Faculty Bibliography

INTRODUCTION/BACKGROUND:KIM-1, TNFRSF1A, and TNFRSF1B have been accepted as early risk markers in diabetic kidney disease by the US Food and Drug Administration. Whether they may be useful in identifying high-risk patients for cardiovascular/kidney clinical trial enrollment in other important subgroups is uncertain. METHODS:We evaluated the potential prognostic enrichment of KIM-1, TNFRSF1A, and TNFRSF1B in four cohorts: the Atherosclerosis Risk in Communities (ARIC) (N = 4,594, mean age 76 years, 55% women, mean eGFR 68 mL/min/1.73 m2), African American Study of Kidney Disease and Hypertension (AASK) (N = 705, mean age 55 years, 39% women, mean mGFR 46 mL/min/1.73 m2), Chronic Renal Insufficiency Cohort (CRIC) (N = 2,943, mean age 59 years, 45% women, mean eGFR 35 mL/min/1.73 m2), and Boston Kidney Biopsy Cohort (BKBC) (N = 434, mean age 54 years, 48% women, mean eGFR 51 mL/min/1.73 m2). We evaluated three outcomes: 40% glomerular filtration rate (GFR) decline, kidney failure, and incident cardiovascular disease (CVD) overall and in two subgroups historically underrepresented in clinical trials: participants with no diabetes, and those with albuminuria <200 mg/g. RESULTS:Published models (40% decline tool, kidney failure risk equation, and PREVENT) using clinical variables had moderate to strong risk discrimination in each cohort: 40% GFR decline, AUROC range: 0.78-0.90; kidney failure, C-statistic range: 0.75-0.93; and CVD, C-statistic range: 0.59-0.79. After addition of biomarkers, there was a small but significant improvement in the meta-analyzed overall population: change in AUROC in 40% GFR decline: 0.02, p < 0.001; change in C-statistic for kidney failure: 0.01, p = 0.02; change in C-statistic for CVD: 0.01, p = 0.03. Among participants without diabetes, the change was statistically significant only for 40% decline; among patient with albuminuria <200 mg/g, the change was statistically significant only for the two kidney outcomes. CONCLUSION/CONCLUSIONS:KIM-1, TNFRSF1A, and TNFRSF1B may not be strong prognostic enrichment biomarkers over and above clinical risk estimates. Clinical trials should test whether they help with predictive enrichment.

INTRODUCTION/BACKGROUND:The National Heart, Lung and Blood Institute (NHLBI), in 2020, funded six implementation research trials in Africa (Botswana, Mozambique, Nigeria, South Africa, Uganda and Zambia) to test implementation strategies for integrating evidence-based cardiovascular disease (CVD) care into primary care for people living with HIV. We identified cross-site implementation strategies used by the six trials to integrate CVD care for people living with HIV in these diverse settings. METHODS:Between December 2022 and September 2023, we reviewed protocols for each trial and followed up with study teams from the six studies to identify implementation strategies targeting the individual (healthcare worker [HCW] and patient), facility and system levels. Guided by the Expert Recommendations for Implementing Change (ERIC) taxonomy of implementation strategies, we grouped and defined strategies used for each study. We then specified each strategy (i.e. actor, the action, action targets, temporality, dose, implementation outcomes addressed and theoretical justification) to understand similarities and differences in how cross-cutting implementation strategies were operationalized. RESULTS:Ten implementation strategies were identified across the six trials for integrating hypertension (six studies) and diabetes (one study) care into existing HIV primary healthcare platforms. Three strategies, HCW training, audit and feedback, and practice facilitation or coaching, were implemented in all trials. Function and form synthesis showed that while these strategies shared the common goal of improving provider capacity and quality of care, their delivery varied across settings. HCW training was adapted in duration, frequency and trainer type; audit and feedback processes differed in how data were used and integrated with district quality improvement structures; and practice facilitation approaches ranged from study-led to health system-led models. These adaptations reflected contextual differences in health system capacity and available resources while maintaining a shared focus on strengthening HIV-CVD service integration. CONCLUSIONS:With the increasing burden of CVD among people living with HIV, identifying implementation strategies for integrating CVD care into HIV primary healthcare is critical. Our study provides contextually relevant information on cross-site implementation strategies aimed at achieving this in six African countries. The findings underscore the necessity of strategies that extend beyond conventional training, highlighting coaching, facilitation and developing data systems as central to approaches to improve integrated CVD care for people living with HIV in low-resource settings.

BACKGROUND:Studies of prenatal exposure to non-persistent chemicals often assume biomarker measurements from a single urine sample can represent exposure pregnancy. The validity of this assumption depends on biomarker concentration variability across gestation, which is not well-characterized for many chemicals. OBJECTIVE:To assess the intra-individual variability of non-persistent chemical concentrations measured in 3 pregnancy urine samples. METHODS:We measured 154 analytes from 12 classes in 3 urine samples collected across gestation from 90 participants in 3 Environmental influences on Child Health Outcomes Cohort sites. For each cohort site, we estimated intraclass correlation coefficients (ICCs) of 58 analytes with >60% detection using log2-transformed concentrations of specific gravity (SG)-standardized values. We classified analyte ICCs by the site-specific median relative to the limits of detection (LODs) to evaluate the influence of exposure levels on reliability estimates. As secondary analyses, we calculated kappa statistics for 56 analytes with 20-60% detection to assess agreement of detection frequencies across the 3 timepoints. RESULTS:ICCs (range: -0.12 to 0.91) varied by cohort site, except for benzophenone-1 and propyl paraben (consistently >0.5) and bisphenol F (consistently <0.1). We observed site-specific trends for parabens, benzophenones, antimicrobials, phthalates, polycyclic aromatic hydrocarbons, and aromatic amines. Analytes with median:LOD ratios >50 were more stable throughout pregnancy (e.g., benzophenones, propyl paraben, antimicrobials, and naphthalenes), except for some phthalate metabolites, which may indicate high sporadic exposures. Analytes with median:LOD ratios <10 had lower ICCs, except for benzophenone-8, which may indicate low-level chronic exposure. Kappa statistics of the 56 analytes with 20-60% detection ranged from -0.22 to 0.53. SIGNIFICANCE/CONCLUSIONS:ICCs varied by cohort site. Lower ICCs were generally observed for analytes with lower concentrations. For the majority of non-persistent chemicals, a single pregnancy measure may better represent exposure near the time of sample collection rather than for the entire pregnancy. IMPACT/CONCLUSIONS:Understanding the intra-individual variability of urinary non-persistent chemical biomarkers across multiple pregnancy timepoints is important to inform study design, statistical analysis, and interpretation in future studies.

INTRODUCTION/BACKGROUND:Data on how sleep architecture relates to progression of plasma Alzheimer's disease biomarkers remains limited. METHODS:Sixty-four cognitively unimpaired older adults (ages 55-90) underwent plasma collection twice 2.6 years apart and polysomnography proximate to the first plasma collection. Plasma amyloid beta (Aβ) 42 and 40 were measured via mass spectrometry. RESULTS:Frontal slow-wave activity (SWA) was inversely associated with plasma Aβ42/40 at cross-section in bivariate analysis and in a covariate-adjusted model. In comparison, low rapid eye movement (REM) sleep percentage was associated with a large longitudinal decline in annualized blood-based Aβ42/40. In exploratory analyses, the association between low REM sleep percentage and faster decline in Aβ42/40 ratio was stronger in the amyloid-positive group. DISCUSSION/CONCLUSIONS:In cognitively unimpaired older adults, non-REM SWA correlates with cross-sectional amyloid load, whereas REM sleep may predict accelerated amyloid accumulation in preclinical stage, suggesting both may serve as early biomarkers and modifiable interventional targets.

The rate of acquisition of genomic changes in cancer has been the topic of much discussion, with several recent investigations finding evidence of punctuated evolution instead of gradual accumulation of such changes. Despite forays into the description and quantification of these punctuated events, the effects of such changes on subsequent cancer evolution remain incompletely understood. Here we investigate how non-gradual mutagenesis affects the ability of tumor cells to acquire and retain fitness-enhancing adaptations. We find that punctuated mutagenesis significantly facilitates adaptation in scenarios where adaptation requires crossing a fitness valley, that is when multiple mutations are required which individually are maladaptive but jointly confer a fitness advantage. By increasing the probability that multiple mutations occur in close succession, punctuation increases the chance that mutants in a fitness valley mutate further to reach a fitness peak before going extinct. Analyzing data from The Cancer Genome Atlas, we find that tumors with signatures of APOBEC mutagenesis, which has been shown to proceed in episodic bursts, exhibit patterns consistent with higher rates of crossing fitness valleys. Lastly, we characterize how the interplay between this enhanced ability to cross fitness valleys and adaptation-limiting effects of clonal interference affects overall adaptability in complex fitness landscapes.

BACKGROUND:Visual evoked potential (VEP) P100 latency is routinely used to assess optic nerve demyelination. However, there is no established methodology for disentangling whether shifts in VEP P100 latency may reflect upstream changes in the visual pathway, such as the level of the retina, or whether these delays could be reflective of downstream disturbances in broader brain structure and functioning. OBJECTIVE:To determine the relationship between VEP-based P100 and MRI-based outcomes in people with MS (PwMS) after accounting for structural retinal changes assessed by spectral domain optical coherence tomography (OCT). METHODS:64 study participants underwent OCT, VEP, and MRI. Standardized VEP assessment derived monocular P100 latency for both eyes. Similarly, OCT performed on Heidelberg Spectralis hardware provided peripapillary retinal nerve fiber layer (pRNFL) thickness. Mediation analyses were performed to assess the relationship between P100 and MRI-based outcomes, adjusting for mediating effects of pRNFL and age. RESULTS:VEP-based P100 was significantly associated with lower whole brain volume (WBV) (p=0.0037), with 87.8% of the total effect being both direct and independent from RNFL and the significant age-WBV covariate effect. Similarly, greater VEP-based P100 latency was directly and independently predictive of lower gray matter volume (GMV) (p=0.015) and greater T2-FLAIR LV (p=0.0036) after adjusting for RNFL and age mediating effects. CONCLUSION/CONCLUSIONS:VEP-based P100 latency shows both age- and RNFL-independent associations with MRI-based MS outcomes. In addition to their established diagnostic utility, VEP measures may provide a neurophysiological, objective metric to assess neurodegeneration.