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Women who inject drugs (WWID) are disproportionately affected by HIV and experience multiple barriers to PrEP use. We conducted a mixed methods study to assess PrEP awareness, interest, and use, and determinants of PrEP utilization among WWID at three community sites in Seattle, Washington from March-May 2023. Participants were ≥ 18 years old, spoke English, identified as women, had a history of injecting drugs, and self-reported a negative or unknown HIV status. We describe survey participant characteristics (n = 30) by PrEP candidacy based on behaviors associated with HIV acquisition. We concurrently recruited 16 WWID for semi-structured interviews, which were analyzed using the Rapid Assessment Process. Survey and interview data were triangulated to enhance interpretations. Among 30 WWID, 25 (83%) were PrEP candidates, of whom 19 (76%) had heard about PrEP; only 2 (8%) were currently using PrEP. Among PrEP candidates, 13 (57%) reported interest in daily oral PrEP and almost half (n = 12, 48%) reported interest in injectable PrEP. Qualitative data revealed cursory PrEP knowledge and a strong interest in daily oral and injectable PrEP among those who perceived they were at risk for HIV. Several barriers to PrEP use were noted including housing instability, adherence challenges, limited perceived risk, and competing priorities like safety and substance use. While most WWID were aware of PrEP, qualitative data suggested significant misconceptions about PrEP, and many described complex, intersecting barriers to use. Our findings highlight the need for increased low-barrier, population-specific interventions to improve uptake and sustained use of PrEP among WWID., Competing Interests: Declarations. Competing Interests: The authors have no competing interests to declare that are relevant to the content of this article., (© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Substance use is associated with decreased antiretroviral therapy (ART) adherence among people with HIV (PWH). Adherence plays a significant role in mediating the negative effects of substance use on HIV suppression and is a principal modifiable patient-level factor in improving HIV suppression and reducing ART drug resistance. Understanding substance use and ART adherence, particularly with rapidly changing substance use epidemiology and ART regimens, is vital to improving HIV care. Among 10,557 PWH (2010-2021) from 8 academic clinical sites nationally we examined longitudinal associations of substance use severity and number of substances used (measured using AUDIT-C and modified ASSIST) with patient-reported ART adherence (visual analog scale). Alcohol (68% any use, 18% unhealthy use [AUDIT-C > 4 men, > 3 women]), marijuana (33%), and methamphetamine (9%) use were most reported. Polysubstance use was common (32%). Both higher severity substance use and higher number of substances used were associated with lower ART adherence. Severity of methamphetamine use had the strongest dose-response association with ART adherence (low severity [ASSIST 1-3]: -3.05%, 95% CI: -4.23%, -1.87%; moderate [ASSIST 4-26]: -6.20%, 95% CI: -7.08%, -5.33%; high [ASSIST > 26]: -10.77%, 95% CI: -12.76%, -8.78%). Severe substance use, especially methamphetamine, and higher number of illicit drugs used were associated with declines in adherence at levels that were likely clinically meaningful in the modern era of ART. Findings support integrating substance use care with HIV care and potential benefits of harm reduction strategies for improving adherence such as encouraging lower levels of substance use and fewer number of substances used., Competing Interests: Declarations. Conflict of Interest: The authors have no relevant conflicts of interests to declare. Ethical Approval and informed consent: All sites have approval from Human Subjects committees at their local institution for the CNICS protocol. Informed consent was obtained from all individuals to participate in CNICS. All data submitted to the CNICS Data Repository are deidentified. No additional formal consent was required for this secondary data analysis of existing data in the CNICS Data Repository. This article does not contain any studies with animals., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Unhealthy alcohol use is an independent, modifiable risk factor for HIV, but limited research addresses alcohol use and HIV prevention synergistically. Groups that experience chronic stigma, discrimination, and/or other marginalization, such as sexual and gender minoritized groups, may have enhanced HIV risk related to unhealthy alcohol use. We described awareness of and experiences with pre-exposure prophylaxis (PrEP) among a community sample of Veterans reporting unhealthy alcohol use (relative to those without), overall and across self-reported sexual orientation and gender identity., Methods: Using data collected from a national online survey of Veterans recruited via Facebook ads, community organizations, and listservs, we assessed variation in four PrEP outcomes (knowledge, experience, willingness, and conversations with doctors) across patterns of unhealthy alcohol use among all respondents reporting any lifetime drinking (n = 1,041) and then within sexual orientation and gender identity groups using Chi-square or Fisher's exact tests., Results: Among 1,041 eligible Veterans, 440 (42%) screened positive for unhealthy alcohol use. Veterans with unhealthy alcohol use were not more likely to have heard of PrEP (58.2% vs. 55.4%, p = 0.37), but trended toward more likely to have taken PrEP (7.5% vs. 5.0%, p = 0.09), to be willing to take PrEP (30.5% vs. 27.6%, p = 0.06), and to have spoken with a doctor about PrEP (11.4% vs. 7.7%, p = 0.04). Those with heavy episodic drinking also trended toward higher prevalence of PrEP awareness (60.0% vs. 54.6%, p = 0.09), and were more likely to have taken PrEP (8.3% vs. 4.7%, p = 0.02), to be willing to use PrEP (34.6% vs. 25.5%, p < 0.01), and to have had conversations with doctors about PrEP (12.7% vs. 7.2%, p < 0.01). Similar patterns were observed for severe unhealthy alcohol use and past-year frequent heavy episodic drinking. Generally, sexual/gender minoritized Veterans with unhealthy alcohol use reported more PrEP-affirming responses than those without but associations with unhealthy alcohol use were similar., Conclusions: Unhealthy alcohol use was prevalent, particularly among Veterans with minoritized sexual orientation/gender identity, but not clearly linked to increased PrEP-literacy and use despite its known status as an HIV risk factor. Across groups, > 25% of individuals were willing to take PrEP. Interventions targeting both alcohol use and HIV prevention should capitalize on this., Competing Interests: Declarations. Ethics approval and consent to participate: Informed consent was obtained from all study participants. All study procedures were approved by the VA Puget Sound Healthcare System IRB. Consent for publication: Not applicable. Competing interests: The authors declare that they have no competing interests., (© 2025. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Syringe services programs (SSPs) provide critical evidence-based public health services that decrease harms from drug use for people who use drugs (PWUD). Many SSPs have experienced significant and evolving COVID-19-related disruptions. We aimed to characterize the impacts of COVID-19 on SSP operations in the United States approximately two years into the pandemic., Participating sites, selected from a national sample of SSPs, completed a semi-structured interview via teleconference and brief electronic survey evaluating the impacts of COVID-19 on program operations. Data collection explored program financing, service delivery approaches, and perspectives on staff morale two years into the pandemic. Interview data were analyzed qualitatively using Rapid Assessment Process. Survey data were analyzed using descriptive statistics and triangulated with qualitative findings., Twenty-five SSPs completed the interview and survey between April - June 2022. Triangulation of qualitative and quantitative data characterized the dynamic ways that demand for SSP services has evolved throughout the pandemic, and how approaches to care delivery have increased in flexibility and participant-centeredness. However, SSPs expressed worry about longer-term barriers to program participant and staff engagement, and a mismatch between available programmatic resources and the "new normal" of service delivery needs., The COVID-19 pandemic has had lasting impacts on multiple facets of syringe service delivery. While SSPs consistently meet barriers with ingenuity, greater programmatic and staff support is needed to ensure SSPs can continue to meet the changing public health needs for PWUD.

Cellular plasticity in prostate cancer promotes treatment resistance. Several independent studies have used mouse models, single-cell RNA sequencing, and genetic lineage tracing approaches to characterize cellular differentiation and plasticity during prostate organogenesis, homeostasis and androgen-mediated tissue regeneration. We review these findings and recent work using immune-competent genetically-engineered mouse models to characterize cellular plasticity and clonal dynamic changes during prostate cancer progression. Collectively these studies highlight the influence of the tumor microenvironment and the function of epigenetic regulators in promoting cellular plasticity. How the epigenetic alternations that promote cell plasticity affect tumor immunogenicity remains an active area of research with implications for disease treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Opioid use disorder (OUD) care engagement rates in primary care (PC) settings are often low. Little is known about PC team experiences when delivering OUD treatment and potential factors that influence their capacity to engage patients in treatment. Exploring PC team experiences may inform needed supports that can optimize OUD care delivery and improve outcomes for patients with OUD., Objective: We explored multidisciplinary PC team perspectives on barriers and facilitators to engaging patients in OUD treatment., Design: Qualitative study using in-depth interviews., Participants: Primary care clinical teams., Approach: We conducted semi-structured interviews (n = 35) with PC team members involved in OUD care delivery, recruited using a combination of criterion and maximal variation sampling. Data collection and analysis were informed by existing theoretical literature about patient engagement, specifically that patient engagement is influenced by factors across individual (patient, provider), interpersonal (patient-provider), and health system domains. Interviews were professionally transcribed and doubled-coded using a coding schema based on the interview guide while allowing for emergent codes. Coding was iteratively reviewed using a constant comparison approach to identify themes and verified with participants and the full study team., Key Results: Analysis identified five themes that impact PC team ability to engage patients effectively, including limited patient contact (e.g., phone, text) in between visits, varying levels of provider confidence to navigate OUD treatment discussions, structural factors (e.g., schedules, productivity goals) that limited provider time, the role of team-based approaches in lessening discouragement and feelings of burnout, and lack of shared organizational vision for reducing harms from OUD., Conclusions: While the capacity of PC teams to engage patients in OUD care is influenced across multiple levels, some of the most promising opportunities may involve addressing system-level factors that limit PC team time and collaboration and promoting organizational alignment on goals for OUD treatment., Competing Interests: Declarations:. Conflict of Interest:: The authors do not have any personal, professional, or financial conflicts of interest to disclose for this work. The authors did not work with or were otherwise influenced by any external sponsors for this work. Dr. Saxon has received travel support from Alkermes, Inc., consulting fees from Indivior, Inc., and royalties from UpToDate, Inc. Anna Ratzliff, MD, PhD, receives royalties from Wiley for her book on integrated care., (© 2024. The Author(s), under exclusive licence to Society of General Internal Medicine.)

Abstract: Climate change and the opioid epidemic in combination may pose significant challenges for individuals with opioid use disorder due to potential disruptions in access to essential addiction treatment services caused by extreme weather events. Despite concerns over the escalating health impacts of climate change, limited research has documented and explored the vulnerability of patients enrolled in opioid treatment programs to disruptions caused by climate change and particularly extreme cold events. In this commentary, we describe the impact of a catastrophic flooding event during record-setting cold temperatures at an opioid treatment program in Seattle, WA. By examining this event, we highlight the potential vulnerabilities the methadone treatment infrastructure faces regarding climate change and future extreme weather events. In doing so, we hope to draw attention to a critical need for research that describes, plans for, and addresses disruptions to opioid use disorder treatment resulting from climate change-related weather events., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 American Society of Addiction Medicine.)

Objective: This study aimed to describe initial experiences and lessons learned conducting a trial focused on recruiting racially and ethnically diverse hospitalized patients with untreated alcohol use disorder (AUD)., Methods: The parent trial is comparing the effectiveness of strategies including Brief Negotiation Interview (BNI), facilitated initiation of medications for AUD, and computer-based training for cognitive behavioral therapy (CBT4CBT) on AUD treatment engagement post-hospitalization. Guided by the Framework for Reporting Adaptations and Modifications-Enhanced, we catalogued protocol changes and evaluated outcomes using study and electronic medical record data during the first 18 months of recruitment., Results: Recipients: (1) Selected entry criterion to intentionally include individuals most likely impacted by structural racism, (2) developed multipronged recruitment approaches, and (3) selected bilingual, multicultural, and ethnically diverse research staff. Intervention: (1) Added scripts in the BNI to consider how cultural factors influence and how racism may impact, alcohol use, and AUD treatment engagement, (2) offered tablets as a compensation alternative with support for CBT4CBT initiation (as relevant), and (3) anticipate and troubleshoot internet access challenges. Setting: (1) Identified community-based AUD treatment options with Spanish-speaking services and (2) identified resources to address social determinants of health. Study: (1) Audited data to monitor whether diverse enrollment is occurring. Among n = 132 randomized as of March 1, 2024, 25% endorsed Black, 24% endorsed Latine, 58% endorsed White, 1% endorsed Indigenous, and 15% endorsed race not listed or declined to disclose. We observed no difference by race or ethnicity in recruitment or retention experiences., Conclusions: Multilevel practices within a hospital-based AUD-focused trial can promote recruitment and retention of a racially and ethnically diverse sample., Competing Interests: The other authors report no conflicts of interest., (Copyright © 2024 American Society of Addiction Medicine.)

Senescent neural progenitor cells have been identified in brain lesions of people with progressive multiple sclerosis (PMS). However, their role in disease pathobiology and contribution to the lesion environment remains unclear. By establishing directly induced neural stem/progenitor cell (iNSC) lines from PMS patient fibroblasts, we studied their senescent phenotype in vitro. Senescence was strongly associated with inflammatory signaling, hypermetabolism, and the senescence-associated secretory phenotype (SASP). PMS-derived iNSCs displayed increased glucose-dependent fatty acid and cholesterol synthesis, which resulted in the accumulation of lipid droplets. A 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase (HMGCR)-mediated lipogenic state was found to induce a SASP in PMS iNSCs via cholesterol-dependent transcription factors. SASP from PMS iNSC lines induced neurotoxicity in mature neurons, and treatment with the HMGCR inhibitor simvastatin altered the PMS iNSC SASP, promoting cytoprotective qualities and reducing neurotoxicity. Our findings suggest a disease-associated, cholesterol-related, hypermetabolic phenotype of PMS iNSCs that leads to neurotoxic signaling and is rescuable pharmacologically., Competing Interests: Declaration of interests S.P. is founder, CSO, and shareholder (>5%) of CITC Ltd. A.D. is a founder of Omix Technologies Inc, Altis Biosciences LLC, and an advisory board member for Hemanext Inc and Macopharma Inc., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Research regarding HIV, substance use disorders (SUD), and SARS-CoV-2 infections after COVID-19 vaccination is limited. In the Veterans Aging Cohort Study (VACS)-HIV cohort, we followed vaccinated persons with HIV (PWH) and without HIV (PWoH) from 12/2020 to 3/2022 and linked SARS-CoV-2 test results for laboratory-confirmed breakthrough infection through 9/2022. We examined associations of substance use (alcohol use disorder [AUD], other SUD, smoking status) and HIV status and severity with breakthrough infections, using Cox proportional hazards regression hazard ratios (HR). To test for potential interactions between substance use and HIV, we fit survival models with a multiplicative interaction term. Among 24,253 PWH and 53,661 PWoH, 8.0% of PWH and 7.1% of PWoH experienced COVID-19 breakthrough. AUD (HR 1.42, 95% CI 1.32, 1.52) and other SUD (HR 1.49, 95% CI 1.39, 1.59) were associated with increased risk of breakthrough, and this was similar by HIV status (p-interaction > 0.09). Smoking was not associated with breakthrough. Compared to PWoH, PWH at all HIV severity levels had increased risk of breakthrough ranging from 9% for PWH with CD4 count ≥ 500 cells/µl (HR 1.09, 95% CI 1.02, 1.17) to 59% for PWH with CD4 count < 200 (HR 1.59, 95% CI 1.31, 1.92). Patients with AUD (HR 1.42, 95% CI 1.33, 1.52) and other SUD (HR 1.48, 95% CI 1.38, 1.59) had increased COVID-19 breakthrough risk, regardless of HIV status. HIV was associated with breakthrough; risk was greatest among PWH with lower CD4 count. In addition to inhibiting HIV treatment adherence and increasing HIV progression, AUD and other SUD may increase COVID-19 breakthrough risk., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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., (© 2023 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Competing Interests: Competing interests E.C.H.W. and N.N.B. are employees of the US Food and Drug Administration and have no conflicts related to this manuscript. R.M.C. is an employee of the US Food and Drug Administration and has no conflicts related to this manuscript; prior to his appointment to the US Food and Drug Administration as Commissioner for Food and Drugs, he was an employee of and held equity in Verily Life Sciences and Google Health (Alphabet) and served on boards of directors for Cytokinetics, Centessa, Clinetic, Keystone Symposia, the Critical Path Institute (C-Path), the Clinical Research Forum and OneFifteen.

Background: The gold-standard treatment for opioid use disorder (OUD) is medication for OUD (MOUD). However, less than a quarter of people with OUD initiate MOUD. Expanding the Collaborative Care Model (CoCM) to include primary care patients with OUD could improve access to and initiation of MOUD. This paper presents the methods and baseline sample characteristics of a Hybrid Type 2a trial comparing the effectiveness of CoCM for OUD and co-occurring mental health symptoms (MHS) to CoCM for MHS only., Method: 42 primary care clinics were cluster randomized and 254 primary care patients with OUD and elevated MHS were enrolled. Recruitment was terminated early by the Data and Safety Monitoring Board for futility. Participants completed research assessments at baseline, 3 months, and 6 months. The multiple primary outcomes were past-month number of days of nonmedical opioid use and SF12 Mental Health Component Summary (MCS) scores., Results: MCS scores were over a standard deviation below the national mean (M = 34.5). Nearly half (47.6 %) of participants had previously overdosed in their lifetimes. Three quarters (76.0 %) were already being prescribed MOUD at baseline, only 30.4 % reported non-medical use of opioids, and only 33.9 % reported being bothered by opioid cravings., Conclusion: The unexpectedly high proportion of enrollees already prescribed MOUD at baseline indicates that most patients were in the maintenance rather than acute phase of treatment. Challenges identifying and enrolling patients in the acute phase of OUD treatment implies that intervention effectiveness will depend on its success preventing the discontinuation of MOUD rather than initiating MOUD., Competing Interests: Declaration of competing interest The authors do not have any personal, professional, or financial conflicts of interest to disclose for this work. Dr. Saxon has received travel support from Alkermes, Inc., consulting fees from Indivior, Inc., and royalties from UpToDate, Inc. Dr. Ratzliff receives royalties from Wiley for her book on integrated care., (Published by Elsevier Inc.)

Background: The Veterans Health Administration (VA) implemented academic detailing (AD) to support safer opioid prescribing and overdose prevention initiatives., Methods: Patient-level data were extracted monthly from VA's electronic health record to evaluate whether AD implementation was associated with changes in all-cause mortality, opioid poisoning inpatient admissions, and opioid poisoning emergency department (ED) visits in an observational cohort of patients with long-term opioid prescriptions (≥45-day supply of opioids 6 months prior to a given month with ≤15 days between prescriptions). A single-group interrupted time series analysis using segmented logistic regression for mortality and Poisson regression for counts of inpatient admissions and ED visits was used to identify whether the level and slope of these outcomes changed in response to AD implementation., Results: Among 955 376 unique patients (19 431 241 person-months), there were 53 369 deaths (29 025 pre-AD; 24 344 post-AD), 1927 opioid poisoning inpatient admissions (610 pre-AD; 1317 post-AD), and 408 opioid poisoning ED visits (207 pre-AD; 201 post-AD). Immediately after AD implementation, there was a 5.8% reduction in the odds of all-cause mortality (95% confidence interval [CI]: 0.897, 0.990). However, patients had a significantly increased incidence rate of inpatient admissions for opioid poisoning immediately after AD implementation (incidence rate ratio = 1.523; 95% CI: 1.118, 2.077). No significant differences in ED visits for opioid poisoning were observed., Conclusions: AD was associated with decreased all-cause mortality but increased inpatient hospitalization for opioid poisoning among patients prescribed long-term opioids. Mechanisms via which AD's efforts influenced opioid-related outcomes should be explored., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: Preperitoneal pelvic packing (PPP) has been advocated as a damage control procedure for pelvic fracture bleeding, despite of weak evidence., Methods: Matched cohort study, TQIP database. Patients with isolated severe blunt pelvic fractures (pelvis abbreviated injury score [AIS] ​≥ ​3, AIS ≤2 in all other body regions) were included. Patients who underwent PPP were matched to patients with no PPP, 1:3 nearest propensity score. Matching was performed based on demographics, vital signs on admission, comorbidities, injury characteristics, type and timing of initiation of VTE prophylaxis, and additional procedures including laparotomy, REBOA, and angioembolization., Results: 64 patients with PPP were matched with 182 patients with No-PPP. PPP patients had higher in-hospital mortality (14.1 ​% vs 2.2 ​% p ​< ​0.001) and higher rates of VTE and DVT (VTE: 14.1 ​% vs 4.4 ​% p ​= ​0.018, DVT: 10.9 ​% vs 2.2 ​% p ​= ​0.008)., Conclusion: PPP is associated with worse survival outcomes and increased rate of VTE and DVT complications., Competing Interests: Declaration of competing interest No conflicts of interests or disclosure by any of the authors., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Engagement is a critical component of successful treatment for opioid use disorder (OUD). However, rates of patient engagement in OUD treatment, especially in outpatient settings, are variable and often low. Little is known about the specific strategies members of primary care teams use to initiate and encourage ongoing participation in OUD treatment. In a national cohort of primary care clinics in the U.S., we explored the perspectives of primary care team members on the meaning of and approaches to OUD treatment engagement., Methods: We conducted semi-structured interviews with 35 providers from multidisciplinary primary care teams in an existing national cohort of 13 clinics across seven states. Teams were delivering OUD treatment via the Collaborative Care Model, a model that combines primary care providers (PCP), behavioral health care managers (BHCM) and consulting psychiatric providers (CPP) in a structured way to provide patient-centered, team-based, and measurement-based care. Interview participants included 14 PCPs, 13 BHCMs, and 8 CPPs. Interviews asked open-ended questions about provider experiences and practices that aided or hindered patient engagement in OUD treatment. Interview transcripts were double-coded by trained qualitative researchers and analyzed using a combination of deductive and inductive approaches to identify themes., Results: Two themes emerged that describe provider perspectives on the meaning of engagement: 1) qualifying engagement by the volume of contact with patients, and 2) the need for more multidimensional measures of engagement. Six themes emerged that characterized provider engagement practices: 1) creating an environment of disclosure, 2) normalizing OUD treatment, 3) offering gentle but persistent outreach, 4) providing human connection and encouragement, 5) tailoring treatment to patient needs, and 6) avoiding stigmatizing responses. Analysis identified multiple replicable strategies that providers used to support these engagement practices., Conclusions: Providers consistently apply a range of strategies when trying to engage patients in OUD treatment. Specific engagement strategies used embodied compassion and pragmatism, hallmarks of patient-centered care. Further research is needed to understand the impact of scaling engagement approaches across all care settings., Competing Interests: Declaration of competing interest The authors do not have any personal, professional, or financial conflicts of interest to disclose for this work. The authors did not work with or were otherwise influenced by any external sponsors for this work. Dr. Saxon has received travel support from Alkermes, Inc., consulting fees from Indivior, Inc., and royalties from UpToDate, Inc. Anna Ratzliff, MD, PhD receives royalties from Wiley for her book on integrated care., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objectives: Medications for alcohol use disorder (MAUDs) are recommended for patients with alcohol use disorder yet are underprescribed. Consistent with Minority Stress and Intersectionality theories, persons with multiple sociodemographically marginalized identities (eg, Black women) often experience greater barriers to care and have poorer health outcomes. We use data from the Veterans Health Administration to assess disparities in Federal Drug Administration (FDA)-approved MAUDs and all effective MAUDs between the following groups: racialized and ethnic identity, sex, transgender status, and their intersections., Methods: Among all Veterans Health Administration outpatients between August 1, 2015, and July 31, 2017, with documented alcohol screenings and an International Classification of Diseases diagnosis for alcohol use disorder in the 0-365 days prior (N = 308,238), we estimated the prevalence and 95% confidence intervals of receiving FDA-approved MAUDs and any MAUDs in the following year and compared them using χ2 or Fisher's exact test. Analyses are unadjusted to present true prevalence and group differences., Results: The overall prevalence for MAUDs was low (FDA-MAUDs = 8.7%, any MAUDs = 20.0%). Within sex, Black males had the lowest rate of FDA-MAUDs (7.3%, [7.1-7.5]), whereas American Indian/Alaskan Native females had the highest (18.4%, [13.8-23.0]). Among those identified as transgender, Asian and Black transgender persons had the lowest rates of FDA-MAUDs (0%; 4.3%, [1.8-8.5], respectively), whereas American Indian/Alaskan Native transgender patients had the highest (33.3%, [2.5-64.1]). Similar patterns were observed for any MAUDs, with higher rates overall., Conclusions: Substantial variation exists in MAUD prescribing, with marginalized veterans disproportionately receiving MAUDs at lower and higher rates than average. Implementation and quality improvement efforts are needed to improve MAUD prescribing practices and reduce disparities., 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: 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., (© 2024. The Author(s), under exclusive licence to Society of General Internal Medicine.)

Background: Diagnosis of alcohol use disorder (AUD) in primary care is critical for increasing access to alcohol treatment. However, AUD is underdiagnosed and may be inequitably diagnosed due to societal structures that determine access to resources (e.g., structural racism that limits opportunities for some groups and influences interpersonal interactions in and beyond health care). This study described patterns of provider-documented AUD in primary care across intersections of race, ethnicity, sex, and community-level socioeconomic status (SES)., Methods: This cross-sectional study used EHR data from a regional healthcare system with 35 primary care clinics that included adult patients who completed alcohol screenings between 3/1/2015 and 9/30/2020. The prevalence of provider-documented AUD in primary care based on International Classification of Diseases-9 (ICD-9) and ICD-10 diagnoses was compared across intersections of race, ethnicity, sex, and community-level SES., Results: Among 439,375 patients, 6.6% were Latine, 11.0% Asian, 5.4% Black, 1.3% Native Hawaiian/Pacific Islander (NH/PI), 1.5% American Indian/Alaska Native (AI/AN), and 74.2% White, and 58.3% women. The overall prevalence of provider-documented AUD was 1.0% and varied across intersecting identities. Among women, the prevalence was highest for AI/AN women with middle SES, 1.5% (95% CI 1.0-2.3), and lowest for Asian women with middle SES, 0.1% (95% CI 0.1-0.2). Among men, the prevalence was highest for AI/AN men with high and middle SES, 2.0% (95% CI 1.1-3.4) and 2.0% (95% CI 1.2-3.2), respectively, and lowest for Asian men with high SES, 0.5% (95% CI 0.3-0.7). Black and Latine patients tended to have a lower prevalence of AUD than White patients, across all intersections of sex and SES except for Black women with high SES. There were no consistent patterns of the prevalence of AUD diagnosis that emerged across SES., Conclusion: The prevalence of provider-documented AUD in primary care was highest in AI/AN men and women and lowest in Asian men and women. Findings of lower prevalence of provider-documented AUD in Black and Hispanic than White patients across most intersections of sex and SES differed from prior studies. Findings may suggest that differences in access to resources, which vary in effects across these identity characteristics and lived experiences, influence the diagnosis of AUD in clinical care., (© 2024. The Author(s).)

Background: There is a growing interest in practice-based implementation research, yet too often research prioritizes and is most successful in academic settings. During a national implementation trial to evaluate the effectiveness of Collaborative Care for co-occurring opioid use and mental health disorders, we lost three of our 11 participating implementation sites, all representing community sites., Method: To better understand needed supports for implementation trial participation, we conducted exit interviews ( n  = 5) with key staff at these community sites. Interview transcripts were double-coded and analyzed using Rapid Assessment Process. Qualitative themes were iteratively reviewed by the study team., Results: Three themes emerged characterizing challenges for community sites, including that: (1) research threatens sites' most precious resource-staff; (2) staff lack comfort with and skills for research; and (3) research participation in its current form does not offer a clear return on investment., Conclusions: Learnings from this work illuminate some of the barriers community sites face when trying to participate in multisite implementation research. An undercurrent of participant perspectives was the belief that community sites like theirs are just not set up to successfully participate in clinical trial research, including population-based implementation trials. Future implementation trials should consider strategies that disrupt traditional approaches, increasing the equitable inclusion of diverse practice settings in implementation research., Competing Interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: The authors do not have any personal, professional, or financial conflicts of interest to disclose for this work. The authors did not work with or were otherwise influenced by any external sponsors for this work. Andrew J. Saxon has received travel support from Alkermes, Inc., consulting fees from Indivior, Inc., and royalties from UpToDate, Inc. Anna D. Ratzliff, MD, PhD, receives royalties from Wiley for her book on integrated care., (© The Author(s) 2024.)

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., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Recent policy changes in Washington State presented a unique opportunity to pair evidence-based interventions with first responder services to combat increasing opioid overdoses. However, little is known about how these interventions should be implemented. In partnership with the Research with Expert Advisors on Drug Use team, a group of academically trained and community-trained researchers with lived and living experience of substance use, we examined facilitators and barriers to adopting leave-behind naloxone, field-based buprenorphine initiation, and HIV and hepatitis C virus (HCV) testing for first responder programs., Methods: Our team completed semi-structured, qualitative interviews with 32 first responders, mobile integrated health staff, and emergency medical services (EMS) leaders in King County, Washington, from February-May 2022. Semi-structured interviews were recorded, transcribed, and coded using an integrated deductive and inductive thematic analysis approach grounded in community-engaged research principles. We collected data until saturation was achieved. Data collection and analysis were informed by the Consolidated Framework for Implementation Research. Two investigators coded independently until 100% consensus was reached., Results: Our thematic analysis revealed several perceived facilitators (ie, tension for change, relative advantage, and compatibility) and barriers (ie, limited adaptability, lack of evidence strength and quality, and prohibitive cost) to the adoption of these evidence-based clinical interventions for first responder systems. There was widespread support for the distribution of leave-behind naloxone, although funding was identified as a barrier. Many believed field-based initiation of buprenorphine treatment could provide a more effective response to overdose management, but there were significant concerns that this intervention could run counter to the rapid care model. Lastly, participants worried that HIV and HCV testing was inappropriate for first responders to conduct but recommended that this service be provided by mobile integrated health staff., Conclusion: These results have informed local EMS strategic planning, which will inform roll out of process improvements in King County, Washington. Future work should evaluate the impact of these interventions on the health of overdose survivors., Competing Interests: Conflicts of Interest: By the WestJEM article submission agreement, all authors are required to disclose all affiliations, funding sources and financial or management relationships that could be perceived as potential sources of bias. This study was supported by a University of Washington Implementation Science Program Pilot Grant (PI van Draanen). There are no other conflicts of interest or sources of funding to declare.

Background: Inadequate income is associated with higher likelihood of experiencing a substance use disorder (SUD). This study tests whether the earned income tax credit (EITC), which issues supplemental income for workers with children in the U.S., is associated with lower rates of SUD and fatal overdose., Methods: We examined the effects of state-level refundable EITC presence and generosity (i.e., state EITC rate as a % of federal rate) on SUD-related outcomes (SUD prevalence and intentional and unintentional fatal overdose) using a difference-in-difference methodology, with both two-way fixed-effects models and event study plots. Several sensitivity analyses were conducted to assess the robustness of findings. Five data sources were used to create a combined state-level longitudinal dataset., Results: We did not find significant effects of refundable EITC presence or generosity on unintentional or intentional fatal overdose or SUD prevalence in two-way models. Event study models detected a very slight upward shift in SUD prevalence following refundable EITC implementation (not seen in sensitivity analyses) and no significant effects of EITC implementation on any of the fatal overdose outcomes., Conclusions: Evidence regarding income support programs is being highly sought by policy makers as income support programs have become increasingly popular policy levers since the start of the COVID-19 pandemic. Our study indicates EITC policies likely have no impact on SUD or overdose, however, other income support programs without family restrictions are important to investigate further., Competing Interests: Declaration of Competing Interest No conflict declared., (Copyright © 2024. Published by Elsevier B.V.)

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/mm 3  (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., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

For many adult human organs, tissue regeneration during chronic disease remains a controversial subject. Regenerative processes are easily observed in animal models, and their underlying mechanisms are becoming well characterized 1-4 , but technical challenges and ethical aspects are limiting the validation of these results in humans. We decided to address this difficulty with respect to the liver. This organ displays the remarkable ability to regenerate after acute injury, although liver regeneration in the context of recurring injury remains to be fully demonstrated. Here we performed single-nucleus RNA sequencing (snRNA-seq) on 47 liver biopsies from patients with different stages of metabolic dysfunction-associated steatotic liver disease to establish a cellular map of the liver during disease progression. We then combined these single-cell-level data with advanced 3D imaging to reveal profound changes in the liver architecture. Hepatocytes lose their zonation and considerable reorganization of the biliary tree takes place. More importantly, our study uncovers transdifferentiation events that occur between hepatocytes and cholangiocytes without the presence of adult stem cells or developmental progenitor activation. Detailed analyses and functional validations using cholangiocyte organoids confirm the importance of the PI3K-AKT-mTOR pathway in this process, thereby connecting this acquisition of plasticity to insulin signalling. Together, our data indicate that chronic injury creates an environment that induces cellular plasticity in human organs, and understanding the underlying mechanisms of this process could open new therapeutic avenues in the management of chronic diseases., (© 2024. The Author(s).)

Objectives: Buprenorphine, a medication for opioid use disorder (OUD), is underutilized in general medical settings. Further, it is inequitably received by racialized groups and persons with comorbidities. The Veterans Health Administration launched an initiative to increase buprenorphine receipt in primary care. The project's objective was to identify patient-related factors associated with buprenorphine receipt and retention in primary care clinics (n = 18) participating in the initiative., Methods: Retrospective cohort quality improvement evaluation of patients 18 years or older with 2 or more primary care visits in a 1-year period and an OUD diagnosis in the year before the first primary care visit (index date). Buprenorphine receipt was the proportion of patients with OUD who received 1 or more buprenorphine prescriptions from primary care providers during the post-index year and retention the proportion who received buprenorphine for 180 days or longer., Results: Of 2880 patients with OUD seen in primary care, 11.7% (95% confidence interval [CI], 10.6%-12.9%) received buprenorphine in primary care, 58.2% (95% CI, 52.8%-63.3%) of whom were retained on buprenorphine for 180 days or longer. Patients with alcohol use disorder (adjusted odds ratio [AOR], 0.39; 95% CI, 0.27-0.57), nonopioid drug use disorder (AOR, 0.64; 95% CI, 0.45-0.93), and serious mental illness (AOR, 0.60; 95% CI, 0.37-0.97) had lower buprenorphine receipt. Those with an anxiety disorder had higher buprenorphine receipt (AOR, 1.42; 95% CI, 1.04-1.95). Buprenorphine receipt (AOR, 0.55; 95% CI, 0.35-0.87) and 180-day retention (AOR, 0.40; 95% CI, 0.19-0.84) were less likely among non-Hispanic Black patients., Conclusions: Further integration of addiction services in primary care may be needed to enhance buprenorphine receipt for patients with comorbid substance use disorders, and interventions are needed to address disparities in receipt and retention among non-Hispanic Black patients., (Copyright © 2024 American Society of Addiction Medicine.)

Objectives: Medication treatment for opioid use disorder (MOUD) is effective and recommended for outpatient settings. We implemented and evaluated the SUpporting Primary care Providers in Opioid Risk reduction and Treatment (SUPPORT) Center-a quality improvement partnership to implement stepped care for MOUD in 2 Veterans Health Administration (VA) primary care (PC) clinics., Methods: SUPPORT provided a dedicated clinical team (nurse practitioner prescriber and social worker) and stepped care ([1] identification, assessment, referral; [2] MOUD induction; [3] stabilization; and [4] maintenance supporting PC providers [PCPs] to initiate and/or sustain treatment) coupled with ongoing internal facilitation (consultation, trainings, informatics support). Qualitative interviews with stakeholders (PCPs and patients) and meeting notes identified barriers and facilitators to implementation. Electronic health record and patient tracking data measured reach, adoption, and implementation outcomes descriptively., Results: SUPPORT's implementation barriers included the need for an X-waiver, VA's opioid tapering policies, patient and PCP knowledge gaps and PCP discomfort, and logistical compatibility and sustainability challenges for clinics. SUPPORT's dedicated clinical staff, ongoing internal facilitation, and high patient and PCP satisfaction were key facilitators. SUPPORT (January 2019 to September 2021) trained 218 providers; 63 received X-waivers, and 23 provided MOUD (10.5% of those trained). SUPPORT provided care to 167 patients, initiated MOUD for 33, and provided education and naloxone to 72 (all = 0 in year before launch)., Conclusions: SUPPORT reached many PCPs and patients and resulted in small increases in MOUD prescribing and high levels of stakeholder satisfaction. Dedicated clinical staff was key to observed successes. Although resource-intensive, SUPPORT offers a potential model for outpatient MOUD provision., Competing Interests: AJS has received travel support from Alkermes, Inc, and served on an Advisory Board for Indivior, Inc. He receives ongoing royalties from UpToDate, Inc. The other authors report no conflicts of interest., (Copyright © 2024 American Society of Addiction Medicine.)

Objectives: Long-term opioid therapy (LTOT) is potentially dangerous among patients with unhealthy alcohol use because of possible adverse interactions. We examined receipt of alcohol-related care among patients with unhealthy alcohol use receiving LTOT and without opioid receipt., Methods: We use data collected from 2009 to 2017 in the Women Veterans Cohort Study, a national cohort of Veterans engaged in Veterans Health Administration care. We included patients who screened positive for unhealthy alcohol use (score ≥5) using the Alcohol Use Disorder Identification Consumption questionnaire. Our primary exposure was LTOT (receipt of prescribed opioids for ≥90 days) versus no opioid receipt at the time of the first positive Alcohol Use Disorder Identification Consumption. Our primary outcome was receipt of brief intervention within 14 days of positive alcohol screen. Unadjusted and 4 adjusted modified Poisson regression models assessed prevalence and relative rates (RRs) of outcomes., Results: Among eligible veterans, 6222 of 113,628 (5.5%) received LTOT at screening. Among patients receiving LTOT, 67.5% (95% confidence interval [CI], 66.3%-68.6%) had a documented brief intervention within 14 days of positive screen, compared with 70.1% (95% CI, 69.8%-70.4%) among patients without opioid receipt (RR, 0.96; 95% CI, 0.95-0.98; P < 0.001). Within adjusted models, the rate of brief intervention among patients receiving LTOT remained lower than patients without opioid receipt., Conclusions: Among patients with unhealthy alcohol use, patients receiving LTOT had significantly lower rates of brief intervention receipt compared with those without opioid receipt, and they should be a focus for interventions to improve alcohol-related care and safer opioid prescribing., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 American Society of Addiction Medicine.)

Importance: Research has demonstrated an association between the COVID-19 pandemic and increased alcohol-related liver disease hospitalizations and deaths. However, trends in alcohol-related complications more broadly are unclear, especially among subgroups disproportionately affected by alcohol use., Objective: To assess trends in people with high-acuity alcohol-related complications admitted to the emergency department, observation unit, or hospital during the COVID-19 pandemic, focusing on demographic differences., Design, Setting, and Participants: This longitudinal interrupted time series cohort study analyzed US national insurance claims data using Optum's deidentified Clinformatics Data Mart database from March 2017 to September 2021, before and after the March 2020 COVID-19 pandemic onset. A rolling cohort of people 15 years and older who had at least 6 months of continuous commercial or Medicare Advantage coverage were included. Subgroups of interest included males and females stratified by age group. Data were analyzed from April 2023 to January 2024., Exposure: COVID-19 pandemic environment from March 2020 to September 2021., Main Outcomes and Measures: Differences between monthly rates vs predicted rates of high-acuity alcohol-related complication episodes, determined using claims-based algorithms and alcohol-specific diagnosis codes. The secondary outcome was the subset of complication episodes due to alcohol-related liver disease., Results: Rates of high-acuity alcohol-related complications were statistically higher than expected in 4 of 18 pandemic months after March 2020 (range of absolute and relative increases: 0.4-0.8 episodes per 100 000 people and 8.3%-19.4%, respectively). Women aged 40 to 64 years experienced statistically significant increases in 10 of 18 pandemic months (range of absolute and relative increases: 1.3-2.1 episodes per 100 000 people and 33.3%-56.0%, respectively). In this same population, rates of complication episodes due to alcohol-related liver disease increased above expected in 16 of 18 pandemic months (range of absolute and relative increases: 0.8-2.1 episodes per 100 000 people and 34.1%-94.7%, respectively)., Conclusions and Relevance: In this cohort study of a national, commercially insured population, high-acuity alcohol-related complication episodes increased beyond what was expected in 4 of 18 COVID-19 pandemic months. Women aged 40 to 64 years experienced 33.3% to 56.0% increases in complication episodes in 10 of 18 pandemic months, a pattern associated with large and sustained increases in high-acuity alcohol-related liver disease complications. Findings underscore the need for increased attention to alcohol use disorder risk factors, alcohol use patterns, alcohol-related health effects, and alcohol regulations and policies, especially among women aged 40 to 64 years.

Aims: Cardiac involvement is common in patients hospitalized with COVID-19 and correlates with an adverse disease trajectory. While cardiac injury has been attributed to direct viral cytotoxicity, serum-induced cardiotoxicity secondary to serological hyperinflammation constitutes a potentially amenable mechanism that remains largely unexplored., Methods and Results: To investigate serological drivers of cardiotoxicity in COVID-19 we have established a robust bioassay that assessed the effects of serum from COVID-19 confirmed patients on human embryonic stem cell (hESC)-derived cardiomyocytes. We demonstrate that serum from COVID-19 positive patients significantly reduced cardiomyocyte viability independent of viral transduction, an effect that was also seen in non-COVID-19 acute respiratory distress syndrome (ARDS). Serum from patients with greater disease severity led to worse cardiomyocyte viability and this significantly correlated with levels of key inflammatory cytokines, including IL-6, TNF-α, IL1-β, IL-10, CRP, and neutrophil to lymphocyte ratio with a specific reduction of CD4+ and CD8+ cells. Combinatorial blockade of IL-6 and TNF-α partly rescued the phenotype and preserved cardiomyocyte viability and function. Bulk RNA sequencing of serum-treated cardiomyocytes elucidated specific pathways involved in the COVID-19 response impacting cardiomyocyte viability, structure, and function. The observed effects of serum-induced cytotoxicity were cell-type selective as serum exposure did not adversely affect microvascular endothelial cell viability but resulted in endothelial activation and a procoagulant state., Conclusion: These results provide direct evidence that inflammatory cytokines are at least in part responsible for the cardiovascular damage seen in COVID-19 and characterise the downstream activated pathways in human cardiomyocytes. The serum signature of patients with severe disease indicates possible targets for therapeutic intervention., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Introduction: Substance use disorders (SUDs) are underdiagnosed in healthcare settings. The Substance Use Symptom Checklist (SUSC) is a practical, patient-report questionnaire that has been used to assess SUD symptoms based on Diagnostic and Statistical Manual of Mental Disorders-5th edition (DSM-5) criteria. This study evaluates the test-retest reliability of SUSCs completed in primary and mental health care settings., Methods: We identified 1194 patients who completed two SUSCs 1-21 days apart as part of routine care after reporting daily cannabis use and/or any past-year other drug use on behavioral health screens. Test-retest reliability of SUSC scores was evaluated within the full sample, subsamples who completed both checklists in primary care (n=451) or mental health clinics (n=512) where SUSC implementation differed, and subgroups defined by sex, insurance status, age, and substance use reported on behavioral health screens., Results: In the full sample, test-retest reliability was high for indices reflecting the number of SUD symptoms endorsed (ICC=0.75, 95% CI:0.72-0.77) and DSM-5 SUD severity (kappa=0.72, 95% CI:0.69-0.75). These reliability estimates were higher in primary care (ICC=0.81, 95% CI:0.77-0.84; kappa=0.79, 95% CI:0.75-0.82, respectively) than in mental health clinics (ICC=0.74, 95% CI:0.70-0.78; kappa=0.73, 95% CI:0.68-0.77). Reliability differed by age and substance use reported on behavioral health screens, but not by sex or insurance status., Conclusions: The SUSC has good-to-excellent test-retest reliability when completed as part of routine primary or mental health care. Symptom checklists can reliably measure symptoms consistent with DSM-5 SUD criteria, which may aid SUD-related care in primary care and mental health settings., Competing Interests: Declaration of Competing Interest All authors declare no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Chronic intestinal inflammation is a poorly understood manifestation of cystic fibrosis (CF), which may be refractory to ion channel CF transmembrane conductance regulator (CFTR) modulator therapy. People with CF exhibit intestinal dysbiosis, which has the potential for stimulating intestinal and systemic inflammation. CFTR is expressed in organ epithelia, leukocytes, and other tissues. Here, we investigate the contribution of intestinal epithelium-specific loss of Cftr [iCftr knockout (KO)] to dysbiosis and inflammation in mice treated with either of two antiobstructive dietary regimens necessary to maintain CF mouse models [polyethylene glycol (PEG) laxative or a liquid diet (LiqD)]. Feces collected from iCftr KO mice and their wild-type (WT) sex-matched littermates were used to measure fecal calprotectin to evaluate inflammation and to perform 16S rRNA sequencing to characterize the gut microbiome. Fecal calprotectin was elevated in iCftr KO relative to WT mice that consumed either PEG or LiqD. PEG iCftr KO mice did not show a change in α diversity versus WT mice but demonstrated a significant difference in microbial composition (β diversity) with included increases in the phylum Proteobacteria, the family Peptostreptococcaceae , four genera of Clostridia including C. innocuum , and the mucolytic genus Akkermansia . Fecal microbiome analysis of LiqD-fed iCftr KO mice showed both decreased α diversity and differences in microbial composition with increases in the Proteobacteria family Enterobacteriaceae , Firmicutes families Clostridiaceae and Peptostreptococcaceae , and enrichment of Clostridium perfringens , C. innocuum , C. difficile , mucolytic Ruminococcus gnavus , and reduction of Akkermansia. It was concluded that epithelium-specific loss of Cftr is a major driver of CF intestinal dysbiosis and inflammation with significant similarities to previous studies of pan Cftr KO mice. NEW & NOTEWORTHY Chronic intestinal inflammation is a manifestation of cystic fibrosis (CF), a disease caused by loss of the anion channel CF transmembrane conductance regulator (CFTR) that is expressed in many tissues. This study shows that intestinal epithelial cell-specific loss of CFTR [inducible Cftr knockout (KO)] in mice is sufficient to induce intestinal dysbiosis and inflammation. Experiments were performed on mice consuming two dietary regimens routinely used to prevent obstruction in CF mice.

Creating a successful small molecule drug is a challenging multiparameter optimization problem in an effectively infinite space of possible molecules. Generative models have emerged as powerful tools for traversing data manifolds composed of images, sounds, and text and offer an opportunity to dramatically improve the drug discovery and design process. To create generative optimization methods that are more useful than brute-force molecular generation and filtering via virtual screening, we propose that four integrated features are necessary: large, quantitative data sets of molecular structure and activity, an invertible vector representation of realistic accessible molecules, smooth and differentiable regressors that quantify uncertainty, and algorithms to simultaneously optimize properties of interest. Over the course of 12 months, Terray Therapeutics has collected a data set of 2 billion quantitative binding measurements of small molecules to therapeutic targets, which directly motivates multiparameter generative optimization of molecules conditioned on these data. To this end, we present contrastive optimization for accelerated therapeutic inference (COATI), a pretrained, multimodal encoder-decoder model of druglike chemical space. COATI is constructed without any human biasing of features, using contrastive learning from text and 3D representations of molecules to allow for downstream use with structural models. We demonstrate that COATI possesses many of the desired properties of universal molecular embedding: fixed-dimension, invertibility, autoencoding, accurate regression, and low computation cost. Finally, we present a novel metadynamics algorithm for generative optimization using a small subset of our proprietary data collected for a model protein, carbonic anhydrase, designing molecules that satisfy the multiparameter optimization task of potency, solubility, and drug likeness. This work sets the stage for fully integrated generative molecular design and optimization for small molecules.

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., (© 2023. The Author(s).)

Objective: The effect of stress on vaccine-induced humoral immunity and therapeutic interventions to mitigate pandemic-related stress remain underexplored., Method: Participants in a longitudinal cohort study ( n = 189) completed a validated measure, GAD-7, and 10-instrument stress measure to assess stress and anxiety after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. Serum was collected to obtain SARS-CoV-2 antibody titer levels., Results: Participants experienced increased stress due to the SARS-CoV-2 pandemic with a positive correlation between GAD-7 scores and peak antibody titers overall; however, there was a negative association with scores commensurate with severe anxiety. Health care workers and younger participants were more significantly affected by anxiety., Conclusions: Mild anxiety levels may have immune-enhancing effects, whereas severe anxiety may cause antibody generation reduction. Mental health-focused interventions are imperative for younger adults and health care workers. Young adults may be more resilient to increased stress levels., Competing Interests: Conflict of Interest: The Icahn School of Medicine at Mount Sinai has filed patent applications relating to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serological assays (US Provisional Application Numbers: 62/994,252, 63/018,457, 63/020,503 and 63/024,436) and NDV-based SARS-CoV-2 vaccines (US Provisional Application Number: 63/251,020), which list Florian Krammer as coinventor. Patent applications were submitted by the Icahn School of Medicine at Mount Sinai. Mount Sinai has spun out a company, Kantaro, to market serological tests for SARS-CoV-2. Florian Krammer has consulted for Merck and Pfizer (before 2020) and is currently consulting for Pfizer, Third Rock Ventures, GSK, and Avimex. The Krammer laboratory is also collaborating with Pfizer on animal models of SARS-CoV-2., (Copyright © 2023 American College of Occupational and Environmental Medicine.)