We examine some of the genetic features of neuroticism (N) taking as an animal model the Maudsley Reactive (MR) and Maudsley Nonreactive (MNR) rat strains which were selectively bred, respectively, for high and low open-field defecation (OFD) starting in the late 1950s. To draw analogies with human genetic studies, we explore the genetic correlation of N with irritable bowel syndrome (IBS). We review progress with the rat model and developments in the field of human complex trait genetics, including genetic association studies that relate to current understanding of the genetics of N. The widespread differences in the tone of the peripheral sympathetic nervous system that have been found between the Maudsley strains, particularly those observed in the colon, may underly the differences in OFD (MNR, higher sympathetic tone and zero defecation). In humans, a large genome-wide association study (GWAS) reported six genes contributing to IBS, four of which were implicated in mood and anxiety disorders or were expressed in the brain, with three of the four also expressed in the nerve fibers and ganglia of the gut. Heritability of N is estimated at around 50% in twin and family studies, and GWASs identified hundreds of loci, enabling estimation of genome-wide correlations (rg) with other traits. Significantly, the estimate for rg between risk of IBS, anxiety, N, and depression was >0.5 and suggested genetic pleiotropy without evidence for causal mechanisms. Findings on the adrenergic pharmacology of the colon, coupled with new understanding of the role of the locus ceruleus in modifying afferent information from this organ, generate hypotheses that challenge traditional cause/effect notions about the relationship of the central nervous system to peripheral events in response to stress, suggest specific targets for gene action in the Maudsley model and emphasize the value of reciprocal evaluation of genetic architecture underlying N in rodents and humans.

While existing work has demonstrated that campaign donations can buy access to benefits such as favorable legislation and preferential contracting, we highlight another use of campaign contributions: buying reductions in regulatory enforcement. Specifically, we argue that in return for campaign contributions, Colombian mayors who rely on donor-funding (compared with those who do not) choose not to enforce sanctions against illegal deforestation activities. Using a regression discontinuity design, we show that deforestation is significantly higher in municipalities that elect donor-funded as opposed to self-funded politicians. Further analysis shows that only part of this effect can be explained by differences in contracting practices by donor-funded mayors. Instead, evidence of heterogeneity in the effects according to the presence of alternative formal and informal enforcement institutions, and analysis of fire clearance, support the interpretation that campaign contributions buy reductions in the enforcement of environmental regulations.

White kidney bean extract (WKBE) is a nutraceutical often advocated as an anti-obesity agent. The main proposed mechanism for these effects is alpha-amylase inhibition, thereby slowing carbohydrate digestion and absorption. Thus, it is possible that WKBE could impact the gut microbiota and modulate gut health. We investigated the effects of supplementing 20 healthy adults with WKBE for 1 week in a randomised, placebo-controlled crossover trial on the composition of the gut microbiota, gastrointestinal (GI) inflammation (faecal calprotectin), GI symptoms, and stool habits. We conducted in vitro experiments and used a gut model system to explore potential inhibition of alpha-amylase. We gained qualitative insight into participant experiences of using WKBE via focus groups. WKBE supplementation decreased the relative abundance of Bacteroidetes and increased that of Firmicutes, however, there were no significant differences in post-intervention gut microbiota measurements between the WKBE and control. There were no significant effects on GI inflammation or symptoms related to constipation, or stool consistency or frequency. Our in vitro and gut model system analyses showed no effects of WKBE on alpha-amylase activity. Our findings suggest that WKBE may modulate the gut microbiota in healthy adults, however, the underlying mechanism is unlikely due to active site inhibition of alpha-amylase.

OBJECTIVES/GOALS: To compare the effects of dietary fiber supplementation based on fermentability and viscosity on phosphorus fractional absorption and the gut microbiome in a rat model of chronic kidney disease-mineral and bone disorder (CKD-MBD). METHODS/STUDY POPULATION: 25-week-old Cy/+ male rats (CKD hereafter) will be randomly assigned to receive one of four fiber treatments (10% w/w each) based on fermentability and viscosity: 1) Cellulose (-fermentability, -viscosity), 2) inulin (+fermentability, -viscosity), 3) psyllium husk (-fermentability, +viscosity), or 4) pectin (+ fermentability, +viscosity). Diets will be formulated with a semipurified diet containing 0.7% phosphorus. Treatments will last for 10 weeks, and rats will be euthanized at 35 weeks of age, where animals have reached kidney failure. Intravenous and oral 33P will be used for intestinal phosphorus fractional absorption and cecal/fecal samples will be obtained at euthanasia for microbiome assessment using shotgun metagenomics. RESULTS/ANTICIPATED RESULTS: Our preliminary data show that fermentable dietary fiber (inulin) impacted phosphorus homeostasis by increasing the circulating levels of fibroblast growth factor-23 (a bone-derived hormone that increases phosphorus excretion in urine) and lowering circulating levels of phosphorus in the Cy/+ male rat model of progressive chronic kidney disease. We hypothesize that dietary fiber impacts phosphorus absorption in gut microbiome-dependent and independent mechanisms. For example, fermentable fiber enhances the production of short-chain fatty acids, lowering the intraluminal pH, and enhancing mineral solubility and absorption. Meanwhile, viscous fibers may encapsulate minerals limiting their absorption if these fibers are non-fermentable. DISCUSSION/SIGNIFICANCE: Hyperphosphatemia, or high circulating phosphorus, is a major factor in the pathogenesis of CKD-MBD. Treatment of hyperphosphatemia is focused on reducing intestinal absorption. However, available therapies vary in their efficacy and focus on phosphorus absorption in the small intestine, ignoring the possible impact of the large intestine.

Community engagement (CE) is critical for advancing health equity and a key approach for promoting inclusive clinical and translational science. However, it requires a workforce trained to effectively design, implement, and evaluate health promotion and improvement strategies through meaningful collaboration with community members. This paper presents an approach for designing CE curricula for research, education, clinical care, and public health learners. A general pedagogical framework is presented to support curriculum development with the inclusion of community members as facilitators or faculty. The overall goal of the curriculum is envisioned as enabling learners to effectively demonstrate the principles of CE in working with community members on issues of concern to communities to promote health and well-being. We highlight transformations needed for the commonly used critical service-learning model and the importance of faculty well-versed in CE. Courses may include didactics and practicums with well-defined objectives and evaluation components. Because of the importance of building and maintaining relationships in CE, a preparatory phase is recommended prior to experiential learning, which should be guided and designed to include debriefing and reflective learning. Depending on the scope of the course, evaluation should include community perspectives on the experience.

The Hierarchical Taxonomy of Psychopathology (HiTOP) has emerged out of the quantitative approach to psychiatric nosology. This approach identifies psychopathology constructs based on patterns of co-variation among signs and symptoms. The initial HiTOP model, which was published in 2017, is based on a large literature that spans decades of research. HiTOP is a living model that undergoes revision as new data become available. Here we discuss advantages and practical considerations of using this system in psychiatric practice and research. We especially highlight limitations of HiTOP and ongoing efforts to address them. We describe differences and similarities between HiTOP and existing diagnostic systems. Next, we review the types of evidence that informed development of HiTOP, including populations in which it has been studied and data on its validity. The paper also describes how HiTOP can facilitate research on genetic and environmental causes of psychopathology as well as the search for neurobiologic mechanisms and novel treatments. Furthermore, we consider implications for public health programs and prevention of mental disorders. We also review data on clinical utility and illustrate clinical application of HiTOP. Importantly, the model is based on measures and practices that are already used widely in clinical settings. HiTOP offers a way to organize and formalize these techniques. This model already can contribute to progress in psychiatry and complement traditional nosologies. Moreover, HiTOP seeks to facilitate research on linkages between phenotypes and biological processes, which may enable construction of a system that encompasses both biomarkers and precise clinical description.

Research on marital quality and child well-being is currently limited by its common use of geographically constrained, homogenous, and often cross-sectional (or at least temporally limited) samples. We build upon previous work showing multiple trajectories of marital quality and data from the National Longitudinal Survey of Youth-1979 (NLSY79) regarding mothers and their children (inclusive of ages 5–14). We examine how indicators of child well-being are linked to parental trajectories of marital quality (happiness, communication, and conflict). Results showed children whose parents had consistently poor marital quality over the life course exhibited more internalizing and externalizing problems, poorer health, lower quality home environments, and lower math and vocabulary scores than children of parents in consistently higher-quality marriages. Group differences remained stable over time for child health, home environment, and vocabulary scores. Group differences for internalizing problems declined over time, whereas group differences increased for externalizing problems and math scores. Initial advantages for females across nearly all indicators of child well-being tended to shrink over time, with boys often moving slightly ahead by mid adolescence. We discuss the implications of these findings in regard to children's development and well-being and suggest treating marriage as a monolithic construct betrays important variation within marriage itself.

ABSTRACT IMPACT: This project seeks to identify unique host responses that are biomarkers for specific urethral pathogens, and which can be used in the development of point-of-care (POC) STI diagnostics. OBJECTIVES/GOALS: How Chlamydia trachomatis (CT) and other common STIs, e.g. Neisseria gonorrhoeae, evade immunity and elicit pathology in the male urethra is poorly understood. Our objective is to determine how STI-infected urethral epithelial cells, as well as the uninfected ‘bystander’ cells with which infected cells communicate, respond to CT and other STIs. METHODS/STUDY POPULATION: We evaluated how immortalized urethral cell lines - including transduced human urethral epithelial cells (THUECs) - respond to increasing doses of CT infectious particles using in vitro one-step progeny assays performed in the presence or absence of cycloheximide, a drug that inhibits eukaryotic protein synthesis. We will perform concurrent single-cell RNA sequencing (scRNA-seq) and multiplex cytokine analyses to determine how different CT doses impact the transcriptomes of infected and bystander urethral epithelial cells and modulate cytokine production of the overall monolayer. Results of these experiments will inform the feasibility of performing similar analyses in situ using urethral swabs from men with clinically diagnosed urethritis. RESULTS/ANTICIPATED RESULTS: Our results demonstrate that immune-competent urethral cell monolayers strongly resist CT infection, unless most of the cells are simultaneously infected. This suggests that uninfected bystander cells sense CT-infected cells and secrete soluble factors that may act to limit CT proliferation in infected cells and to inform remaining uninfected cells that a potential pathogen is present. We anticipate that our scRNA-seq and cytokine analyses will identify both specific effector pathways that protect against CT and intracellular signals that modulate them. We speculate that these pathways and signals may differ during infection with CT and other STIs. Importantly, we anticipate that our in vitro model of CT infection will be highly representative of in situ immune responses observed in urethras of infected men. DISCUSSION/SIGNIFICANCE OF FINDINGS: In men, common STIs including CT are usually managed syndromically due to a lack of POC diagnostics. By determining how STIs elicit urethral inflammation and identifying countermeasures that STIs use to evade urethral immunity, we can identify host responses that serve as biomarkers for urethritis, generally, and for specific urethral pathogens.

ABSTRACT IMPACT: Our research focuses on determining rural-urban disparities in chronic obstructive pulmonary disease (COPD) management to improve COPD health outcomes in rural areas. OBJECTIVES/GOALS: Several methods exist to distinguish rural from urban areas, but it is not clear which method relates most directly to rural-urban health care disparities. To address this, we compared different measures of rurality to measures of chronic obstructive pulmonary disease (COPD) processes of care among a national sample of veterans. METHODS/STUDY POPULATION: Retrospective analysis of patients with COPD (2016-2019 by ICD-10 codes) using national Veterans Affairs (VA) data. We assessed rurality by: 1) patient’s residential address, 2) assigned primary care clinic address, and 3) drive time from the patient’s residence to closest primary care clinic. Rurality designations of the residential address and primary care clinic address into urban, rural, and highly rural areas are based on the Rural Urban Commuting Area (RUCA) codes. The dependent variables were binary outcomes of: 1) documentation of a pulmonary clinic encounter and 2) evidence of spirometry to confirm the diagnosis of COPD. RESULTS/ANTICIPATED RESULTS: Of 6,765,951 veterans, 1,157,002 (17%) had COPD (Table 1). Although approximately 40% of patients with COPD reside in addresses that are rural and highly rural, a large majority are assigned to primary care clinics in urban areas (82.8%) and reside within 30 minutes to the closest primary care clinic (76.7%) (Table 2). Compared to defining rurality based on patient’s residential address or drive time to closest primary care, defining rurality based on the assigned primary care clinic address was associated with a larger disparity in rates of pulmonary encounter. In contrast, the drive time from the patient’s residence to the closest primary care was the strongest predictor of receipt of spirometry (Figure 1 and Table 3). DISCUSSION/SIGNIFICANCE OF FINDINGS: Estimates of the severity of rural-urban disparities varied based on the definition of rurality used. For two process measures, definitions of rurality based on where the patient received primary care generated more evidence of disparities than definitions based solely on the patient’s residential address.