OBJECTIVES/GOALS: DR-TB care in South Africa includes decentralized treatment with shorter, all-oral regimens. Treatment guidelines direct regular clinical and laboratory evaluation to assess patient improvement. We therefore measured sputum collection frequency and follow-up time to assess fidelity to these guidelines in Gauteng Province, South Africa. METHODS/STUDY POPULATION: We included Rifampicin-resistant (RR) sputum specimens from the South African National Health Laboratory Service, which provides pathology services to 80% of the population, submitted between August 2022-September 2023. Patient data were obtained from a DR-TB registry and additional sputum specimen data were collected from follow-up laboratory worksheets. Follow-up spanned from first sputum collection date (baseline) to patient outcome date (e.g., completion, lost) or study closure date (if still on treatment). Monthly sputum submission rate was measured for those with ≥1 additional sputum submitted. We compared patient data by treatment site: at the specialized hospital vs. any other site, using Wilcoxon ranksum and χ2 tests. RESULTS/ANTICIPATED RESULTS: Baseline RR-TB specimens were available for 142 patients, of whom 28 (20%) had specimens submitted from the specialized hospital. Patients at the specialized hospital were older (median age 41 vs. 35.5 years, p=0.03), had higher baseline fluoroquinolone resistance (10% vs. 1%, p=0.01), and longer follow-up (median 5.2 vs. 3.5 months, p=0.01) compared to patients elsewhere. Further, 43 (30%) patients had ≥1 additional sputum submitted during follow-up. Among these, monthly sputum collection rates did not differ by site (0.3 vs. 0.3 sputum per month, p=0.89). We anticipate that increased sputum frequency will be associated with successful TB treatment outcomes based on preliminary findings. DISCUSSION/SIGNIFICANCE: These findings highlight ongoing challenges with routine laboratory follow-up according to DR-TB guidelines across treatment sites in South Africa. Future research is needed to determine reasons for low sputum collection rates, such as low patient adherence, variation in practice of healthcare workers, loss to follow-up, and clinical challenges.

OBJECTIVES/GOALS: The overall goals of this project are: (1) to demonstrate the utility of staff with cross-disciplinary skills in biostatistics and epidemiology as program managers for CTSA BERD Cores, and (2) examine streamlined processes in project triaging, consultations, and data extractions for CTSA service requests when individuals are in this role. METHODS/STUDY POPULATION: Biostatistics and epidemiology are partnered disciplines incorporated in a variety of research areas, especially in human health sciences and health care. For interdisciplinary teams, including individuals trained in both specialties results in efficient research collaborations. When these individuals are program managers for research navigation, processes become more effective and expedited for project timelines and workflows across the CTSA. Examples of this integration are described in vignettes from project triaging, statistical consultations, and data extractions from CTSA service requests. Process comparisons of previous and current workflows are presented to show the advantages of utilizing this type of program manager within these areas of BERD. RESULTS/ANTICIPATED RESULTS: This project defines three areas of integration for a program manager with cross-disciplinary training in biostatistics and epidemiology: (1) project triaging to statistical teams, (2) study design and analysis consultations, and (3) data extractions. Each of these areas demonstrates prior processes that once would require multiple steps in CTSA service requests (including time, resources, and personnel) and identified common issues (slow response to requests, data re-extractions, and challenges providing statistical support) that are now avoided with a manager with cross-training in biostatistics and epidemiology methods. The advantages and disadvantages of integrating these individuals are also described. DISCUSSION/SIGNIFICANCE: BERD Cores seeking improvements to research navigation processes can gain efficiency by incorporating program managers with cross-disciplinary training in biostatistics and epidemiology. BERD Cores may also use this as a case study for translational science with innovation to longstanding challenges in CTSA research workflows.

OBJECTIVES/GOALS: We aimed to conduct an updated genome-wide meta-analysis of keloids in expanded populations, including those most afflicted by keloids. Our overall objective was to improve understanding of keloid development though the identification and further characterization of keloid-associated genes with genetically predicted gene expression (GPGE). METHODS/STUDY POPULATION: We used publicly available summary statistics from several large-scale DNA biobanks, including the UK Biobank, FinnGen, and Biobank Japan. We also leveraged data from the Million Veterans Program and performed genome-wide association studies of keloids in BioVU and eMERGE. For each of these datasets, cases were determined from ICD-9/ICD-10 codes and phecodes. With these data we conducted fixed effects meta-analysis, both across ancestries and stratified by broad ancestry groups. This approach allowed us to consider cumulative evidence for genetic risk factors for keloids and explore potential ancestry-specific components of risk. We used FUMA for functional annotation of results and LDSC to estimate ancestry-specific heritability. We performed GPGE analysis using S-PrediXcan with GTEx v8 tissues. RESULTS/ANTICIPATED RESULTS: We detected 30 (23 novel) genomic risk loci in the cross-ancestry analysis. Major risk loci were broadly consistent between ancestries, with variable effects. Keloid heritability estimates from LDSC were 6%, 21%, and 34% for European, East Asian, and African ancestry, respectively. The top hit (P = 1.7e-77) in the cross-ancestry analysis was at a replicated variant (rs10863683) located downstream of LINC01705. GPGE analysis identified an association between decreased risk of keloids and increased expression of LINC01705 in fibroblasts (P = 3.6e10-20), which are important in wound healing. The top hit in the African-ancestry analysis (P = 5.5e-31) was a novel variant (rs34647667) in a conserved region downstream of ITGA11. ITGA11 encodes a collagen receptor and was previously associated with uterine fibroids. DISCUSSION/SIGNIFICANCE: This work significantly increases the yield of discoveries from keloid genetic association studies, describing both common and ancestry-specific effects. Stark differences in heritability support a potential adaptive origin for keloid disparities. Further work will continue to examine keloids in the broader context of other fibrotic diseases.

Translation is the process of turning observations in the research laboratory, clinic, and community into interventions that improve people’s health. The Clinical and Translational Science Awards (CTSA) program is a National Center for Advancing Translational Sciences (NCATS) initiative to advance translational science and research. Currently, 64 “CTSA hubs” exist across the nation. Since 2006, the Houston-based Center for Clinical Translational Sciences (CCTS) has assembled a well-integrated, high-impact hub in Texas that includes six partner institutions within the state, encompassing ∼23,000 sq. miles and over 16 million residents. To achieve the NCATS goal of “more treatments for all people more quickly,” the CCTS promotes diversity and inclusion by integrating underrepresented populations into clinical studies, workforce training, and career development. In May 2023, we submitted the UM1 application and six “companion” proposals: K12, R25, T32-Predoctoral, T32-Postdoctoral, and RC2 (two applications). In October 2023, we received priority scores for the UM1 (22), K12 (25), T32-Predoctoral (20), and T32-Postdoctoral (23), which historically fall within the NCATS funding range. This report describes the grant preparation and submission approach, coupled with data from an internal survey designed to assimilate feedback from principal investigators, writers, reviewers, and administrative specialists. Herein, we share the challenges faced, the approaches developed, and the lessons learned.

OBJECTIVES/GOALS: To quantify changing trends in hepatocellular carcinoma (HCC) etiologies, mainly hepatitis C related HCC (HCV-HCC), nonalcoholic fatty liver disease related HCC (NAFLD-HCC), and alcoholic liver disease related HCC (ALD-HCC), at a single center as well as compared to large national databases. METHODS/STUDY POPULATION: This is a retrospective longitudinal study using a single-center database of patients presenting with HCC from January 1995 to September 2023. Etiologies were confirmed through patient history, clinical exam, and viral serologies. Trends in rate of etiology were analyzed using linear regression. Further investigation will include survival analysis. To improve generalizability, the single-center data were supplemented with national cross-sectional data from the NHANES database on liver disease prevalence from March 1999 to August 2023. Data were provided through questionnaire, clinical exam, and viral serologies. Trends in rates will be analyzed using linear regression. RESULTS/ANTICIPATED RESULTS: Among the single center cohort, NAFLD-HCC increased at an average rate of 1.3% per year (95% Confidence Interval (CI) = 1.1% to 1.4%) and HCV-HCC decreased at an average rate of -0.56% per year (95% CI = -0.83% to -0.29%). Projecting the linear models for the past ten years forward, HCV-HCC is predicted to take up a lower proportion than NASH-HCC by 2026 and lower proportion than ALD-HCC by 2028. Future results will include analysis of the changing proportions of etiologies for liver transplant and survival analysis for HCC by etiology from the single center cohort. Additionally, national trends in HCC etiologies will be provided from the NHANES database. The trends from liver transplant etiology and NHANES are expected to parallel the preliminary results. DISCUSSION/SIGNIFICANCE: As the prevalence of NAFLD increases in the general population, more cases of NAFLD-HCC will be seen in the future. Understanding the changing trends can guide surveillance recommendations, shape treatment algorithms, and frame research priorities.

Despite federal regulations mandating the inclusion of underrepresented groups in research, recruiting diverse participants remains challenging. Identifying and implementing solutions to recruitment barriers in real time might increase the participation of underrepresented groups. Hence, the present study created a comprehensive dashboard of barriers to research participation. Barriers to participation were recorded in real time for prospective participants. Overall, 230 prospective participants expressed interest in the study but were unable to join due to one or more barriers. Awareness of the most common obstacles to research in real time will give researchers valuable data to meaningfully modify recruitment methods.

OBJECTIVES/GOALS: The objective is to assess the effect of pesticide exposure (individually and pesticide mixtures) on the immune response to COVID-19 in children. The goal is to improve scientific knowledge on factors affecting COVID-19 and identify a potentially modifiable factor to reduce disparities in COVID-19 morbidity. METHODS/STUDY POPULATION: Blood samples will be obtained from 50 children with asthma two time points; baseline and 12 months later. SARS-CoV-2 infection or vaccination will be determined with blood exposome RNA analyses.. Immunological response will be measured using neutralizing, phagocytizing, and NK-activating anti-body responses biomarkers. Pesticide exposure will be measured via urinary pesticide metabolites (UPMs). For individual metabolites multivariable analyses for each pesticide will be conducted using generalized estimating equation (GEE) models with compound symmetry correlation to account for the repeated measures design. To assess the pesticide mixture, weighted quantile sum regression (WQS) will be used. RESULTS/ANTICIPATED RESULTS: The main hypothesis is that increased pesticide exposure results in a reduction in the immunological response to SARS-CoV-2 infection and the COVID-19 vaccine. Therefore, we anticipate that increasing concentrations of individual UPMs as well as the increasing index will result in reductions in markers of the immune response to SARS-CoV-2 infection and the COVID-19 vaccine. DISCUSSION/SIGNIFICANCE: Exposure to pesticides is a modifiable environmental factor. If pesticides are found to alter the immune response to COVID-19 infection and vaccination, these data will provide an evidence base for efforts to reduce pesticide exposure in children.

OBJECTIVES/GOALS: There is an excess risk of upper respiratory infection (URI) among Black and Mexican-American children in the US. Factors that underpin these disparities are largely unknown. We evaluated the extent to which socioeconomic status (SES), serum cotinine, obesity, and household size explained the association between race/ethnicity and URI. METHODS/STUDY POPULATION: We studied children, 6-17 years of age, who identified as Black, Mexican-American, or White in the National Health and Nutritional Examination Survey (2007-2012). URI was defined as a self-reported cough, cold, phlegm, runny nose, or other respiratory illness (excluding hay fever and allergies) in the past 7 days. The proportion of the association between race/ethnicity and URI explained by SES, serum cotinine, obesity, and household size was estimated as the average causal mediation effect (i.e., the indirect effect of race/ethnicity via the mediator) divided by the total effect of race/ethnicity. The average causal mediation effect was derived from survey weighted logistic regression models adjusted for age and sex. RESULTS/ANTICIPATED RESULTS: Black children were nearly 40% and Mexican American children were ~60% more likely to report a URI than those who identified as White (OR, 1.37; 95% CI, 1.06-1.77 and OR, 1.61; 95% CI, 1.21-2.13, respectively). Lower SES explained ~25% of the association between Black and Mexican American identity and URI (percent mediated 24.7; 95% CI, 23.0-26.6 and 26.1; 95% CI, 24.2-28.2, respectively). Obesity explained ~7% of the association between Black and Mexican-American identity and URI (percent mediated, 7.6; 95% CI, 7.3-8.0 and percent mediated, 6.7; 95% CI, 6.4-6.9, respectively). Nicotine exposure explained 8% of the association between Black identity and URI (percent mediated, 7.9; 95% CI, 5.6-10.1). DISCUSSION/SIGNIFICANCE: Lower SES explained a quarter of the association between race/ethnicity and URI. Low SES is a broad concept that may work through different mechanisms to lead to disparities in URI by race/ethnicity. Future research is needed to better understand these mechanisms and to identify modifiable aspects that can serve as targets for intervention.

OBJECTIVES/GOALS: It is estimated that 357,000 children have experienced a school shooting since 1999, yet due to limitations in the firearm violence field broadly, the sequalae are not well understood. The objective of this work is to examine the mental health impacts of school shootings, providing insight into the lasting effects of firearm violence on our communities. METHODS/STUDY POPULATION: We will first conduct a quasi-experimental study using controlled interrupted time series with repeated cross-sectional data to assess school shootings’ impact on US mental health. School shooting data is from the K-12 School Shooting Database, and mental health data will be collected via the Behavioral Risk Factor Surveillance System. Second, we will conduct focus groups with community organizations, school administrators, and the public. Interview guides will be developed to explore the mental health impacts of school shootings, to guide the quantitative results interpretation, and assess educational materials’ usefulness. Qualitative analysis will occur in NVivo software with codebook refinement through thematic analysis. Results will be triangulated through convergence coding. RESULTS/ANTICIPATED RESULTS: This research is situated within the context of the pervasive mental health challenges in the US, where mental illness poses significant health, social, and economic burdens. Thus, we anticipate finding an association between school shootings and decreased self-reported mental well-being among US adults. Literature suggests that there may be a stronger association among specific subgroups, such as parents with school-aged children or individuals living in close proximity to such incidents. We expect to find heterogeneity in the effect estimate based on school shooting attributes, such as the number of casualties. Through focus groups, we anticipate furthering our comprehension of the broad-ranging effects of school shootings on less quantifiable outcomes and the unique trajectories of recovery. DISCUSSION/SIGNIFICANCE: This project will contribute needed information on the impact of school shootings and mental health and assist in reducing the frequency and impact of school shootings. Furthermore, we aim to extend our findings beyond the scientific community, translating them into educational resources advocating for policy and public health interventions.

OBJECTIVES/GOALS: More young adults (age <50 years) are diagnosed with metastatic gastric cancer (mGC) every year. We will evaluate the association between environmental risk factors (including historical racial residential segregation) clinical, pathologic, molecular features and H.pylori associated early-onset mGC (mE-GC). METHODS/STUDY POPULATION: This retrospective matched case-control study of patients (1:2 by diagnosis year) with mGC (early-onset [E-GC; <50 years]; vs older-onset [O-GC; >50 years]) from 2000-2022 from the Los Angeles Cancer Surveillance Program (LA-CSP) will be enriched by a chart-abstracted cohort from USC Norris Comprehensive Cancer (NCCC). This annotated database captures sociodemographic, medical, and pathologic features of patients treated for mGC at NCCC. It will link to LA-CSP data exploring neighborhood features (obesity rate, poverty, insurance, access to care, ethnic enclave, historical segregation, etc.) of cases and controls to identify, characterize, and compare geographic “hotspot” neighborhoods of mE-GC. We hypothesize younger Hispanic and Asian patients are at higher risk of H.pylori associated mGC. RESULTS/ANTICIPATED RESULTS: From 2000-2022, 339 patients (mE-GC n = 113; mO-GC n=226) were treated at NCCC. We will have characterized clinical and pathological features of mE-GC vs mO-GC. We determined the proportion of H. pylori associated mE-GC vs mO-GC. We will have established the geographical distribution of patients with mE-GC vs mO-GC to identify high-risk neighborhoods. We will link neighborhood risk factors such as food scarcity, poverty, health care access, ethnic enclaves, to the distinct clinical and pathological features of mE-GC, including H. pylori status. Descriptive statistics, chi-square, t-tests, and multivariable regression will be used to compare mE-GC to mO-GC. After controlling for underlying demographics and tumor features, we anticipate clusters of mE-GC and mO-GC in areas of historical racial segregation. DISCUSSION/SIGNIFICANCE: Linking neighborhood and individual risk factors for mE-GC will inform early detection and prevention efforts for vulnerable individuals in high-risk neighborhoods. Building community partnerships within these neighborhoods is essential for developing interventions targeting H. pylori treatment to reduce health disparities in mE-GC.

OBJECTIVES/GOALS: As mortality and morbidity from acute COVID-19 decline, the impact of COVID-19 on short- and long-term quality of life (QoL) becomes critical to address. We assessed the impact of re-purposed COVID-19 therapies on QoL as a secondary outcome measure in ACTIV-6, a decentralized platform trial. METHODS/STUDY POPULATION: Adults aged ≥30 with mild-to-moderate COVID-19 enroll in ACTIV-6 online or through a study site. Patients are randomized to a medication of interest or placebo. Medications are mailed and symptoms are tracked using electronic diaries. QoL is measured#_msocom_1 using the PROMIS-29 questionnaire. Adjusted Bayesian logistic regression models are used to measure effects of treatment on the seven PROMIS-29 QoL domains at days 7, 14, 28#_msocom_2 and 90. Covariates are treatment, age, gender, symptom duration and severity, vaccination status, geographic region, call center#_msocom_3#_msocom_4, and calendar time. Treatment effects are described using ORs, 95% credible intervals, and posterior probabilities of efficacy, P(eff). RESULTS/ANTICIPATED RESULTS: There are 5,362 patients included, representing four of the study arms in ACTIV-6. We report results where P(eff)<0.025 and P(eff)>0.975 in the table below. Table 1. Scale Day: OR* (95% credible interval, P(eff)) Therapy Physical Anxiety Depression Fatigue Sleep Social Pain Ivermectin 400 — Ivermectin 600 D7: 0.77 (0.61-0.96, 0.01) D14: 0.65 (0.49-0.85, <0.01) D28: 0.69 (0.52-0.92, 0.01) — D7: 0.79 (0.64-0.97, 0.01) — D14 0.78 (0.60-1.00, 0.02) D28: 0.66 (0.50-0.87, <0.01) Fluticasone - D14: 0.77 (0.60-0.99, 0.02) — D7: 0.76 (0.62-0.93, <0.01) D90: 0.79 (0.64-0.98, 0.01) — D7: 0.74 (0.59-0.93, 0.01) Fluvoxamine D7: 0.66 (0.51-0.84, 0.01) — D28: 1.38 (1.02, 1.85, 0.98) D7: 0.78 (0.63-0.97, 0.01) D7: 0.77 (0.62-0.95, 0.01) — *OR > 1 favors active intervention DISCUSSION/SIGNIFICANCE: Results suggest fluvoxamine may improve depression scores by day 28, while placebo is favored in several other scales across treatments. Differences between treatment and placebo are not seen at most other timepoints. This trial is ongoing and future work will include results from additional ACTIV-6 study arms.

OBJECTIVES/GOALS: Metabolic syndrome (MetS), defined as a cluster of cardiometabolic disease risk factors, is seldom coded using the ICD-10 system in electronic medical records (EMR). The goal of this study was to use EMR to construct MetS with a digital phenotype to amplify the pool of patients available to assess risk for neurocognitive disease in this population. METHODS/STUDY POPULATION: A digital phenotype using the EMR platform TriNetX (n=38 million patients between age 50 and 80) was created by clustering codes for the individual components of MetS (insulin resistance, hypertension, dyslipidemia, and central adiposity). The research network database on TriNetX was utilized to elucidate risk ratios for neurocognitive decline, Alzheimer’s disease and related dementias (ADRDs), and cerebrovascular disease between a preclinical sample of older adults with and without MetS. Propensity score matching was used to match cohorts on demographic variables, medication use, and relevant comorbidities. Risk ratios (RR) and confidence intervals (95% CI) were presented for all outcomes. RESULTS/ANTICIPATED RESULTS: The digital phenotype for MetS expanded the sample from 29,830 to 274,703, a 10-fold increase. Sensitivity to the standard MetS ICD-10 code was 95.1%, showing strong agreement between coding schema. Older adults with MetS had higher risk of cognitive decline (RR: 1.30, 95% CI: 1.15–1.48, p <0.001), ADRDs (RR: 1.48, 95% CI: 1.25–1.75, p <0.001), and cerebrovascular issues (RR: 1.62, 95% CI: 1.55–1.70, p <0.001) when controlling for demographics, medication, and comorbidities. MetS individuals with cerebrovascular dysfunction had even greater risks for neurocognitive decline (RR: 1.70, 95% CI: 1.38–2.08, p < 0.001) and ADRDs (RR: 2.09, 95% CI: 1.56–2.80, p < 0.001) than those with only MetS. DISCUSSION/SIGNIFICANCE: Implementing a digital MetS phenotype in EMR effectively increased sample size and power for analyses. Older adults with MetS have higher risk for neurocognitive decline, especially among those with cerebrovascular dysfunction, highlighting a critical intervention window prior to overt cardiometabolic disease.

Empowering the Participant Voice (EPV) is an NCATS-funded six-CTSA collaboration to develop, demonstrate, and disseminate a low-cost infrastructure for collecting timely feedback from research participants, fostering trust, and providing data for improving clinical translational research. EPV leverages the validated Research Participant Perception Survey (RPPS) and the popular REDCap electronic data-capture platform. This report describes the development of infrastructure designed to overcome identified institutional barriers to routinely collecting participant feedback using RPPS and demonstration use cases. Sites engaged local stakeholders iteratively, incorporating feedback about anticipated value and potential concerns into project design. The team defined common standards and operations, developed software, and produced a detailed planning and implementation Guide. By May 2023, 2,575 participants diverse in age, race, ethnicity, and sex had responded to approximately 13,850 survey invitations (18.6%); 29% of responses included free-text comments. EPV infrastructure enabled sites to routinely access local and multi-site research participant experience data on an interactive analytics dashboard. The EPV learning collaborative continues to test initiatives to improve survey reach and optimize infrastructure and process. Broad uptake of EPV will expand the evidence base, enable hypothesis generation, and drive research-on-research locally and nationally to enhance the clinical research enterprise.