Faculty Bibliography

Cerebrospinal fluid (CSF) studies consistently show that CSF levels of amyloid-beta 1-42 (Aβ42) are reduced and tau levels increased prior to the onset of cognitive decline related to Alzheimer's disease (AD). However, the preclinical prediction accuracy for low CSF Aβ42 levels, a surrogate for brain Aβ42 deposits, is not high. Moreover, the pathology data suggests a course initiated by tauopathy contradicting the contemporary clinical view of an Aβ initiated cascade. CSF Aβ42 and tau data from 3 normal aging cohorts (45-90 years) were combined to test both cross-sectional (n = 766) and longitudinal (n = 651) hypotheses: 1) that the relationship between CSF levels of Aβ42 and tau are not linear over the adult life-span; and 2) that non-linear models improve the prediction of cognitive decline. Supporting the hypotheses, the results showed that a u-shaped quadratic fit (Aβ2) best describes the relationship for CSF Aβ42 with CSF tau levels. Furthermore we found that the relationship between Aβ42 and tau changes with age-between 45 and 70 years there is a positive linear association, whereas between 71 and 90 years there is a negative linear association between Aβ42 and tau. The quadratic effect appears to be unique to Aβ42, as Aβ38 and Aβ40 showed only positive linear relationships with age and CSF tau. Importantly, we observed the prediction of cognitive decline was improved by considering both high and low levels of Aβ42. Overall, these data suggest an earlier preclinical stage than currently appreciated, marked by CSF elevations in tau and accompanied by either elevations or reductions in Aβ42. Future studies are needed to examine potential mechanisms such as failing CSF clearance as a common factor elevating CSF Aβxx analyte levels prior to Aβ42 deposition in brain.

Objective/UNASSIGNED:To review available literature on the prevalence, risk factors, pathophysiology, and clinical outcomes of dysglycemia among people living with HIV (PLHIV) in sub-Saharan Africa (SSA). Methods/UNASSIGNED:Database search on PUBMED for eligible studies describing the prevalence, risk factors, pathophysiology, or clinical outcomes of dysglycemia in SSA PLHIV. Results/UNASSIGNED:Prevalence of diabetes mellitus (DM) and pre-DM among SSA PLHIV ranged from 1% to 26% and 19% to 47%, respectively, in 15 identified studies. Older age and an elevated body mass index (BMI) were common risk factors for dysglycemia. Risk factors potentially more specific to PLHIV in SSA included exposure to older-generation thymidine analogues or protease inhibitors, malnutrition at ART initiation, a failure to gain fat mass on treatment, and elevated serum lipids. There is evidence of higher nephropathy and neuropathy rates among PLHIV in SSA with comorbid DM compared to HIV-negative individuals with DM. Conclusion/UNASSIGNED:There is a need for longitudinal studies to enhance understanding of the risk factors for dysglycemia among PLHIV in SSA, further research into optimal therapies to reduce pre-DM progression to DM among SSA PLHIV, and studies of the burden and phenotype of diabetic complications and other health outcomes among PLHIV with comorbid DM in SSA.

Background: Partnership, engagement, and collaboration (PEC) are critical factors in dissemination and implementation (D&I) research. Despite a growing recognition that incorporating PEC strategies in D&I research is likely to increase the relevance, feasibility, impacts, and of evidence-based interventions or practices (EBIs, EBPs), conceptual frameworks and methodologies to guide the development and testing of PEC strategies in D&I research are lacking. To address this methodological gap, a review was conducted to summarize what we know, what we think we know, and what we need to know about PEC to inform D&I research. Methods: A cross-field scoping review, drawing upon a broad range of PEC related literature in health, was conducted. Publications reviewed focused on factors influencing PEC, and processes, mechanisms and strategies for promoting effective PEC. The review was conducted separately for three forms of partnerships that are commonly used in D&I research: (1) consumer-provider or patient-implementer partnership; (2) delivery system or implementation team partnership; and (3) sustainment/support or interagency/community partnership. A total of 39 studies, of which 21 were review articles, were selected for an in-depth review. Results: Across three forms of partnerships, four domains (cognitive, interpersonal/affective, behavioral, and contextual domains) were consistently identified as factors and strategies for promoting PEC. Depending on the stage (preparation or execution) and purpose of the partnership (regulating performance or managing maintenance), certain PEC strategies are more or less relevant. Recent developments of PEC frameworks, such as Partnership Stage of Change and multiple dynamic processes, provide more comprehensive conceptual explanations for PEC mechanisms, which can better guide PEC strategies selection and integration in D&I research. Conclusions: This review contributes to D&I knowledge by identifying critical domain factors, processes, or mechanisms, and key strategies for PEC, and offers a multi-level PEC framework for future research to build the evidence base. However, more research is needed to test PEC mechanisms.

Background: Environmental chemical exposures are linked to oxidative stress and kidney injury in children and adults. This applies to short-lived organic compounds such as bisphenol A and phthalates and persistent synthetic chemicals such as perfluoroalkyl acids (PFAAs). Most investigations to date have been conducted in developed countries with few data about environmental chemical exposures in children living in Africa.
Method(s): Clinical and laboratory data about pediatric patients enrolled in the H3 Africa observational cohort study including age, gender, BMI, serum creatinine, eGFR, proteinuria were collected. Serum samples that had been collected at enrollment were retrieved from the Biorepository and analyzed for PFAAs and polybrominated diphenyl ethers (PBDEs) and DDE presticides using established methods. Proteinuria was assessed in a first morning urine sample. Results are presented as mean+/-SD.
Result(s): 86 patients with CKD (41 M:45 F), age 12.6+/-2.6 yr old, were included in this nested case control study. The eGFR was 75+/-4 and the albumin:creatinine ratio was 65+/-186. The chemical exposures are summarized in the Table. There was no association between exposure (log of serum concentration) to PFAAs and proteinuria. However, controlling for age, gender, and BMI, there was an inverse relationship between eGFR and exposure to PFNA, -21.2 [95% CI:-41.6 -0.8] and PFDA -18.3 [95% CI:-35.3 --1.3] ml/min/log unit increase in exposure and a trend towards a similar effect for PFOS. PBDE/DDEs were detected in a small fraction of children and because of small sample size associations with effect markers were not made
Conclusion(s): PFAA exposure is substantially lower in H3 Africa participants than in healthy US children, age 12-19 enrolled in NHANES 2003-2010. However, even at these lower levels of exposure there was an adverse association between select PFAAs and GFR. These studies indicate the feasibility of measuring environmental chemical exposure in developing countries. The impact of these chemical exposures on kidney function will require larger cohorts of children followed for more extended periods of time

In this study, factor analysis and mass regression were used to identify four fine particulate matter sources and estimate their contributions to the ambient air pollution in Beijing. The identified sources were traffic re-suspended soil, mixed industrial sources, oil combustion, and secondary sulfate. The estimated source contributions were then introduced into two models as exposure variables to explore the relationships between cardiovascular responses in mice and PM exposures. We observed that PM2.5 has a small negative acute effect on heart rate, but the individual source factors showed much more significant effects. Traffic re-suspended soil had the most significant effect on heart rate, with a positive contribution on the day of exposure and a negative one on day lag 1. Acute heart rate variability outcomes were better explained by the total PM2.5 than by the source components. Chronic effects were observed as a decreased heart rate but an increased number of heart rate variability outcomes

United States Veterans are at excess risk for type 2 diabetes, but population differentials in risk have not been characterized. We determined risk of type 2 diabetes in relation to prediabetes and dyslipidemic profiles in Veterans at the VA New York Harbor (VA NYHHS) during 2004-2014. Prediabetes was based on American Diabetes Association hemoglobin A1c (HbA1c) testing cut-points, one of several possible criteria used to define prediabetes. We evaluated transition to type 2 diabetes in 4,297 normoglycemic Veterans and 7,060 Veterans with prediabetes. Cox proportional hazards regression was used to relate HbA1c levels, lipid profiles, demographic, anthropometric and comorbid cardiovascular factors to incident diabetes (Hazard Ratio [HR] and 95% confidence intervals). Compared to normoglycemic Veterans (HbA1c: 5.0-5.6%; 31-38 mmol/mol), risks for diabetes were >2-fold in the moderate prediabetes risk group (HbA1c: 5.7-5.9%; 39-41 mmol/mol) (HR 2.37 [1.98-2.85]) and >5-fold in the high risk prediabetes group (HbA1c: 6.0-6.4%; 42-46 mmol/mol) (HR 5.59 [4.75-6.58]). Risks for diabetes were increased with elevated VLDL (≥40mg/dl; HR 1.31 [1.09-1.58]) and TG/HDL (≥1.5mg/dl; HR 1.34 [1.12-1.59]), and decreased with elevated HDL (≥35mg/dl; HR 0.80 [0.67-0.96]). Transition to diabetes in Veterans was related in age-stratified risk score analyses to HbA1c, VLDL, HDL and TG/HDL, BMI, hypertension and race, with 5-year risk differentials of 62% for the lowest (5-year risk, 13.5%) vs. the highest quartile (5-year risk, 21.9%) of the risk score. This investigation identified substantial differentials in risk of diabetes in Veterans, based on a readily-derived risk score suitable for risk stratification for type 2 diabetes prevention.

Thyroid hormones are crucial in normal brain development. Transient and mild thyroid hormone insufficiency in pregnancy is also associated with impaired neurodevelopment in the offspring (e.g., 3-4 IQ score loss in association with maternal free thyroxine in the lowest fifth percentile). While inadequate iodine intake remains the most common underlying cause of mild thyroid hormone insufficiency in vulnerable populations including pregnant women, other factors such as exposure to environmental contaminants have recently attracted increasing attention, in particular in interaction with iodine deficiency. Endocrine-disrupting chemicals (EDCs) are natural and synthetic substances with ubiquitous exposure in children and adults including pregnant women. EDCs interfere, temporarily or permanently, with hormonal signaling pathways in the endocrine system by binding to hormone receptors and modifying gene expression. Other mechanisms involve alterations in production, metabolism, and transfer of hormones. Experimental studies have shown that exposures to EDCs affect various brain processes such as neurogenesis, neural differentiation and migration, as well as neural connectivity. Neuroimaging studies confirm brain morphological abnormalities (e.g., cortical thinning) consistent with neurodevelopmental impairments as a result of EDC exposures at standard use levels. In this review, we provide an overview of present findings from toxicological and human studies on the anti-thyroid effect of EDCs with a specific attention to fetal and early childhood exposure. This brief overview highlights the need for additional multidisciplinary studies with a focus on thyroid disruption as an underlying mechanism for developmental neurotoxicity of EDC, which can provide insight into modifiable risk factors of developmental delays in children.