Institute of Translational Health Sciences

Novel treatments are needed for the primary and secondary prevention of heart failure in patients with type 2 diabetes, including individuals with and those without a history of heart failure. Conflicting trial evidence exists on whether glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduce the risk of hospitalization for heart failure (HHF) in this broad population and whether this is a class effect or varies by specific agent. Furthermore, their comparative effectiveness against sodium-glucose cotransporter-2 inhibitors (SGLT-2is) is unknown. We emulated 2 target trials using population-based health care data from Stockholm, Sweden (2010-2021). Target trial 1 included adult patients with type 2 diabetes who newly initiated GLP-1RA versus dipeptidyl peptidase-4 inhibitors (DPP-4is), and target trial 2 compared GLP-1RA with SGLT-2i. The primary outcome was HHF. Cox regression was used to estimate intention-to-treat hazard ratios, with inverse probability of treatment weighting used to balance 72 confounders. Major adverse cardiovascular events were used as the positive control outcome. Analyses were conducted for the GLP-1RA class overall and for individual agents, including liraglutide and semaglutide. Target trial 1 included 32 979 patients (42% GLP-1RA and 58% DPP-4i) with a mean age of 64 years and 40% female; and target trial 2 included 30 104 patients (49% GLP-1RA and 51% SGLT-2i) with a mean age of 63 years and 38% female. Starting a GLP-1RA was associated with a lower 3-year absolute risk of HHF than starting a DPP-4i (3.4% versus 4.3%), corresponding to a weighted hazard ratio of 0.77 (95% CI, 0.66-0.91). Absolute 3-year risks for GLP-1RA compared with SGLT-2i on HHF were 3.6% and 3.3% with a weighted hazard ratio of 1.02 (95% CI, 0.85-1.18). The absolute risk difference was largest for patients with higher predicted risk of heart failure at baseline. Results were consistent for single agents, in per-protocol analyses, and in the majority of subgroups. In positive control outcome analyses, GLP-1RA use was associated with a lower rate of major adverse cardiovascular events than DPP-4i use (weighted hazard ratio, 0.85 [95% CI, 0.74-0.99]), consistent with trial findings. GLP-1RA use is associated with a lower risk of HHF compared with DPP-4i and similar risks compared with SGLT-2i in routine clinical care for patients with type 2 diabetes.

Polychlorinated biphenyls (PCBs) are persistent environmental toxicants that bioaccumulate in the food chain and readily cross the placenta, raising concerns for developmental toxicity. Although PCB exposure has been associated with metabolic and neurodevelopmental disorders, its cell type-specific effects on liver development remain poorly understood. This study aimed to investigate how maternal exposure to an environmentally relevant Fox River PCB mixture affects liver development in female offspring at single-cell resolution. We hypothesized that developmental PCB exposure disrupts hepatic metabolic and immune function in a cell-type-specific manner. Using single-cell RNA sequencing on liver tissue from postnatal day 28 female mice exposed to PCBs throughout gestation and lactation, we identified major hepatic and immune cell populations and assessed cell-specific transcriptional responses. PCB exposure significantly altered the proportions of endothelial cells and Kupffer cells and reduced neutrophil abundance in the liver. Transcriptomic analysis revealed that PCBs dysregulated key functional pathways in hepatocytes and nonparenchymal cells, including endoplasmic reticulum stress responses, drug metabolism, and glucose/insulin signaling. Notably, hepatocytes exhibited upregulation of phase I drug-metabolizing enzymes and uptake transporters, but downregulation of phase II enzymes and efflux transporters. Kupffer cells and endothelial cells exhibited altered immune and metabolic gene expression, and intercellular communication analysis predicted that PCB exposure disrupted fibronectin, collagen, and chemokine signaling. Reverse transcription-quantitative polymerase chain reaction validation confirmed increased expression of hepatic endoplasmic reticulum stress markers. Together, these findings demonstrate that developmental PCB exposure induces persistent, cell-type-specific transcriptomic reprogramming in the liver, impairing metabolic and immune functions. This study highlights the utility of single-cell transcriptomics for revealing toxicant effects with cellular precision during critical windows of development. SIGNIFICANCE STATEMENT: Our findings showed that developmental exposure to a persistent organic pollutant led to transcriptomic changes that differed across cell types that form the liver. Our study highlights the use of single cell technology to investigate toxic effects for mechanistic insights with greater precision.

Diabetes is the leading cause of chronic kidney disease (CKD), with nearly half of all cases of kidney failure requiring kidney replacement therapy. While attention is often focused on the profound effects kidney failure has on the quality of life, the principal cause of complications and death among patients with diabetes and CKD is cardiovascular disease (CVD). These risks are often underappreciated by both healthcare professionals and patients. Sodium–glucose cotransporter 2 (SGLT-2) inhibitors were originally developed and approved as glucose-lowering agents for treating type 2 diabetes (T2D). However, agents within the SGLT-2 inhibitor class have since demonstrated robust benefits for CKD, atherosclerotic cardiovascular disease (ASCVD), and heart failure (HF) outcomes. Specifically, dedicated kidney disease and HF outcome trials have shown markedly reduced rates of kidney failure, CVD and HF events, and death among people (with and without diabetes) with CKD. SGLT-2 inhibitors will be used by primary care clinicians, nephrologists, and cardiologists across a range of cardiovascular and kidney conditions and diabetes. Knowledge and awareness of the benefits and key safety considerations, and risk mitigation strategies for these medications is imperative for clinicians to optimize the use of these life-saving therapies.

OBJECTIVES/GOALS: Despite efforts to improve COVID-19 health outcomes through testing and vaccination, SARS-CoV-2 has exacerbated health disparities in underserved populations. Through this study we examined socio-contextual factors impacting decisions to test for COVID-19 among Native Americans in the Flathead Reservation and Hispanics in the Yakima Valley. METHODS/STUDY POPULATION: A series of 28 key informant interviews and 6 focus groups (N=39 focus group participants) were completed with community and tribal leaders using an interview guide informed by the Theory of Planned Behavior, Social Cognitive Theory, and the Social Contextual Factor Frameworks. The interview guide was designed to examine the socio-contextual factors impacting decisions to test for COVID-19 among Native Americans and Hispanics in the Northwest. A codebook was developed to apply deductive coding to informant responses, followed by an inductive, constant comparison approach. Three analysts met to refine the codebook and conduct inter-rater agreement. RESULTS/ANTICIPATED RESULTS: Five themes (social, cultural, health, religious and political factors) were identified that impacted testing for COVID-19. For social factors, participants discussed the influence of families and friends and unfair employment practices influencing decisions to test. Cultural factors included deep rooted distrust for the government and historical trauma. Health factors participants reported included the importance of testing to save lives, distrust for medical system, and health communications around COVID-19 affecting decisions to test. There was some interaction between religious and political factors. While participants mentioned beliefs in putting things in God’s hands, some decisions to test seemed to be affected by their political views. DISCUSSION/SIGNIFICANCE: Several socio-cultural factors influence decisions to test for COVID-19. Understanding the community’s perception of COVID-19 testing is critical for successful implementation of preventive strategies.