Objectives/Goals: 1) Determine the association between wildfire smoke-driven PM2.5 and risk of persistent respiratory symptoms and repeated asthma exacerbations after the acute wildfire period among adults with asthma. 2) Examine how measures to reduce personal exposure to wildfire smoke, including avoiding outdoor activities, modify this association. Methods/Study Population: This is a retrospective study of adults with asthma in WHAT-NOW, a cohort study of people living in Northern California during the 2018 Camp Fire. Daily smoke-driven PM2.5 was estimated for each participant based on their home address or evacuation location. We examined the association between mean PM2.5 exposure and the presence of respiratory symptoms at both the time of the survey (6–16 months post-wildfire) and at least one other post-wildfire time-period, as well as whether they had a medically attended respiratory illness (saw a doctor, visited the ER, or were hospitalized for a respiratory symptom). We examined the interaction of PM2.5 with spending time outdoors during the wildfires. Poisson regression models with robust standard errors were adjusted for age, sex, race, smoking, allergies, and education. Results/Anticipated Results: Among 337 adults with asthma in the WHAT-NOW cohort, one standard deviation higher smoke-driven PM2.5 was associated with higher risk of any persistent respiratory symptom (risk ratio (RR) 1.38, 95% CI 1.07 – 1.78) and having at least one medically attended respiratory illness (RR 1.33, 95% CI 1.07 – 1.65), but not significantly associated with repeated asthma exacerbations (RR 1.30, 95% CI 0.92 – 1.81). However, there was a significant interaction between PM2.5 and outdoor activities during the wildfire on the outcomes of any persistent respiratory symptoms (p = 0.041) and repeated asthma exacerbations (p = 0.028). The association between PM2.5 and repeated asthma exacerbations was greater among people who spent time outdoors (RR 3.36, 95% CI 1.47 – 10.23) than those who did not (RR 1.00, p = 0.99). Discussion/Significance of Impact: This study provides evidence that exposure to wildfire smoke increases respiratory morbidity among adults with asthma beyond the acute wildfire period. Additionally, it suggests that avoiding outdoor activities on smoky days can significantly decrease the risk of future repeated asthma exacerbations associated with smoke exposure.

Objectives/Goals: Infectious keratitis is the leading cause of corneal blindness worldwide, causing two million cases of monocular blindness per year. Of these cases, developing countries are disproportionately affected, in part due to sociodemographic disparities. Our study examined risk factors for severe keratitis presentation in a South Indian population. Methods/Study Population: 156 patients aged ≥ 16 years with clinically diagnosed infectious keratitis presenting to Aravind Eye Hospital in Pondicherry, India, from January 1, 2023 to July 31, 2024, were retrospectively reviewed. Univariate logistic regression was used to evaluate associations between specific potential risk factors (including age, sex, awareness of keratitis, travel distance to hospital, education level, missed work wages, and ability to afford care) and keratitis clinical severity (defined using thresholds of poor visual acuity, size of stromal infiltrate measured on slit lamp examination, occurrence of perforation, and need for corneal transplant surgery). Individual risk factors found to be significant were incorporated into a multivariable logistic regression model. Results/Anticipated Results: We anticipate that the results of this study will identify multiple risk factors for more severe keratitis presentations among patients at baseline. We expect these factors to include increased travel distance from the patient’s home to the base hospital, delays between time of diagnosis and initiation of treatment, treatment nonadherence, lower educational levels, lack of familiarity with keratitis, treatment and transportation costs, increased time off work, and missed work wages, among others. Discussion/Significance of Impact: This study elucidates barriers to early keratitis diagnosis in a low-resource setting. Study findings can inform strategies to improve keratitis prevention using decentralized care approaches such as community eye screenings and expanding outreach via vision centers. Such strategies can improve timely access to care for vulnerable populations.

Objectives/Goals: This study aim to identify cervical cancer prevention barriers and facilitators, assess the associations between social determinants of health factors and cervical cancer prevention, and examine the association between levels of health literacy and willingness to undertake HPV vaccine and cervical cancer screening among Black and Hispanic women. Methods/Study Population: To achieve Aim 1, we will conduct a quantitative survey on barriers and facilitators to cancer prevention among non-Hispanic Black and Hispanic women. For Aim 2, we will assess the relationship between Social Determinants of Health and HPV vaccination/cervical cancer screening using the AHC Health-Related Social Needs Screening Tool. For Aim 3, health literacy will be measured using the SAHL–S&E test and its association with willingness to vaccinate or cervical cancer screening. We will analyze the results using chi-square and logistic regression models. Participants will be recruited through multiple methods. We will recruit 250 individuals who were assigned female at birth and identify as non-Hispanic Black or Hispanic, aged 18–26 years, from Caddo and Bossier Parishes. Results/Anticipated Results: We expect to identify several barriers and facilitators to cervical cancer prevention among non-Hispanic Black and Hispanic women, including factors like access to care, cultural beliefs, and knowledge gaps. Social determinants of health (SDOH), such as income, education, and healthcare access, will likely show a strong association with lower HPV vaccination, Pap smear, and HPV screening rates. Additionally, we anticipate that lower health literacy will correlate with reduced willingness to vaccinate or screen for HPV. These findings can bridge the gap between research and practical health applications by guiding the design of community-based behavioral interventions that enhance cervical cancer prevention among minority populations. Discussion/Significance of Impact: This research is the first to assess how SDOH factors impact cervical cancer prevention among Blacks and Hispanic women in North Louisianawhile also exploring the role of health literacy in HPV vaccination and screening. Findings will drive practical interventions to reduce disparities and improve outcomes.

Objectives/Goals: Tacrolimus (TAC) is an immunosuppressant used after hematopoietic stem cell transplant (HSCT). Recently, TAC was found to be metabolized to a novel, less active metabolite by common gut microbiota. Our objective is to determine a microbiome signature that influences oral TAC pharmacokinetic (PK) and to develop a clinical tool to select the TAC dose. Methods/Study Population: This is an observational IRB approved microbiome-pharmacogenomic study using banked biospecimens and clinical data, TAC dose, and PK information from the electronic health record. Adult HSCT patients with pre-transplant DNA and stool specimens were included in this analysis if they received TAC in the first 100 days post-HSCT. A global diversity array was used for DNA pharmacogenomic (PGx) genotyping, and metagenomic shotgun sequencing was used for stool microbiome analysis. Spearman correlation will be used to identify potential stool microbiota associated with TAC PK. TAC trough concentrations at steady state will be modeled using nonlinear mixed effects (NLME) modeling to identify potential genetic and microbiota covariates that influence TAC clearance. Results/Anticipated Results: We identified 53 eligible patients who had available DNA and 90 stool samples. The majority (n = 49, 92.5%) were of European ancestry. These patients had 920 (oral  =  622, IV infusion  =  298) TAC trough blood concentrations. We expect that patients who have high abundance of bacteria that metabolize or reduce the absorption of TAC will have lower blood concentrations and will require a higher IV to oral dose conversion ratio than those with lower abundance. Those patients will also require higher oral TAC daily doses. Low stool microbial diversity is expected to be associated with high oral TAC trough intra-patient variability in the first 100 days post-transplant. In the NLME model, PGx when combined with potential bacterial signature will better explain variability in TAC clearance. Discussion/Significance of Impact: Combining PGx and microbiome biomarkers will provide a better understanding of the factors influencing TAC PK and lead to models for individualized dosing. To our knowledge, this is the first study to investigate the combined influence of microbiome and PGx on drug PK. The study is limited to the availability of samples in the biobank.

Objectives/Goals: The neighborhoods children grow up in are critical drivers of social, emotional, and cognitive development. This study utilized factor scores of environment, education, and socioeconomic variables in the Adolescent Brain Cognitive Development Study (ABCD) and its association with cognitive functioning in youth. Methods/Study Population: This study used ABCD (n  =  9,543) linked external data, cognitive performance, and self-reported data from youth (ages 9–10) and their caregivers. We utilized four factor scores of the Child Opportunity Index 2.0 (COI), including socioeconomic attainment, poverty, neighborhood enrichment, and child education. Furthermore, this study investigated the association between the COI factors and youth cognitive functioning via the NIH Toolbox. Covariates included age, sex, county level crime rates, perceptions of neighborhood threat, parent education, and family income; site and family relationship were held as random effects. Results/Anticipated Results: Increased Socioeconomic Attainment and Child Education factor scores were distinctly associated with increased cognitive performance across all subscales and composite scores that include aspects of overall cognitive ability, executive functioning, and learning and memory. Increased poverty factor scores were significantly associated with decreased cognitive performance across all substances and composite scores. Finally, increased neighborhood enrichment factor scores were significantly associated with increased oral reading recognition task scores only and no other cognitive task. Discussion/Significance of Impact: Findings suggest distinct dimensions of neighborhood opportunity associated with aspects of cognition. The present study can help to inform public health efforts and policy on improving modifiable built and natural environmental structures that may aid in supporting cognitive development.

Objectives/Goals: Identify risks in the regulatory reliance ecosystem, specifically for generic reliance pathways, using system theoretic process analysis (STPA), a proactive hazard analysis method, and create sustainable solutions to ensure global accessibility to the highest attainable standard of health. Methods/Study Population: A systematic literature review will assess the regulatory reliance ecosystem and interactions among National Regulatory Agencies (NRAs). This will involve using a hierarchical control structure (HCS) to identify operational loop failures, decision-making, and information flow. The HCS will inform an STPA to prevent adverse outcomes like patient harm or regulatory non-compliance. With IRB approval, 10 regulatory experts will also be interviewed to gather insights on risk scenarios. Their input will be used to integrate regulatory pathways into the HCS for adaptability, and a second round of interviews will be conducted to validate the scenarios and assess the effectiveness of recommendations. Results/Anticipated Results: A preliminary literature review on regulatory reliance pathways from PubMed, WHO guidelines, and the DIA global forum, revealed potential risks in NRA interactions, such as overly redacted reports obscuring critical details and discrepancies in product versions or incomplete reviews affecting evaluations. Diverging guidelines and failure to adapt to country-specific needs are potential risks that also impact patient access to essential medicines. The STPA framework, along with expert feedback, will uncover unknown risks like “secondary-reliance” and soft risks, leading to sustainable recommendations to improve and optimize the safety of regulatory reliance. Discussion/Significance of Impact: Safe regulatory reliance is crucial for global health equity and patient access to essential and innovative medicines. STPA will identify and address different layers of risk in the system, improving safety, efficiency, and innovation for timely patient access to therapeutics.

Objectives/Goals: Mathematical models of airborne virus transmission lack supporting field and clinical data such as viral aerosol emission rates and airborne infectious doses. Here, we aim to measure inhalation exposure to influenza aerosols in a room shared with persons with community-acquired influenza and estimate the infectious dose via inhalation. Methods/Study Population: We recruited healthy volunteer recipients and influenza donors with polymerase chain reaction (PCR)-confirmed community-acquired infection. On admission to a hotel quarantine, recipients provided sera to determine baseline immunity to influenza virus, and donor infections were confirmed by quantitative real-time polymerase chain reaction. Donors and recipients were housed in separate rooms and interacted in an “event room” with controlled ventilation (0.2 – 0.5 air changes/hour) and relative humidity (20–40%). We collected ambient bioaerosol exposure samples using NIOSH BC-251 samplers. Donors provided exhaled breath samples collected by a Gesundheit-II (G-II). We analyzed aerosol samples using dPCR and fluorescent focus assays for influenza A and sera by hemagglutinin inhibition assay (HAI) against donor viruses and vaccine strains. Results/Anticipated Results: Among two cohorts (24b and 24c), we exposed 11 recipients (mean age: 36; 55% female) to 5 donors (mean age: 21; 80% female) infected with influenza A H1N1 or H3N2. Eight G-II and two NIOSH bioaerosol samples (1–4 µm and ≥4 µm) were PCR positive. We cultured virus from one G-II sample. Based on previous literature, we hypothesized that ~50% of immunologically naïve people (HAI Discussion/Significance of Impact: We demonstrated that it is feasible to recruit donors with community-acquired influenza and expose recipients to measurable virus quantities under controlled conditions. However, baseline immunity was high among volunteers. Our work sets the stage for designing studies with increased sample sizes comprising immunologically naïve volunteers.

Objectives/Goals: Understanding the interconnections among over 20,000 human diseases spanning organ systems could inform more precise diagnosis and treatment of diseases. Here, we examine whether the ability of large language models (LLMs) to learn universal representations of concepts can be leveraged to discover complex relationships across human diseases. Methods/Study Population: To address the challenge of computationally representing thousands diseases spanning multiple organ systems, we used internal representations of concepts by LLMs to encode diseases based on their descriptions from standard disease ontologies (ICD10 and Phecodes). To do this, we leveraged application programming interfaces (APIs) of three LLMs-GPT3.5, Mistral and Voyage to encode disease relationships. We then performed unsupervised clustering of the diseases using their encodings (embeddings) from each LLM to determine whether the resulting clusters reflect disease relationships. To enable deeper exploration of disease relationships, we developed interactive plots that provide a system level view of the relationships between thousands of diseases and their association with specific organ systems. Results/Anticipated Results: We found that unsupervised analysis of disease relationships using the LLM encodings reveal high similarities among diseases based on organ systems they affect. All the LLMs clustered diseases into groups largely defined by the organ systems they affect without being trained to specifically classify diseases into their corresponding organ system classification. An exception to this was tumors in which we observed that most tumors cluster together as a group irrespective of the organs they affect. Interestingly, we found that tumors affecting anatomically related organs show higher similarity to each other than to those affecting distantly related organs. In addition to anatomical relationships between diseases, we found that the LLM embeddings capture genetic relationships between diseases. Discussion/Significance of Impact: Overall, we found that the LLM-derived encodings uphold biologically and clinically significant relationships across organ systems and disease types. These results suggest that LLM encodings could provide a universal framework for representing diseases as computable phenotypes and enable the discovery of complex disease relationships.

Objectives/Goals: Historically, the Univ. of Missouri (MU) Sch. of Medicine (SOM) is known for its strong clinical and education programs. In 2020, MU recruited an Executive Vice Chancellor (EVC) for Health Affairs and subsequently Dean of the SOM who initiated programmatic steps to develop and establish a centralized clinical and translational research (CTR) infrastructure. Methods/Study Population: In order to develop and establish a CTR infrastructure, the EVC/Dean of the SOM created and recruited to the combined position of the Associate Dean (AD) for CTR and Associate Director (ADR) of clinical research (CR) for the Ellis Fischel Cancer Ctr. (EFCC) in 2021. The AD CTR was appointed the Chair of the Clinical and Translational Science Unit (CTSU) Steering Committee with the charge of establishing a 10,000 sq. ft. CTSU to be housed in the newly built $225M Roy Blunt NextGen Precision Health Bldg. and for re-building the Clinical Trials Support Office (CTSO), and the Clinical Trials Office (CTO) at the EFCC in his other role as the ADR CR. The AD CTR was also charged with implementing the OnCore clinical trial management system (CTMS) to centrally track and fiscally manage SOM clinical trials. Results/Anticipated Results: Between 2021 and 2023, a CTR infrastructure was developed and established at the MU SOM. A total of 25 new clinical research staff (CRS) and leadership were hired that included a Sr. Dir. of CR Operations, clinical research nurses (CRNs) and coordinators (CRCs), Regulatory/Data/Fiscal/Project/Compliance/Coverage Analysis Coordinators between the CTSU/CTSO and the CTO of the EFCC. The CTSU was built with 10 FTE CRS [CRNs  =  5, CRCs  =  2, administrative staff  =  2, Sr. Lab. Tech.  =  1, and a manager]; the CTSO was re-built with 9 FTE CRS [Fiscal (n = 3), Project (n = 2), Compliance (n = 2), Coverage Analysis (n = 1) and Recruitment (n = 1) coordinators]. The EFCC CTO was re-built with 8 FTE CRS [CRNs  =  4, Fiscal (n = 1), Data (n = 1) & Regulatory (n = 2) coordinators]. The implementation of the OnCore CTMS tracking function was also completed. Discussion/Significance of Impact: Overall, the development and establishment of the CTR infrastructure has led to a significant increase and enhancement (e.g., capacity) to conduct clinical trials at the MU SOM. For example, this has led to a significant increase in the average annual enrollment to interventional oncology clinical trials [n = 82 (2021–2023) vs. n = 42 (2016–2020), p = 0.004].

Objectives/Goals: • To determine the impact of liraglutide on inflammation and organ injury during sepsis. • To investigate the protective effects of liraglutide on microvascular dysfunction in a clinically relevant model of sepsis. • To provide evidence for the potential therapeutic use of GLP-1 receptor agonists in endothelial dysfunction in sepsis. Methods/Study Population: Sepsis was induced in mice (N = 34) by intraperitoneal injection of cecal contents (1.8 mg/g body weight) and 24-hour hyperoxia (FiO2 90–95%). Mice received saline or liraglutide (0.1 mg/kg) at 6 and 18 hours post-injection and fluids and antibiotics at 12 hours. At 24 hours, mice were euthanized for plasma, bronchoalveolar lavage (BAL), and tissue collection. Plasma inflammatory markers, organ injury markers, and BAL components were measured. In vitro, primary human lung microvascular endothelial cells (HLMVECs) were treated with saline or liraglutide for 24 hours before exposure to saline or LPS (100 ng/mL). HLMVEC barrier dysfunction was evaluated using express permeability testing (XPerT) and electric cell-substrate impedance sensing (ECIS) to measure transendothelial electrical resistance (TER). Results/Anticipated Results: In murine sepsis, illness severity scores and lung injury were improved in mice pretreated with liraglutide (N = 10). Plasma blood urea nitrogen (BUN; P = 0.0036), alanine transaminase (ALT; P = 0.0311) and vascular inflammatory markers MCP-1 (P = 0.0172), ICAM-1 (P = 0.0356), and Pecam-1 (P = 0.0493) in plasma were reduced in mice treated with liraglutide. In HLMVECs, liraglutide (1.5 nM) significantly reduced LPS-induced barrier dysfunction measured by XPerT assay (P = 0.0030) and ECIS (P = 0.0075). Discussion/Significance of Impact: Liraglutide reduces illness severity, vascular inflammation, and organ injury in a two-hit model of sepsis. Liraglutide has direct effects in the microvascular endothelium, limiting LPS-mediated barrier dysfunction. These findings support a protective role for GLP-1 receptor agonism in sepsis, mediated through the microvasculature.