The National Center for Advancing Translational Science (NCATS) seeks to improve upon the translational process to advance research and treatment across all diseases and conditions and bring these interventions to all who need them. Addressing the racial/ethnic health disparities and health inequities that persist in screening, diagnosis, treatment, and health outcomes (e.g., morbidity, mortality) is central to NCATS’ mission to deliver more interventions to all people more quickly. Working toward this goal will require enhancing diversity, equity, inclusion, and accessibility (DEIA) in the translational workforce and in research conducted across the translational continuum, to support health equity. This paper discusses how aspects of DEIA are integral to the mission of translational science (TS). It describes recent NIH and NCATS efforts to advance DEIA in the TS workforce and in the research we support. Additionally, NCATS is developing approaches to apply a lens of DEIA in its activities and research – with relevance to the activities of the TS community – and will elucidate these approaches through related examples of NCATS-led, partnered, and supported activities, working toward the Center’s goal of bringing more treatments to all people more quickly.

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

OBJECTIVES/SPECIFIC AIMS: Previous research suggests that weight loss during early TB treatment (first two months of anti-TB therapy) is a predictor of poor tuberculosis (TB) treatment outcomes among HIV-negative populations, but the relationship has not been well studied in the context of HIV. We examined the association between HIV and weight change during the first two months of anti-tuberculosis treatment, and also assessed the effects of HIV and early weight change on tuberculosis (TB) treatment outcomes. METHODS/STUDY POPULATION: Adults with culture-confirmed, drug-susceptible, pulmonary TB, regardless of HIV status, were enrolled into the Regional Prospective Observational Research for Tuberculosis (RePORT)-Brazil cohort and followed on standard anti-TB therapy. For the primary analysis, we compared weight change in persons living with HIV (PLWH) and HIV-negative patients between baseline and two months using multivariable bootstrapped quantile regression and modified Poisson regression. For secondary analysis, we examined the separate effects of HIV and weight change on poor TB treatment outcome (treatment failure, TB recurrence, or death) using Cox proportional hazards regression. RESULTS/ANTICIPATED RESULTS: Among 323 participants, 45 (14%) were HIV-positive. On average, PLWH lost 0.7% (interquartile range (IQR): −5.1%, 4.4%) of their baseline body weight between baseline and two months; those without HIV gained 3.5% (IQR: 0.8%, 6.7%). After adjusting for age, sex, and baseline BMI, PLWH lost 4.1% (95% confidence interval (CI): −6.5%, −1.6%) more weight during the first two months of anti-TB treatment than HIV-negative individuals. HIV infection was associated with weight loss ≥5% (adjusted odds ratio = 9.3; 95% CI: 4.2-20.6). Regarding the secondary analysis, 14 patients had a poor TB treatment outcome: 2 treatment failures, 4 cases of recurrent TB, and 8 deaths. PLWH and patients who lost ≥5% weight had significantly increased risk of poor TB treatment outcome with hazard ratios of 8.77 (95% CI: 2.96-25.94) and 4.09 (95% CI: 1.11-15.14), respectively. DISCUSSION/SIGNIFICANCE OF IMPACT: Our results suggest that HIV is associated with weight loss during early TB treatment, and both HIV and early weight loss were associated with poor treatment outcome. Future research should examine the potential etiologies of these findings and identify the types of interventions that would best promote weight gain during TB treatment, especially among PLWH, in order to prevent poor TB treatment outcomes.

ABSTRACT IMPACT: Implementation of digital and mobile applications in clinical research crisis response protocols can mitigate their impact on clinical research. OBJECTIVES/GOALS: Crisis management is fundamental to ensuring the protection of human subjects during a clinical trial. Mobile apps have the capacity to allow for quick access to crisis response plans and can serve to mitigate their impact on clinical research. Electronic data capture tools can be used to create digital applications for such a response. METHODS/STUDY POPULATION: The Clinical Research Center at Rutgers University transferred a paper-based crisis management response plan to a digital mobile application format using Vanderbuilt’s Research Electronic Data Capture Tool (REDCap). REDCap’s branching logic allowed for programming a decision support functionality to guide users through 3 specific crises. (1) threatening or aggressive study subject behavior; (2) clinical research center break in or theft; and (3) adverse event observed for ongoing or closed clinical research study. Applicable U.S. Code of Federal Regulations, IRB guidelines, institutional policies and procedures were also used as a component of the mobile development. RESULTS/ANTICIPATED RESULTS: The Crisis Management Decision-Support Portal within the Clinical Research Center has an interactive structure. The use of branching logic demonstrates the ability for users to answer each question and be guided to appropriate responses specific to selected criteria related to each event. The tool contains a self-correct function by providing a reset option after answering each section. The portal itself can be accessed using any computer or cellphone with an internet connection. It provides the users with appropriate criteria to determine to exact communication and management protocols for reporting for the crisis event they are witnessing. As users access the portal, usage data can be collected, tracked, and stored. DISCUSSION/SIGNIFICANCE OF FINDINGS: The REDCap platform offers the opportunity to digitize crisis management protocols that ensure professionals have easy access to appropriate responses to crises at the center. The use a digital application rather than paper allows for a CTSA sponsored hub to mitigate damage, simply build new protocols, modify existing protocols, and track usage.

OBJECTIVES/GOALS: There are few training programs for health research staff and clinicians like The Practice-Oriented Research Training program, that include opportunities to conduct funded clinical and translational research. The goal of this study is to evaluate the long-term impact of this program on participants professional development and advancement. METHODS/STUDY POPULATION: The Practice-Oriented Research Training program for health research staff and clinicians was operated by the Michigan Institute for Clinical and Health Research from 2008 through 2018. Participants received training and formed teams that received financial support to conduct a clinical or translational study with a faculty mentor. Eleven cohorts comprising 111 individuals participated. The long-term impact of the program was evaluated using sequential mixed methods. All participants were invited to evaluate the program via an online survey in 2021. Respondents were invited to participate in interviews in 2022. Secondary records of the participants’ publications, grants, and professional advancement were collected. RESULTS/ANTICIPATED RESULTS: 68 participants in the PORT program published 345 papers in peer-reviewed scientific journals following the program, averaging over 5 publications per participant. These publications have been cited over 4000 times with an average of over 13 citations per paper. Large proportion of program participants have continued contributing to health research; the vast majority of program participation chose to continue at the University of Michigan. Survey results indicate participants’ belief that the program had wide-ranging and enduring impacts on key aspects of their careers, including their application of research to practice. Interviews confirmed that the program helped many participants make substantial advancement in their careers. DISCUSSION/SIGNIFICANCE: Training programs for health research staff and clinicians can have a substantial and enduring impact on their professional development and advancement. The need for programs like PORT will increase as the health research workforce grows. These results inform recommendations for translational scientists.

OBJECTIVES/GOALS: To demonstrate the value of the Competency Index for Clinical Research Professional (CICRP) as a tool in program evaluation using a pre- and post- design to evaluate student perceived self-efficacy in clinical trial competencies at program entry and at program completion. METHODS/STUDY POPULATION: Using a separate-sample pre-post study design, we administered the CICRP questionnaire to students in the entry and exit courses of the Master of Clinical Research (MCR) Program during the 2021-2022 academic year, using QualtricsTM (Provo, Utah) survey instrument for use on desktop or mobile device. We included the 20 CICRP competency items asking students to rate their self-efficacy in performing each item using a Likert Scale (from 0-10) (0=not at all confident; 10= extremely confident). Links to the survey were included in the courses for the foundational entry course and for the final culminating project course. RESULTS/ANTICIPATED RESULTS: Overall, 54 students took the CICRP during the entry course and 56 during the exit. Cronbach’s alpha for each assessment ranged from 0.93 to 0.98. Both the Welch’s two-sample t-test and Wilcoxon rank-sum test show very significant differences between the group of students entering the program and leaving the program (p value < 0.001). A significant increase in mean CICRP total score is seen at each experience level between program entry and program exit (p<0.001) A linear regression, adjusting for available covariates, individuals taking the exit course have a mean CICRP total score 92.690 (p value < 0.001) higher than individuals taking the entry course. DISCUSSION/SIGNIFICANCE: Competency indices have been used to measure self-efficacy in translational research scientists, thus the use of CICRP to measure self-efficacy can be useful in assessing whether our competency-based program is meeting the JTF Competency needs of students.

OBJECTIVES/SPECIFIC AIMS: One of the driving mechanisms of cancer progression is the reprogramming of metabolic pathways in intermediary metabolism. Cancers increase their energy expenditure by increasing ATP production for utilization in anabolic pathways to increase production of proteins, nucleic acids and lipids. The Warburg effect, where cancer cells predominantly use aerobic glycolysis rather than oxidative phosphorylation to produce ATP, was long thought to be the main initiating pathway in increasing tumor burden. However, compelling new evidence shows that there exists metabolic heterogeneity among and within tumors. Mitochondrial respiration often plays a major role in tumor progression, as many different cancers contain a subpopulation of slow-cycling tumor-initiating cells that are multidrug-resistant and dependent on oxidative phosphorylation. These cells represent a target for cancer therapy. In this study, we identification a novel endogenous regulator of mitochondrial respiration, retinoic acid receptor responder 1 (RARRES1). METHODS/STUDY POPULATION: We assessed the metabolic phenotype of RARRES1-depleted normal epithelial cells through metabolomics, a flux analyzer and blotting for phosphorylation of AMP kinase, a major regulator of energy homeostasis. We further examined mitochondrial energetics by staining the mitochondria with TMRM and Mito-Tracker. We then analyzed the apoptotic phenotype of epithelial cells with depletion of RARRES1 with fluorescence-activated cell sorting analysis of annexin V-staining. RESULTS/ANTICIPATED RESULTS: Remarkably, fluorescence-activated cell sorting analysis of annexin V-stained epithelial cells with depletion of RARRES1 were resistant to all studied modes of cell death, implying an effect on a fundamental cell process. By using proteomics, metabolomics, cellular and molecular analyses, our data show that RARRES1 regulates mitochondrial membrane potential and subsequently alters 1-carbon metabolism by modulating the function of the mitochondrial voltage-dependent anion channel. We believe this is the first example of a tumor suppressor protein that functions to directly regulate mitochondrial energetics. Using an extracellular flux analyzer, our data also show that depletion of RARRES1 causes an increase in mitochondrial respiration and ATP production, thus enhancing biosynthetic pathways that drive the pathogenicity and survival of cancer. The metabolic and anti-apoptotic phenotype of RARRES1-depleted cells was reversed by treatment of metformin, a mitochondrial inhibitor. DISCUSSION/SIGNIFICANCE OF IMPACT: These data lay the foundation for metabo-therapy of the many tumor types that exhibit RARRES1 depletion and may have the added benefit of targeting drug-resistant tumor-initiating cells.

OBJECTIVES/SPECIFIC AIMS: Triple-negative breast cancer (TNBC) accounts for one-fifth of the breast cancer patient population. The heterogeneous nature of TNBC and lack of options for targeted therapy make its treatment a constant adventure. The deficiency of tumor suppressors p53 and ARF is one of the known genetic signatures enriched in TNBC. Crucial questions remain about how TNBC is regulated by these genetic alterations. METHODS/STUDY POPULATION: In order to address this issue, we established p53/ARF-defective murine embryonic fibroblast and mammary epithelial cell to study the molecular and phenotypic consequences. Moreover, transgenic mice were generated to investigate the effect of p53/ARF deficiency on mammary tumor development in vivo. RESULTS/ANTICIPATED RESULTS: Increased proliferation and transformation capability were observed in p53/ARF-defective cells, and an aggressive form of mammary tumor was also seen in p53−/−ARF−/− mice. Gene expression profiling and knock-down experiments using shRNAs were conducted to identify inflammatory marker ISG15 and RNA-editing enzyme ADAR1 as potential culprits for the elevated oncogenic potential. Interestingly, we found that the overexpression of ISG15 and ADAR1 is also prevalent in human TNBC cell lines. Reducing ADAR1 expression abrogated the oncogenic potential of human TNBC cell lines, while non-TNBC cells are less susceptible. DISCUSSION/SIGNIFICANCE OF IMPACT: These results indicate critical roles played by the tumor suppressors p53 and ARF in the pathogenesis of TNBC, likely through regulating ADAR1-mediated RNA modifications. Further understanding of this pathway promises to shed light on genetics-driven vulnerabilities of TNBC and inform development of more effective therapeutic strategies.

OBJECTIVES/GOALS: The Title V project team is offering an elective course to teach the historical development of CTR, make a compelling scientific presentation, and use bibliographic databases. In addition, students learn: to write the research question, design a career development plan, protect human subjects in research, and the mentor-mentee relationship. METHODS/STUDY POPULATION: The course includes a variety of educational strategies and activities that allow the student to increase their knowledge and initiate their interest in the field of CTR. Both academic semesters (August to December and January to May) are offered remotely in two-hour synchronous sessions on Fridays from 3:00 p.m. to 5:00 p.m. through videoconferences, in addition to asynchronous activities. Invited expert lecturers and faculty reinforce the course content in each topic they address. In addition, course coordinators assign guided tasks where the students perform the work. Then, they present or send their work to the course coordinators for evaluation. RESULTS/ANTICIPATED RESULTS: The course began in January 2020 and has had six offerings, including one in the current academic semester (August to December 2023). Its first offering was in the semester from January to May, and due to the interest generated in students in August 2022, it is now available in both semesters. From its beginning to the present, the course has included students from the University of Puerto Rico (UPR) Bayamon, Cayey, Humacao, Mayagüez, and Rio Piedras campuses, impacting all geographic areas of Puerto Rico. The course has also represented an opportunity for graduate faculty to teach CTR to undergraduate students. Until 2023, 56 students have enrolled. DISCUSSION/SIGNIFICANCE: Upon completing six-course offerings, the evaluation carried out by the students demonstrates satisfaction with the learning obtained. The knowledge and skills achieved have led them to participate in CTR with the mentoring of collaborating course professors and starting a new professional development opportunity for undergraduate students.

OBJECTIVES/GOALS: Youth with comorbid asthma and overweight/obesity (OW/OB) are at risk for increased morbidity. Physical activity (PA) engagement can mitigate risks, but the majority of youth do not meet national PA guidelines. This study examines caregiver and youth perspectives about ways physicians can promote PA in this population. METHODS/STUDY POPULATION: Participants included 20 adolescents (M age = 16.0; 55% male) with asthma and OW/OB and a primary caregiver (90% mothers). Caregivers and adolescents participated in separate semi-structured interviews about adolescent PA engagement, including questions regarding strategies for physicians to promote PA. Interviews were audio recorded, transcribed, and analyzed using NVivo. Two authors assigned conceptual codes to the transcripts to identify key concepts and then met to create a codebook. Authors independently coded 4 transcripts and met to resolve discrepancies. Authors then independently coded 2 additional transcripts (final kappa = .62) and met to reach consensus before dividing the remainder for coding. Codes were collapsed and sorted into themes, and attributes of each theme were determined. RESULTS/ANTICIPATED RESULTS: Dyads discussed the importance of physicians providing general (positive statements) and PA-specific encouragement. Dyads also stated that physicians should encourage teens to set and reach PA-related goals. Caregivers and youth reported that physicians should provide education about the importance of PA and ways to engage in PA, awareness about adolescents weight and its impact on health, and resources (camps, events, and locations). Additionally, caregivers and a teen noted that physicians should talk directly to and address questions toward teens. Dyads mentioned the importance of focusing on overall health (instead of weight) as well. Dyads also noted that physicians should avoid judgmental and shaming statements when talking about weight. DISCUSSION/SIGNIFICANCE: Results provide information about strategies physicians can use to promote PA among adolescents with asthma and OW/OB, a population that is at risk for low PA and poor health outcomes. Findings suggest that physicians may effectively motivate behavior change by providing health guidelines, encouragement, resources, and positive reinforcement.

OBJECTIVES/GOALS: For patients suffering from respiratory failure there are limited options to support gas exchange aside from mechanical ventilation. Our goal is to design, investigate, and refine a novel device for extrapulmonary gas exchange via peritoneal perfusion with perfluorocarbons (PFC) in an animal model. METHODS/STUDY POPULATION: Hypoxic respiratory failure will be modeled using 50 kg swine mechanically ventilated with subatmospheric (10-12%) oxygen. Through a midline laparotomy, two cannulas, one for inflow and one for outflow, will be placed into the peritoneal space. After abdominal closure, the cannulas will be connected to a device capable of draining, oxygenating, regulating temperature, filtering, and pumping perfluorodecalin at a rate of 3-4 liters per minute. During induced hypoxia, the physiologic response to PFC circulation through the peritoneal space will be monitored with invasive (e.g. arterial and venous blood gases) and non-invasive measurements (e.g. pulse oximetry). RESULTS/ANTICIPATED RESULTS: We anticipate that the initiation of oxygenated perfluorocarbons perfusion through the peritoneal space during induced hypoxia will create an increase in hemoglobin oxygen saturation and partial pressure of oxygen in arterial blood. As we expect gas exchange to be occurring in the microvascular beds of the peritoneal membrane, we expect to observe an increase in the venous blood oxygen content sampled from the inferior vena cava. Using other invasive hemodynamic measures (e.g. cardiac output) and blood samples taken from multiple venous sites, a quantifiable rate of oxygen delivery will be calculable. DISCUSSION/SIGNIFICANCE: Peritoneal perfluorocarbon perfusion, if able to deliver significant amounts of oxygen, would provide a potentially lifesaving therapy for patients in respiratory failure who are unable to be supported with mechanical ventilation alone, and are not candidates for extracorporeal membrane oxygenation.

OBJECTIVES/GOALS: Many clinical prediction models have been developed to guide tuberculosis (TB) treatment, but their results and methods have not been formally evaluated. We aimed to identify and synthesize existing models for predicting TB treatment outcomes, including bias and applicability assessment. METHODS/STUDY POPULATION: Our review will adhere to methods that developed specifically for systematic reviews of prediction model studies. We will search PubMed, Embase, Web of Science, and Google Scholar (first 200 citations) to identify studies that internally and/or externally validate a model for TB treatment outcomes (defined as one or multiple of cure, treatment completion, death, treatment failure, relapse, default, and lost to follow-up). Study screening, data extraction, and bias assessment will be conducted independently by two reviewers with a third party to resolve discrepancies. Study quality will be assessed using the Prediction model Risk Of Bias Assessment Tool (PROBAST). RESULTS/ANTICIPATED RESULTS: Our search strategy yielded 6,242 articles in PubMed, 10,585 in Embase, 10,511 in Web of Science, and 200 from Google Scholar, totaling 27,538 articles. After de-duplication, 14,029 articles remain. After screening titles, abstracts, and full-text, we will extract data from relevant studies, including publication details, study characteristics, methods, and results. Data will be summarized with narrative review and in detailed tables with descriptive statistics. We anticipate finding disparate outcome definitions, contrasting predictors across models, and high risk of bias in methods. Meta-analysis of performance measures for model validation studies will be performed if possible. DISCUSSION/SIGNIFICANCE OF IMPACT: TB outcome prediction models are important but existing ones have not been rigorously evaluated. This systematic review will synthesize TB outcome prediction models and serve as guidance to future studies that aim to use or develop TB outcome prediction models.

OBJECTIVES/SPECIFIC AIMS: To explore the racial differences in rotational thromboelastometry findings using whole blood and plasma samples from healthy volunteers. METHODS/STUDY POPULATION: We studied a cohort of patients at Tulane University Hospitals who came into the pre-op clinic to get blood drawn for labs. The cohort included a total of 44 patients who were otherwise healthy adult volunteers with no history of cardiovascular nor thromboembolic events, 30 African Americans and 14 Caucasians. Patients who required lab work for their upcoming surgery were asked to participate in the study by giving a sample of blood collecting in a light blue-top sodium citrate tube. We excluded patients who were currently on any anticoagulation or antiplatelet medications. We also excluded those with current or previous history of cancer, those with known bleeding disorder, and those who were on chronic transfusion protocol, or had received a blood transfusion within the last 21 days. Data collection was carried out after informed consent was obtained; we collected citrated whole-blood (WB) samples. WB samples were processed within 3 hours of phlebotomy. Platelet free plasma, obtained after centrifugation at 2500 cGy of whole blood for 20 minutes, was kept frozen at −70°C. Frozen plasma was thawed at 37°C for 5 minutes before testing. Samples were recalcified with star-tem reagent, and then the in-tem reagent was added. The latter contains an optimized concentration of ellagic acid and partial thromboplastin phospholipid from rabbit brain. Thromboelastometry (ROTEM) parameters including clotting time, clot formation time, alpha angle, maximum clot firmness, and Lysis Index after 30 and 45 minutes were determined. Data was then retrieved from the ROTEM database and put into an Excel sheet to be analyzed. RESULTS/ANTICIPATED RESULTS: Our results showed that the CFT was higher in both the plasma and the WB of Caucasians when compared with African Americans with a difference between means 137.5±233.7 (p=0.56) and 11±7.85 (p=0.168), respectively; while MCF was increased in the WB and plasma of AA with a difference between means of 1.719±1.974 (p=0.38) and 5.37±2.49 (p=0.037), respectively. In other words, the plasma of Caucasians did seem to take longer to reach the maximum firmness (however not statistically significant p>0.05), while the maximum clot firmness was significantly higher in plasma of AA. In summary and compatibly with the previously published data, our results showed significantly increased prothrombotic profile in the plasma of African Americans when compared with Caucasians. DISCUSSION/SIGNIFICANCE OF IMPACT: This reinforces the role of the whole vascular system and the interaction between its different components in the pathophysiology of thromboembolic events. In one case control study, African ethnicity was associated with increased risk of DVT in parallel with significantly increased peak thrombin on thrombin generation when compared with Caucasians. With our preliminary results, we confirm these data using another tool for the assessment of the plasma in addition to comparing WB samples too. More prospective studies, with higher number of subjects evaluating the value of the results in predicting the risk of development of thromboembolic events in different ethnicities, are needed for better understanding of this disease. In addition, thromboelastometry might require adjustment for ethnicity in studies evaluating ethnically diverse populations.

OBJECTIVES/SPECIFIC AIMS: The study aims to identify the short and long-term associations of HTPR and presence of CYP2C19 polymorphism in the occurrence of major adverse cardiovascular events (MACE). The primary outcome of the study will be the presence of MACE including stent thrombosis, need for revascularization, acute limb ischemia events, myocardial infarction and death in relation to the presence of HTPR and CYP2C19 polymorphism. Secondary outcomes will include the prevalence of HTPR and CYP2C19 polymorphism in patients with PAD, and association with other medications including aspirin and cilostazol. METHODS/STUDY POPULATION: Patients above 21 years of age with the diagnosis of PAD using clopidogrel therapy for at least for seven days will be recruited at the University of Puerto Rico District Hospital and Cardiovascular Hospital of Puerto Rico and the Caribbean. RESULTS/ANTICIPATED RESULTS: A total of 200 patients from Puertorrican, Dominican and Cuban ethnicity will be expected to be recruited. The most common comorbidities will include, coronary artery disease, hypertension, dyslipidemia, and diabetes mellitus type 2. No significant distr DISCUSSION/SIGNIFICANCE OF IMPACT: The status quo as it pertains to resistance to clopidogrel in PAD patients is to improve antiplatelet resistance using antiplatelet therapy guided by platelet assays in order to reduce MACE occurrence. Although HTPR and presence of CYP2C19 polymorphisms have been studied on the PAD population, currently there is no gold standard test for measuring antiplatelet resistance. In that regard, this study will expect to identify the contribution that HTPR and CYP2C19 polymorphism might have on MACE in patients with PAD. In this way, the results will allow identification of abnormality parameters in HTPR and CYP2C19 testing in relation to the impact on risk of having MACE. Once the association of these variables with MACE is established, testing for clopidogrel resistance could become a potential strategy to optimize antiplatelet therapy and reduce the impact that MACE have in this population.

OBJECTIVES/GOALS: To address investigator frustration and appropriate oversight for student interns performing clinical research activities, we created infrastructure to support matchmaking with clinical research teams and onboarding of student interns, thereby allowing for more meaningful internship experiences with access to clinical research systems. METHODS/STUDY POPULATION: Internship requests may be initiated by a student, an affiliated institution, or an investigator. Requests are triaged accordingly. Affiliation agreements define the parameters for these placements. Unaffiliated institutions may request an agreement by contacting CRISP; otherwise, unaffiliated interns will be classified as visiting scholars with restricted access. If a student is from an affiliated institution, the Clinical Research Internship Portal (CRISP) is used to collect and track information regarding the internship. CRISP provides: Matchmaking for student interns with placements Compilation of onboarding documentation Tools (e.g., learning agreements) for student intern supervisors Professional development workshop series for all student interns RESULTS/ANTICIPATED RESULTS: Launched in 2021, CRISP is a relative newcomer to the Duke research training landscape, but preliminary impact may be measured by the following metrics: Affiliated institutions: 8 agreements in place, 4 pending 25 student interns from 7 institutions placed across 11 departments/institutes 7-session professional development series garnering positive feedback from interns and supervisors Improved access to clinical and research systems aligned with clinical research activities Enhanced oversight and tracking of student interns across Duke enterprise Expansion of program to include internal and external student interns CRISP has engaged invested parties within and outside of Duke to ensure robust oversight of these valuable training opportunities and to create new pathways into our workforce. DISCUSSION/SIGNIFICANCE: Streamlining intern placements has lessened pain points related to including students in our research environment, both for investigators and institutional partners. Future plans include expanding the number of affiliation agreements, creating an interface to quickly triage intern requests, and scaling up the professional development series.

OBJECTIVES/SPECIFIC AIMS: To identify brain regions with the highest and least variable rate of multiple sclerosis (MS)-specific atrophy using an agnostic approach, and to perform simulation-based sample size calculations for Phase II s using these regions as primary endpoint. METHODS/STUDY POPULATION: In total, 601 subjects (2638 MRI scans) were analyzed; 520 subjects with relapsing forms of MS across the spectrum of disease severity and duration were followed in a single-center prospective cohort study at an academic MS Center between 2005 and 2010 with annual 3 T MRIs and clinical visits for 5 years, including standardized 1 mm3 3D T1-weighted images (3DT1s; 2483 MRIs). Separately, a convenience sample of 81 healthy controls (HC) was recruited from the same center and scanned longitudinally using the same MRI scanner and protocol (155 MRIs). 3DT1s were processed using FreeSurfer’s longitudinal pipeline (software version 5.3). Rates of change in all cortical and subcortical regions (n=119 brain regions) were estimated in MS patients and HC with linear mixed effects models. An effect size was calculated for each region as the difference in change over time between MS patients and HC divided by the standard error of the difference [d=β(MS×time)/SE β(MS×time)]. Regions were ranked according to absolute effect size, and the top regions were chosen for simulation-based sample size calculations to estimate the number of subjects needed to achieve 80% power to detect a slowing of MS atrophy down to normal aging, assuming significance levels of 5% and 10%. Ten percent was included because some have advocated for a more relaxed alpha in Phase II s. RESULTS/ANTICIPATED RESULTS: Four regions (putamen, subcortical grey matter, caudate, and thalamus) yielded the smallest sample sizes. At 80% power, ~50 subjects per arm would be needed with putamen or subcortical grey matter volume, or ~80–85 subjects per arm with caudate or thalamic volume as primary endpoint. For the remaining regions, >140 subjects per arm would be needed. A 20%–30% increase in sample size was observed when α=5% was used. DISCUSSION/SIGNIFICANCE OF IMPACT: Using an agnostic approach considering all brain regions and simulation-based sample size calculations specifically designed for longitudinal studies, putaminal, subcortical grey, caudate, and thalamic volumes are sensitive to change over time and yield feasible sample sizes for Phase II studies in MS. Because the effect size estimates incorporate normal aging, these regions represent the most sensitive outcomes for testing therapeutic interventions that target irreversible, MS-specific brain atrophy. The clinical relevance of these regions is our next focus to help inform which of these regions should be favored as primary endpoint.

OBJECTIVES/GOALS: To determine predictors of mortality in non-severe hemophilia A (NSHA) patients. METHODS/STUDY POPULATION: The ATHNdataset was used to identify NSHA patients who have authorized the sharing of their demographic and clinical information for research. Factors examined included race, ethnicity, hemophilia severity, Hepatitis B, Hepatitis C and HIV infections. A mortality rate was calculated for each factors examined. The relative risk of death between patients in different categories of the factors was assessed by using the ratio of these mortality rates. To adjust for the effects of all of the studied factors with mortality, a multivariate analysis was performed using logistic regression. All hypothesis testing was two-tailed, with a significance level of .05. RESULTS/ANTICIPATED RESULTS: A total of 6,606 NSHA patients were followed for an average of 8.5 years. During 56,064 person years of observation, 136 (2.1%) NSHA patients died; 20% of deaths were malignancy-related. Mortality rates were similar across racial group. Hispanic patients were 60% less likely to die than non-Hispanic patients (p = 0.006). Patients with Hepatitis C infection and HIV infection were 7 times as likely to die compared to those without infections (p<0.001). After adjusting for the effects of all examined factors in a multivariate analysis, patients with hepatitis C and HIV infection remain significantly associated with increased mortality at 6.1 times and 3.6 times the risk, respectively. DISCUSSION/SIGNIFICANCE OF IMPACT: Despite significant improvement in the therapeutic approaches for infectious diseases, Hepatitis C and HIV infections remain strong predictors of mortality in this NSHA cohort. CONFLICT OF INTEREST DESCRIPTION: N/A.

ABSTRACT IMPACT: My work evaluates the impact of electronic data capture/eSource on several aspects of clinical trial efficiency and scale, aiming to demonstrate how eSource can be used to improve the way we run clinical trials. OBJECTIVES/GOALS: Using eSource may increase the efficiency of data collection in clinical trials. However, adoption of eSource has been slow. We reviewed over 100 large multinational clinical trials to analyze how eSource use correlated with trial size, sponsor collaborations, time to complete, and time to publication. METHODS/STUDY POPULATION: We searched ClinicalTrials.gov for completed, interventional, Stage II-IV clinical trials with posted results and an uploaded study protocol document. This produced 3,962 trials. We identified all studies with over 1,200 participants and sites in multiple countries (or at least 100 sites in one country). After eliminating ten studies with duplicate protocols, we had a database of 123 trials. From the ClinicalTrials.gov listing, the study protocol, and any published papers, we determined the start, end, and publication dates, data collection protocol, sponsors and collaborators, and any reasons given for delays for each trial. We performed statistical tests comparing trial delay, participant and country count, and collaboration status (yes or no) between the two groups (eSource users and non-eSource users). RESULTS/ANTICIPATED RESULTS: Of our 123 trials, 60 (48.7%) used eSource, 48 (39.1%) used paper source documentation, and 15 (12.2%) used some combination. We found no statistically significant difference between eSource and non-eSource trials in terms of trial delay (p=0.43), time to publish (p=0.33), collaboration status (p=0.54), number of participants (p=0.36), or number of countries (p=0.12). However, our analysis was limited by what data was publically available. To investigate the effects of eSource on site efficiency, data accuracy, and data security, which are three major factors behind the FDA’s 2013 eSource recommendation, we would need access to proprietary information from trial sponsors. DISCUSSION/SIGNIFICANCE OF FINDINGS: The use of eSource in large multinational clinical trials is not correlated with a change in time to completion or publication nor a higher number of participants or countries. We aim to acquire proprietary data to further analyze the impacts of eSource on trial efficiency, data accuracy, and data security.

OBJECTIVES/SPECIFIC AIMS: This study applied a syndemic framework to 1) assess whether the concurrence of unhealthy alcohol use, smoking, and depressive symptoms is associated with increased risk for incident CVD among people living with and without HIV and 2) determine whether the association between this syndemic and incident CVD is differential by HIV status. METHODS/STUDY POPULATION: We evaluated 5731 participants (50.3% HIV+) without baseline CVD from the Veterans Aging Cohort Study, a prospective, observational cohort of PLWH and matched uninfected veterans enrolled in 2002 and followed through 2015. We assessed baseline number of conditions (syndemic score: 0-3; unhealthy alcohol use (>14 drinks per week for men [women] or 5 or more drinks in one occasion for men [women]), cigarette smoking (former/current), and depressive symptoms (Patient Health Questionnaire-9 score ≥ 10) and incident CVD through 14 years. Clinical ICD-9 codes identified incident cases of CVD (acute myocardial infarction, heart failure, revascularization, and stroke). We constructed age-adjusted survival curves and CVD rates. Multivariable Cox proportional hazards regressions estimated the hazard ratio (HR) and 95% confidence intervals (CI) of the syndemic score on incident CVD by HIV status, adjusting for baseline demographic, health status, and HIV-related factors. RESULTS/ANTICIPATED RESULTS: Under 10% of all veterans had zero conditions; 25.8% had one; 49.6% had two, and 14.3% had all three. Based on the prevalence of each individual condition in the cohort (unhealthy drinking: 41.5%, cigarette smoking: 75.0%, and depressive symptoms: 21.3%), the observed prevalence of all three conditions was more than double that expected by chance (6.6%). There were 835 cases of incident CVD (50.4% HIV+) during the median follow-up (10.6 years). Overall, age-adjusted incidence rates/1000 person-years increased with greater number of conditions (zero 10.1, one 12.5, two 15.8, three 19.6). Compared to uninfected people with zero conditions, the adjusted hazard ratios of incident CVD were similar by HIV status for each number of conditions. DISCUSSION/SIGNIFICANCE OF IMPACT: The syndemic of unhealthy drinking, cigarette smoking, and depressive symptoms is common and associated with high CVD risk. However, this risk was similar by HIV status. Our results underscore the need to screen for and treat these co-occurring conditions.