Objectives/Goals: The bromodomain PHD finger transcription factor (BPTF) is an oncogenic driver of neuroblastoma. Our objective is to pioneer the discovery of the first class of chemical compounds that engage the PHD finger of BPTF and inhibit its biological function in cellulo, thereby establishing first-in-class chemical probes for this epigenetic reader. Methods/Study Population: Our previous work has identified a collection of small molecules that engage BPTF PHD in vitro. Following structure–activity relationships analysis, candidates will be used in a neuroblastoma cell model to validate BPTF PHD interaction in cellulo and predict therapeutic potential. Nanoluciferase bioluminescence resonance energy transfer (NanoBRET) will be used to confirm BPTF PHD engagement by compounds. Selective toxicity in neuroblastoma cells upon inhibitor treatment will be gauged by comparing cell growth and viability in the IMR-32 cell line against the HEK293 cell line. Treated HEK293 cells will be subjected to the assay for transposase-accessible chromatin (ATAC) and RNA sequencing methods to monitor changes in chromatin structure and transcriptional signatures against untreated cells. Results/Anticipated Results: We hypothesize that compounds with low micromolar potency for BPTF PHD in vitro will engage the target in cellulo and displace NanoLuciferase tagged protein from its HaloTagged® peptide binding partner. Additionally, we anticipate that our inhibitors will show cytotoxicity for IMR-32 cells with limited effects on HEK293 cells. We envision that inhibitor treatment in HEK293 cells will correlate with reduced chromatin exposure, suggesting that blocking the BPTF–histone interaction via PHD finger inhibition hinders the remodeling of transcriptionally silent heterochromatin into a transcriptionally active state. Finally, we expect that inhibitor treatment will result in diminished gene expression of oncogenic transcription factors, including N-Myc, a biomarker of neuroblastoma. Discussion/Significance of Impact: These first-in-class chemical probes for BPTF PHD will enable further investigation of BPTF and high-risk neuroblastoma progression, as well as its role in other diseases. In addition, these compounds will serve as a platform for the development of new anticancer agents that may improve outcomes for children that suffer from high-risk neuroblastoma.

Objectives/Goals: Large-scale tumor sequencing efforts have led to annotations of novel cancer hotspot mutations that may underlie driver or cooperative function. We have sought to define the molecular consequences of such hotspots associated with pediatric DICER1 syndrome cancers, with the ultimate goal of revealing novel targets that may inform new standards of care. Methods/Study Population: We have performed genomic analysis to identify tumor types (in TCGA and MSK-IMPACT patient data) for which mutations in the Dicer1 gene (encoding Dicer protein) emerge as the dominant signature of driver function. As Dicer is a critical RNA processing factor responsible for the generation of microRNAs, which are posttranscriptional gene regulatory molecules, we have modeled these mutations in human embryonic stem cells in order to study the direct effects on miRNAs and their target genes in an isogenic background. In addition to providing the required setting for unambiguous attribution of function to specific mutations, clonal human ES cells offer an opportunity for modeling of both developmental and cancer requirements associated with altered Dicer function. Results/Anticipated Results: Through generation of genomics and functional datasets from matched genotypes in Dicer mutated human ES cells, we have identified specific alterations in miRNAs and their effects on target genes. Unexpectedly, we found direct evidence for both loss of function and gain of function attributable to Dicer mutations. In addition, through integrated analysis of genomic data from tumor sequencing datasets and our human ES cell models, we have identified potential miRNA and target gene alterations that underlie tumorigenic potential, nominating gene candidates for targeted therapy in DICER1 syndrome. Direct mouse modeling of such candidate gene targets has revealed evidence for driver function of identified miRNA and their targets. Discussion/Significance of Impact: DICER1 syndrome cancers comprise a wide variety of rare pediatric tumor types. Presently, we still lack an effective standard of care. Furthermore, the previous lack of molecular profiling precluded targeted therapy opportunities. Our precise knock-in modeling of Dicer hotspots and deep profiling of relevant tumors now provide candidate targets.

Objectives/Goals: The growing burden of hypertension in the USA disproportionately impacts individuals with lower socioeconomic status and those in rural communities. This study aims to investigate specific social determinants of health associated with uncontrolled hypertension among rural, underserved patients residing in Alabama. Methods/Study Population: A retrospective review of electronic health records data from the UAB Selma Family Medicine clinic was conducted. The deidentified data were entered into the Population Health Assessment Engine (PHATE) to render social characteristics and community vital sign (CVS) scores, a social deprivation index, by census tracts. We provide descriptive statistics and compare the stated factors between patients with controlled and uncontrolled hypertension using logistic regression models. We are conducting phone surveys to gather individualized data on social determinants of health to assess the perceived social needs of patients with hypertension. The Protocol for Responding to & Assessing Patients’ Assets, Risks & Experience tool was used to develop the survey, and survey responses will be compared with the PHATE results. Results/Anticipated Results: Among 2129 patients, 375 (17.6%) had uncontrolled hypertension with a mean age of 58.7 ± 14.4 years. Women comprised 66.7% (250) and 65.1% (1142) of the uncontrolled and controlled hypertension populations, respectively. The prevalence of uncontrolled hypertension was 19.1% among Black patients and 8.2% in White patients. Patients with uncontrolled hypertension had a CVS of 82.37 ± 7.31 and 81.81 ± 8.40 patients with controlled hypertension. Patients with uncontrolled hypertension lived in areas where an average of 46 ± 11% were not employed, 36 ± 9% rented, and 28 ± 1% lived below the federal poverty line (FPL). Adjusting for age, race, and sex, a unit increase in the proportion of people below the FPL was associated with 43% higher odds of uncontrolled versus controlled hypertension (OR  =  1.43, 95% CI 0.44, 4.64). Discussion/Significance of Impact: Rural, underserved patients with hypertension experience multiple adverse social determinants, such as nonemployment rates, low income, and rental housing. Survey results will allow us to compare assessed and individualized social determinants that may be important to address when caring for this population.

Objectives/Goals: Endometrial cancer is one of the few cancers that has both a rising incidence and mortality rate. Molecular classification is becoming more important for the management of endometrial cancer but the ability to translate this into clinical practice remains constrained. Our goal is to use AI to predict the molecular subtype from histopathology slides. Methods/Study Population: We utilized the open source endometrial cancer datasets from The Cancer Genome Atlas (TCGA) (N = 387) and Cancer Proteomics Transcriptomic Tumor Analysis Consortium (CPTAC) (N = 135) to develop and train a vision transformer AI model. We used a proprietary cohort of patients (N = 548) for external validation. Whole slide images (WSI) and molecular subtype data were collected. Subtypes include POLE ultramutated (POLE), microsatellite instability (MSI-H), copy-number low (CNV-L), and copy-number high (CNV-H). WSI were preprocessed, and features were extracted. Modified STAMP protocol was used in training, utilizing a pretrained foundation transformer model (Virchow2). Cross-validation of the TCGA was used for initial training, followed by testing on the CPTAC dataset and validation on our proprietary cohort. Results/Anticipated Results: Fivefold cross-validation of the TCGA database (60% training, 20% testing, and 20% validation) developed a best overall model with a mean AUC of 0.74 (POLE 0.78, MSI-H 0.76, CNV-H 0.86, CNV-L 0.77). Overall precision 0.58, recall 0.55. CNV-H was the subtype with the most accurate prediction. CPTAC holdout testing revealed moderately high AUC (POLE 0.63, MSI-H 0.62, CNV-H 0.98, and CNV-L 0.76). Overall precision 0.54 and recall 0.58. Again, CNV-H was the most accurate prediction. Validation on our proprietary cohort revealed a drop in performance with overall mixed results by AUC (POLE 0.50, MSI-H 0.69, CNV-H 0.78, and CNV-L 0.61). Overall precision 0.57, recall 0.45. Again, CNV-H with the most accurate prediction but F1 score dropped from 0.77 in the CPTAC to 0.47 on validation. POLE was the least accurate prediction subtype. Discussion/Significance of Impact: The CNV-H subtype demonstrated robust performance, suggesting the model effectively captures the features associated with this subtype. CNV-L had moderate performance. MSI-H and POLE were notably lower. WSI-based AI models show translational potential for subtype prediction in the management of endometrial cancer but more work is necessary.

Objectives/Goals: Our research goal is to translate medical guidelines for adolescent-centered contraceptive counseling into improved clinical practice. Here, we describe the process of co-designing a training program for adolescent-serving primary care clinicians with teen, caregiver, and clinician advisory boards. Methods/Study Population: We recruited teens, caregivers, and clinicians residing in North Carolina to participate in three virtual advisory boards separated by role. Eligible teen advisors were assigned female at birth and 15–19 years old; eligible clinicians provided care for teen patients; and all groups were purposively sampled to reflect diverse identities and experiences. At each advisor meeting, we used human-centered design techniques to elicit participant priorities, generate training content and engagement strategies, and obtain feedback on the final training program. We conducted a focus group at our final meetings and used rapid qualitative analysis to understand our advisors’ experiences participating in program co-development. Results/Anticipated Results: We partnered with 20 advisors with diverse identities across geographic location, race and ethnicity, sexuality, and experiences with disability. During 15 meetings from January to May 2024 (five with each advisor group), we developed a 3-hour virtual, synchronous training for adolescent-serving primary care providers to improve their contraceptive counseling skills. The curriculum includes five interactive modules and a resource toolkit. Advisors described motivations to participate (e.g., chance to share their perspective, desire to make change), positive experiences with the advisory boards (e.g., opportunities to learn, to connect with others), and opportunities for improvement (e.g., better technology orientation). Discussion/Significance of Impact: We describe developing a successful longitudinal partnership with three community advisory boards and co-creating a training program that incorporates community-led priorities and perspectives, including youth. This approach can be adapted for other clinician training programs seeking to center community voices.

Objectives/Goals: A summer research program for medical students was implemented using real-world evidence (RWE) – electronic health record (EHR) databases to develop and answer research questions. Medical students were trained in capabilities of traversing the large RWE-EHR so they may query, extract, and analyze data as well as refine their research questions. Methods/Study Population: Ten medical students and 9 non-data scientist mentors underwent training in how to use the IU School of Medicine-Evansville RWEdataLab (CRC/Sidus Insights) national real-world cardiology and psychiatry deidentified EHR databases. The program began with students attending introductory training teaching database, spreadsheet, and statistical program usage. During the remainder of the program, a weekly best practices meeting took place among mentors and a weekly cohort meeting of students and mentors discussed student presented findings. At the end of the program, students generated abstracts and poster or podium presentations to share their findings at local symposia. A survey was also distributed to students to assess the impact of the tools, trainings, and program. Results/Anticipated Results: All students were able to define a question of interest, query and extract data related to their research question, and analyze multiple aspects of their data. Projects were well received at local symposia, with 2 receiving special honors, and 2 projects have been presented at regional/national conferences. Students rated the program highly and were likely to recommend the program to other students. They self-rated improvements in asking scientific questions, using excel, data presentations, and problem-solving. Students valued weekly “check-in” meetings and interactions with mentors more than lectures or technical “help desk” support. Discussion/Significance of Impact: The program provides mechanisms for non-data scientists and medical trainees, to learn and access RWE-EHR databases to address research questions. The cohort interactions fostered discussion among mentors and students promoting research question refinement and clarity findings. The program also introduces a new tool for potential patient care.

Objectives/Goals: To design and implement programming that better prepares graduate students for diverse roles in a variety of workforce environments, our study models the training landscape and programming needs of graduate students in behavioral, clinical, and biomedical graduate programs at a large Midwestern school of medicine and public health. Methods/Study Population: We conducted six focus groups (two graduate program manager focus groups and four graduate student focus groups), to assess the programming, career development, and training needs of graduate students. Using a grounded theory approach, we first engaged in open coding of a sample of transcripts. After developing a codebook, we continued with an iterative coding process interspersed with coder meetings to discuss emerging and changing codes. Using the framework of landscape analysis allowed our coding and modeling to go beyond graduate student needs and study the varying relationships and contexts that impact graduate students throughout their training, such as relationship to supervisor or institutional policies. Results/Anticipated Results: Preliminary results indicate that students wrestle with their status as both students and workers. Specifically, conflict arises between graduate and supervisor expectations around time spent in class, lab, and other career development activities based on these divergent roles. Students and program managers also note the disparities that arise from the university’s lack of standard, formalized policy on labor issues, such as paid leave. Data also suggest that students on training grants note the difference in access to career development resources compared to colleagues. In many cases, students themselves coordinate ad hoc programming to better suit their career and professional development needs, although this work is not a required aspect of their training. Discussion/Significance of Impact: We characterize current graduate training landscapes, which continue to shift as graduate student bodies diversify, unionize, and express interest in increasingly varied biomedical careers. Data from multiple perspectives facilitate creating, implementing, and evaluating supportive training programs that meet identified student needs.

Objectives/Goals: To identify clinical trial teams that are at risk of not meeting their recruitment goals as early in the recruitment period as possible, this project aims to provide timely accrual information and projected forecasts for accruals by the end of the recruitment period across all trials at USC. Methods/Study Population: This project aggregates recruitment accrual data periodically from OnCore to create per-study accrual pages that contain an up-to-date accrual chart, metrics like expected and actual accrual per month, and projected recruitment based on an X-month moving average (3 months by default). Trials at risk are identified as early as possible by using these projections to classify risk. In this initial phase, we’ve classified trials as medium risk (80%–99% accrual) or high risk (less than 80% accrual). The dashboard is currently available for all clinical trials at USC and users are automatically restricted to the studies that they administer or work on depending on their role. Results/Anticipated Results: The dashboard will provide visibility across the institution for the current accrual for all clinical trials in a standard, user-friendly format and use the same metrics and definitions of risk for trial accruals not meeting their targets. This will allow the institution to identify trials that need intervention to get back on track using a single set of criteria across all research teams. Users in different roles, whether department heads, principal investigators, or study coordinators can view the current accrual for all the trials that they administer or work on in one central location. The dashboard will also help to identify quality issues in OnCore by performing data quality checks nightly. Discussion/Significance of Impact: By providing a central location for role-based access to timely clinical trial accrual for the institution, the dashboard helps to identify trials at risk of not meeting their recruitment targets as early as possible to provide corrective advice/measures.

Objectives/Goals: The creatine (Cr) system is impaired in Alzheimer’s disease (AD). Data show that creatine monohydrate (CrM) supplementation may improve AD symptoms in AD mouse models, but no human studies have been reported. Thus, we investigated whether an eight-week CrM supplementation was feasible and associated with increased brain creatine in patients with AD. Methods/Study Population: Twenty participants with probable AD were allocated to an open-label, eight-week intervention of 20 g/day CrM. Fasting blood draws were taken at baseline, 4-, and 8-week visits to measure serum creatine (Quest Diagnostics). 1H magnetic resonance spectroscopy was performed at baseline and 8-week visits to measure brain Cr as a ratio to unsuppressed water. Self-reported compliance (with assistance from study partners) was assessed with daily CrM trackers. The mean compliance percentage across all participants was used to describe overall compliance with the intervention. We used paired t-tests to analyze the mean changes in serum Cr levels from baseline to 4- and 8-week visits and the mean change in brain Cr from baseline to 8-week visits. Statistical significance was set at p<0.05. Results/Anticipated Results: Participants were 65% male with a mean age of 73.1±6.3 years. All participants completed the study, with 19 out of 20 achieving the dose compliance target of ≥80%. The mean self-reported dose intake was 90%. Serum Cr levels were significantly increased at 4- and 8-week visits compared to baseline (0.6±0.4 mg/dL vs. 14.0±9.9 mg/dL and 15.0±13.6 mg/dL, respectively; p<0.001). Brain Cr levels also significantly increased (330.5±36.80 i.u. vs. 366.9±57.52 i.u., p<0.001). Discussion/Significance of Impact: We are the first to demonstrate that 20 g/day of CrM for eight weeks is feasible and associated with increased brain Cr in patients with AD. Our findings support further investigation of brain target engagement of CrM and its efficacy in AD. With AD cases expected to rise, CrM could serve as an effective, affordable therapeutic to slow AD progression.

Objectives/Goals: Youth with IBD have preventive, psychosocial, and acute care needs beyond those of peers, yet receipt of services does not match those needs. Our objectives are to assess the feasibility of (1) an individualized care plan intervention to improve perceived and measured care quality and (2) a pragmatic trial design embedded in pediatric IBD practice. Methods/Study Population: This is a pilot rollout-design randomized trial (n = 60) at a regional academic medical center. Eligible patients are 13–19 years old with IBD for at least 3 months and scheduled for a follow-up visit during the trial. Research staff recruits from one cluster at a time until goal enrollment (14–16). Enrollees are randomized 1:1 to intervention (MyIBD now) or control (MyIBD after the trial). MyIBD combines a tabular summary of individualized acute, chronic, and preventive care needs with nurse facilitator support for patients to use the information. Surveys at baseline, 6 and 12 months measure care quality (Patient Assessment of Chronic Illness Care scale, vaccines, health services) and patient self-management skills (Partners in Health scale). Implementation outcomes are collected via chart review. Results/Anticipated Results: To date, 44 subjects have been randomized. Among subjects, the mean age is 16 years; 73% have Crohn’s disease, 77% have commercial insurance, 75% receive anti-TNF therapy, and 14% live in a rural area. Mean baseline perceived care quality (PACIC scale) is 76.9 (sd 16.3; out of 100); mean baseline perceived self-management skill (PIH scale) is 78.1 (sd 13.4; out of 96). On objective care quality measures, 59% have completed the HPV vaccine series, 32% have received an additional pneumonia vaccine; in the past year 68% have had a screening for mood disorders, 20% an emergency department visit for IBD, and 18% an IBD hospitalization. To date, the IBD clinical team has achieved 100% completion (intervention subjects receive MyIBD plus nurse facilitation) and 0% contamination (control subjects inappropriately receive MyIBD). Discussion/Significance of Impact: Study results to date support the feasibility of the pragmatic, embedded trial design and indicate opportunities for improvement in care quality as perceived by patients and as measured by common preventive and acute care quality indicators. An individualized care plan supported with nurse facilitation may improve pediatric IBD care quality.

Objectives/Goals: The goal of this poster is to 1) describe the development of a graduate certificate program for community-engaged research for health (CEnRH) in a Clinical and Translational Science Awards-funded institution; 2) describe the initial impact of the program; and 3) discuss strengths, implications, and potential improvements for the future. Methods/Study Population: The CEnRH graduate certificate is a 12-credit, postbaccalaureate program offered at the University of Cincinnati co-created by faculty from the Community Engagement and Translational Workforce Cores of the CCTST with community partners. The goal is to support learning about community-engaged research (CEnR) and enhances capacity for academic-community partnered research. Student demographics are collected as part of university registration. Quantitative course evaluations are collected each semester. Program evaluations including qualitative data are collected from students enrolled in the program during and upon completion of the certificate. Results/Anticipated Results: The CEnRH curriculum includes 3 existing courses/electives in the College of Medicine and Psychology and three new courses in social justice and action research methodologies. Notably, the committee advocated for a scholarship to cover tuition for the certificate program to promote access for community partners. Since the fall of 2022, 17 students have enrolled in the CEnRH program, including 9 Faculty/Staff within CCTST institutions, 2 University of Cincinnati PhD Students, 5 Fellows, and 1 Community Member (who receives the scholarship). Notably, 24% of these students are from underrepresented minority backgrounds. Impact and evaluation data, as well as lessons learned, will be presented. Future directions for the CEnRH program will also be discussed. Discussion/Significance of Impact: The CEnRH is an impactful program for trainees, faculty, and staff who are planning to conduct CEnR, while also strengthening research capacity among community partners and advocates. This certificate program may be especially valuable to academic researchers as more funding agencies require community and stakeholder engagement in their proposals.

Objectives/Goals: This study aimed to identify preferences for nutrient-dense foods with critical nutrients associated with reduced neuroinflammation and perinatal depression risk. Aim two evaluated the acceptability of daily intake and preparation methods of select foods in Black American pregnant and postpartum people living in food apartheid in St. Louis. Methods/Study Population: The study included a mixed-methods sequential explanatory design with data collection at the YWCA of Metro St. Louis during Early Head Start programming with 21 participants living in geographies with low grocery-to-convenience store ratios. We conducted an open-ended online survey to determine participants’ preferences for specific foods with high nutrient density. Food preferences were subjected to nutrient analyses using FoodData Central, and foods with the highest concentrations of critical nutrients associated with reduced neuroinflammation and perinatal depression risk were identified. We presented results during a focus group with participants who completed the survey and evaluated the acceptability of daily intake and preparation methods. Results/Anticipated Results: Preferred food choices with the highest concentrations of critical nutrients associated with reduced neuroinflammation and perinatal depression risk included dark red kidney beans, black beans, pinto beans, black-eyed peas, peanuts, almonds, pistachios, walnuts, pecans, carrots, spinach, red bell pepper, sweet potatoes, and salmon. Participant justifications for low acceptance of daily intake included allergic reactions, “dry” or “slimy” texture, undesirable taste or appearance, absence of cravings, preferring alternatives, complicated preparation methods, and financial tradeoffs. Participant justifications for high acceptance included desirable taste and texture, diverse modification and preparation options, and nutrient composition critical for anemia treatment. Discussion/Significance of Impact: The study identified nutrient-dense food preferences within a sample vulnerable to nutrient-poor alternatives and health consequences. Participant acceptance of nutrient-dense intake was contingent upon recipes fulfilling cravings, acceptance among persons preparing meals, and diverse options to prevent boredom with preparation methods.

Objectives/Goals: Our study’s objective is to evaluate RadOnc-GPT, a GPT-4o powered LLM, in generating responses to in-basket messages related to prostate cancer treatment in the Radiation Oncology department. By integrating it with electronic health record (EHR) systems, the goal is to assess its impact on clinician workload, response quality, and efficiency in healthcare communication. Methods/Study Population: RadOnc-GPT was integrated with patient EHRs from both hospital-wide and radiation-oncology-specific databases. The study examined 158 pre-recorded in-basket message interactions from 90 non-metastatic prostate cancer patients. Quantitative natural language processing analysis and two randomized single-blinded grading studies, involving four clinicians and four nurses, were conducted to evaluate RadOnc-GPT’s response quality in completeness, correctness, clarity, empathy, and estimated editing time. Response times were measured to estimate the time saved for clinicians and nurses. The study population included patient messages across all phases of care (pre-, during, and post-treatment) for those undergoing radiotherapy. Results/Anticipated Results: In the single-blinded grader study, clinician graders evaluated 316 responses (158 from human care teams and 158 from RadOnc-GPT). Results showed RadOnc-GPT outperformed human responses in empathy and clarity, while humans excelled in completeness and correctness. Sentiment analyses using TextBlob and VADER revealed RadOnc-GPT responses had a positive mean score of 0.25, whereas human responses clustered around neutral. VADER analysis indicated a high median score for RadOnc-GPT, nearing 1.0, reflecting predominantly positive sentiment, while human responses displayed a broader sentiment range, indicating sensitivity to context. Clinicians averaged 3.60 minutes (SD 1.44) to respond, compared to 6.39 minutes (SD 4.05) for nurses, highlighting RadOnc-GPT’s efficiency in generating timely responses. Discussion/Significance of Impact: RadOnc-GPT effectively generated responses to individualized patient in-basket messages, comparable to those from radiation oncologists and nurses. While human oversight is still necessary to avoid errors, RadOnc-GPT can speed up response times and reduce pressure on care teams, shifting their role from drafting to reviewing responses.

Objectives/Goals: This study aims to harmonize quality indicators (QIs) across University of Toronto-affiliated microbiology labs to establish universal benchmarks that enhance performance, patient safety, and health outcomes. Harmonized QIs will enable effective comparisons and enhance the consistency of care. Methods/Study Population: The study employed the Delphi method, a structured and iterative process to build consensus. An expert panel of clinical microbiology trainees, medical microbiologists, trainees, and site leads from five University of Toronto-affiliated microbiology labs was assembled. Initial insights were gathered through surveys and a comprehensive scoping review of the literature. The study involved two rounds of feedback, a SurveyMonkey-based survey, with a defined consensus of 75% agreement among participants. Followed by an implementation survey conducted through REDCap to assess how these QIs were adopted in practice and identify barriers to implementation. Results/Anticipated Results: The study achieved consensus on nine high-impact quality indicators, including blood culture volume and contamination rates, cerebrospinal fluid transport time, and turnaround times for Gram stain results. Blood culture contamination and positivity rates garnered the highest agreement, at 100% and 91%, respectively. While some indicators were widely accepted and implemented, others faced resistance due to feasibility concerns. The study also identified significant variability in the level of adoption across the participating laboratories, pointing to operational challenges and the need for further efforts to address these barriers. Discussion/Significance of Impact: This study highlights the importance of QI harmonization in improving lab services and patient safety. It reveals challenges in standardizing practices but promotes uniformity in QIs, laying the groundwork for better inter-lab collaboration, consistent outcomes, and improvements in microbiology.

Objectives/Goals: We investigate how the gut microbiome protects against arsenic toxicity, showing antibiotic perturbation increases toxicity and causes interindividual susceptibility to a sepsis-like disease state in mice. Here, we aim to understand how baseline microbiomes from various mouse vendors impact these outcomes and characterize the observed disease. Methods/Study Population: We developed a novel mouse model where mice are exposed to an antibiotic (cefoperazone) for 2 days, followed by co-exposure to the antibiotic and 100 ppm arsenate. So far, we have evaluated C57BL/6N mice from MSU’s in-house colony, Taconic Biosciences (TAC), and Jackson Labs (JAX), along with C57BL/6J mice from JAX. To determine if the baseline microbiome drives inter-vivarium differences, we established in-house breeding colonies of TAC- and JAX-origin mice at MSU. This allowed us to assess whether, when housed under identical conditions, these mice still show differences in mortality based on their original microbiomes. To characterize the arsenic-induced sepsis-like disease, we performed blood biochemistry assays to quantify the white blood cell populations, and sepsis biomarkers used in clinical settings. Results/Anticipated Results: We observed differences in survival rates between genetically identical mice from MSU (45%), TAC (30%), and JAX (2.5%) in our model. From this, we characterized the baseline composition of the gut microbiomes of these mice and found they were significantly different from each other. We are still awaiting results from our in-house TAC and JAX experiments but expect them to have similar gut microbiome compositions to those directly purchased from TAC and JAX and respond similarly. In our blood biochemistry analysis, we found sick mice presented with low WBC counts and notable biomarkers indicative of liver, heart, and kidney distress. We also anticipate that 16S sequencing results of cecal contents will further support findings by providing evidence of a bacterial infection in the ceca of sick mice. Discussion/Significance of Impact: Collectively, our work demonstrates that antibiotic perturbation of the gut microbiome induces an inter-individual and inter-vivarium susceptibility to an arsenic-induced sepsis-like disease state. This work highlights the importance of considering antibiotic use in the risk assessment of arsenic to better protect the health of those exposed.

Objectives/Goals: To assess the feasibility, safety, and preliminary efficacy of implementing a supervised, outpatient aerobic and strength exercise regimen in newly diagnosed pediatric patients with acute lymphoblastic leukemia (ALL). We hypothesize that early implementation of exercise is feasible and may prevent well-known cardiometabolic late effects. Methods/Study Population: We will enroll 10–20 children (both males and females) with newly diagnosed ALL between the ages of 11–21 years to participate in a 12-month supervised, structured outpatient exercise regimen (STRONGER ALL). This regimen will consist of low- to moderate-intensity aerobic and strength exercises (either in person or coached virtually per patient preference) 3 times a week. This study will include 2 physical fitness assessments: 1) baseline and 2) end of study. Assessments will include resting energy expenditure, peak oxygen uptake, bone density, upper and lower extremity strength, flexibility, and questionnaires (feasibility and quality of life). Additionally, blood and urine specimens will undergo metabolomic analysis to identify biomarkers predictive of future cardiometabolic outcomes. Results/Anticipated Results: We expect that early implementation of STRONGER ALL in children undergoing chemotherapy will be feasible and preliminarily effective at mitigating risk factors for long-term cardiometabolic outcomes in survivors. Feasibility will be defined by recruitment capability (at least 50% of eligible patients agree to enroll), acceptance/compliance (at least 50% of participants complete the program with participation in at least 50% of sessions), data acquisition (collection and outcomes measures are appropriate), and practicability (program shows promise of being successful with pediatric ALL patients as measured by validated surveys administered to patients and caregivers). We anticipate that ALL patients participating in STRONGER ALL will have improved fitness and quality of life. Discussion/Significance of Impact: Evidence on the benefits of physical activity for ALL patients has not changed clinical practice. We aim to overcome the translational science barrier of patient- and system-level blockade in implementation of exercise in children with ALL. The evidence generated from this research may also be generalizable to other childhood cancer survivors.

Objectives/Goals: Present a framework for hosting Community Grand Rounds, where community and academic partners showcase completed community-engaged research (CEnR) projects. This highlights innovative dissemination methods, engages diverse audiences, elicits community responses, and advances the translational science of CEnR. Methods/Study Population: Our approach involves planning and outreach to collaborate with promotion of academic and community engaged grantees to develop community dissemination events that translate the science of CE into accessible, relatable, culturally relevant formats for diverse audiences. These events incorporate interactive presentations that encourage active participation and feedback from attendees. Following each event, an evaluation is completed to assess community impact. Key strategies for hosting, facilitating, and utilizing diverse marketing to ensure that events are tailored to culturally diverse community groups, including regional implementation when practical. This collaborative approach meets a critical need and strengthens the bond between researchers and the communities they aim to serve. Results/Anticipated Results: These events create a feedback loop between the community and academic researchers. It was not just about telling people what was found. We created opportunities for community members and academics to build trust, give us feedback, ask questions, and discuss how findings could be practically applied. By presenting the findings in an accessible way within the community, community members are more informed and empowered to make decisions or advocate for changes in their own lives based on the research. Academics also benefited from community feedback, which provided new insights to help refine future research questions and methods. The goal is for shared conversation and understanding between community members and academics to inspire real-world applications and policy change directly informed by the research. Discussion/Significance of Impact: Community Grand Rounds are one dissemination strategy to leverage community–academic collaboration to present tailored research, fostering engagement, understanding, and action between researchers and community members. This approach effectively enhances the translational science of CEnR by involving and benefiting the community.

Objectives/Goals: This qualitative study evaluated facilitators and barriers to clinical research participation among lower-income, predominately racial/ethnic minority communities to inform a Co-Learning series. The Co-Learning series of community members, stakeholders, and researchers developed strategies to improve diversity in research. Methods/Study Population: Community focus group (FG) participants were recruited from urban communities experiencing poverty, whereas stakeholder FGs included diverse community leaders and researchers. The Social Ecological Model was used as the guiding theoretical framework throughout the qualitative design. Directed content analysis using three independent coders reaching 100% consensus identified prominent factors for increasing diversity in research. The co-learning series was comprised of community members, stakeholders, and researchers who discussed the prominent FG factors over seven in-person meetings to develop a toolkit to increase diversity in research. Results/Anticipated Results: Community (n = 51) and stakeholder (n = 50) FG participants were 54.0±16.0 years of age, 81.2% female, 39.6% Black/African American, 51.5% Hispanic, and 60% had Discussion/Significance of Impact: Due to the lack of inclusivity in clinical research, findings are typically not applicable to health disparity populations limiting the benefit of research to all. This study provides practical community-driven strategies to increase diversity in clinical research, highlighting the role of trust, relationships, and cultural relevancy.

Objectives/Goals: To determine the heterogeneity in CD4:CD8 ratio in a well-characterized cohort of PWH and to investigate the predictors of intestinal CD4:CD8 ratio reconstitution (CD4:CD8>1) and its impact on systemic inflammation. Methods/Study Population: We enrolled 52 PWH on ART and with peripheral HIV-RNA Results/Anticipated Results: PWH had a lower CD4:CD8 ratio both in the peripheral blood [p1. This subset of PWH was more likely female (62% vs. 38%, p = 0.0158), diagnosed with HIV for a longer time [p = 0.0347] have longer duration of most recent viral suppression [p = 0.0365] higher CD4+ T cells at enrollment [p =  0.0262] and higher CD4+ T cell nadir. Multiple logistic regression showed that duration of HIV infection [OR 1.13 (95% C.I. 1.02–1.3)] and CD4 =  T cell nadir[OR 1.01 (95% C.I. 1.001–1.016)] were associated with colonic CD4:CD8 >1. Colonic CD4:CD8 ratio partially correlated with the peripheral blood CD4:CD8 ratio (r = 0.274, p = 0.068) and with the pro-inflammatory cytokines IL-20 (r =  -0.413, p = 0.036) and SLAMF-1 (r =  -0.329, p = 0.074). Discussion/Significance of Impact: In PWH, CD4:CD8 ratio

Objectives/Goals: Adolescence is a critical period where brain networks are thought to be influenced by environmental factors. This presentation examines violence exposure’s impact on brain connectivity and identifies potential protective factors. Methods/Study Population: A secondary data analysis was conducted using data from a subsample of the Adolescent Brain Cognitive Development Study (release 5.1). Youth who completed victimization questionnaires at two time points were eligible for inclusion, resulting in 2016 participants. Linear regression was utilized to analyze associations between violence exposure measured by the juvenile victimization questionnaire and functional connectivity of specified regions of interests using the Gordon functional parcellation for cortical regions and the Freesurfer parcellation for subcortical regions. Moderation analysis will be utilized to assess the effects of peer and caregiver support on the associations between violence exposure and functional connectivity, currently ongoing. Results/Anticipated Results: Between 18 and 59% of the sample reported experiencing at least one form of violence exposure, with racial differences noted in missing versus complete data. Multiple domains of violence and cumulative exposure were associated with both increased and decreased functional connectivity across within-network, between-network, and network-subcortical regions. At baseline, internet violence was linked to lower within-network connectivity, while peer victimization was associated with higher connectivity at both baseline and follow-up. Between network analysis showed lower connectivity with witnessing violence at baseline and higher connectivity with internet victimization at follow-up. Discussion/Significance of Impact: These findings emphasize the need for further exploration of the underlying mechanisms that link violence exposure to developmental trajectories and identification of protective factors such as caregiver and peer support, to inform interventions and promote resilience in affected youth.