Faculty Bibliography

People with HIV are at increased risk of cardiovascular events; thus, care delivery strategies that increase access to comprehensive cardiovascular disease (CVD) risk management are a priority. We report the results of a multi-component telemedicine-based strategy to improve blood pressure control among people with HIV-Assess and Adapt to the Impact of COVID-19 on CVD Self-Management and Prevention Care in Adults Living with HIV (AAIM-High). The AAIM High strategy is a virtual adaptation of our previously published EXTRA-CVD strategy and consisted of hypertension education and six components: nurse-led care coordination (delivered by teleconference or telephone), home systolic blood pressure (SBP) monitoring, evidence-based treatment algorithms, electronic health records tools, technology coach, and communication preferences assessment. People with HIV (n = 74) with comorbid hypertension at three academic medical centers were enrolled in a single arm implementation study from January 2021 to December 2022. Over 12 months, the average patient-performed home SBP decreased by 7.7 mmHg (95% CI -11.5, -3.9). The percentage of patients at treatment goal, defined as average SBP <130 mmHg, increased from 46.0% to 72.5% at 12 months. By adapting to the growing use of telemedicine in healthcare delivery, our study effectively improved hypertension control in people with HIV through a virtual, nurse-led intervention.

SARS-CoV-2 infection is associated with platelet hyperreactivity and increased rates of arterial and venous thrombosis. SARS-CoV-2 mutations have resulted in several variants with differences in transmissibility, infectivity, and patient outcomes. This study investigates the effects of the ancestral strain of SARS-CoV-2 (WA1) and two variants of concern, Delta and Omicron, on the human megakaryocyte (MK) phenotype and transcriptome. Human CD34⁺-derived MKs were incubated with WA1, Delta or Omicron SARS-CoV-2 variants for 24 hours. MK activation markers were measured under resting and thrombin-stimulated conditions. RNA-seq and cytokine release in response to the viruses were assessed. Plasma cytokines were measured in hospitalized COVID-19 patients. Treatment of MKs with WA1, Delta or Omicron variants of SARS-CoV-2 resulted in similar increases in classical activation markers. However, SARS-CoV-2 variants mediated distinct transcriptomic changes. Across variants, 60 genes overlapped, including CXCL8. Consistent with transcriptomic changes, SARS-CoV-2-incubated MKs secreted significantly elevated levels of IL-8. Among hospitalized COVID-19 patients, plasma IL-8 levels were highest in COVID-19 patients who subsequently experienced thrombotic events or died. In conclusion, WA1, Delta, and Omicron similarly induce classical MK activation responses while mediating distinct transcriptomic changes. Increased IL-8 levels may serve as a biomarker to inform platelet hyperreactivity and thrombotic events associated with COVID-19.

BACKGROUND/UNASSIGNED:Despite their efficacy, medications for opioid use disorder (MOUD) remain underutilized in patients with infections from intravenous opioid use (I-IOU). This study evaluates the impact of an Expanded MOUD Access Initiative (EMAI) on MOUD uptake and other clinical outcomes in patients hospitalized for I-IOU at an institution without addiction medicine consultation. METHODS/UNASSIGNED:We performed a retrospective pre-post study of hospital admissions for I-IOU before (January 2019-June 2021) and after (January 2022-December 2023) EMAI introduction. Data was collected via chart review. The EMAI eliminated restrictions on methadone use and established a new order set for buprenorphine inductions. The primary outcome was MOUD receipt; secondary outcomes included patient directed discharge (PDD) and 30-day re-hospitalization. RESULTS/UNASSIGNED:There were 129 hospitalizations prior to the intervention (control) and 98 after (EMAI). MOUD receipt was significantly higher in the EMAI group (75.5% vs 31.0%; OR, 6.86 [95% CI, 3.84-12.61]). In patients not receiving MOUD prior to admission (n = 176), new inductions occurred more frequently in the EMAI group (68.0% vs 11.9%; OR, 15.76 [95% CI, 7.50-35.78]). PDD was lower in the EMAI group (23.5% vs 48.8%; OR, 0.32 [95% CI, 0.10-0.57]), as was 30-day re-hospitalization (12.2% vs 22.5%; OR, 0.48 [95% CI, 0.22-0.98]). In a multivariable logistic regression model, the EMAI was the only variable to show a statistically significant association with MOUD receipt (aOR, 6.89 [95% CI, 3.75-13.11]). CONCLUSIONS/UNASSIGNED:The EMAI was associated with increased MOUD uptake, reduced PDD, and fewer 30-day re-hospitalizations despite the lack of addiction medicine consultation.

INTRODUCTION/BACKGROUND:Poor social connection is a risk factor for mortality comparable to smoking or obesity. Expert recommendations encourage clinicians to identify and address isolation, loneliness and absent social support; however, screening and documentation norms remain unstandardised in graduate medical education (GME) social determinants of health (SDOH) curricula. We assessed the knowledge, attitudes, and behaviours (KAB) of internal medicine resident physicians in a large, urban, academic medical centre regarding screening for and documenting social connection. METHODS:Between October 2022 and February 2023, a voluntary, anonymous mixed-methods survey was disseminated to assess resident physicians' KAB about social connection as a SDOH. Quantitative data were analysed descriptively. Qualitative responses underwent content analysis. An electronic medical record (EMR) chart review of resident notes corroborated survey data. RESULTS:Sixty-three residents of an eligible 153 responded to the survey (41% participation). Sixty-five per cent reported never receiving formal GME about social connection as a SDOH. Familiarity with validated screening tools was low. Although 51% of respondents reported often/always documenting patients' social support systems, few chart notes explicitly mentioned social contacts. Respondents agreed that physicians are responsible for assessing and documenting social connection and noted key challenges of time constraints, inadequate screening and documentation norms and EMR navigation difficulty. Targeted didactics, EMR improvements and interdisciplinary learning opportunities were identified as potential solutions. CONCLUSIONS:This study identified notable gaps in resident physician KAB to address social connection as a SDOH. Challenges could be addressed with standardised screening and documentation norms and skill development in patient communication and interdisciplinary teamwork.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Vascular dysfunction contributes to Alzheimer disease (AD) and related dementias (ADRDs), but the underlying mechanisms remain unclear. Previous studies link midlife hemostasis and platelet aggregation measures to late-life dementia risk. We aimed to determine whether platelet aggregation in midlife is associated with imaging markers of AD pathology. METHODS:F-flortaucipir) PET uptake in dementia-free, middle-aged adults from the Framingham Heart Study. Co-primary outcomes included amyloid and tau uptake in AD-vulnerable regions. We also examined an MRI-based cortical thickness signature of AD risk as a secondary outcome. We used multivariable regression models adjusted for demographic and clinical factors, considering potential nonlinear associations. RESULTS:< 0.035), consistent with a neurodegenerative pattern. DISCUSSION/CONCLUSIONS:Our findings indicate that platelet aggregation is linked to PET and MRI markers of AD pathology as early as midlife. These findings support further investigation of platelet-mediated mechanisms in AD pathogenesis.

BACKGROUND:People with opioid use disorder (POUD) who are incarcerated are disproportionately impacted by the overdose crisis. We sought to identify overdose policies that allocate resources with maximal efficiency to reduce mortality among POUD in the New Jersey (NJ) Department of Corrections. MAIN OUTCOMES/MEASURES/METHODS:We created a probabilistic state-transition model of a simulated cohort of POUD incarcerated in NJ to simulate maximizing medication for opioid use disorder (MOUD) during incarceration and/or post-release in the community and naloxone in the community. We estimated how maximizing each intervention individually and in combinations compared to current provision would impact five-year overdose deaths (ODDs), life-years (LYs), and quality-adjusted life-years (QALYs) among the simulated cohort, who moved between different modeled settings and opioid use statuses. Inputs were derived from literature reviews and expert opinion. Costs were in 2021 USD, employing a health sector perspective in base-case analyses and a limited societal perspective in sensitivity analyses, a 3% discount rate, cost-effectiveness criterion of ≤ $100,000/QALY, and life-year and lifetime horizons. RESULTS:At status quo, 141 five-year ODDs will occur in the cohort (n = 2,592), and the cohort will live an average of 17.0 discounted LYs, experiencing 13.3 discounted QALYs. Evaluating interventions individually compared to status quo, maximizing MOUD in incarceration prevents 14 five-year ODDs, adds 0.2 LYs, 0.3 QALYs per-person at a favorable incremental cost-effectiveness ratio (ICER; $34,000/QALY). Maximizing MOUD in the community prevents 40 five-year ODDs, adds 0.9 LYs, 1.1 QALYs at a favorable ICER ($25,000/QALY). Maximizing naloxone prevents 24 five-year ODDs, adds 0.3 LYs, 0.2 QALYs at a favorable ICER ($17,000/QALY). Comparing all combinations of interventions to status quo and each other, the most beneficial combination meeting cost-effectiveness criterion was jointly maximizing community MOUD and naloxone (ICER $25,000/QALY), preventing 56 five-year ODDs, adding 1.2 LYs, 1.3 QALYs. In sensitivity analyses using a limited societal perspective, all interventions were cost-saving. Maximizing all interventions was both most beneficial (42% reduction in death) and cost-saving ($300,000 per capita) over the cohort lifetime. CONCLUSION/CONCLUSIONS:Maximizing MOUD and community naloxone in New Jersey can reduce five-year ODDs by 40%. Considering societal cost-savings, maximizing all three also saves money.

Understanding therapy resistance requires deconvolving heterogeneous cell populations and tracking clonal trajectories. While CRISPR-based cellular barcoding is powerful for lineage tracing, many platforms suffer from low efficiency and limited compatibility with single-cell transcriptomics. We developed Oligo-CALL (Oligonucleotide-inducible CRISPR transcriptional activator-Assisted Lineage Labeling), an advanced barcoding system enabling precise lineage tracing, live clone isolation, and seamless integration with single-cell RNA sequencing. Applied to lung cancer cells treated with a KRAS^G12C inhibitor, Oligo-CALL identified clones consistently enriched posttreatment, supporting a model of predestined resistance. Oligo-CALL achieved >95% efficiency in linking lineage identity to transcriptomes, uncovering diverse clone-specific pathways with underlying resistance. Paired analysis of barcode-matched clones from naïve and resistant populations revealed transient and fixed resistance phenotypes. Notably, DNA repair pathways are recurrently altered in resistant clones, and inhibition of poly(adenosine 5'-diphosphate-ribose) polymerase synergizes with KRAS G12C inhibition to overcome resistance. Together, Oligo-CALL provides a versatile platform for dissecting lineage evolution and molecular dynamics of targeted therapy resistance.

BACKGROUND:Age is the strongest factor determining disease expression in multiple sclerosis (MS). We previously demonstrated biological age acceleration in pediatric-onset MS (POMS) compared to controls with both epigenetic clocks (DNAm) and telomere length (TL). It is unknown whether these markers report overlapping or distinct aging-related processes. OBJECTIVES/OBJECTIVE:To determine the correlation between DNAm and TL aging markers. METHODS:We conducted a cross-sectional case-control study within the US Network of Pediatric MS Centers. We calculated age acceleration residuals for the Horvath, Hannum, PhenoAge, and GrimAge epigenetic clocks and measured TL from whole blood samples to estimate telomere to somatic DNA ratios (T/S ratio). We employed multivariable analysis of covariance to assess the correlation between DNAm estimates and TL. RESULTS: = 0.06). CONCLUSIONS:DNAm did not correlate with TL in this sample of POMS and controls, suggesting that these biomarkers may capture complementary and non-overlapping elements of aging-related biology.

BACKGROUND:With rapid changes in the management landscape of chronic hepatitis B (CHB), this technical systematic review addresses four critical Population, Intervention, Comparator, Outcome (PICO) questions to provide guidance to the formulation of recommendations to the 2025 AASLD practice guidelines for management of CHB. METHODS:The review was reported in accordance with PRISMA guidelines. Outcomes were evaluated across four key PICOs: (1) antiviral therapy for prevention of horizontal HBV transmission in high-risk groups, (2) antiviral therapy versus observation for persons in the immune-tolerant phase, (3) discontinuation versus continuation of nucleos(t)ide analogue therapy in HBeAg-negative individuals with undetectable HBV DNA, and (4) hepatocellular carcinoma (HCC) surveillance in non-cirrhotic individuals with HBsAg clearance or co-infections with HCV, HDV, or HIV. RESULTS:For PICO 1, limited evidence suggests antiviral therapy may reduce horizontal transmission risk, though with low certainty. PICO 2 analyses reveal uncertain benefits of treating persons in the immune-tolerant phase, with very low certainty due to heterogeneity and bias. PICO 3 analyses demonstrate that discontinuing antiviral therapy in persons who are HBeAg negative with undetectable HBV DNA increases HBsAg loss rates (OR 12.65, 95% CI 1.58-101.51) but carries moderate risks of virologic relapse (OR 47.17, 95% CI 2.79-797.35), and clinical flares. PICO 4 analyses on several cohort studies showed that in patients co-infected with HCV, HBV, or HIV, annual incidence of HCC was higher than the level where screening becomes cost-effective, suggesting that regular liver cancer screening could be beneficial for these patients. CONCLUSIONS:Despite low certainty, the findings support shared decision-making in high-risk horizontal transmission scenarios or in treating individuals in the immune tolerance phase, caution in discontinuing antiviral therapy in virologically suppressed individuals without HBsAg loss, and tailored HCC surveillance for those with co-infection or cirrhosis.