Faculty Bibliography

Depression is a major contributor to the global burden of disease. There is limited understanding of how environmental exposures may contribute to depression etiology. We used Wave IV of the National Longitudinal Study of Adolescent to Adult Health (Add Health) to examine associations between low-level ambient air pollution exposure and depressed mood in a generally healthy population of over 10,000 24-32 year olds. Annual mean PM2.5 levels in the 2008-2009 study were close to the current U.S. standard. In fully adjusted quasi-binomial logistic regression models, there were no meaningful associations between IQR increases in air pollutant and change in depressed mood status regardless of specific pollutant or moving average lags. In interaction effects models, an IQR increase in lag day 0-30 PM2.5 resulted in 1.20 (95% CI, 1.02-1.41) times higher likelihood of having depressed mood, but only for persons with chronic lung disease (interaction P=0.04); the association was null for participants without chronic lung disease (OR 0.98, 95% CI, 0.91, 1.05). Our findings suggest that among persons with a lifetime history of chronic lung disease, greater exposure to even low-level PM2.5, PM10, and sulfate may be associated with modest increases in the likelihood of having depressed mood.

OBJECTIVE:Little is known about how parenting interventions might influence families' access to related healthcare services during early childhood. This study describes the effects of a parenting intervention, Smart Beginnings (SB), on referrals to early intervention (EI) or early childhood special education (ECSE) after evaluation within a predominantly Black/Latine sample with low incomes. SB is a tiered intervention integrating a universal parenting program delivered in primary care clinics (PlayReadVIP) with a targeted home visiting program (Family Check-Up). METHODS:Data were drawn from a randomized controlled trial of SB, with sites in NYC and Pittsburgh, PA. The 280 families (132 treatment; 148 control) were 43% Black, 47% Latine, 37% Spanish-speaking, and 100% Medicaid-eligible. Hierarchical logistic regressions examined associations between expressive vocabulary and problem behaviors (internalizing and externalizing symptoms) at 2 years, and the impact of the SB intervention on the likelihood of EI/ECSE evaluation and service referrals based on evaluation results by 4 years. RESULTS:Across sites, children's lower expressive vocabulary and higher problem behaviors at 2 years predicted receiving EI/ECSE evaluation and service referrals by age 4. Assignment to the SB intervention reduced the likelihood of evaluations leading to referrals for EI/ECSE service. CONCLUSIONS:Results from this RCT showed that children with early behavior and language challenges were more likely to receive EI/ECSE evaluation and services by preschool-age. Children assigned to SB were less likely to be referred for services. Studying factors that predict EI/ECSE involvement for children from historically marginalized populations can help promote equity in early care systems.

BACKGROUND:Childhood environmental factors back to the prenatal environment can contribute to MS risk. Childhood adversity, which causes biological, behavioral, and epigenetic changes that can be passed down through families, has been understudied in MS. Here, we emphasize the need to understand the role that intergenerational adversity may play among families affected by MS. OBJECTIVE:To evaluate the frequency and types of adverse childhood experiences among parents of children with MS. METHODS:Individuals with pediatric MS (n = 68) were enrolled in a longitudinal study of cognition. At enrollment, the patient and one caregiver or parent completed questionnaires. As the pediatric participants were under age 18 at time of enrollment, one parent completed the Adverse Childhood Experiences (ACEs, a 10-item self-report measure) about the parents' own childhood. Results from the ACE questionnaire among parents of pediatric healthy controls (n = 96) and adults in a national cohort are also reported for comparison. RESULTS:Over half of pediatric MS parents reported at least one ACE exposure. Of parents that did have ACE exposures, the exposures were broad in terms of abuse, neglect, and household dysfunction. Over 10 % of parents reported total ACE scores of 7 or above. CONCLUSION/CONCLUSIONS:Over half of pediatric MS parents experienced some degree of childhood adversity. The impact of intergenerational adversity on the development of pediatric onset MS warrants further study.

INTRODUCTION/BACKGROUND:Foundational preacademic skills are crucial for academic success and serve as predictors of socioeconomic status, income and access to healthcare. However, there is a gap in our understanding of neurodevelopmental patterns underlying preacademic skills in children across low-income and middle-income countries (LMICs). It is essential to identify primary global and regional factors that drive children's neurodevelopment in LMICs. This study aims to characterise the typical development of healthy children and factors that influence child development in Bahir Dar, Ethiopia. METHODS AND ANALYSIS/METHODS:The Bahir Dar Child Development Study is a cross-sectional study implemented in two health centres, Shimbit and Abaymado and in Felege Hiwot Comprehensive Specialized Hospital (FHCSH) in Bahir Dar, Amhara, Ethiopia. Healthy children between 6 and 60 months of age will be recruited from the health centres during vaccination visits or via community outreach. Young children aged 6-36 months will complete the Global Scale for Early Development. A battery of paper and tablet-based assessments of neurocognitive outcomes including visual and verbal reasoning, executive functions and school readiness will be completed for children aged 48-60 months. Caregivers will respond to surveys covering sociodemographic information, the child's medical history and nutrition, and psychosocial experiences including parental stress and mental health. During a second visit, participants will undergo a low-field MRI scan using the ultra-low-field point-of-care Hyperfine MRI machine at FHCSH. Analyses will examine relationships between risk and protective factors, brain volumes and neurocognitive/developmental outcomes. ETHICS AND DISSEMINATION/BACKGROUND:The study is approved by the Institutional Review Boards of Addis Continental Institute of Public Health (ACIPH/lRERC/004/2023/Al/05-2024), Mass General Brigham Hospital (2022P002539) and Brown University (STUDY00000474). Findings will be disseminated via local dissemination events, international conferences and publications. TRIAL REGISTERATION NUMBER/BACKGROUND:NCT06648863.

BackgroundBreast conserving surgery represents the preferred surgical treatment option for patients with early-stage breast cancer. Reexcision rates are generally higher for patients undergoing lumpectomies for ductal carcinoma in situ (DCIS) compared to invasive breast cancer, as the microscopic extent of disease is difficult to assess during excision. This study investigated the clinicopathological characteristics of patients undergoing BCS for pure DCIS and reexcision rates over time, including the effect of the MarginProbe™ device.MethodsWe queried our prospectively maintained Institutional Breast Cancer Database for patients diagnosed with DCIS and treated with BCS as their primary procedure from 2010-2021. The primary endpoint was the rate of reexcision. Variables of interest included age at diagnosis, race/ethnicity, mode of diagnostic imaging, mammographic breast density, method of core biopsy, nuclear grade, size of DCIS, multifocality, DCIS subtype, and MarginProbe™ use.ResultsPapillary DCIS (P < 0.004) and larger size (P < 0.001) was associated with an increased reexcision rate. There were also differences in the method of core biopsy (P < 0.001), with stereotactic core biopsy predominating among patients who did not require reexcision (71.3% vs 49.5%). In an unadjusted estimate for the odds ratio for association, patients who had MarginProbe™ used were 81% less likely to require reexcision (OR = 0.19, 95% CI = 0.12, 0.31, P < 0.0001).ConclusionYounger age, papillary DCIS, larger DCIS size, and non-stereotactic core biopsy method were found to be associated with higher reexcision rates. Additionally, patients whose primary procedures included intraoperative margin assessment with the MarginProbe™ were significantly less likely to require reexcision.

INTRODUCTION/BACKGROUND:The number of assays on proteomic platforms has grown rapidly. The leading platforms, SomaScan and Olink, have strengths and limitations. Comparisons of precision on the latest platforms-SomaScan 11k and Olink Explore HT-have not yet been established. METHODS:Among 102 participants in the Atherosclerosis Risk in Communities Study (mean age 74 years, 53% women, 47% Black), we used split plasma samples to measure platform precision. CV and Spearman correlations were calculated for each assay. Cross-platform agreement was assessed for overlapping proteins. RESULTS:SomaScan 11k demonstrated a median correlation of 0.85 for the 10 778 assays and a median CV of 6.8%, similar precision to earlier versions. The 5420 assays on Olink Explore HT exhibited a median correlation of 0.65 and median CV of 35.7%, which was higher than observed in its predecessors (e.g., 19.8% for Olink Explore 3072). Precision of Olink assays was inversely correlated with the percentage of samples above the limit of detection (LOD) (r = -0.77). Upon replacing Olink values below the LOD with values half the LOD, the median correlation for Olink assays measured in duplicate increased to 0.79; the median CV decreased to 13.3%. The distribution of between-platform correlations for the 4443 overlapping proteins had peaks at r approximately 0 and at r approximately 0.8. One-tenth of the protein pairs had cross-platform correlations r ≥ 0.8. CONCLUSIONS:Precision of these 2 proteomics platforms in human plasma has diverged as the coverage has increased. These results highlight the need for careful consideration in platform selection based on specific research requirements.

BACKGROUND AND HYPOTHESIS/OBJECTIVE:Early steroid withdrawal (ESW) is often preferred over conventional steroid maintenance (CSM) therapy for kidney transplant recipients with low immunological risks because it may minimize immunosuppression-related adverse events while achieving similar transplant outcomes. However, the risk-benefit balance of ESW could be less favorable in retransplant recipients given their unique immunological risk profile. We hypothesized that the association of ESW with transplant outcomes would differ between first-transplant and retransplant recipients. METHODS:To assess whether the impact of ESW differs between first and retransplant recipients, we studied 210 086 adult deceased-donor kidney transplant recipients using the Scientific Registry of Transplant Recipients. Recipients who discontinued maintenance steroids before discharge from transplant admission were classified with ESW; all others were classified with CSM. We quantified the association of ESW (vs. CSM) with acute rejection, death-censored graft failure, and death, addressing retransplant as an effect modifier, using logistic/Cox regression with inverse probability weights to control for confounders. RESULTS:In our cohort, 26 248 (12%) were retransplant recipients. ESW was used in 30% of first-transplant and 20% of retransplant recipients. Among first-transplant recipients, ESW was associated with no significant difference in acute rejection (aOR = 1.04 [95% CI = 1.00-1.09]), slightly higher hazard of graft failure (HR = 1.09 [95% CI = 1.05-1.12]), and slightly lower mortality (HR = 0.93 [95% CI = 0.91-0.95]) compared to CSM. Nonetheless, among retransplant recipients, ESW was associated with notably higher risk of acute rejection (OR = 1.42 [95% CI = 1.29-1.57]; interaction p < 0.001) and graft failure (HR = 1.24 [95% CI = 1.14-1.34]; interaction p = 0.003), and similar mortality (HR = 1.01 [95% CI = 0.94-1.08]; interaction p = 0.04). CONCLUSIONS:In retransplant recipients, the negative impacts of ESW on transplant outcomes appear to be non-negligible. A more conservatively tailored approach to ESW might be necessary for retransplant recipients.

IMPORTANCE/UNASSIGNED:Evidence regarding suppressive valacyclovir treatment on postherpetic neuralgia is necessary to guide care. OBJECTIVE/UNASSIGNED:To test the hypothesis that suppressive treatment with 1000 mg/d of oral valacyclovir for 12 months reduces the prevalence, severity, and duration of postherpetic neuralgia compared with placebo at 12 and 18 months in participants with herpes zoster ophthalmicus (HZO). DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:Multicenter, placebo-controlled randomized clinical trial including 527 immunocompetent, nonpregnant adults with history of HZO rash, documented keratitis, or iritis within 1 year and an estimated glomerular filtration rate of 45 mL/min/1.73 m2 or greater. The study was conducted at 95 participating sites (in Canada, New Zealand, and the US) from November 2017 to June 2024 and participant visits occurred every 3 months. INTERVENTION/UNASSIGNED:Treatment with 1000 mg/d of valacyclovir or placebo for 12 months. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Prevalence of postherpetic neuralgia, severity as determined by pain score (a score of ≥3 on a scale of 1-10), pain duration (≥3 months after HZO onset), and total daily dose of pain medication. RESULTS/UNASSIGNED:Of the 527 participants (490 completed 12 months of treatment and 460 completed 18 months), 73 (14%) had postherpetic neuralgia and were analyzed by age at HZO onset (<60 years or ≥60 years) and disease duration (recent [<6 months] or chronic [≥6 months]). Of the 73 participants with postherpetic neuralgia (34 in the valacyclovir group and 39 in the placebo group), the mean age was 62.4 years (SD, 13.6 years), 59% were female, 5% were Black or African American, and 10% were Hispanic. The prevalence of postherpetic neuralgia at 12 months was not reduced by valacyclovir (12/32 [38%]) compared with placebo (14/35 [40%]) (between-group difference, 2.5% [95% CI, -20.8% to 25.8%]; P>.99). The participants who were younger than 60 years at HZO onset and had a chronic disease duration had lower pain scores in the valacyclovir group (mean score, 0.3 [SD, 0.9]) vs the placebo group (mean score, 0.8 [SD, 1.9]) at 12 months (P = .045) and at 18 months (mean score, 0.2 [SD, 0.9] vs 1.0 [SD, 2.3], respectively; P = .02). There was a decrease in pain duration in the valacyclovir group at 18 months (mean, 13.6 [SD, 11.4] months) vs the placebo group (mean, 18.7 [SD, 29.5] months) (linear mixed-effects model between-group difference, -3.39 months [95% CI, -6.73 to -0.04 months]; P = .046). The total daily dose of neuropathic pain medication was lower in the valacyclovir group (mean, 271.4 [SD, 593.8] mg/d) vs the placebo group (mean, 363.4 [SD, 592.2] mg/d) at 12 months (linear mixed-effects model P = .006) and at 18 months (mean, 209.0 [SD, 412.8] mg/d vs 286.2 [SD, 577.9] mg/d, respectively; linear mixed-effects model P = .01). CONCLUSIONS AND RELEVANCE/UNASSIGNED:One year of suppressive treatment with valacyclovir was associated with a lower dosage of neuropathic pain medication. Participants in the valacyclovir group, who were younger at HZO onset and had a chronic disease duration, had lower pain scores. These secondary outcomes support consideration of 1 year of suppressive treatment with valacyclovir to reduce dosage of pain medications and pain due to HZO. TRIAL REGISTRATION/UNASSIGNED:ClinicalTrials.gov Identifier: NCT03134196.

BACKGROUND:As the inflammatory bowel disease (IBD) patient population is aging, the prevalence of polypharmacy is rising. However, data exploring the prevalence, risk factors, and clinical outcomes associated with polypharmacy among older adults with IBD are limited. AIMS/OBJECTIVE:To determine (i) prevalence of polypharmacy (≥5 medications) and potentially inappropriate medication (PIM) utilization in older adults with IBD, (ii) changes in medications over time (iii) predictors of polypharmacy, and (iv) the impact of polypharmacy/PIMs on one-year hospitalization rates. METHODS:We conducted a retrospective single-center study of older adults with IBD from September 1st 2011 to December 31st 2022. Wilcoxon-signed rank and McNemar's tests were used to assess changes in polypharmacy between visits, with ordinal logistic regression and Cox proportional hazards models used to determine risk factors for polypharmacy and time to hospitalization, respectively. RESULTS:Among 512 older adults with IBD, 74.0% experienced polypharmacy at initial visit, with 42.6% receiving at least one PIM. Additionally, severe polypharmacy (≥10 medications) was present among 28.6% individuals at index visit and increased to 38.6% by last visit (p<0.01). Multivariable analysis revealed that age ≥70 years, BMI ≥30.0 kg/m2, prior IBD-related surgery, and the presence of comorbidities were associated with polypharmacy. Moreover, severe polypharmacy (adjHR 1.95, 95%CI 1.29-2.92), as well as PIM use (adjHR 2.16, 95%CI 1.37-3.43) among those with polypharmacy, were significantly associated with all-cause hospitalization within a year of index visit. DISCUSSION/CONCLUSIONS:Severe polypharmacy was initially present in more than 25% of older adults with IBD and increased to 34% within 4 years of index visit. Severe polypharmacy, as well as PIM utilization among those with polypharmacy, were also associated with an increased risk of hospitalization at one-year, highlighting the need for deprescribing efforts in this population.

Significant quality gaps exist in the management of chronic liver diseases and cirrhosis. Clinical decision support (CDS) systems-information-driven tools based in and launched from the electronic health record-are attractive and potentially scalable prospective interventions that could help standardize clinical care in hepatology. Yet, CDS systems have had a mixed record in clinical medicine due to issues with interoperability and compatibility with clinical workflows. In this review, we discuss the conceptual origins of CDS systems, existing applications in liver diseases, issues and challenges with implementation, and emerging strategies to improve their integration in hepatology care.