Faculty Bibliography

BACKGROUND:One-carbon metabolism (OCM), a biochemical pathway dependent on micronutrients including B vitamins, plays an essential role in aging-related physiological processes. DNA methylation-based aging biomarkers may be influenced by OCM. OBJECTIVES/OBJECTIVE:This study investigated associations of OCM-related biomarkers with epigenetic aging biomarkers in the cross-sectional National Health and Nutrition Examination Survey (1999-2002). METHODS:Blood DNA methylation was measured in adults aged ≥50 y. The following epigenetic aging biomarkers were included: Horvath1, Horvath2, Hannum, PhenoAge, GrimAge2, Dunedin Pace-of-Aging (DunedinPoAm), and DNA methylation telomere length (DNAmTL). We tested for associations of serum folate, red blood cell folate, vitamin B12, homocysteine (Hcy), and methylmalonic acid (MMA) concentrations with epigenetic age deviation (EAD) among 2346 participants with epigenetic and nutritional status biomarkers using adjusted survey-weighted general linear regression models. RESULTS:A doubling of serum folate concentration was associated with -0.82 y (95% confidence interval: -1.40, -0.23) lower GrimAge2 EAD, -0.13 SDs (-0.22, -0.03) lower DunedinPoAm, and 0.02 kb (0.00, 0.04) greater DNAmTL EAD. Conversely, a doubling in Hcy concentration was associated with 1.05 y (0.06, 2.04) greater PhenoAge EAD, 1.93 y (1.16, 2.71) greater GrimAge2 EAD, and 0.26 SDs (0.10, 0.41) greater DunedinPoAm. Associations of serum folate with EAD were attenuated after adjusting for smoking status, alcohol intake, and estimated glomerular filtration rate. Furthermore, smoking modified the associations of Hcy with GrimAge2 EAD. Chronic kidney disease modified associations of B12 and MMA with Horvath1 and GrimAge2 EAD, respectively. CONCLUSIONS:In a nationally representative sample of United States adults, higher concentration of folate, a carbon donor, was associated with lower EAD, and higher concentration of Hcys, an indicator of OCM deficiencies, was associated with greater EAD; however, some associations were influenced by smoking and renal function. Future research should focus on high-risk populations. Long-term randomized controlled trials are also needed to establish causality and investigate the clinical relevance of changes in EAD.

BACKGROUND/UNASSIGNED:Family history of substance use (FHSU), along with sociodemographic and psychosocial factors, has been identified as a key risk factor for adolescent substance use and progression to substance use disorders (SUD). However, the interaction between distinct sociodemographic and psychosocial profiles in adolescents with FHSU and constitutional factors, such as psychopathological symptom severity, impulsivity, and reward processing, remains unclear. Given the complexity of these factors, it is crucial to explore how these elements contribute to the differential vulnerability to SUD among youth with family history of substance use. Particularly as, the identification of clinically relevant subgroups of at-risk youth may inform precision prevention and treatment approaches to reduce adverse outcomes related to SUDs. METHODS/UNASSIGNED: = 4,369; female 48.33%, White 61.16%), respectively]. We used K-means clustering to identify latent subgroups in the FHSU-P population based on psychosocial variables and then compared the resulting subgroups on internalizing, externalizing, and total psychopathology, impulsivity, and reward prediction errors. RESULTS/UNASSIGNED: = 443) were characterized by lower engagement across peer, school, and parental domains. Group comparisons showed that Subgroups 1 and 2 had comparable levels of psychopathology and impulsivity, while Subgroups 3, 4, and 5 displayed higher psychopathology and impulsivity. Reward prediction errors were similar across all subgroups. Other group differences are also presented and discussed in the main text. CONCLUSION/UNASSIGNED:These findings highlight significant heterogeneity within the FHSU-P group and emphasize the importance of stratifying adolescents based on sociodemographic and psychosocial factors. Such stratification can help identify adolescents at higher risk for psychopathologies, including SUDs, offering insights for targeted prevention and intervention strategies.

Reproductive aging, including timing of menarche and menopause, influences long-term morbidity and mortality in women, yet underlying biological mechanisms remain poorly understood. Using DNA methylation-based biomarkers, we assessed associations of age at menarche (N = 1,033) and menopause (N = 658) with epigenetic aging in a nationally representative sample of women ≥ 50 years. Later age at menopause was associated with lower GrimAge epigenetic age deviation (

BACKGROUND/UNASSIGNED:Immigrant status and citizenship influence health and well-being, yet their associations with DNA methylation (DNAm)-based biomarkers of aging - key predictors of healthspan and lifespan, also known as epigenetic aging - remain underexplored. METHODS/UNASSIGNED:Using a representative sample of 2,336 United States (U.S.) adults from the 1999-2000 and 2001-2002 cycles of the National Health and Nutrition Examination Survey (NHANES), we analyzed cross-sectional associations of immigrant status and U.S. citizenship with seven epigenetic aging biomarkers: HannumAge, HorvathAge, SkinBloodAge, PhenoAge, GrimAge2, DNAm Telomere Length, and DunedinPoAm. RESULTS/UNASSIGNED: = 0.02) were attenuated after adjusting for other lifestyle/health variables. Immigrant status and citizenship were associated with estimated levels of several GrimAge2 DNAm component proteins, including adrenomedullin and C-reactive protein. CONCLUSION/UNASSIGNED:Our results support the paradigm of the immigrant mortality advantage and highlight the potential value of epigenetic age measures in studying socioeconomic and broader factors influencing citizen and immigrant health.

BACKGROUND:Permanent supportive housing (PSH) is an evidence-based intervention for people experiencing homelessness which integrates permanent housing with voluntary support services. PSH tenants are at high risk for overdose death, yet little research to date has examined overdose in PSH. We sought to examine overdose risk and existing responses in PSH, which can shed light on opportunities for future overdose prevention efforts. METHODS:We conducted focus groups with PSH tenants, staff, and leaders in New York City and New York's Capital Region. Focus groups were recorded and professionally transcribed. Two investigators independently completed rapid turnaround qualitative analysis, completing templated summaries of each focus group and compiling key content in an analysis matrix, which a third investigator reviewed; discrepancies were resolved by consensus. RESULTS:From October to December 2022, we held 8 focus group sessions with PSH tenants (3 focus groups, n = 10 total participants), staff (3 focus groups, n = 13), and leaders (2 focus groups, n = 11) grouped by role and region. Participants were diverse in age (26-67 years), gender (18 women, 16 men), race (3 Asian, 12 Black, 11 White, 5 multiracial, 3 other), and ethnicity (5 Latinx, 29 not Latinx). Analysis revealed four main themes: (1) Overdose was a large concern in PSH and created significant trauma for tenants and staff; (2) Environmental factors in PSH contributed to overdose risk; (3) There was heterogeneity in PSH buildings' current overdose prevention efforts and adoption of harm reduction principles; and (4) Multifactorial barriers resulted in limited tenant use of opioid agonist treatment. CONCLUSIONS:Overdose is a major concern for PSH tenants, staff, and leaders. Our findings shed new light on overdose in PSH settings, providing insight into risk factors, existing responses, and barriers and facilitators to future overdose prevention efforts. These findings can inform future overdose prevention interventions within PSH. TRIAL REGISTRATION/BACKGROUND:ClinicalTrials.gov, NCT05786222, registered 27 March 2023.

OBJECTIVE/UNASSIGNED:Social support interventions may enhance access and use of evidence-based tobacco cessation treatments (EBCTs). We assessed the feasibility of a proactive social support intervention for Veterans who smoke. METHODS/UNASSIGNED:We used national Veterans Health Administration (VHA) data to identify Veterans who smoke cigarettes in the United States. We mailed invitation letters to a random national sample, followed by telephone outreach. Veteran-support person dyads were randomly assigned to intervention or control conditions. Support persons in the intervention group additionally received a 1-call coaching session. Assessments were conducted at baseline, 1-month, and 4-months post-randomization. Data collection occurred from March 2021 - August 2022. RESULTS/UNASSIGNED:A total of 27 dyads were randomized. Two-thirds of Veteran participants were women. Veteran follow-up survey response rates were 81.5 %. Intervention participants reported a higher rate of cessation medication use (57.1 % vs. 30.8 %), use of any EBCT (64.3 % vs. 38.5 %), and biochemically confirmed seven-day point-prevalence abstinence (14.3 % vs 7.7 %) than control participants. The proactive recruitment rate was 6 % for Veterans, 74 % for support persons, and a 93 % support person completion rate for the coaching call intervention. CONCLUSIONS/UNASSIGNED:Recruitment methods were feasible, especially for women Veterans. A proactive social support intervention shows promise for increasing Veteran utilization of EBCTs.

INTRODUCTION/BACKGROUND:Process evaluation provides insight into how interventions are delivered across varying contexts and why interventions work in some contexts and not in others. This manuscript outlines the protocol for a process evaluation embedded in a hybrid type 1 effectiveness-implementation randomised clinical trial of incremental-start haemodialysis (HD) versus conventional HD delivered to patients starting chronic dialysis (the TwoPlus Study). The trial will simultaneously assess the effectiveness of incremental-start HD in real-world settings and the implementation strategies needed to successfully integrate this intervention into routine practice. This manuscript describes the rationale and methods used to capture how incremental-start HD is implemented across settings and the factors influencing its implementation success or failure within this trial. METHODS AND ANALYSIS/METHODS:We will use the Consolidated Framework for Implementation Research (CFIR) and the Reach, Effectiveness, Adoption, Implementation and Maintenance (RE-AIM) frameworks to inform process evaluation. Mixed methods include surveys conducted with treating providers (physicians) and dialysis personnel (nurses and dialysis administrators); semi-structured interviews with patient participants, caregivers of patient participants, treating providers (physicians and advanced practice practitioners), dialysis personnel (nurses, dieticians and social workers); and focus group meetings with study investigators and stakeholder partners. Data will be collected on the following implementation determinants: (a) organisational readiness to change, intervention acceptability and appropriateness; (b) inner setting characteristics underlying barriers and facilitators to the adoption of HD intervention at the enrollment centres; (c) external factors that mediate implementation; (d) adoption; (e) reach; (f) fidelity, to assess adherence to serial timed urine collection and HD treatment schedule; and (g) sustainability, to assess barriers and facilitators to maintaining intervention. Qualitative and quantitative data will be analysed iteratively and triangulated following a convergent parallel and pragmatic approach. Mixed methods analysis will use qualitative data to lend insight to quantitative findings. Process evaluation is important to understand factors influencing trial outcomes and identify potential contextual barriers and facilitators for the potential implementation of incremental-start HD into usual workflows in varied outpatient dialysis clinics and clinical practices. The process evaluation will help interpret and contextualise the trial clinical outcomes' findings. ETHICS AND DISSEMINATION/BACKGROUND:The study protocol was approved by the Wake Forest University School of Medicine Institutional Review Board (IRB). Findings from this study will be disseminated through peer-reviewed journals and scientific conferences. TRIAL REGISTRATION NUMBER/BACKGROUND:NCT05828823.

Epigenetic clocks are valuable tools for assessing biological age. Exposure to secondhand smoke (SHS) and polycyclic aromatic hydrocarbons (PAHs) has been linked with epigenetic age deviation (EAD) in adults. However, associations in children remain largely unexplored. We investigated relationships between exposure-spanning prenatal, early postnatal, current (36-60 months, time of sample collection) periods-and EAD in preschool-aged children. DNA methylation was measured in buccal cells from 43 children (mean age: 4.1 years) in the CAries Risk from exposure to Environmental tobacco Smoke-Household Air Pollution Intervention Network cohort. SHS exposure was assessed using urinary cotinine and 3-hydroxycotinine (3-HC), while PAHs exposure was assessed via urinary 2-naphthol (2-NAP) and 1-hydroxypyrene (1-PYR). Nicotine equivalents were calculated as molar sum of cotinine + 3-HC. EAD was estimated using Horvath, Skin&Blood, Pediatric Buccal Epigenetic (PedBE), and DNA methylation-based telomere length (DNAmTL) clocks. Associations between exposures and EAD were evaluated using linear regression, adjusting for study site, mother's education, child's body mass index z-score, age, and sex. Chronological age significantly correlated with all epigenetic clocks (r = 0.37-0.78) and with DNAmTL estimator (r = -0.38). Current SHS exposure, as measured by urinary cotinine, was associated with Horvath EAD (B = 0.23 years, P = .05). Similarly, current 3-HC and nicotine equivalents were positively associated with PedBE EAD (B = 0.08 years, P = .04; B = 0.11 years, P = .05, respectively). Among PAH metabolites, current 2-NAP levels were associated with principal component-based Skin&Blood EAD (B = 0.21 years, P = .02) and PedBE EAD (B = 0.13 years, P = .05). Findings suggest early-life SHS and PAHs exposure may contribute to accelerated epigenetic aging in children.

BACKGROUND:The Enhanced Quality in Primary Care for Elders with Diabetes-ADRD (EQUIPED-ADRD) is a quality improvement and pragmatic cluster-randomized controlled trial that uses clinical decision guidelines to streamline the care of older adults with diabetes mellitus and Alzheimer's disease/Alzheimer's disease-related Dementia (DM-AD/ADRD). This study tests whether the EQUIPED-ADRD intervention will increase the proportion of older adults with DM and AD/ADRD with desirable glycemic ranges, and reduce treatment burden, dementia severity, and healthcare utilization among participants and their care partners in the intervention arm compared to those in the control arm. METHODS:We will recruit older adults (≥65 years) with both DM and AD/ADRD diagnoses, who have care partners, and receive care at the enrolled New York University clinics. The intervention involves the use of panel managers to streamline the integration of clinical decision guidelines among primary care providers and improve the experiences of care partners and patients. Those in the control arm will have no panel management. We will conduct surveys and interviews, and extract data from EMR and Medicare claims to assess the association between the intervention and primary and secondary outcomes. The primary outcome is achieving within-range HbA1c, while the secondary outcomes include measures of healthcare utilization. Patient and care partner treatment burden, dementia symptoms, and care partner diabetes care distress. CONCLUSIONS:The EQUIPED-ADRD intervention (implemented between 2018 and 2021) will assess the effect of an institutional guideline on the quality of life and health outcomes of older adults with DM-AD/ADRD and their care partners. Clinical Trial NumberNCT03723707.

Repetitive head impacts are common in contact and collision sports and are linked to structural brain changes and an elevated risk of neurodegenerative diseases such as Chronic Traumatic Encephalopathy. Identifying early in vivo structural markers remains challenging. Although diagnosis currently requires post-mortem confirmation, clinical symptoms, including cognitive impairment and behavioural changes, are reflected in the diagnosis of Traumatic Encephalopathy Syndrome. These symptoms align with dysfunction in key brain regions-amygdala, hippocampus and thalamus-which support memory, emotion and behaviour and commonly show tau pathology in Chronic Traumatic Encephalopathy. This study uses shape analysis to examine structural differences in these regions between former American football players and unexposed asymptomatic controls and evaluates the influence of age, head impact exposure and clinical diagnosis on brain structure. We analyzed brain morphology in former American football players (n = 163) and unexposed, asymptomatic controls (n = 53). Structural segmentation was performed with FreeSurfer 7.1, and the shape analysis pipeline was used to generate subregional reconstructions. Vertex-level morphometry, based on the logarithm of the Jacobian determinant and radial distance, quantified local surface area dilation and thickness. Group differences were examined with covariate-adjusted linear regression models contrasting football players and controls, as well as participants with and without a Traumatic Encephalopathy Syndrome diagnosis. Partial correlations examined the influence of age, age of first football exposure and cumulative head impact index metrics, including frequency, linear acceleration and rotational force. Models were adjusted accordingly for age, body mass index, education, race, imaging site, apolipoprotein