Antibodies to Costimulatory Receptor 4-1BB Enhance Anti-tumor Immunity via T Regulatory Cell Depletion and Promotion of CD8 T Cell Effector Function.

The costimulatory receptor 4-1BB is expressed on activated immune cells, including activated T cells. Antibodies targeting 4-1BB enhance the proliferation and survival of antigen-stimulated T cells in vitro and promote CD8 T cell-dependent anti-tumor immunity in pre-clinical cancer models. We found that T regulatory (Treg) cells infiltrating human or murine tumors expressed high amounts of 4-1BB. Intra-tumoral Treg cells were preferentially depleted by anti-4-1BB mAbs in vivo. Anti-4-1BB mAbs also promoted effector T cell agonism to promote tumor rejection. These distinct mechanisms were competitive and dependent on antibody isotype and FcγR availability. Administration of anti-4-1BB IgG2a, which preferentially depletes Treg cells, followed by either agonistic anti-4-1BB IgG1 or anti-PD-1 mAb augmented anti-tumor responses in multiple solid tumor models. An antibody engineered to optimize both FcγR-dependent Treg cell depleting capacity and FcγR-independent agonism delivered enhanced anti-tumor therapy. These insights into the effector mechanisms of anti-4-1BB mAbs lay the groundwork for translation into the clinic.

Systemic immunosuppression depletes peripheral blood regulatory B cells in patients with immune thrombocytopenia.

Regulatory B (Breg) cells are potentially implicated in the pathogenesis of immune thrombocytopenia (ITP). We analysed a prospective cohort of newly diagnosed steroid naïve ITP patients enrolled in the multicentre FLIGHT trial and found that the numbers of Bregs in their peripheral blood were similar to healthy controls. In contrast, Breg numbers were significantly reduced in ITP patients treated with systemic immunosuppression (glucocorticoids or mycophenolate mofetil). We also demonstrate that glucocorticoid treatment impairs Breg interleukin-10 production via an indirect T-cell-mediated mechanism.

Assessing Substance Use Disorder Symptoms with a Checklist among Primary Care Patients with Opioid Use Disorder and/or Long-Term Opioid Treatment: An Observational Study.

BACKGROUND: Primary care (PC) offers an opportunity to treat opioid use disorders (OUD). The Substance Use Symptom Checklist ("Checklist") can assess DSM-5 substance use disorder (SUD) symptoms in PC. OBJECTIVE: To test the psychometric properties of the Checklist among PC patients with OUD or long-term opioid therapy (LTOT) in Kaiser Permanente Washington (KPWA). DESIGN: Observational study using item response theory (IRT) and differential item functioning (DIF) analyses of measurement consistency across age, sex, race and ethnicity, and receipt of treatment. PATIENTS: Electronic health records (EHR) data were extracted for all adult PC patients visiting KPWA 3/1/15-8/30/2020 who had ≥ 1 Checklist documented and indication of either (a) clinically-recognized OUD (i.e., documented OUD diagnosis and/or OUD medication treatment) or (b) LTOT in the year prior to the checklist. MAIN MEASURE: The Checklist includes 11 items reflecting DSM-5 criteria for SUD. We described the prevalence of 2 SUD symptoms reported on the Checklist (consistent with mild-severe DSM-5 SUD). Analyses were conducted in the overall sample and in two subsamples (clinically-recognized OUD and LTOT only). KEY RESULTS: Among 2007 eligible patients, 39.9% endorsed ≥ 2 SUD symptoms (74.3% in the clinically-recognized OUD subsample and 13.1% in LTOT subsample). IRT indicated that a unidimensional model for the 11 checklist items had excellent fit (comparative fit index = 0.998) with high item-level discrimination parameters for the overall sample and both subsamples. DIF across age, race and ethnicity, and treatment was observed for one item each, but had minimal impact on expected number of criteria (0-11) patients endorse. CONCLUSIONS: The Substance Use Symptom Checklist measured SUD symptoms consistent with DSM-5 conceptualization (scaled, unidimensional) in patients with clinically-recognized OUD and LTOT and had similar measurement properties across demographic subgroups. The Checklist may support symptom assessment in patients with OUD and diagnosis in patients with LTOT.

Pain Care Disparities and the Use of Virtual Care Among Racial-Ethnic Minority Groups During COVID-19.

BACKGROUND AND OBJECTIVE: COVID-19 led to an unprecedented reliance on virtual modalities to maintain care continuity for patients living with chronic pain. We examined whether there were disparities in virtual specialty pain care for racial-ethnic minority groups during COVID-19. DESIGN AND PARTICIPANTS: This was a retrospective national cohort study with two comparison groups: primary care patients with chronic pain seen immediately prior to COVID-19 (3/1/19-2/29/20) (N = 1,649,053) and a cohort of patients seen in the year prior (3/1/18-2/28-19; n = 1,536,954). MAIN MEASURES: We assessed use of telehealth (telephone or video) specialty pain care, in-person care specialty pain care, and any specialty pain care for both groups at 6 months following cohort inclusion. We used quasi-Poisson regressions to test associations between patient race and ethnicity and receipt of care. KEY RESULTS: Prior to COVID-19, there were Black-White (RR = 0.64, 95% CI [0.62, 0.67]) and Asian-White (RR = 0.63, 95% CI [0.54, 0.75]) disparities in telehealth use, and these lessened during COVID-19 (Black-White: RR = 0.75, 95% CI [0.73, 0.77], Asian-White: RR = 0.81, 95% CI [0.74, 0.89]) but did not disappear. Individuals identifying as American Indian/Alaska Native used telehealth less than White individuals during early COVID-19 (RR = 0.98, 95% CI [0.85, 1.13] to RR = 0.87, 95% CI [0.79, 0.96]). Hispanic/Latinx individuals were less likely than non-Hispanic/Latinx individuals to use telehealth prior to COVID-19 but more likely during early COVID-19 (RR = 0.70, 95% CI [0.66, 0.75] to RR = 1.06, 95% CI [1.02, 1.09]). Disparities in virtual pain care occurred over the backdrop of overall decreased specialty pain care during the early phase of the pandemic (raw decrease of n = 17,481 specialty care encounters overall from pre-COVID to COVID-era), including increased disparities in any VA specialty pain care for Black (RR = 0.81, 95% CI [0.80, 0.83] to RR = 0.79, 95% CI [0.77, 0.80]) and Asian (RR = 0.91, 95% CI [0.86, 0.97] to RR = 0.88, 95% CI [0.82, 0.94]) individuals. CONCLUSIONS: Disparities in virtual specialty pain care were smaller during the early phases of the COVID-19 pandemic than prior to the pandemic but did not disappear entirely, despite the rapid growth in telehealth. Targeted efforts to increase access to specialty pain care need to be concentrated among racial-ethnic minority groups.

"I Thought Cancer was a Tobacco Issue": Perspectives of Veterans with and without HIV on Cancer and Other Health Risks Associated with Alcohol and Tobacco/Nicotine Use.

U.S. Veterans and people living with HIV (PWH) experience higher rates of unhealthy alcohol and tobacco/nicotine use than non-Veterans and people without HIV (PWoH). Both groups are susceptible to adverse health outcomes associated with alcohol and tobacco/nicotine use. We explored awareness of alcohol- and tobacco/nicotine-related cancer and immune health risks among Veterans Health Administration (VA) patients with and without HIV. Among a sample of 41 (46% PWH; 73% male; 39% Black) purposively-selected VA patients receiving care 2020-2021 we conducted semi-structured interviews via telephone; interviews were recorded, transcribed and analyzed using a Rapid Assessment Process. Purposive selection was based on HIV status, alcohol and/or tobacco/nicotine use, and demographics. Among participants, 66% reported current smoking, and most screened positive for unhealthy alcohol use. Participants had high awareness of cancer and other health risks related to smoking but low awareness of synergistic risks and cancer risks associated with alcohol use despite awareness of a range of other alcohol-related risks. Awareness of alcohol and/or tobacco/nicotine's impacts on the immune system was variable. Findings did not distinctly differ between PWH and PWoH. Low awareness of alcohol-related cancer risk, risks of co-occurring use, and varying awareness of the impacts of alcohol and tobacco/nicotine on the immune system suggest a need for improved messaging regarding substance use-related cancer and immune risk. This may be especially important among PWH, for whom the prevalence and adverse effects of alcohol and tobacco use, and immune dysfunction are higher.

Socioeconomic Status and CD4 Count Among People with HIV Who Inject Drugs in St. Petersburg, Russia.

Lack of access to resources is a "fundamental cause" of poor HIV outcomes across the care cascade globally and may have the greatest impact on groups with co-existing marginalized identities. In a sample of people living with HIV (PWH) who inject drugs and were not on antiretroviral therapy (ART), we explored associations between access to resources and HIV severity. Fundamental Cause Theory (FCT) sees socioeconomic status/access to resources as a root cause of disease and emphasizes that individuals with limited resources have fewer means to mitigate health risks and implement protective behaviors, which ultimately generates disparities in health outcomes. Guided by the FCT, we hypothesized that resource depletion (primary aim) and lower income (secondary aim) were associated with increased HIV severity. Using baseline data from the Linking Infectious and Narcology Care (LINC-II) trial of ART-naive PWH who inject drugs in St. Petersburg, Russia (n = 225), we examined the association between "past year resource runout" (yes vs. no) and "low-income (< 300 USD a month)" and the outcome HIV severity (CD4 count, continuous). We fit two separate linear regression models adjusted for gender, age, time since HIV diagnosis, and prior ART use. Participants had a mean age of 37.5 years and were 60% male. Two thirds (66%) reported resource depletion, and 30% had income below 300 USD a month. Average CD4 count was 416 cells/mm3 (SD 285). No significant association was identified between either resource depletion or low-income and HIV severity (adjusted mean difference in CD4 count for resource depletion: - 4.16, 95% CI - 82.93, 74.62; adjusted mean difference in CD4 count for low-income: 68.13, 95% CI - 15.78, 152.04). Below-average income and running out of resources were common among PWH who inject drugs and are not on ART in St. Petersburg, Russia. Resource depletion and low-income were not significantly associated with HIV disease severity as captured by CD4 count. The nuanced relationship between socioeconomic status and HIV severity among people with HIV who inject drugs and not on ART merits further examination in a larger sample.

Patient and Provider Perspectives on Processes of Engagement in Outpatient Treatment for Opioid Use Disorder: A Scoping Review.

Effective treatment for opioid use disorder (OUD) is available, but patient engagement is central to achieving care outcomes. We conducted a scoping review to describe patient and provider-reported strategies that may contribute to patient engagement in outpatient OUD care delivery. We searched PubMed and Scopus for articles reporting patient and/or provider experiences with outpatient OUD care delivery. Analysis included: (1) describing specific engagement strategies, (2) mapping strategies to patient-centered care domains, and (3) identifying themes that characterize the relationship between engagement and patient-centered care. Of 3,222 articles screened, 30 articles met inclusion criteria. Analysis identified 14 actionable strategies that facilitate patient engagement and map to all patient-centered care domains. Seven themes emerged that characterize interpersonal approaches to OUD care engagement. Interpersonal interactions between patients and providers play a pivotal role in encouraging engagement throughout OUD treatment. Future research is needed to further evaluate promising engagement strategies.

Enhanced Identification of Hispanic Ethnicity Using Clinical Data: A Study in the Largest Integrated United States Health Care System.

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.

Integrating Routine Screening for Opioid Use Disorder into Primary Care Settings: Experiences from a National Cohort of Clinics.

BACKGROUND: The U.S. Preventive Services Task Force recommends routine population-based screening for drug use, yet screening for opioid use disorder (OUD) in primary care occurs rarely, and little is known about barriers primary care teams face. OBJECTIVE: As part of a multisite randomized trial to provide OUD and behavioral health treatment using the Collaborative Care Model, we supported 10 primary care clinics in implementing routine OUD screening and conducted formative evaluation to characterize early implementation experiences. DESIGN: Qualitative formative evaluation. APPROACH: Formative evaluation included taking detailed observation notes at implementation meetings with individual clinics and debriefings with external facilitators. Observation notes were analyzed weekly using a Rapid Assessment Process guided by the Consolidated Framework for Implementation Research, with iterative feedback from the study team. After clinics launched OUD screening, we conducted structured fidelity assessments via group interviews with each site to evaluate clinic experiences with routine OUD screening. Data from observation and structured fidelity assessments were combined into a matrix to compare across clinics and identify cross-cutting barriers and promising implementation strategies. KEY RESULTS: While all clinics had the goal of implementing population-based OUD screening, barriers were experienced across intervention, individual, and clinic setting domains, with compounding effects for telehealth visits. Seven themes emerged characterizing barriers, including (1) challenges identifying who to screen, (2) complexity of the screening tool, (3) staff discomfort and/or hesitancies, (4) workflow barriers that decreased screening follow-up, (5) staffing shortages and turnover, (6) discouragement from low screening yield, and (7) stigma. Promising implementation strategies included utilizing a more universal screening approach, health information technology (HIT), audit and feedback, and repeated staff trainings. CONCLUSIONS: Integrating population-based OUD screening in primary care is challenging but may be made feasible via implementation strategies and tailored practice facilitation that standardize workflows via HIT, decrease stigma, and increase staff confidence regarding OUD.

Datamining approaches for examining the low prevalence of N-acetylglutamate synthase deficiency and understanding transcriptional regulation of urea cycle genes.

Ammonia, which is toxic to the brain, is converted into non-toxic urea, through a pathway of six enzymatically catalyzed steps known as the urea cycle. In this pathway, N-acetylglutamate synthase (NAGS, EC 2.3.1.1) catalyzes the formation of N-acetylglutamate (NAG) from glutamate and acetyl coenzyme A. NAGS deficiency (NAGSD) is the rarest of the urea cycle disorders, yet is unique in that ureagenesis can be restored with the drug N-carbamylglutamate (NCG). We investigated whether the rarity of NAGSD could be due to low sequence variation in the NAGS genomic region, high NAGS tolerance for amino acid replacements, and alternative sources of NAG and NCG in the body. We also evaluated whether the small genomic footprint of the NAGS catalytic domain might play a role. The small number of patients diagnosed with NAGSD could result from the absence of specific disease biomarkers and/or short NAGS catalytic domain. We screened for sequence variants in NAGS regulatory regions in patients suspected of having NAGSD and found a novel NAGS regulatory element in the first intron of the NAGS gene. We applied the same datamining approach to identify regulatory elements in the remaining urea cycle genes. In addition to the known promoters and enhancers of each gene, we identified several novel regulatory elements in their upstream regions and first introns. The identification of cis-regulatory elements of urea cycle genes and their associated transcription factors holds promise for uncovering shared mechanisms governing urea cycle gene expression and potentially leading to new treatments for urea cycle disorders.

Following the feeder: A global synthesis of disturbance-based foraging associations of birds.

Species interactions link animal behaviour to community structure and macroecological patterns of biodiversity. One common type of trophic species interaction is disturbance foraging-the act of obtaining food at a disturbance created by another organism. Disturbance foraging is widespread across the animal kingdom, especially among birds, yet previous research has been largely anecdotal and we still lack a synthetic understanding of how this behaviour varies geographically, phylogenetically and ecologically. To address these gaps, we conducted a comprehensive literature review to test focal hypotheses about disturbance foraging behaviour in birds. We found that avian disturbance foraging was geographically ubiquitous, occurring in both aquatic and terrestrial habitats across six continents and four oceans. Consistent with predictions based on established species diversity gradients in different habitat types, the majority of terrestrial observations occurred at tropical latitudes, whereas aquatic observations took place most frequently in temperate marine waters. Although disturbance foraging was widespread across the avian phylogeny, contrary to our prediction, the behaviour was also conserved phylogenetically (Pagel's λ = 0.7) and clustered within suboscine landbirds in terrestrial environments and seabirds in aquatic environments. Similarly, although disturbers were taxonomically diverse as we predicted, interactions were unexpectedly dominated by swarm-raiding ants in terrestrial environments and cetaceans in aquatic environments. Diet and body mass were also important predictors of disturbance foraging associations: Responders followed disturbers with similar diets and larger body sizes. Overall, our hypothesis-testing framework provides insight into the importance of geography, phylogeny and ecology as predictors of disturbance foraging behaviour. We anticipate that this comprehensive assessment of disturbance foraging will serve to generate additional hypotheses and spark future research and management considerations about this fascinating but poorly studied suite of species interactions, especially as biotic interactions face unprecedented risks in our rapidly changing world.

Co-infection with Leucocytozoon and Other Haemosporidian Parasites Increases with Latitude and Altitude in New World Bird Communities.

Establishing how environmental gradients and host ecology drive spatial variation in infection rates and diversity of pathogenic organisms is one of the central goals in disease ecology. Here, we identified the predictors of concomitant infection and lineage richness of blood parasites in New Word bird communities. Our multi-level Bayesian models revealed that higher latitudes and elevations played a determinant role in increasing the probability of a bird being co-infected with Leucocytozoon and other haemosporidian parasites. The heterogeneity in both single and co-infection rates was similarly driven by host attributes and temperature, with higher probabilities of infection in heavier migratory host species and at cooler localities. Latitude, elevation, host body mass, migratory behavior, and climate were also predictors of Leucocytozoon lineage richness across the New World avian communities, with decreasing parasite richness at higher elevations, rainy and warmer localities, and in heavier and resident host species. Increased parasite richness was found farther from the equator, confirming a reverse Latitudinal Diversity Gradient pattern for this parasite group. The increased rates of Leucocytozoon co-infection and lineage richness with increased latitude are in opposition with the pervasive assumption that pathogen infection rates and diversity are higher in tropical host communities.

Characterizing Unhealthy Alcohol Use Patterns and Their Association with Alcohol Use Reduction and Alcohol Use Disorder During Follow-Up in HIV Care.

Outcomes of PWH with unhealthy alcohol use, such as alcohol use reduction or progression to AUD, are not well-known and may differ by baseline patterns of unhealthy alcohol use. Among 1299 PWH screening positive for NIAAA-defined unhealthy alcohol use in Kaiser Permanente Northern California, 2013-2017, we compared 2-year probabilities of reduction to low-risk/no alcohol use and rates of new AUD diagnoses by baseline use patterns, categorized as exceeding: only daily limits (72% of included PWH), only weekly limits (17%), or both (11%), based on NIAAA recommendations. Overall, 73.2% (95% CI 70.5-75.9%) of re-screened PWH reduced to low-risk/no alcohol use over 2 years, and there were 3.1 (95% CI 2.5-3.8%) new AUD diagnoses per 100 person-years. Compared with PWH only exceeding daily limits at baseline, those only exceeding weekly limits and those exceeding both limits were less likely to reduce and likelier to be diagnosed with AUD during follow-up. PWH exceeding weekly drinking limits, with or without exceeding daily limits, may have a potential need for targeted interventions to address unhealthy alcohol use.

Temporal dynamics of normalization reweighting.

For decades, neural suppression in early visual cortex has been thought to be fixed. But recent work has challenged this assumption by showing that suppression can be reweighted based on recent history; when pairs of stimuli are repeatedly presented together, suppression between them strengthens. Here we investigate the temporal dynamics of this process using a steady-state visual evoked potential (SSVEP) paradigm that provides a time-resolved, direct index of suppression between pairs of stimuli flickering at different frequencies (5 and 7 Hz). Our initial analysis of an existing electroencephalography (EEG) dataset (N = 100) indicated that suppression increases substantially during the first 2-5 seconds of stimulus presentation (with some variation across stimulation frequency). We then collected new EEG data (N = 100) replicating this finding for both monocular and dichoptic mask arrangements in a preregistered study designed to measure reweighting. A third experiment (N = 20) used source-localized magnetoencephalography and found that these effects are apparent in primary visual cortex (V1), consistent with results from neurophysiological work. Because long-standing theories propose inhibition/excitation differences in autism, we also compared reweighting between individuals with high versus low autistic traits, and with and without an autism diagnosis, across our three datasets (total N = 220). We find no compelling differences in reweighting that are associated with autism. Our results support the normalization reweighting model and indicate that for prolonged stimulation, increases in suppression occur on the order of 2-5 seconds after stimulus onset.

Association of Race and Ethnicity With Initial Prescription of Antiretroviral Therapy Among People With HIV in the US.

Importance: Integrase strand transfer inhibitor (INSTI)-containing antiretroviral therapy (ART) is currently the guideline-recommended first-line treatment for HIV. Delayed prescription of INSTI-containing ART may amplify differences and inequities in health outcomes. Objectives: To estimate racial and ethnic differences in the prescription of INSTI-containing ART among adults newly entering HIV care in the US and to examine variation in these differences over time in relation to changes in treatment guidelines. Design, Setting, and Participants: Retrospective observational study of 42 841 adults entering HIV care from October 12, 2007, when the first INSTI was approved by the US Food and Drug Administration, to April 30, 2019, at more than 200 clinical sites contributing to the North American AIDS Cohort Collaboration on Research and Design. Exposures: Combined race and ethnicity as reported in patient medical records. Main Outcomes and Measures: Probability of initial prescription of ART within 1 month of care entry and probability of being prescribed INSTI-containing ART. Differences among non-Hispanic Black and Hispanic patients compared with non-Hispanic White patients were estimated by calendar year and time period in relation to changes in national guidelines on the timing of treatment initiation and recommended initial treatment regimens. Results: Of 41 263 patients with information on race and ethnicity, 19 378 (47%) as non-Hispanic Black, 6798 (16%) identified as Hispanic, and 13 539 (33%) as non-Hispanic White; 36 394 patients (85%) were male, and the median age was 42 years (IQR, 30 to 51). From 2007-2015, when guidelines recommended treatment initiation based on CD4+ cell count, the probability of ART initiation within 1 month of care entry was 45% among White patients, 45% among Black patients (difference, 0% [95% CI, -1% to 1%]), and 51% among Hispanic patients (difference, 5% [95% CI, 4% to 7%]). From 2016-2019, when guidelines strongly recommended treating all patients regardless of CD4+ cell count, this probability increased to 66% among White patients, 68% among Black patients (difference, 2% [95% CI, -1% to 5%]), and 71% among Hispanic patients (difference, 5% [95% CI, 1% to 9%]). INSTIs were prescribed to 22% of White patients and only 17% of Black patients (difference, -5% [95% CI, -7% to -4%]) and 17% of Hispanic patients (difference, -5% [95% CI, -7% to -3%]) from 2009-2014, when INSTIs were approved as initial therapy but were not yet guideline recommended. Significant differences persisted for Black patients (difference, -6% [95% CI, -8% to -4%]) but not for Hispanic patients (difference, -1% [95% CI, -4% to 2%]) compared with White patients from 2014-2017, when INSTI-containing ART was a guideline-recommended option for initial therapy; differences by race and ethnicity were not statistically significant from 2017-2019, when INSTI-containing ART was the single recommended initial therapy for most people with HIV. Conclusions and Relevance: Among adults entering HIV care within a large US research consortium from 2007-2019, the 1-month probability of ART prescription was not significantly different across most races and ethnicities, although Black and Hispanic patients were significantly less likely than White patients to receive INSTI-containing ART in earlier time periods but not after INSTIs became guideline-recommended initial therapy for most people with HIV. Additional research is needed to understand the underlying racial and ethnic differences and whether the differences in prescribing were associated with clinical outcomes.

Longitudinal analysis of the prevalence and correlates of heavy episodic drinking and self-reported opioid use among a national cohort of patients with HIV.

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.

Effects of a lifestyle intervention on depression and anxiety among adults at risk for diabetes in India: A secondary analysis of the Kerala Diabetes Prevention Program.

The impact of lifestyle interventions on diabetes and mental health conditions have been documented among people with diabetes. However, the mental health benefits of lifestyle interventions designed for diabetes prevention have not been systematically investigated among people at high risk of diabetes, particularly in low- and middle-income countries. We examined the effects of a 12-month peer support lifestyle intervention designed for diabetes prevention on depression and anxiety symptomology in the sample population of the Kerala Diabetes Prevention Program. Mixed-effects linear regression models were used to examine the effect of the intervention on depression and anxiety scores at 12 and 24 months in the total sample of 1007 adults at risk for diabetes and among those with mild-severe depressive or anxiety symptoms at baseline (n = 326 for depression; n = 203 for anxiety). Among all participants, the intervention group had a significantly higher reduction of depressive symptoms as compared to the control group at 12 months (mean diff score = -0.51; 95% CI: -0.95, -0.07; P = 0.02). This effect was not sustained at 24 months. There were no significant intervention effects for anxiety. Among those with mild-severe symptoms at baseline, the intervention group had a significantly higher reduction of depressive symptoms (mean diff score = -1.55; 95% CI -2.50, -0.6; P = 0.001) and anxiety symptoms (mean diff score = -1.64; 95% CI -2.76, -0.52; P = 0.004) at 12 months. The effect was sustained at 24 months for depression, but not anxiety. Lifestyle interventions designed for prevention of diabetes might improve depressive and anxiety symptoms in the short-term, particularly among those with mild-severe symptoms.

Patient-Reported Bothersome Symptoms Attributed to Alcohol Use Among People With and Without HIV.

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.

Functional Impairment and Cognitive Symptoms Among People with HIV Infection on Chronic Opioid Therapy for Pain: The Impact of Gabapentin and Other Sedating Medications.

Gabapentin is associated with dizziness, falls, and somnolence yet commonly prescribed to people with HIV (PWH) treated with chronic opioid therapy (COT). Physical function and cognition are understudied when prescribed together. Among PWH on COT, we evaluated whether co-prescribed gabapentin is associated with (a) functional impairment; (b) trouble thinking clearly; and (c) difficulty controlling drowsiness using logistic regression models adjusted for prescribed opioid dose, other (non-gabapentin) sedating medication, substance use disorder, and mental/physical health indicators in a cross-sectional study. Among 166 participants, 40% were prescribed gabapentin, 41% reported functional impairment, 41% trouble thinking clearly, and 38% difficulty controlling drowsiness. Gabapentin co-prescribed with COT was significantly associated with trouble thinking clearly but not with functional impairment or difficulty controlling drowsiness. Clinicians should be cognizant of potential problems with thinking clearly when co-prescribing gabapentin and opioid medication.

Program Adaptations to Provide Harm Reduction Services During the COVID-19 Pandemic: A Qualitative Study of Syringe Services Programs in the U.S.

Syringe services programs (SSPs) are essential to preventing injection drug use-related infections and overdose death among people who use drugs (PWUD). The novel coronavirus (COVID-19) pandemic initially impeded SSPs' operations. To effectively support these programs, information is needed regarding SSPs' experiences adapting their services and the challenges posed by COVID-19. We conducted qualitative interviews with leadership and staff from a sample of 31 U.S. SSPs. Respondents discussed urgent concerns including reduced reach of services, suspended HIV/hepatitis C testing, high COVID-19 risk among PWUD, and negative impacts of isolation on overdose and mental health. They also noted opportunities to improve future services for PWUD, including shifting to evidence-based distribution practices and maintaining regulatory changes that increased access to opioid use disorder medications post-pandemic. Findings can inform efforts to support SSPs in restoring and expanding services, and provide insight into SSPs' role in engaging PWUD during the COVID-19 response and future emergencies.

RESUMEN: Los programas de servicios de jeringas (reconocido como SSP en inglés) son esenciales para prevenir las infecciones relacionadas con el consumo de drogas inyectables y la muerte por sobredosis entre las personas que consumen drogas (reconocidos como PWUD en ingles). La nueva pandemia del coronavirus (COVID-19) inicialmente impidió las operaciones de los SSP. Para apoyar eficazmente estos programas, se necesita información sobre las experiencias de los SSP que adaptan sus servicios y los desafíos que plantea COVID-19. Realizamos entrevistas cualitativas con el liderazgo y el personal de una muestra de 31 SSPs de EE.UU. Los encuestados discutieron las preocupaciones urgentes, incluyendo la reducción del alcance de los servicios, la suspensión de las pruebas de VIH/hepatitis C, el alto riesgo de COVID-19 entre la PWUD, y los impactos negativos del aislamiento en las sobredosis y la salud mental. También identificaron las oportunidades de mejorar los servicios futuros para las PWUD, incluyendo el cambio a prácticas de distribución basadas en evidencias y el mantenimiento de cambios regulatorios que aumentaran el acceso a medicamentos para el trastorno por consumo de opiáceos después de la pandemia. La información que se encontró en este estudio se puede utilizar junto los esfuerzos para apoyar a los SSP en la restauración y expansión de los servicios, y proporcionar información sobre el papel de los SSP en la participación de PWUD durante la respuesta covid-19 futuras emergencias.