Objectives/Goals: pT217-tau is a novel fluid biomarker that predicts onset of Alzheimer’s disease (AD) symptoms, but little is known about how pT217-tau arises in brain, as soluble pT217-tau is dephosphorylated postmortem in the humans. Aging macaques naturally develop tau pathology with the same qualitative pattern and sequence as humans, including cortical pathology. Methods/Study Population: The etiology of pT217-tau in aging brains can be probed in rhesus macaques, where perfusion fixation allows capture of phosphorylated proteins in their native state. We utilized multi-label immunofluorescence and immunoperoxidase and immunogold immunoelectron microscopy to examine the subcellular localization of early-stage pT217-tau in entorhinal cortex (ERC) and dorsolateral prefrontal cortex (dlPFC) of aged rhesus macaques with naturally occurring tau pathology and assayed pT217-tau levels in blood plasma using an ultrasensitive nanoneedle approach. Results/Anticipated Results: pT217-tau labeling is primarily observed in postsynaptic compartments, accumulating in: 1) dendritic spines on the calcium-storing smooth endoplasmic reticulum spine apparatus near asymmetric glutamatergic-like synapses and 2) in dendritic shafts, where it aggregated on microtubules, often “trapping” endosomes associated with Aβ42. The dendrites expressing pT217-tau were associated with autophagic vacuoles and dysmorphic mitochondria, indicative of early neurite degeneration. We observed trans-synaptic pT217-tau trafficking between neurons within omega-shaped bodies and endosomes, specifically near excitatory, but not inhibitory synapses. We also examined pT217-tau in blood plasma in macaques across age-span and observed a statistically significant age-related increase in pT217-tau. Discussion/Significance of Impact: We provide direct evidence of pT217-tau trafficking between neurons near synapses to “seed” tau pathology in higher brain circuits, interfacing with the extracellular space to become accessible to CSF and blood. The expression of pT217-tau in dendrites with early signs of degeneration may help to explain why this tau species can herald future diseases.

Objectives/Goals: The University of Minnesota (UMN) CTSI and Medical School sought to increase the diversity of translational research-intensive faculty by recruiting highly promising new-to-UMN tenure track faculty in the Medical School. Increased resources and career development will increase recruitment and address barriers to their promotion and success. Methods/Study Population: In 2019, the Medical School Dean committed to fund 15 Early Career Research Awards (ECRA) Scholars to recruit outstanding new-to-UMN, tenure track faculty. Supplementing usual departmental recruitment packages, ECRA Scholars receive: 75% salary and fringe benefit support for 3 years; an additional $500,000 of research funds; and augmented mentoring and coaching with required participation in the relevant CTSI career development program. Department Chairs propose meritorious candidates for Review Committee consideration based on the Chair nomination letter, scientific plan, mentoring plan, CV, and additional letters of recommendation. To foster community building, there is an annual mini-retreat for the ECRA Scholars and other underrepresented CTSI Scholars with an external visiting professor. Results/Anticipated Results: Fifteen tenure-track faculty have been recruited as ECRA Scholars since 2019 into 9 different departments. One additional Scholar has been accepted and three have completed the program. Three ECRA Scholars were K awardees at the time of recruitment. The CTSI career development programs utilized were the K Accelerator (10), KL2 Scholar (2), and K-R01 (5) Programs, with 3 involved in two programs. The Scholar degrees include 10 PhDs, 3 MD/PhDs, and 2 MDs, with additional MPH/MS (5), MSW (1), and DPT (1) degrees. ECRA Scholars have been awarded multiple NIH R21, Foundation, and internal grants currently under review include Ks and R01s with 5 additional K, 2 new R01, and 1 revised R01 submissions planned for the 2024–2025 academic year. Discussion/Significance of Impact: The ECRA program has successfully augmented recruitment of outstanding underrepresented research-oriented early-stage faculty to the University of Minnesota School of Medicine, contributing to many Departments. The CTSI has provided career development, networking, and a broader community of Scholars, with increased diversity in CTSI programs.

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: Pregnancy increases vulnerability to stress and mental health symptoms, particularly among Hispanic women in Puerto Rico (PR), a population with unique socioenvironmental adversities, such as poverty and natural disasters. This study examined the relationships between life adversities and psychological distress in this at-risk population. Methods/Study Population: Participants (n = 50) in this cross-sectional study were recruited from an obstetrician’s office in Southern PR. All participants provided written consent and completed the Adverse Life Experiences Scale (ALES, Cronbach’s alpha = 0.71) to identify lifelong adversities faced and the overall duration (chronicity). Measures of psychological distress included the Perinatal Anxiety Screening Scale (PASS, Cronbach’s alpha = 0.96), the Edinburg Postnatal Depression Scale (EDPS, Cronbach’s alpha = 0.87), the Perceived Stress Scale (PSS, Cronbach’s alpha = 0.79), and the Brief Resilience Scale (BRS, Cronbach’s alpha = 0.86). Descriptive and Spearman’s rho correlation analyses were conducted. Results/Anticipated Results: The mean age of the participants was 27.90 years (SD = 6.05), with most in the first trimester (66.0%). On average, participants reported 4.32 (SD = 3.1) out of 23 lifetime adversities. The most common adversities were natural disasters (60.0%), loss of a beloved (58.0%), and financial difficulties (38.0%). Nearly half (44.0%) experienced five or more adversities. A significant number of participants met the clinical threshold for anxiety (38.0%, PASS), depression risk (22.0%, EPDS), moderate-to-severe perceived stress (52.0%, PSS), and low resilience (24.0%, BRS). The overall duration of adversities was significantly associated with anxiety (rs = 0.50, p = 0.001) and stress (rs = 0.50, p = 0.007). Discussion/Significance of Impact: Hispanic pregnant women in PR face high levels of adversity and distress, which can negatively affect both maternal health and fetal development, influencing long-term child outcomes. Early identification and targeted interventions addressing adversities, can improve maternal mental health and child health-development outcomes.

Objectives/Goals: To design a flexible, comprehensive framework for Data Science Units to cultivate sustainable, long-term relationships with Clinical and Translational Science Research Units. Best practices for managing Data Science collaborations are presented to improve the quality and efficiency of research conducted throughout academic health centers. Methods/Study Population: Leaders of Data Science Units across six institutions formed a workgroup to develop guidance and best practices for Data Science Units to establish long-term, sustainable collaborations with Clinical and Translational Science Research Units. This guidance is based on tools and protocols developed and employed by the participating units, which range from larger groups with over 20 partnerships to a unit with three partnerships that is actively working to expand. Importantly, partnerships are highly variable, with some partnerships at one institution representing engagement with over 500 faculty, whereas some partnerships at another institution involve the lab of a single investigator. Results/Anticipated Results: We offer guidance in three domains: (1) Identifying the needs for a new partnership, including assessing required effort and data science expertise, setting partnership priorities, developing formal agreements, and identifying goals and metrics; (2) managing data science teams by implementing regular meetings, creating project intake and prioritization processes, and effort monitoring; and (3) evaluating the successes and failures/gaps of the collaboration by measuring the metrics mapped to the goals. For each domain, we provide specific suggestions on which parties should be involved and how frequently the processes should occur. This guidance is applicable both to larger collaborative partnerships and to smaller, single faculty or staff partnerships, whether they are new or well-established. Discussion/Significance of Impact: Effective collaboration between data scientists and clinical and translational investigators is key to advancing data-driven research. The guidance and resources are presented to support Data Science Units in successfully managing long-term collaborations through goal-development, evaluation, and adapting to evolving research needs.

Objectives/Goals: Primary sclerosing cholangitis (PSC) manifests with an inflammatory milieu that leads to fibrotic scarring of the liver. Human PSC liver bile ducts are enriched with neutrophils; however, their infiltration and functional role is unexplored. Our goal is to investigate the mechanism and impact of peribiliary neutrophil infiltration observed in PSC. Methods/Study Population: Primary cholangiocytes (bile duct cells) isolated from WT and mouse models of PSC (3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-fed mice and Mdr2-/- mice) were analyzed by RNA-sequencing. Immunofluorescence (IF) was performed on liver tissues from PSC patients and mouse models of PSC for markers of bile ducts and neutrophils (KRT19 and MPO). Intrahepatic leukocytes (IHL) isolated from mice livers were evaluated for neutrophil abundance and activation state. Anti-Ly6G antibody-mediated neutrophil depletion in Mdr2-/- mice was analyzed by IF, histology, and cytometry by time-of-flight (CyTOF). Cholangiocytes stimulated with TNFα (to induce an inflammatory phenotype) were analyzed for neutrophil chemoattractants with genetic and pharmacological interventions. Results/Anticipated Results: RNA-seq analysis of primary cholangiocytes from PSC mouse models revealed enrichment in inflammatory and neutrophil degranulation pathways. Flow cytometry and RT-PCR analysis revealed an increase in the neutrophil population in PSC mice with activated phenotype. Peripheral depletion of neutrophils in Mdr2-/- mice alleviated liver injury and inflammation, along with a reduction in peribiliary neutrophil infiltration and attenuated bridging fibrosis. CyTOF analysis showed a significant reduction in CD8+ T cells upon neutrophil depletion, implying neutrophils sustain CD8+ T cells in PSC liver. Mechanistically in cholangiocytes, TNFα mediates expression of neutrophil chemoattractants, CXCL1 and CXCL8, through the cyclic GMP-AMP synthase stimulator of interferon genes (cGAS-STING) pathway. Discussion/Significance of Impact: Our findings suggest that activation of the STING pathway in cholangiocytes in cholestatic liver disease triggers an immune response resulting in peri-portal neutrophil infiltration via CXC chemokines. The sustained presence of these activated neutrophils engages the adaptive immune system to perpetuate the inflammation and fibrosis seen in PSC.

Objectives/Goals: This study aims to uncover immuno-endotypes in sepsis-associated pediatric acute respiratory distress syndrome (SA-PARDS) by using single-cell RNA sequencing (scRNA seq) to analyze the immune cell populations of the lower respiratory tract of intubated pediatric subjects with SA-PARDS. Methods/Study Population: Inclusion criteria are age less than 18 years, admission to the PICU, diagnosis of SA-PARDS, and intubation. Both sepsis and PARDS will be defined using the most recent consensus definitions. Exclusion criteria include an order of limited resuscitation and clinician discretion. After informed consent is obtained, a tracheal aspirate and blood sample will be obtained on days 1, 3, and 7. Both samples will be processed for single-cell RNA seq via the HIVE platform per manufacturer protocol. cDNA libraries will then be sent for 150 base pair paired-end sequencing. Sequences will be aligned to a reference genome, and count matrices will be generated. The Seurat package in R will be used for cell-type annotation and analysis of differential gene expression. Clinical variables, labs, and outcomes will be recorded in REDCap. Results/Anticipated Results: We expect to find that subjects with nonresolving SA-PARDS, defined as intubation and mechanical ventilation, will have a monocyte/macrophage transcriptome characterized by continued hyper-inflammation (M1-like phenotype) that does not transition over time to an anti-inflammatory and pro-repair phenotype (M2-like). Additionally, we expect to see that subjects with non-resolving SA-PARDS will have evidence of continued inflammation driven by hyper-inflammatory neutrophils. Finally, we expect that subjects with non-resolving SA-PARDS will have epithelial cells characterized by continued upregulation of canonical pathways of innate immunity including interferon signaling and the damage associated molecular pattern recognition pathway. Discussion/Significance of Impact: The discovery of immuno-endotypes in SA-PARDS would represent a major step toward developing precision medicine therapies for this group of patients. It would simultaneously provide a strategy to reduce biological heterogeneity and identify novel pathways and targets for therapy.

Objectives/Goals: The standard care for malignant gliomas includes maximal tumor resection, but challenges arise near functional (speech) areas. Direct cortical stimulation (DCS) identifies functional (nonresectable) cortex. We aim to identify electrophysiologic (via subdural electrode recordings [ECOG]) biomarkers of DCS-positive (functional) areas. Methods/Study Population: Our lab maintains one of the largest datasets of electrophysiology analysis of glioma infiltrated brain cortex in the USA. Recordings of intraoperative brain mapping were analyzed to identify cortical sites that were found to be positive (functional) during DCS. DCS positive and negative (nonfunctional) sites were aligned to corresponding subdural electrodes. Future analysis: We plan to compare the temporal and spectral electrophysiologic variations associated with cortical sites found to be DCS positive versus negative during brain mapping. We plan to train machine learning classifiers that utilize these electrophysiologic biomarkers to discriminate between DCS positive and negative sites. Results/Anticipated Results: In total, our database comprised of 110 resections with brain mapping (DCS) and ECOG, including 4 patients who underwent a second procedure for resection. Eight patients were excluded as their resections were for brain metastases, not glioma. Our final cohort was comprised of 98 glioma resections, including 4 patients who underwent surgery twice for recurrence. During these resections, a total of 1393 sites were mapped via DCS for language function (including picture naming, word reading, and sentence syntax tasks). Of these 1393 sites, 100 sites were found to be DCS positive (7.1% positivity rate). (Currently in the process of conducting analysis comparing electrophysiologic features and biomarkers of DCS positive versus negative sites.) Discussion/Significance of Impact: This research is ongoing. Identifying electrophysiologic biomarkers of critical DCS-positive regions may provide a durable alternative to stimulation mapping. Due to its resource intensity, DCS has access barriers. Future neurosurgeons may use biomarkers from subdural electrode recordings to plan safer cortical resections.

Objectives/Goals: Lung transplant is a life-saving surgery for patients with advanced lung diseases yet long-term survival remains poor. The clinical features and lung injury patterns of lung transplant recipients who die early versus those who survive longer term remain undefined. Here, we use cell-free DNA and rejection parameters to help elucidate this further. Methods/Study Population: Lung transplant candidacy prioritizes patients who have a high mortality risk within 2 years and will likely survive beyond 5 years. We stratified patients who died within 2 years of transplant as early death (n = 50) and those who survived past 5 years as long-term survivors (n = 53). Lung transplant recipients had serial blood collected as part of two prospective cohort studies. Cell-free DNA (cfDNA) was quantified using relative (% donor-derived cfDNA {%ddcfDNA}) and absolute (nuclear-derived {n-cfDNA}, mitochondrial-derived {mt-cfDNA}) measurements. As part of routine posttransplant clinical care, all patients underwent pulmonary function testing (PFT), surveillance bronchoscopy with bronchoalveolar lavage (BAL), transbronchial biopsy (TBBx), and donor-specific antibody testing (DSA). Results/Anticipated Results: Over the first 2 years after transplant, the number of episodes of antibody-mediated rejection (p) Discussion/Significance of Impact: Clinically, early-death patients perform worse on routine surveillance PFTs and experience a worse degree of CLAD. These patients also have higher levels of cfDNA as quantified by n-cfDNA and mt-cfDNA. These results provide preliminary evidence that early-death patients have worse allograft rejection, dysfunction, and molecular injury.

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: Substantial evidence supports the use of community engagement in CTS. Yet, there is a lack of empirical basis for recommending a particular level of community engagement over others. We aimed to identify associations between level of community involvement and study process outcomes, focusing on procedures to promote enrollment and inclusion. Methods/Study Population: Using manifest content analysis, we analyzed community engagement (CEn) strategies of studies indexed in ClinicalTrials.gov, focusing on studies 1) associated with 20 medical schools located in 8 southern states in the Black Belt, 2) conducted in 2015–2019, and 3) on 7 topics: cancer, depression, anxiety, hypertension, substance use disorder, cardiovascular disease, and HIV/AIDS. Data source was the ClinicalTrials.gov entry and publication for each study. We categorized each study on level of community involvement as described by the study protocol CTSA Consortium Community Engagement Key Function Committee Task Force on the Principles of Community Engagement continuum. Outcomes included recruitment and representativeness. Other codes included funder type, study phase, study status, and time to enrollment. Results/Anticipated Results: Of 890 studies that met inclusion criteria, only 493 had published findings. 286 studies (58%) met enrollment targets. Only 9 studies described any level of CEn (1 outreach, 3 consult, 1 involvement, 3 collaboration, and 1 shared leadership). Time to enrollment for these 9 studies (mean 28.78 mos.) was shorter than for studies without CEn (mean 37.43 months) (n.s.). CEn studies reached significantly higher enrollment (CEn mean  = 2395.11, non-CEn mean  = 463.93), p Discussion/Significance of Impact: Results demonstrate the substantial effect of CEn on enrollment and inclusion in clinical studies. However, the infinitesimal number of studies that reported CEn did not allow comparisons of level of engagement on the outcomes. Findings highlight ethical questions surrounding the lack of publishing incomplete studies.

Objectives/Goals: This study aims to evaluate diversity of participants in GLP-1 T2DKM clinical research with regard to sex, race, and ethnicity by using results data available through the ClinicalTrials.gov database. Sample population estimates for studies were calculated using the 2020 Census and compared within groups with respect to sex, race, and ethnicity. Methods/Study Population: The public ClinicalTrials.gov database was searched for interventional studies with GLP1 inclusion as treatment (n = 2,397). This search was then filtered to studies where results were reported (n = 772). From these studies, 466 studies focused on type 2 diabetes as a condition and thus became the analysis dataset. Participant and protocol information for these 466 studies were obtained from the clinical trials transformation initiative (CTTI) as an AACT data download. Observed to expected ratios were calculated for each subgroup-based population estimates from the 2020 Census and using the baseline counts of participants for studies where sex, race, and ethnicity were provided. In addition to within group comparisons, study characteristics (e.g. phase) were included in models to assess influence of covariates. Results/Anticipated Results: Of the 466 studies, 430 (92%) reported sex, 171 (37%) reported race, and 145 (31%) reported Hispanic ethnicity. Among those found to be underrepresented in studies (defined as a ratio < 1): females (mean  =  0.89, median  =  0.92); Black/African Americans (mean  =  0.88, median  =  0.39). Hispanic or Latinos mean ratio was 1.16 (95% CL: 0.97, 1.35) but had the least available data. When including covariates in the models, there were statistically significant differences in ratios with respect to sex as females had significantly lower odds compared to males (ratio > =  1), with the odds being about 21% of those for males. With respect to race, Black or African American individuals had significantly lower odds (about 32% of those of White individuals) (ratio > =  1). Discussion/Significance of Impact: This study reveals significant underrepresentation of females (mean ratio 0.89) and Black/African Americans (mean ratio 0.88) in clinical trials for GLP-1 drugs in type 2 diabetes. These disparities highlight the need for more inclusive research to ensure diverse populations benefit equally from medical advancements.

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: This study tests how fiber microstructural integrity and myelination levels within the cingulum connectome are associated with information processing speed (IPS) in relapsing-remitting multiple sclerosis (RRMS). We investigate the functional impact of structural coherence, myelin content, and white matter hyperintensities (WMH) load on IPS. Methods/Study Population: Data from 63 RRMS and 25 healthy controls (HC) were used. We hypothesize that the structural integrity of the cingulum bundle and its structural network – or connectome – is distinctly associated with IPS function in people with RRMS (vs. HC) due to myelin-related plasticity across the wiring. Using diffusion spectrum imaging and high-resolution tract segmentation, we constructed individualized white matter connectomes. Diffusion quantitative anisotropy (QA) and myelin fractions (MWF) were used to quantify structural coherence and myelination. WMH load was measured with T2-FLAIR imaging. Bayesian–Pearson correlations, mixed-linear, and moderation models explored how fiber-specific QA, MWF, and WMH load relate to IPS function in RRMS, as measured by Symbol Digit Modalities Test (SDMT). Results/Anticipated Results: We theorize that (1) QA in the cingulum connectome correlates with SDMT performance dimensionally, indicating that structural coherence in the white matter supports IPS function among both groups; (2) increased myelination will strengthen the positive association between QA and SDMT scores, suggesting that connectome-specific myelin content facilitates IPS; (3) conversely, WMH load within the cingulum connectome is expected to inversely correlate with SDMT scores, reflecting the detrimental impact of lesion burden on IPS function; (4) myelination in specialized tracts within the cingulum connectome play a compensatory role to support IPS function in the RRMS group. These investigations can offer a mechanistic clue to potential neuroplastic targets for cognitive interventions in MS. Discussion/Significance of Impact: By linking white matter integrity to cognitive function at the connectome level, this study can support neuroregenerative strategies to mitigate cognitive burden in RRMS. Our findings may advance understanding of how structural coherence, tract myelination, and WMH affect IPS, shaping personalized prognostic and therapeutic interventions.

Objectives/Goals: Trainees in clinical and translational science (CTS) take courses in biostatistics, epidemiology, and other quantitative areas. To be most successful, trainees require competency in algebra. We developed a quantitative assessment and study guide to assess trainee’s quantitative skills and provide review material to address weaknesses. Methods/Study Population: The Tufts CTS Graduate Program is the training core of the Tufts CTSI and its associated pre- and post-doctoral T32 awards. Approximately 10 trainees with a range of backgrounds (e.g., physicians, medical students, master’s-level researchers, and basic science PhDs) and varying math education experiences matriculate each year. We wanted to address the resulting range of quantitative skills to help students succeed in our program. In Spring 2023, we met with faculty teaching quantitative courses to identify core algebra concepts needed to succeed in their classes. A graduate student in computational mathematics with extensive tutoring experience then drafted assessment questions, a comprehensive study guide, and brief cheat sheet. The material was reviewed and revised with input from quantitative faculty. Results/Anticipated Results: We developed a 20-item quantitative assessment covering properties of operators; identity elements and inverses; simplification of arithmetic and algebraic expressions; solving algebraic equations; functions; equations of a line; and exponents/logarithms. A cheat sheet provided trainees with a brief refresher for these topics. A study guide provided more detailed instruction, example exercises and solutions, and referenced publicly available, online resources (e.g., Khan Academy). During the introductory summer course for the Tufts CTS Program, trainees were allowed to use the cheat sheet and were given 1 hour to complete the assessment. Trainees who got questions incorrect were directed to relevant sections in the study guide. We anticipate collecting formal feedback to evaluate the material. Discussion/Significance of Impact: Trainees must have adequate foundational algebra skills to succeed in CTS graduate programs and as future researchers. Developing a quantitative assessment allowed us to identify areas of weakness resulting from educational disparities or reflecting other aspects of their backgrounds and to provide material to reinforce their preparation.

Objectives/Goals: To screen community members for prediabetes and diabetes in the grocery stores located in urban areas, identify gaps in healthcare access, promote healthy food, teach participants about diabetes prevention and management, and learn from them via interactive community-based educational sessions. Methods/Study Population: 303 Tops Friendly Market customers in urban Buffalo, NY participated in this program. Customers without a diabetes diagnosis took a CDC Prediabetes Risk Test (score >5  =  prediabetes risk). Those with a previous diabetes diagnosis took a survey about their diabetes knowledge/management, healthcare access, and social determinants of health. Participants received a $5 voucher for fruit and vegetables. We conducted 5 educational sessions using an adult learning, participatory education approach. A $10 gift card was given for attendance. Participants shared questions/concerns and strategies to overcome barriers. We answered questions and collected information on barriers to diabetes care. Results/Anticipated Results: Seven-six participants (25%) had a diabetes diagnosis. Of these, 91% saw a doctor every 3 months, but 28% did not know the importance of HbA1c. 18% had trouble paying for medications, 15% had inadequate transportation. 227 took the Prediabetes Risk Test: 58% had a score >5, 47% had diabetes family history, 51% had hypertension, and 75% had a BMI that put them at risk for diabetes. 86% of those with a score5. 55 people (34 unique) participated in 5 sessions. We actively listened to diabetes perceptions, concerns, successes and barriers/facilitators to self-management, and discussed diabetes management strategies for heathier eating and lifestyle. Discussion/Significance of Impact: It is feasible to screen for health conditions in the supermarket setting, which can be an equalizer in enhancing access to healthcare. This study helped identify gaps in care and provided education. Importantly, people receiving this intervention lived in the poorest neighborhoods in Buffalo.

Objectives/Goals: Physical therapy (PT) is a recognized and evidence-based component of oncology care that has been shown to benefit people with various cancers, such as breast, lung, head and neck, thyroid, or prostate cancer. The goal of this evaluation was to determine the level of PT service utilization by World Trade Center (WTC) Health Program members with cancer. Methods/Study Population: The Program is a limited benefits federal program that serves responders and survivors of the September 11th attacks in New York City, the Pentagon, and Shanksville PA. Our analyses include enrolled Program members with a cancer certification. Cancer types were divided into two categories, Category A (breast, lung, head and neck, thyroid, or prostate cancer) and Non-Category A (all other cancer types). Data included medical claims, certification, and enrollment data from July 2011 to December 2023. The 2023 Current Procedural Terminology (CPT) code list from the Centers for Medicare and Medicaid Services were used to identify claims associated with PT interventions. Our analyses describe trends in PT claims, CPT codes, cancer certifications by subtype, and number of members with Category A cancers and PT claims. Results/Anticipated Results: Since the Program’s inception in 2011, PT claims had gradually increased except for in 2020 when there was a sudden decrease, most likely due to the interruption of in-person services due to the COVID-19 pandemic. From 2021 to 2023, PT claims began to increase again. The most common types of PT interventions were therapeutic exercises, manual therapy, and neuromuscular reeducation. In 2023, the most recent year of full data available, Category A cancers made up 38% of all cancer certifications, with prostate and breast cancer being the most common. Category A cancers were evaluated together due to prior existing evidence outlining significant benefit from PT intervention. In total, Category A cancers represent over 14,000 Program members. Less than 1% of members with a Category A cancer had a PT related claim in 2023. Discussion/Significance of Impact: The mission of the Program is to provide quality and compassionate medical care and treatment to our members. Better understanding the utilization of PT services provided by the Program will allow us to increase awareness and support of interventions for members of our Program who could benefit from PT services.

Objectives/Goals: Communication between clinicians and parents of seriously ill infants is understudied. This study aims to 1) define high-quality communication with parents of critically ill infants and 2) evaluate the psychometric properties and validity of a measure of high-quality communication in parents of critically ill infants. Methods/Study Population: 1) Using participant observation and semi-structured interviews of 35 parents of hospitalized infants, I will conduct content analysis to describe high-quality prognostic communication with parents of infants in the pediatric intensive care unit. Using descriptions captured during participant observation and in semi-structured interviews, I will produce a novel definition of high-quality communication with parents of seriously ill infants. I will also explore parent experiences of communication by race. 2) I will validate a measure of communication quality in parents of 200 neonatal and pediatric intensive care unit patients. I will use factor analysis to evaluate the extent to which responses map onto an established construct and assess dimensionality and reliability. Results/Anticipated Results: 1) I anticipate finding that identification of high-quality communication will be consistent between participant observation and interviews and will track with Wreesmann’s framework. I hypothesize that minoritized parents are more likely to receive low-quality communication. 2) I hypothesize that the measure of communication quality will be valid and reliable in the neonatal and pediatric intensive care units. Discussion/Significance of Impact: I will explore communication quality in a novel setting for which limited data are currently available, establishing a measure for future pediatric communication research and identifying targets for interventions to improve communication quality. Better understanding of communication with parents of sick infants will lead to improved outcomes.

Objectives/Goals: The gut microbiome and its metabolites, such as short-chain fatty acids (SCFA), are dysregulated in rheumatoid arthritis (RA); however, the significance of this observation and its implications in pathogenesis and therapeutics is unclear. Here, we explore the role of the SCFA, butyrate, in treatment efficacy in new-onset rheumatoid arthritis. Methods/Study Population: We designed a proof-of-principle study to determine the effects of butyrate supplementation in new-onset RA (NORA) patients that fulfilled 2010 ACR/EULAR RA criteria. We evaluated the effects of methotrexate (MTX) plus butyrate in NORA (n = 17; 1 gm butyrate, 3 times daily) compared to MTX alone (n = 19) over 4 months. MTX responders were defined by a change in disease activity score (DAS)-28 ESR of > 1.8 at 4 months. Fecal samples were collected at baseline and followed up for 16s rRNA sequencing and metabolite quantification by 1H NMR spectroscopy. Unpaired-t, paired-t, Wilcox and Fisher’s exact test were performed as appropriate. Results/Anticipated Results: MTX responders in the MTX-only group had a higher concentration of fecal butyrate than nonresponders at baseline (p = 0.045). Fecal butyrate concentration decreased over time in treatment responders in MTX group (p = 0.05), whereas butyrate concentration remained similar in MTX/butyrate group. Prior to treatment, both MTX and MTX/butyrate groups demonstrated similar levels of gut bacterial alpha diversity (Shannon index), yet only the MTX/butyrate group demonstrated a significant increase in alpha diversity by 4 months (p = 0.022). LefSe analysis demonstrated increased abundances of Bacteroides, Clostridium, and Phascolarctobacterium in responders in the MTX/butyrate group by 4 months. Ten (52.6%) patients in MTX and 11 (64.7%) in MTX/butyrate group were considered MTX responders by 4 months (p = 0.516). Discussion/Significance of Impact: Butyrate supplementation increased gut microbial diversity in patients and led to increased abundance of Bacteroides, which has been implicated in efficacy of methotrexate, a first line medication in rheumatoid arthritis. Butyrate may have implications for the maximization of therapeutic effectiveness in rheumatoid arthritis.

Objectives/Goals: To fully understand the scientific objectives, overall financial commitment, and outcome of the pilot projects. Methods/Study Population: We evaluated pilots reported in the in the annual, interim, and final Research Performance Progress Reports (RPPRs) for Clinical and Translational Science Awards (CTSA) Program UM1 and UL1 grants from FYs 2021–2023 to assess research categories across the translational science spectrum. We analyzed the number of pilots involving human subjects, vertebrate animals, both, or neither; financial allocations; publication outputs; and other characteristics. Pilots reported across multiple years were deduplicated and assigned to the latest reporting year. Each pilot was classified into broad (Category 1) and specific (Category 2) areas. Descriptive statistics, including means and frequency distributions, were generated. Multi-year pilots with NA or 0 values used the most recent prior value. Results/Anticipated Results: In the period from FY 2021 to 2023, 61 hubs reported 1,811 unique pilot projects in their RPPRs, receiving a total of approximately $62 million, of which two-thirds were expended. On average, each hub conducted 30 pilots with an award size of about $35K. Just over half of the pilots involved human subjects research (HSR), while about one-third were neither HSR nor vertebrate animal studies (VAS), with the remaining focused primarily on VAS. Notably, only 13% of pilots resulted in peer-reviewed publications. Collaborative efforts were observed in one-third of the projects. The majority of pilots fell into Preclinical Research (46%), followed by Clinical Research (33%) and Public Health (20%). Limitations in data quality were identified, and ten pilots reported $0 awarded funds, which may be captured in future RPPRs. Discussion/Significance of Impact: Analysis of pilots reported in RPPRs from FYs 2021–2023 across 61 hubs shows a strong focus on HSR, highlighting collaborative efforts that enhance translational science and align with CTSA goals. Future analysis will help assess the pilots’ impact and their alignment with NCATS’ mission to expedite research translation into health solutions.