Faculty Bibliography

OBJECTIVE:To evaluate the association of premature atrial contraction (PAC) frequency with cognitive test scores and prevalence of dementia or mild cognitive impairment (MCI). MATERIALS AND METHODS:We conducted a cross-sectional analysis using Atherosclerosis Risk in Communities study visit 6 (January 1, 2016, through December 31, 2017) data. We included 2163 participants without atrial fibrillation (AF) (age mean ± SD, 79±4 years; 1273 (58.9%) female; and 604 (27.97.0% Black) who underwent cognitive testing and wore a leadless, ambulatory electrocardiogram monitor for 14 days. We categorized PAC frequency based on the percent of beats: less than 1%, minimal; 1% to <5%, occasional; greater than or equal to 5%, frequent. We derived cognitive domain-specific factor scores (memory, executive function, language, and global z-score). Dementia and MCI were adjudicated. RESULTS:During a mean analyzable time of 12.6±2.6 days, 339 (15.7%) had occasional PACs and 107 (4.9%) had frequent PACs. Individuals with frequent PACs (vs minimal) had lower executive function factor scores by 0.30 (95% CI, -0.46 to -0.14) and lower global factor scores by 0.20 (95% CI, -0.33 to -0.07) after multivariable adjustment. Individuals with frequent PACs (vs minimal) had higher odds of prevalent dementia or MCI after multivariable adjustment (odds ratio, 1.74; 95% CI, 1.09 to 2.79). These associations were unchanged with additional adjustment for stroke. CONCLUSION:In community-dwelling older adults without AF, frequent PACs were cross-sectionally associated with lower executive and global cognitive function and greater prevalence of dementia or MCI, independently of stroke. Our findings lend support to the notion that atrial cardiomyopathy may be a driver of AF-related outcomes. Further research to confirm these associations prospectively and to elucidate underlying mechanisms is warranted.

Social determinants of health influence child health behavior, development, and outcomes. This paper frames social capital, or the benefits that a child receives from social relationships, as a positive social determinant of health that helps children exposed to adversity achieve healthy outcomes across the life course. Children are uniquely dependent on their relationships with surrounding adults for material and non-material resources. We identify and define three relevant aspects of social capital: 1) social support, which is embedded in a 2) social network, which is a structure through which 3) social cohesion can be observed. Social support is direct assistance available through social relationships and can be received indirectly through a caregiver or directly by a child. A child's social network describes the people in a child's life and the relationships between them. Social cohesion represents the strength of a group to which a child belongs (e.g. family, community). Pediatric primary care practices play an important role in fostering social relationships between families, the health care system, and the community. Further research is needed to develop definitional and measurement rigor for social capital, to evaluate interventions (e.g. peer health educators) that may improve health outcomes through social capital, and to broaden our understanding of how social relationships influence health outcomes.

BACKGROUND:For people with advanced stage cystic fibrosis (CF), tailored survival estimates could facilitate preparation for decision-making in the event of acutely deteriorating respiratory function. METHODS:We used the US CF Foundation national database (2008-2013) to identify adult people with incident advanced stage CF (forced expiratory volume in 1 s (FEV1) ≤45% predicted). Using the lasso method for variable selection, we divided the dataset into training and validation samples (2:1), and developed two multivariable Cox proportional hazards models to calculate probabilities of survival from baseline (T0 model), and from 1 year after (T12 model). We also performed Kaplan-Meier survival analyses. RESULTS:colonisation; cirrhosis; depression; dialysis; current smoking; unclassifiable mutation class and cumulative CF exacerbations predicted increased mortality. Baseline transplant evaluation status of 'accepted, on waiting list' predicted decreased mortality. For the T12 model, interim decrease in FEV1 >10%, and pulmonary exacerbations additionally increased predicted mortality. Lung transplantation was associated with lower mortality. Of the 4752, 93.5%, 86.4%, 79.7% and 73.9% survived to 1, 2, 3 and 4 years, respectively, without considering any confounding variables. The models had moderate predictive ability indicated by the area under the time-dependent receiver operating characteristic curve (0.787, 95% CI 0.769 to 0.794 for T0 model; and 0.779, 95% CI 0.767 to 0.797 for T12 model). CONCLUSION/CONCLUSIONS:We have developed models predicting survival in people with incident advanced stage CF, which can be reapplied over time to support shared decision-making about end-of-life treatment choices and lung transplantation. These estimates must be updated as data become available regarding long-term outcomes for people treated with CF transmembrane conductance regulator modulators.

The standard log-rank test has been extended by adopting various weight functions. Cancer vaccine or immunotherapy trials have shown a delayed onset of effect for the experimental therapy. This is manifested as a delayed separation of the survival curves. This work proposes new weighted log-rank tests to account for such delay. The weight function is motivated by the time-varying hazard ratio between the experimental and the control therapies. We implement a numerical evaluation of the Schoenfeld approximation (NESA) for the mean of the test statistic. The NESA enables us to assess the power and to calculate the sample size for detecting such delayed treatment effect and also for a more general specification of the non-proportional hazards in a trial. We further show a connection between our proposed test and the weighted Cox regression. Then the average hazard ratio using the same weight is obtained as an estimand of the treatment effect. Extensive simulation studies are conducted to compare the performance of the proposed tests with the standard log-rank test and to assess their robustness to model mis-specifications. Our tests outperform the G^ρ,γ class in general and have performance close to the optimal test. We demonstrate our methods on two cancer immunotherapy trials.

This activity is a paper presentation on a secondary analysis of factors associated with opioid abstinence three months following the treatment trial. While abstinence is not required for improvement in opioid use outcomes, better understanding of abstinence-related factors can inform efforts to facilitate stable recovery for opioid-dependent individuals. XXBackground(s): Opioid use disorder (OUD) is associated with substantial mortality. There are effective treatments in reducing opioid use and overdose events. However, many patients that successfully initiate OUD pharmacotherapy will discontinue treatment within the first few weeks or months. Upon treatment discontinuation, patients are at risk for relapse and overdose, however, not all patients relapse. There is a need to better understand predictors of relapse and abstinence after medication discontinuation. XXObjective(s): 1) Demonstrate general understanding of effective treatments for OUD and current barriers to treatment retention. 2) Describe factors associated with opioid abstinence from this secondary analysis. 3) Identify limitations in analyses and interpreting results. XXMethod(s): This secondary analysis examines correlates of opioid abstinence in 428 participants at week 36 follow-up from the National Drug Abuse Treatment Clinical Trials Network CTN-0051) X:BOT trial. X:BOT randomized participants to buprenorphine-naloxone (BUP-NX) or extended-release injectable naltrexone (XR-NTX) for up to 24 weeks of outpatient treatment. Study medications were discontinued at study completion or relapse. Follow-up assessments in the community were done at weeks 28 and 36. XXResult(s): Participants had higher odds of being abstinent at week 36 if randomized to XR-NTX compared with BUP-NX (odds ratio [OR] [95% confidence interval [CI]] = 2.47 [1.63, 3.74]), were on XR-NTX at follow-up compared with those off medication (OR = 2.33 [1.40, 3.90]), had longer time to relapse (OR = 1.04 [1.02, 1.07]), successfully inducted onto study medication compared with those who failed induction (OR = 3.16 [1.45, 6.92]), had longer time on study medication (OR = 1.03[1.01, 1.05]), and had more abstinent weeks during the trial (OR = 1.04 [1.02, 1.07]). XXConclusion(s): In general, participants that had better outcomes during the treatment trial were found to be abstinent from opioids at follow-up in the community. This included successful induction onto study medication, longer time on medication, greater time to relapse, and more abstinent weeks. While abstinence is not required for improvement in opioid use outcomes, better understanding of abstinence-related factors can inform efforts to facilitate stable recovery for opioid-dependent individuals. Scientific Significance: There is a need to better understand predictors of relapse and abstinence after medication discontinuation in order to better advise patients that may discontinue medications. Barriers to treatment retention and sustained abstinence are factors generally considered to be proxies for greater disease severity. Less is understood about factors associated with sustained abstinence

The plasma proteomic changes that precede the onset of dementia could yield insights into disease biology and highlight new biomarkers and avenues for intervention. We quantified 4,877 plasma proteins in nondemented older adults in the Atherosclerosis Risk in Communities cohort and performed a proteome-wide association study of dementia risk over five years (n = 4,110; 428 incident cases). Thirty-eight proteins were associated with incident dementia after Bonferroni correction. Of these, 16 were also associated with late-life dementia risk when measured in plasma collected nearly 20 years earlier, during mid-life. Two-sample Mendelian randomization causally implicated two dementia-associated proteins (SVEP1 and angiostatin) in Alzheimer's disease. SVEP1, an immunologically relevant cellular adhesion protein, was found to be part of larger dementia-associated protein networks, and circulating levels were associated with atrophy in brain regions vulnerable to Alzheimer's pathology. Pathway analyses for the broader set of dementia-associated proteins implicated immune, lipid, metabolic signaling and hemostasis pathways in dementia pathogenesis.

BACKGROUND:Adults age ≥ 50 are among the fastest growing populations in correctional supervision and are medically underserved while experiencing unique health disparities. Community-living older adults, referred to as "justice-involved," are people who have been recently arrested, or are on probation or parole. Although medical complexity is common among incarcerated older adults, the occurrence of medical morbidity, substance use disorder (SUD), and mental illness among justice-involved older adults living in US communities is poorly understood. OBJECTIVE:To estimate the prevalence of medical multimorbidity (≥ 2 chronic medical diseases), SUDs, and mental illness among justice-involved adults age ≥ 50, and the co-occurrence of these conditions. DESIGN/METHODS:Cross-sectional analysis. PARTICIPANTS/METHODS:A total of 34,898 adults age ≥ 50 from the 2015 to 2018 administrations of the US National Survey on Drug Use and Health. MAIN MEASURES/METHODS:Demographic characteristics of justice-involved adults age ≥ 50 were compared with those not justice-involved. We estimated prevalence of mental illness, chronic medical diseases, and SUD among adults age ≥ 50 reporting past-year criminal justice system involvement. Logistic regression was used to estimate the odds of these conditions and co-occurrence of conditions, comparing justice-involved to non-justice-involved adults. KEY RESULTS/RESULTS:An estimated 1.2% (95% confidence interval [CI] = 1.1-1.3) of adults age > 50 experienced criminal justice involvement in the past year. Compared with non-justice-involved adults, justice-involved adults were at increased odds for mental illness (adjusted odds ratio [aOR] = 3.04, 95% CI = 2.09-4.41) and SUD (aOR = 8.10, 95% CI = 6.12-10.73), but not medical multimorbidity (aOR = 1.15, 95% CI = 0.85-1.56). Justice-involved adults were also at increased odds for all combinations of the three outcomes, including having all three simultaneously (aOR = 8.56, 95% CI = 4.10-17.86). CONCLUSIONS:Community-based middle-aged and older adults involved in the criminal justice system are at high risk for experiencing co-occurring medical multimorbidity, mental illness, and SUD. Interventions that address all three social and medical risk factors are needed for this population.

BACKGROUND:Children residing in communities near metalworking industries are vulnerable to multiple toxic metal exposures. Understanding biomarkers of exposure to multiple toxic metals is important to characterize cumulative burden and to distinguish potential exposure sources in such environmental justice neighborhoods impacted by industrial operations. Exposure to metal mixtures has not been well-characterized among children residing in the United States, and is understudied in communities of color. METHODS:In this study we used toenail clippings, a noninvasive biomarker, to assess exposure to arsenic (As), cadmium (Cd), mercury (Hg), manganese (Mn), lead (Pb), antimony (Sb), selenium (Se), and vanadium (V). We used nonnegative matrix factorization (NMF) to identify "source" signatures and patterns of exposure among predominantly working class Latinx children residing near an industrial corridor in Southeast Los Angeles County. Additionally, we investigated the association between participant demographic, spatial, and dietary characteristics with identified metal signatures. RESULTS:Through NMF, we identified three groupings (source factors) for the metal concentrations in children's toenails. A grouping composed of Sb, Pb, As, and Cd, was identified as a potential industrial source factor, reflective of known airborne elemental emissions in the industrial corridor. We further identified a manganese source factor primarily composed of Mn, and a potential dietary source factor driven by Se and Hg. We observed differences in the industrial source factor by age of participants, while the dietary source factor varied by neighborhood. CONCLUSION/CONCLUSIONS:Utilizing an unsupervised dimension reduction technique (NMF), we identified a "source signature" of contamination in toenail samples from children living near metalworking industry. Investigating patterns and sources of exposures in cumulatively burdened communities is necessary to identify appropriate public health interventions.

BACKGROUND AND AIMS/OBJECTIVE:Three to ten minutes of smoking cessation advice by physicians is effective to increase quit rates but not routinely practised. We examined the effectiveness of physicians' very brief (about 30 seconds) smoking cessation intervention on quit rates among Chinese outpatient smokers. DESIGN/METHODS:A pragmatic, open-label, individually randomized controlled trial. SETTING/METHODS:Seventy-two medical outpatient departments of hospitals and/or community health centers in Guangdong, China. PARTICIPANTS/METHODS:Chinese adults who were daily cigarette smokers (N = 13,671, 99% males) were invited by their physician to participate during outpatient consultation. Smokers who were receiving smoking cessation treatment or were judged to needed specialist treatment for cessation were excluded. INTERVENTIONS/METHODS:The intervention group (n = 7,015) received a 30-second intervention including physician's very brief advice, a leaflet with graphic warnings, and a card with contact information of available cessation services. The control group (n = 6,656) received a very brief intervention on consuming vegetables and fruits. A total of 3,466 participants in the intervention group were further randomized to receive a brief booster advice from trained study personnel through telephone one month following their doctor visit. MEASUREMENTS/METHODS:The primary outcome was self-reported 7-day point prevalence abstinence in the intervention and control group at the 12-month follow-up. Secondary outcomes included self-reported 30-day abstinence and biochemically validated abstinence at 12-month follow-up. FINDINGS/RESULTS:By intention-to-treat, the intervention (vs. control) group had greater self-reported 7-day abstinence (9.1% vs. 7.8%; odds ratio (OR) 1.14; 95% Confidence Interval (CI) 1.03-1.26; P = .008) and 30-day abstinence (8.0% vs. 6.9%; OR 1.14 95% CI 1.03-1.27; P=0.01) at 12-month follow-up. The effect size increased when only participants who received the intervention from compliant physicians were included (7-day PPA OR = 1.42; 1.11-1.74). The group difference in biochemically validated abstinence was small (0.8% vs. 0.8%; OR 1.00 95% CI 0.71-1.42; P=0.99). CONCLUSION/CONCLUSIONS:A 30-second smoking cessation intervention increased self-reported abstinence among mainly male smokers in China at 12-month follow-up (risk difference = 1.3%) and should be feasible to provide in most settings and delivered by all healthcare professionals.