applied the PRECIS-2 criteria. We discuss key PRECIS-2 domains of interest for designing and performing PCTs and cite specific examples from the published literature as potential models for future PCTs., Results: We found 13 nonpharmacological PCTs. They were heterogeneous in size, recruitment, follow-up time, and location. The lessons learned from these studies led us to explicate key features of trials on the explanatory-pragmatic continuum across the PRECIS-2 domains that can be used by future investigators when designing their clinical trials of nonpharmacological approaches to pain management., Conclusions: We encourage the increased application of PCTs to produce timely and valuable results and products that will inform the development of safe and effective integrated pain care plans that optimize important patient-centered outcomes., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)