Faculty Bibliography

BACKGROUND/UNASSIGNED:Early childhood is a critical window for cardiac development, yet the impact of prenatal factors and early growth patterns on heart structure and function in children with structurally normal hearts remains incompletely described. This study investigates the roles of birth weight (BW), gestational age (GA), birthweight-for-gestational-age (BW/GA) z-score, and weight gain z-score in shaping cardiac dimensions. METHODS/UNASSIGNED:-scores for cardiac dimensions and volumes were used to standardize for body surface area (BSA). BW, BW/GA z-score, GA, and weight gain z-score were analyzed as predictors of these parameters. RESULTS/UNASSIGNED:Higher weight gain z-score was independently associated with smaller cardiac dimension z-scores, particularly in the aortic root, ascending aorta, left atrium diameter, left ventricular internal diameter at end-diastole, left ventricular internal diameter at end-systole, end-systolic volume, end-diastolic volume, and left ventricular mass. While birth characteristics influenced some cardiac parameters, postnatal weight gain emerged as a more significant predictor of cardiac size. Ejection fraction and fractional shortening were not influenced by the predictors in our analysis. CONCLUSIONS/UNASSIGNED:Our findings suggest that postnatal weight gain was more consistently associated with cardiac structure z-scores than anthropometric characteristics at birth. Specifically, contractile myocardial thicknesses were relatively stable across weight gain patterns, whereas vascular structures showed inverse scaling with higher weight gain.

BACKGROUND:In eastern and southern Africa, HIV and depression lead to substantial morbidity and mortality. Each condition affects the other: people living with HIV (PLHIV) have higher depression rates, while depression increases HIV acquisition and hinders treatment. The combined impact of HIV-depression interactions on HIV and mental health remains poorly understood. METHODS:We adapted the EMOD-HIV simulation model to incorporate depression incidence, recovery and relapse. We modelled a bidirectional scenario between HIV and depression: HIV increased depression incidence; depression increased HIV incidence and reduced HIV care outcomes. In a counterfactual scenario, all HIV-depression interactions were removed. We estimated how interactions impacted depression episodes, HIV acquisitions, HIV-related deaths and HIV treatment benefits in a high-prevalence region of Western Kenya, 1985-2035. RESULTS:Without interactions, the model projected 1.23 million (95% CI 1.21M to 1.24M) HIV acquisitions, 658 000 (95% CI 650 000 to 666 000) HIV deaths and 12.88 million (95% CI 12.87M to 12.89M) depression episodes. HIV-depression interactions increased depression episodes by 9.76% (95% CI 9.67% to 9.87%), HIV acquisitions by 12.3% (95% CI 12.0% to 12.6%) and HIV deaths by 12.5% (95% CI 12.2% to 12.9%). These interactions also diminished HIV treatment benefits, with 7.72% (95% CI 7.39% to 8.07%) fewer HIV acquisitions and 3.88% (95% CI 3.71% to 4.05%) fewer deaths averted per person-year on treatment. In secondary analyses, increased depression incidence among PLHIV had the greatest effect on HIV outcomes, contributing 7.26% of acquisitions and 7.55% of deaths. CONCLUSION/CONCLUSIONS:HIV-depression interactions have worsened both epidemics. Depression's effects on HIV incidence have been especially deleterious, while its effect on HIV care engagement is increasingly important.

Microglia perform the function of CNS macrophages and act as the primary immune cells in the brain. They surveil the environment, phagocytose cellular debris, maintain homeostasis and respond to tissue damage. While under physiological conditions they play a role in supporting neurons, activated microglia participate directly in the degeneration of neurons in the substantia nigra, as the hallmark of the Parkinsons disease (PD). Their detrimental effects result from direct phagocytosis of dopaminergic neurons as well as via neuroinflammation and release of toxic reactive oxygen and nitrogen species. This pathological shift is driven by a complex interplay of genetic predispositions, such as LRRK2 and GBA mutations, and environmental triggers like toxins and gut dysbiosis.A central mechanism of this neurodegeneration involves extracellular α-synuclein acting as a danger signal (DAMP), which activates microglial Toll-like receptors (e.g., TLR2) to initiate a severe inflammatory cascade. Furthermore, the extreme biophysical stability of aggregated α-synuclein overwhelms the microglial endolysosomal network, leading to lysosomal failure, "frustrated phagocytosis," and the active propagation of the disease via exosomal shedding. Relieving this maladaptive chronic neuroinflammation is a primary therapeutic goal. Modern strategies aim to break this vicious cycle through precise interventions like NLRP3 inflammasome inhibition and autophagy enhancement. Concurrently, advanced fluid biomarkers, such as seed amplification assays (SAA), alongside multidimensional neuroimaging techniques (PET, SPECT, MRI), are proving crucial for detecting these early microglial and pathological changes to guide personalized, disease-modifying therapies of PD.

UNLABELLED:Pelvic fractures result in prolonged pain and immobility. In a randomized controlled trial of patients with pelvic fracture, whether abaloparatide (ABL) vs. placebo (PBO) improves healing at 3 months was evaluated. There was no significant difference in CT radiologic healing, physical performance, or change in pain in ABL vs. placebo. PURPOSE/OBJECTIVE:To determine if abaloparatide (ABL) vs. placebo (PBO) improves radiologic healing, pain, and functional outcome at 3 months in patients with pelvic fracture. METHODS:Postmenopausal women and men ≥ 50 years old, enrolled within 4 weeks of pelvic fracture (n = 48), were randomized to blinded ABL vs. PBO. The primary endpoint, fracture healing at 3 months, was assessed by two radiologists using a 5-point scale for cortical bridging from CT images comparing groups by Jonckheere-Terpstra test. The odds of healing (3 or 4 cortices bridged) were analyzed with Mantel-Haenszel relative risks (RR). Pain was assessed monthly by Numeric Rating Scale (NRS). The Short Physical Performance Battery (SPPB; walk speed, chair stands, and balance) evaluated functional mobility. RESULTS:Groups were balanced with a mean age = 82, 93% were female, 98% had multiple rami fractures, 67% had sacral fracture, and 36% had ≥ 1 displaced fracture. CT images at 3 months showed no significant difference in bridging score distribution (indicator of healing) in patients with ABL vs. PBO (p = 0.15) after adjusting for age, sacral fracture, displacement, or compliance. When evaluating individual fractures (n = 81), similar bridging scores were seen with ABL and PBO (p = 0.13). When patients were stratified as healed or not healed, 39% were healed with ABL and 64% healed with PBO (RR 0.61; 95% CI 0.33, 1.12). When looking at the 81 individual fractures, 47% were healed with ABL and 53% healed with PBO (RR = 0.88; 95% CI 0.55, 1.40). Using least square means controlling for age, sacral, and displaced fracture, NRS pain score was higher in the placebo than the ABL group at baseline (p < 0.05), but there were no further group differences in change in pain score SPPB and TUG scores improved over time in both groups without group differences. CONCLUSION/CONCLUSIONS:In this small study, there was no significant difference in CT radiologic healing, physical performance, or change in pain with ABL vs. placebo in patients with acute pelvic fracture. TRIAL REGISTRATION/BACKGROUND:ClinicalTrials.gov identifier: NCT04249232 registered January 27, 2020.

We investigated the joint associations of circulating neurodegeneration markers-neurofilament light (NfL) and glial fibrillary acidic protein (GFAP)-ambient air pollution, and plasma metabolomic profiles with transitions from a healthy state to dementia, Parkinson's disease (PD), and all-cause mortality in the UK Biobank. The analytic sample included 19,645 participants aged ≥ 50 years with complete proteomic, metabolomic, and environmental data. Time-to-event analyses used Cox proportional hazards and multistate Weibull models to evaluate associations and statistical interactions across health transitions. Higher NfL concentrations were associated with increased risks of transitions from healthy to PD, dementia, and death, whereas higher GFAP concentrations were specifically associated with dementia (HR = 2.65, 95% CI: 2.17-3.25). At the nominal level, particulate matter (PM_2.5, PM₁₀) showed positive statistical interactions with NfL for mortality, while nitrogen oxides (NO₂/NO_x) showed negative interactions with GFAP. There was little evidence of interaction between PM_2.5 and either biomarker for dementia. Metabolomic principal components reflecting lipid, amino acid, and energy pathways were associated with variation in the relationships of NfL and GFAP with dementia and mortality and interacted with PM_2.5 for PD and dementia. A branched-chain amino acid-related component showed a negative interaction with GFAP for dementia, indicating weaker associations at higher levels. These findings highlight complex relationships linking air pollution, metabolic dysregulation, and neurodegeneration, and support integrative multi-omics approaches to identify pathways relevant to prevention of neurodegenerative diseases and premature mortality.

BACKGROUND/UNASSIGNED:Despite recent improvements in radiation safety, interventionalists are increasingly exposed to radiation during cardiac catheterization laboratory (CCL) procedures. The RADPAD was designed as a protective scatter-radiation absorbing shield with early studies demonstrating a 20% to 62% reduction in scatter-radiation. The objective of this study was to examine the impact of the protective scatter-radiation absorbing shield in a large contemporary randomized controlled trial across multiple CCL procedures. METHODS/UNASSIGNED:The investigator-initiated, prospective, randomized, controlled ATTENUATE (rAdpad proTecTion drapE iN redUcing rAdiaTion Exposure) trial randomized CCL procedures 1:1 to use of the RADPAD vs no use of the RADPAD. The primary outcome of interest was the most proximal operator's dose area product (DAP)-normalized operator dose (E). RESULTS/UNASSIGNED:= .1094). CONCLUSIONS/UNASSIGNED:In the largest randomized controlled trial to date evaluating the RADPAD protective scatter-radiation absorbing shield, encompassing contemporary coronary and structural CCL procedures, use of the protective scatter-radiation absorbing shield led to a marked decrease in proximal operator radiation exposure when adjusted for the total radiation delivered during each procedure.

BACKGROUND:Prostate cancer is associated with increased cardiovascular risk. Among androgen deprivation therapy (ADT) modalities, the gonadotropin-releasing hormone (GnRH) antagonist relugolix appears to confer a lower risk for cardiovascular events than the GnRH agonist leuprolide. OBJECTIVES/OBJECTIVE:The aim of this prospective study was to investigate the impact of relugolix and leuprolide on platelet phenotype. METHODS:Patients with prostate cancer initiating first-line ADT were prospectively enrolled. Blood samples were collected at baseline and 8 ± 4 weeks after treatment initiation. Platelet activation was assessed using flow cytometry (P-selectin, PAC-1, CD40, CD40L, and monocyte-platelet aggregates). Platelet RNA sequencing was performed to characterize treatment-associated transcriptomic changes. RESULTS:inhibition of patient-derived platelets attenuated activation induced by epinephrine, ADP, and AA. CONCLUSIONS:Prostate cancer is associated with heightened platelet activation and thromboinflammatory signaling. Treatment with leuprolide, but not relugolix, was associated with further augmented platelet activity. These findings support further studies to clarify links with platelet-mediated cardiovascular risk and the potential role of platelet-targeted strategies.

Lung cancer is the leading cause of cancer-related deaths globally, and early diagnosis and treatment are important for improving prognosis. Pulmonary nodules (PNs) are small pulmonary lesions frequently identified during clinical practice, with incidental detection increasing due to advances in imaging techniques and the expanded use of computed tomography scans for thoracic evaluation. The majority of incidental PNs (IPNs) are benign, however some represent early-stage lung cancer, therefore distinguishing benign from malignant IPNs is key to improving lung cancer outcomes. Current management guidelines differ by nodule type and involve biopsy to determine the malignancy status of the nodule. Here, we review current knowledge on the classification, prevalence, and detection of PNs, as well as the current management and risk stratification of PNs. We outline the role of oncogenic driver mutations in the pathobiology of PNs and assess current literature on targeted treatment of oncogene-driven PNs. Finally, we discuss evidence gaps and areas for future research.

BACKGROUND:Social determinants of health (SDOH) influence cancer prevention and outcomes. Among SDOH, economic stability-including food insecurity, income, employment, and housing stability-has a major impact on health. However, data linking food security status with cancer screening completion remain limited. We examined whether lower food security status was associated with lower completion of colorectal, breast, cervical, and prostate cancer screening. METHODS:We performed a retrospective analysis of the 2018-2023 National Health Interview Survey. Analyses were limited to cancer-specific complete-case cohorts: colorectal (N = 59,849), breast (N = 30,867), cervical (N = 56,229), and prostate (N = 20,518). Food security was categorized as high, marginal, or low/very low. Screening completion was the dependent variable. Multivariable logistic regression estimated adjusted odds ratios (aORs) for screening by food security status, controlling for sociodemographic and clinical covariates. Sensitivity analyses used age-stratified eligibility definitions across survey years. RESULTS:Compared with high food security, marginal food security was associated with lower odds of screening across cancers (aOR range, 0.63-0.88), and low/very low food security showed similar or larger deficits (aOR range, 0.60-0.88). Associations were significant for all four cancers and were similar in sensitivity analyses. CONCLUSIONS:Lower food security status was associated with lower completion of cancer screening. Addressing food insecurity may improve screening equity and reduce cancer disparities. IMPACT/CONCLUSIONS:Lower food security status was associated with lower completion of guideline-recommended screening across four cancers, even after multivariable adjustment. Future work should test whether interventions addressing food insecurity can improve screening.

BACKGROUND:Lomitapide is an oral microsomal triglyceride transfer protein inhibitor approved for homozygous familial hypercholesterolemia (HoFH). OBJECTIVE:Evaluate data from the Lomitapide Observational Worldwide Evaluation Registry (LOWER; NCT02135705). METHODS:LOWER is a global, prospective observational registry initiated in March 2014 to evaluate the real-world effectiveness and safety of lomitapide in patients with HoFH. RESULTS:A total of 246 individuals were enrolled (43.5% male; mean age 50.3 years, SD 15.3; range 18-83). Mean lomitapide daily dose was 12.1 mg (SD 8.7; range 1.4-50.0). Patients received lomitapide for an average of 45.6 months (SD 38.4; range 0.3-142.1). Baseline mean low-density lipoprotein cholesterol (LDL-C) was 241.1 mg/dL (SD 109.1; range 71-672). Following treatment initiation, 86.8% of patients on lomitapide achieved ≥50% LDL-C reduction at some time point (72.2% in the full analysis set [FAS]). In the FAS, 74.3% achieved LDL-C <100 mg/dL, 51.0% <70 mg/dL, and 38.4% achieved <55 mg/dL LDL-C at any time. Adverse events were mostly gastrointestinal in nature (n = 111; 45.3%). Hepatic events of special interest (ESIs) were reported in 21.6%, and gastrointestinal ESIs occurred in 13.9% of patients. Major adverse cardiovascular events (MACE) occurred in 15.9% of patients, and no MACE were attributed to lomitapide. Exposure-adjusted MACE incidence was 2.8 events per 100-person years on lomitapide, vs 4.3 after lomitapide discontinuation. CONCLUSION/CONCLUSIONS:LOWER supports lomitapide's long-term effectiveness and safety for up to 11 years, enabling substantial LDL-C reductions and treatment goal achievement in HoFH with a manageable safety profile. Tentative evidence of reduced MACE during lomitapide treatment warrants further investigation.