OBJECTIVES/GOALS: Although many physicians conduct clinical trials as Principle Investigators, a systematic training is often lacking. Instead, most receive on-site training, potentially compromising data quality and human subject safety. This research assesses the landscape for physician training through medical school curriculums. METHODS/STUDY POPULATION: This project explored training programs for physician researchers, specifically in the emerging field of quality management systems (QMS). To understand the scope of academic research available for QMS and Good Clinical Practice (GCP) training and lack of clinical trial training implemented in medical school curricula, a literature review was conducted. Available training for physicians was assessed through existing training programs from the FDA, NIH, DIAMOND, ACRP, and Google for accessibility in terms of costs, completion timelines and certification, format (online vs. in-person), and inclusion of GCP and QMS training in the curriculum RESULTS/ANTICIPATED RESULTS: Literature review revealed that not much is known about physician researcher training beyond the institutional requirement for minimal GCP review. Examination of select medical school curriculum also discovered a lack of clinical trial training for students interested in clinical research. Furthermore, existing training programs and modules available for physicians are limited as their syllabi do not include QMS training. In addition, these programs commonly have inaccessible registration links, are expensive, and have significant time commitments for in-person courses. These findings support the need for more accessible and effective training and certification tools for physician researchers. DISCUSSION/SIGNIFICANCE OF IMPACT : QMS training is not included medical school curricula or programs for physician researchers, potentially compromising data integrity and subject protection. This research supports the development of essential QMS training concepts and practical approaches for physician researcher clinical trials.

OBJECTIVES/SPECIFIC AIMS: Opioids are the first-line treatment for moderate to severe cancer-related pain. Increased awareness of opioid prescription misuse and adverse outcomes has prompted statements on their use from multiple national medical groups. In this study we characterize national-level opioid prescription patterns among gynecologic oncologists treating Medicare beneficiaries. METHODS/STUDY POPULATION: The Centers for Medicare and Medicaid Services (CMS) database was used to access Medicare Part D beneficiary data (2016). All available opioid claims prescribed by gynecologic oncologists were identified. Medication type, prescription length and other prescribing factors were recorded. Physician demographics were obtained from departmental websites and accrediting bodies. Physicians with <10 opioid claims are not included in the CMS database. Bivariate statistical analysis including chi-squared, Fisher’s exact test and Wilcoxon rank-sum test were performed to compare variables with threshold for significance set at p<0.05. Linear regression modeling was also performed to examine association of gender with number of opioids prescribed. RESULTS/ANTICIPATED RESULTS: A total of 494 board-certified gynecologic oncologists were included in this analysis. In 2016, gynecologic oncologists wrote 23,584 opioid prescriptions for 267,824 days of treatment (average of 9.24 prescribed days per claim). The most commonly prescribed opioid was oxycodone/acetaminophen (41%). Male physicians had significantly more opioid prescription claims than females (p<0.01) including after adjusting for differences in years of experience. The majority of physicians had 11-50 opioid prescription claims (68%). A minority were high prescribing physicians with >100 opioid claims (11%). Of these, the overwhelming majority were male (82%) and late career (46%, >15 years since board certification). Physicians in the South had the greatest number of opioid prescription claims and significantly more than physicians in the Northeast, who had the fewest (p<0.01). Mean number of opioid claims increased with increasing years of experience (p<0.05). DISCUSSION/SIGNIFICANCE OF IMPACT: Among gynecologic oncologists, there were gender-based, regional and experience-related variations in opioid prescribing in the Medicare population in 2016. Further longitudinal studies are required to elucidate secular trends in opioid prescription practice.

OBJECTIVES/SPECIFIC AIMS: Falls are a major source of morbidity and disability in the aging population. Twenty to thirty percent of older adults who fall suffer moderate to severe injuries such as lacerations, hip fractures, and head traumas. A serious component of falling often overlooked is the fear of falling. The fear of falling is part of a debilitating spiral that leads to decreased activity and muscle weakness. The goal of this investigation was to determine if a novel 2-phase rehabilitation program designed to reduce the fear of falling and increase muscle strength could improve postural control during falls in older adults with balance impairments. METHODS/STUDY POPULATION: Four older adults participated in 8 cognitive restructuring workshops entitled A Matter of Balance (AMOB): 2 hours/week, total of 16 hours, designed to restructure thought patterns relative to falls and reduce the fear of falling. Within 1–2 weeks of completion, participants enrolled in Phase II: a standardized 10-week lower-extremity strengthening program. Participants performed high-intensity concentric resistance exercise on a modified seated ergometer (Eccentron, BTE Technologies) twice per week for up to 20 minutes per session. Fear of falling was assessed using the Activities-Specific Balance Confidence (ABC) scale. Postural control was assessed during reproducible falls at 3 phases: baseline (T0), after Phase I AMOB (T1), and after Phase II strengthening (T2). Falls were induced by treadmill perturbations (VGait system, MotekForce Link) occurring at slow and fast belt accelerations. A 3×3 ANOVA was conducted on postural control outcomes with phase and stepping cycle as independent factors. Pairwise comparisons were analyzed with the Bonferroni correction. RESULTS/ANTICIPATED RESULTS: Statistically significant main effects were found for phase and stepping cycle (p=0.003, p=0.00). No statistically significant interaction effects were found. However, a trend toward increasing Center of Pressure-Center of Mass (COP-COM) distance occurred after each intervention phase (T1 and T2) during fast treadmill perturbations. The greatest increase in COP-COM distance was found at 100% of the stepping cycle during fast perturbations following 10 weeks of resistance training compared with baseline (p=0.006). No significant differences were found in fear of falling between phases (p=0.682). DISCUSSION/SIGNIFICANCE OF IMPACT: A large COP-COM distance suggests the individual is able to allow straying of the COM outside of the functional base while recovering balance. Meanwhile, a small COP-COM distance represents a conservative approach to postural tasks, in that the performer does not feel stable enough to allow separation of the COP and COM. These pilot data suggest that a 2-phase rehabilitation program can improve specific components of postural control during recovery from falls. Rehabilitation interventions aimed at reducing falls in older adults should consider adding a component of cognitive restructuring in conjunction with standard of care resistance training.

OBJECTIVES/GOALS: Pancreatic ductal adenocarcinoma (PDAC) is a relatively radioresistant disease, and inhibition of DNA homologous recombination (HR) repair in combination with radiation therapy (RT) is a potentially attractive strategy to overcome radioresistance. We have found that the expression of the HR protein RAD18 is upregulated in PDAC cells. METHODS/STUDY POPULATION: Standard clonogenic assays, γH2aX foci staining, HR-GFP reporter assay, and western blot analysis of DNA damage response proteins were performed in MIA-PaCa2 (MP2) and PANC-1 cells following knockdown of RAD18 in cells via short hairpin RNA (shRNA). Drug targeting of RAD18 was achieved through the use of a USP-7 inhibitor, P5091. Cells with or without stable knockdown of RAD18 were implanted orthotopically in the pancreas of athymic nude mice and treated with sham radiation or radiation to a dose of 20 Gy in 5 daily fractions once tumors reached 100-150 mm3. RESULTS/ANTICIPATED RESULTS: Stable knockdown of RAD18 in MP2 and PANC-1 resulted in decreased radiation clonogenic survival in vitro (dose enhancement factor (DEF)=1.52 and 1.51, respectively), decreased DNA repair after radiation as measured by the increased number of γH2aX nuclear foci assay at 6, 12, and 24 hours (all p<0.05), decreased HR activation following DNA damage via an HR-GFP reporter assay (p=0.039), and increased tumor growth delay following radiation in vivo (p<0.001). P5091 treatment of both MP2 and PANC-1 resulted in efficient knockdown of RAD18, which was confirmed through western blotting, qRT-PCR, and luciferase reporter assays. P5091 increased radiosensitization, yH2aX nuclear foci remained elevated at 12 and 24 hours (p<0.05), and HR repair was also reduced (p=0.014). DISCUSSION/SIGNIFICANCE: Herein, we show the HR repair protein RAD18, and that modulation of RAD18 expression correlates with in vitro and in vivo radiosensitization through altered HR-mediated DNA repair. USP7 inhibition successfully reduced RAD18 expression and resulted in enhanced radiosensitization.

OBJECTIVES/GOALS: The objective of this study was to use NIH RePORTER (Research Portfolio Online Reporting Tools) to analyze K99 funding trends and determine if R00 to R01 or R21 achievement time correlates with the future success of an early-stage NIH-funded investigator. METHODS/STUDY POPULATION: All award data were collected from NIH RePORTER. All K99 awards and funding data in this study were limited to All Clinical Departments (ACD). All researchers (n = 1,148) and awards (n = 2,022) were identified through a K99 search from FY 2007 to FY 2022 across ACD. Historic trends in K99 awards and funding from NIH Fiscal Year (FY) 2007 to FY 2022 were investigated. An R00 dataset was generated from NIH RePORTER. The K99 to R00 achievement statistics from FY 2007 to FY 2022 was investigated. NIH annual datafiles for FY 2007 to FY 2021 were aggregated to generate a master datafile of all R01 (n = 395,505) and R21 awards (n = 61,766). R01 and R21 award data were linked to the researcher previously identified through the K99 search. The connection between K99/R00 awardees and subsequent R01 or R21 awards was focused on. RESULTS/ANTICIPATED RESULTS: From FY 2008 to FY 2022, the number of K99 awards per year increased 123.4%, from 94 to 210. Over the same period, after correcting for inflation, the NIH K99 budget increased 127.0% while the NIH program level budget increased 17.3%. For researchers who achieved their first R01 or R21 0–3 years versus 3–6 years after the start of their R00, their average funding per year since the start of the R00 phase was $467,425 versus $290,604, respectively (p < 0.001). In summary, NIH investment in the K99 award pathway has substantially outpaced the NIH program level budget increase, and there is a strong relationship between average funding per year since the start of the R00 phase and time from R00 to R01 or R21. DISCUSSION/SIGNIFICANCE: Our study offers additional evidence of the Matthew effect in science, where previous success generates future success. This analysis may be useful to clinical departments as they evaluate selecting new and retaining current biomedical scientists for independent research positions.

OBJECTIVES/GOALS: Intraocular pressure is the most significant risk factor for glaucoma. Mechanosensitive proteins may have a critical role in transducing mechanical stimuli that ultimately lead to death of retinal ganglion cells. Our goal is to use genetic and functional approaches to discover mechanosensitive ion channels that mediate the progression of glaucoma. METHODS/STUDY POPULATION: Association data, obtained using a logistic regression model that included age, gender and population substructure as co-variates, for 2,576 SNPs located in the PIEZO1 and PIEZO2 genomic regions were extracted from the NEIGHBORHOOD genome-wide association study results for primary open angle glaucoma (POAG) (3,853 cases and 33,480 controls) and the subset of cases with intraocular pressure (IOP) measurements > 21mmHg (high-tension, HTG) (1868 cases and 33,480 controls). Rare coding PIEZO1 and PIEZO2 variants were evaluated using logistic regression and SNP data from the Human Exome array in 2606 POAG cases and 2606 controls and the subset of 1868 HTG cases and 2606 controls. Immunohistochemistry was used to characterize the expression of Piezo1 and Piezo2 in mouse eye sections. RESULTS/ANTICIPATED RESULTS: Exome data analysis identified two protein-altering variants associated with lower glaucoma risk (P<0.05): a PIEZO1 missense allele (Arg1527His; OR= 0.18, P= 0.001) and a variant disrupting a splice donor site (c.1107+1G>C; OR=0.38, P= 0.02), that prematurely truncates the protein. Investigation of the NEIGHBORHOOD GWAS dataset identified nominal association with common PIEZO2 variants (minor allele frequency > 0.3) in POAG overall (top SNP rs264179, P= 0.008) and in the HTG subgroup (top SNP rs264160, P= 0.001). The associated PIEZO2 SNPs are significantly associated with gene expression in lymphocytes (P< 1x10-8) with the risk allele correlated with decreased gene expression. Piezo1 and Piezo2 are expressed in many ocular tissues in the mouse, including cornea, ciliary body and retina. DISCUSSION/SIGNIFICANCE: We identify rare, protein-altering PIEZO1 variants associated with lower glaucoma risk and show that Piezo1 and Piezo2 are broadly expressed in the eye. Common variants influencing PIEZO2 expression also show nominal association with POAG risk. Inhibition of Piezo1 or augmentation of Piezo2 could be novel therapeutic strategies for glaucoma.

OBJECTIVES/SPECIFIC AIMS: Objectives and goals of this study are to (i) determine whether IBS-D patients randomized to either rifaximin or low FODMAP diet show improvement in IBS-related symptoms; and (2) identify using longitudinal analyses how SIBO status and fecal microbiota features associate with response to either rifaximin or low FODMAP dietary intervention. METHODS/STUDY POPULATION: 42 patients ≥ 18 years of age who meet Rome IV criteria for IBS-D will be randomized to receive either rifaximin or low FODMAP diet intervention. The primary outcome will be the proportion of responders to intervention which is defined as ≥ 30% reduction in mean daily abdominal pain or bloating by visual analog scale compared with baseline. Exclusion criteria will include: (a) history of microscopic colitis, inflammatory bowel disease, celiac disease, or other organic disease that could explain symptoms, (b) prior gastrointestinal surgery, other than appendectomy or cholecystectomy > 6 months prior to study initiation, (c) prior use of rifaximin or formal dietary interventions for IBS-D, (d) use of antibiotics within the past 3 months, or (e) use of probiotics within 1 month of study entry. Glucose hydrogen breath tests will be performed at the beginning and end of the trial to evaluate for SIBO. Fecal samples will be collected at 0, 2, and 6 weeks to determine changes in fecal microbial composition and structure. RESULTS/ANTICIPATED RESULTS: This study seeks to examine whether longitudinal analyses of small intestinal and colonic microbiota can subtype IBS-D subjects into clinically relevant phenotypes. A total of 18 subjects have been enrolled into the study. Clinical variables, hydrogen breath test results, and fecal microbiota data are being collected for ongoing analysis. DISCUSSION/SIGNIFICANCE OF IMPACT: Results from this study may help move treatment of IBS from a purely symptom based approach to a more individualized approach by stratifying IBS-D patients into distinct clinical phenotypes which are amenable to targeted therapeutic approaches.

OBJECTIVES/GOALS: Older adults are often underrepresented in research due to recruitment and retention barriers, among others. Frameworks have been developed to address these barriers but have not been disseminated to research teams without aging expertise. We aimed to test Age-Friendly tools among non-aging-trained research teams. METHODS/STUDY POPULATION: Our team developed and/or adapted seven Age-Friendly research tools to improve inclusion of older adults in research. Tools included a communication guide, Age-Friendly research checklist, knowledge consent check, and condolence card template, among others. Non-aging-trained research team members (n= 21) were invited to pilot test them and share strengths, limitations, and areas for improvement for each tool. Feedback was collected for up to 4 months using REDCap surveys and analyzed for common themes. Participants provided written informed consent and received a stipend of $1000 upon the completion of the surveys. RESULTS/ANTICIPATED RESULTS: Sixteen participants (76%) from primarily cancer and neurology departments completed at least one survey. The communication guide, research checklist, and knowledge check were implemented the most within the participants' study populations. Participants shared that the tools were user-friendly, easy to access, and well-explained through webinar trainings (offered separately) or instruction sheets. The most frequently reported barriers were lack of time, industry-sponsored trial restrictions, and lack of age-appropriate study populations. DISCUSSION/SIGNIFICANCE: Age-Friendly tools were acceptable and valuable among non-aging-trained research members. Dissemination of these tools could improve the experience for research teams and older adults and help align demographics of enrolled study populations with demographics of the condition being studied.

ABSTRACT IMPACT: Long-acting insulin containing protamine is more likely to be associated with skin depigmentation. OBJECTIVES/GOALS: An acquired disorder, skin depigmentation was found to be significantly correlated with diabetes. While a recent meta-analysis pointed at a possible similar pathogenesis, the possibility of vitiligo occurring as a drug-induced disease was never explored. This study aimed at elucidating whether utilization of specific insulins may play a role. METHODS/STUDY POPULATION: Records from the Medical Panels Expenditure Survey (MEPS) database made available by the Agency for Healthcare Research and Quality were used to identify all injectable insulin users (n=8867). ICD-9/10 codes were abstracted from the medical conditions files for all the subjects reporting any type of injectable insulin use (1996-2017). Skin depigmentation codes identified in our dataset were 709 and L81. Insulins were categorized based on duration of action, short-acting (SA), intermediate-acting (IA), and long-acting (LA), as well as based on formulation ingredients (zinc, protamine-zinc, other), and insulin combination (SA with or without IA/LA containing or not protamine-zinc). The association between skin depigmentation occurrence and insulin type and/or category was assessed by Fisher’s exact test. RESULTS/ANTICIPATED RESULTS: A total of 225 out of 8867 individuals were diagnosed with skin depigmentation. Incidence of skin depigmentation was 2.25% in SA users (n1=3606, p=0.355), 2.24% in LA users (n2=3910, p=0.337), and 2.39% in IA users (n3=4015, p=0.062). Occurrence of skin depigmentation was similar between users of insulin mono- or combo therapy (p=0.758). Interestingly, among IA insulins, insulin protamine-zinc insulin (n4=3992) distinguished as being mainly responsible for the association with the occurrence of skin depigmentation (p=0.062), whereas insulin zinc was not (n5=37, p=1.000). The highest skin depigmentation incidence was observed among Pacific Islanders (2.66%, p=0.110). Males distinguished by a skin depigmentation incidence of 2.34% vs. 1.91% in females (p=0.086). DISCUSSION/SIGNIFICANCE OF FINDINGS: We report that presence of protamine-zinc may play a role in the development of skin depigmentation. It is uncertain whether this risk may be shared equally by insulin users diagnosed with type 1 and type 2 diabetes. Of note, we observed a higher skin depigmentation incidence than that reported by community- (0.2%) or hospital-based (1.8%) studies.

ABSTRACT IMPACT: Our may suggest that delta hsTrop could be of prognostic value in patients with sepsis. OBJECTIVES/GOALS: - METHODS/STUDY POPULATION: We analyzed data of those presenting to the ED over an 18-month period with sepsis and at least one episode of hypotension after 1 liter of IV fluids. We performed a retrospective analysis using a cohort derived from modified inclusion and exclusion criteria from the CLOVERS study. The outcomes of patients found to have a delta (at least 6 pg/dL) in high sensitivity troponin T were compared to patients who did not have a delta or have a troponin level measured. We examined demographic and treatment characteristics of this cohort and the incidence of adverse outcomes were determined. We used multivariable logistic regression analysis to test the association of hsTrop and mortality. RESULTS/ANTICIPATED RESULTS: 778 patients met criteria to be included in the cohort. 279 patients had a change in high sensitivity troponins, an incidence of 35.9%. Patients with a delta were more likely to be older, male, and have a higher Charlson index than patients without a delta or those that had no troponin measured. They were also more likely to have a history of chronic lung disease, heart failure and hypertension. Change in high sensitivity troponins were associated with higher in-hospital mortality. When adjusted for age, gender, and Charlson Index, the association between a positive delta troponin and mortality remained statistically significant. DISCUSSION/SIGNIFICANCE OF FINDINGS: In patients with severe sepsis and septic shock, the presence of a positive or negative delta hsTrop at 2 hours is associated with increased mortality. Measurement of high sensitivity troponin early in the patient’s hospital course may have prognostic utility.

OBJECTIVES/SPECIFIC AIMS: The Empower Lab was established in 2015 with the goal of providing students with hands-on research experience in sexual and gender-based violence and health. METHODS/STUDY POPULATION: The Empower Lab consists of 10–12 undergraduate, graduate, and medical students at a time. Students undergo a rigorous application process, and agree to volunteer 8 hours per week for at least 1 year. Students are assigned to teams, and learn research skills such as literature searches, systematic reviews, research question generation, study design, IRB procedures, database creation and management, data collection and analysis, oral and poster presentation, manuscript preparation, team collaboration and communication, advocacy, and leadership. Students start as research assistants, and can be promoted to team leader, and associate director of research. Students mentor and teach each other, and are supervised by the principal investigator (PI). A survey skill self-assessment is administered to lab members on entry to the lab, every 4–6 months, and upon exit. RESULTS/ANTICIPATED RESULTS: In total, 20 students have participated in the lab to date, and 12 are currently enrolled. Eighty percent of the lab members are women. The students are 45% undergraduates, 15% graduate (nursing, social work, public health), 20% medical students, and 10% not currently enrolled in school (gap year). Twenty students completed entry surveys, 11 students have completed interim surveys, and 5 students have completed exit surveys. Examination of current surveys indicates that students are gaining skills throughout the lab experience. Free-text feedback provided further insight. Currently, the lab has 5 IRB-approved studies actively recruiting participants, 4 manuscripts being written, and 3 studies in the development phase. Students have presented at three local and 2 national meetings to date. Changes have been made to the lab structure over time in order to provide clear expectations and feedback, and strengthen student performance. DISCUSSION/SIGNIFICANCE OF IMPACT: The Empower Lab is an innovative public health lab that provides opportunities for real-world research experience for students. The teamwork, collaboration, and structure of the lab permit mentoring, support, and teaching from peers, as well as from the PI. The Lab increases the PI’s productivity. Students are encouraged to develop and implement their own research ideas, further encouraging independence and initiative. Although the number of surveys is limited to date, they indicate improvement in skills and confidence among lab members. The predominance of women in the lab suggests that this is a strong model for recruitment and retention of women in STEM.

OBJECTIVES/GOALS: Sexism harms women’s well-being, affecting life satisfaction and self-doubt in complex ways (Shattell etal., 2008; Oswald etal., 2018). This study examines how hostile and benevolent sexist attitudes moderates the link between experiences of benevolent sexism, self-doubt, and life satisfaction in Latinx women. METHODS/STUDY POPULATION: Participants included 57 English-speaking Latinx women residing in the United States, with a mean age of 31.89 (SD=10.14) years. The majority (61.4%, n=35) identified as Mexican, and most identified as second generation or later (80.7%, n=46). Participants completed surveys assessing hostile and benevolent sexist attitudes (Glick & Fiske, 1996), self-doubt (Oleson etal., 2000), life satisfaction (Diener etal., 1985), and experiences with three aspects of benevolent sexism – protective paternalism (PP), heterosexual intimacy (HI), and complimentary gender differentiation (CGD) (Oswald etal., 2018). RESULTS/ANTICIPATED RESULTS: Moderation analyses were conducted to examine the moderating role of hostile and benevolent sexist attitudes between experiences of benevolent sexism (PP, HI, & CGD) and well-being measures (self-doubt and life satisfaction). An example finding revealed a significant interaction effect between benevolent sexist attitudes and experiences with CGD on satisfaction with lifeF(1,53)=8.34,p<.01. For participants who endorsed high benevolent sexist attitudes, experiences with CGD was associated with increased satisfaction with life (b=.78, p<.001), while the effect of experiences with CGD on life satisfaction was attenuated for those who endorsed low benevolent sexist attitudes (b=.30, p<.05). DISCUSSION/SIGNIFICANCE: These findings have important implications on the well-being of Latinx women as they indicate that those who reject sexist attitudes risk their well-being when confronted with benevolent sexism, unlike those who endorse to such beliefs, potentially gaining increased life satisfaction at the cost of embracing benevolent sexist behavior.

OBJECTIVES/GOALS: The impact of baseline BMI on glycemic response to group medical visits (GMV) and weight management (WM)-based interventions is unclear. Our objective is to determine how baseline BMI class impacts patient responses to GMV and interventions that combine WM/GMV. METHODS/STUDY POPULATION: We will perform a secondary analysis of Jump Start, a randomized, controlled trial that compared the effectiveness of a GMV-based low carbohydrate diet-focused WM program (WM/GMV) to traditional GMV-based medication management (GMV) on diabetes control. The primary and secondary outcomes will be change in hemoglobin A1c (HbA1c) and weight at 48 months, respectively. Study participants will be stratified into BMI categories defined by BMI 27-29.9kg/m2, 30.0-34.9kg/m2, 35.0-39.9kg/m2, and ≥40.0kg/m2. Hierarchical mixed models will be used to examine the differential impact of the WM/GMV intervention compared to GMV on changes in outcomes by BMI class category. RESULTS/ANTICIPATED RESULTS: Jump Start enrolled 263 overweight Veterans (BMI ≥ 27kg/m2) with type 2 diabetes. At baseline, mean BMI was 35.3 and mean HbA1c was 9.1. 14.5% were overweight (BMI 27–29.9) and 84.5% were obese (BMI ≥ 30). The proposed analyses are ongoing. We anticipate that patients in the higher BMI obesity classes will demonstrate greater reductions in HbA1c and weight with the WM/GMV intervention relative to traditional GMV. DISCUSSION/SIGNIFICANCE OF IMPACT: This work will advance the understanding of the relationship between BMI and glycemic response to targeted interventions, and may ultimately provide guidance for interventions for type 2 diabetes.

OBJECTIVES/SPECIFIC AIMS: The primary goal of this project is to verify findings from a murine prostatitis model in the human setting. METHODS/STUDY POPULATION: Methods include primary cell isolation and culture, FACS, adoptive transfer, 3D cell culture, histology, immunofluorescence, xenograft, and tissue recombination. The study population includes patients undergoing HoLEP or radical prostatectomy due to hyperplasia or adjacent bladder or prostate cancer. RESULTS/ANTICIPATED RESULTS: Having verified similar sensitivities to androgen receptor (AR) inhibitors between naive murine and human basal prostate stem cells, we anticipate that autoimmune inflammation in humans affects the response of basal prostate stem cells in a manner similar to the murine setting as well. This includes increased proliferation, increased differentiation, and decreased response to AR inhibitors. DISCUSSION/SIGNIFICANCE OF IMPACT: The identification of survival mechanisms used by basal prostate stem cells in an androgen deprived environment may give insight to the process by which prostate cancer becomes androgen independent. The effect of inflammation on proliferation, survival, and AR signaling in these cells may also provide information relevant to cancer initiation and progression.

OBJECTIVES/GOALS: Surgical training is constrained by duty hour limits, bias, and a trial-and-error learning process. Surgeon skill variation is a healthcare system disparity that can impact patient outcomes. Incorporating validated, standardized assessment tools and machine learning (ML) algorithms may help to standardize and reduce bias in surgeon education. METHODS/STUDY POPULATION: To support assessment tool and ML algorithm development, we are curating an annotated video registry of neurosurgical procedures. Point-of-view video of resident and attending neurosurgeons performing craniotomies is recorded via an eye-tracking headset. A Delphi panel of neurosurgeons will review the video and determine which represent expert versus trainee performance. Neurosurgery attendings will be interviewed to provide descriptions of craniotomies which will be used to develop an assessment rubric. A Delphi panel will determine what rubric components should be maintained. New craniotomy videos will be viewed by attendings in a blinded fashion while completing the assessment rubric. An online feedback platform is being developed allowing residents to prospectively track assessment data. RESULTS/ANTICIPATED RESULTS: We anticipate development of an annotated, institutional video database featuring craniotomies performed by residents and attending neurosurgeons. Using a Delphi approach, we anticipate achieving consensus on which videos reflect expert versus trainee performance. We anticipate development of a novel craniotomy assessment rubric that is both valid and reliable. Our online feedback platform will allow prospective tracking of assessment data from multiple sources and enhanced transparency in the feedback process. The video registry and assessment data will enable development of novel ML algorithms able to recognize craniotomy segments and estimate operator skill. DISCUSSION/SIGNIFICANCE: Building a video registry of procedures, validated assessment tools, and a prototype feedback platform enables a pipeline for ML algorithm development. Together these tools will help to standardize and optimize resident education translating to earlier operative independence, improved patient safety, and reduced bias during surgical training.

OBJECTIVES/GOALS: Scholarly achievement metrics are essential for academic researchers since they are used for promotion and funding opportunities. Our objective was to create awareness among pilot project PIs about how these scholarly activities are evaluated and about the need for continuous auto-evaluation. METHODS/STUDY POPULATION: NIH-sponsored Clinical & Translational Research (CTR) infrastructure grants are a critical mechanism to increase scholarly activity. The Pilot Project Program Core (PPP) of The Alliance IDeA-CTR created a weighted metrics system to evaluate activities including presentations, publications, promotion, honors, & community service. We used the revised evidence-based medicine pyramid to develop the metric instrument. Pilot project PIs received the metric table and met quarterly with a PPP member to discuss progress. The top PIs were acknowledged during the Alliance Research Day with a platform presentation and a monetary award for research expenses or travel to scientific meetings. RESULTS/ANTICIPATED RESULTS: During our first 2 pilot project calls (2020-2022) the PPP funded 7 one-year pilot projects for ($50,000 each). We had a total of 10 PIs, 2 of the projects were MPI. Seven PIs were early or new stage investigators (ESI/NSI). Using the productivity award metric we had a total of 33 presentations, 10 publications, 12 events of community service, and 2 external grant funding. These are significant outcomes considering the pandemics impact on clinical & translational research. A total of 3 awards were given, one award per year for funding and an overall award. The activity was well received by the PIs who actively participated in the tracking of their scholarly activities using the metric. DISCUSSION/SIGNIFICANCE: Productivity metrics are crucial for the career development of ESI and NSI by raising awareness regarding the importance of scholarly activities in their career. This activity will help them track their productivity in an ongoing manner while becoming independent researchers.

OBJECTIVES/SPECIFIC AIMS: (1) Evaluate safety of a novel influenza vaccination strategy in patients with plasma cell disorders. (2) Measure laboratory-confirmed influenza infection rates following a novel influenza vaccination strategy in patients with plasma cell disorders. (3) Evaluate clinical correlates of response following a novel influenza vaccination strategy in patients with plasma cell disorders. METHODS/STUDY POPULATION: We conducted a double-blind, randomized study over the 2015–16 flu season, comparing 2 doses of Fluzone® High-Dose influenza vaccination (separated by 30 d) to the current standard of care influenza vaccination. Patients were allocated to the experimental arm in 2:1 ratio compared with standard of care arm. Standard of care influenza vaccination was considered single age-based vaccination (standard dose for those <65 y and high dosefor those ≥65 y) and patients in this arm received a saline placebo injection at 30 days to assist in blinding. Eligibility criteria allowed any patient with a PCD and no contraindication to trivalent inactivated influenza vaccine. The primary endpoint was laboratory-confirmed flu infection rate. Protocol-driven surveillance screened patients for flu-like illnesses and performed laboratory testing for influenza until the end of the flu season in May 2016. Secondary endpoints include HAI titer serologic response rates, clinical correlates of protection from influenza infection, and exploratory studies of cell-mediated immunity through characterization of T cell subpopulations, cytokine profiles, and flu-specific T-cell responsiveness. RESULTS/ANTICIPATED RESULTS: In total, 122 plasma cell disorder patients were enrolled (97 with disease requiring therapy and 25 with asymptomatic gammopathy). Of those 48 patients received a single standard of care influenza vaccination and 74 patients received 2 doses of Fluzone® high-dose vaccine. Median age was 67 years (range 42–90). This 2-dose vaccination strategy was safely tolerated in all patients with no grade 2 adverse events attributed to vaccine. With close clinical follow-up, only 4% of patients receiving 2 vaccine doses developed laboratory confirmed influenza Versus 8.3% of those receiving single vaccine. When compared to the expected CDC influenza infection rate of 10%–15%, 1 sample, 2-tailed binomial testing revealed patients receiving 2 vaccines experienced a significantly lower rate of infection than the expected rate (p<0.05) whereas those receiving single vaccine showed no significant difference (p=0.38). DISCUSSION/SIGNIFICANCE OF IMPACT: This randomized study demonstrates that the 2 dose strategy of Fluzone® high-dose influenza vaccine is safely tolerated in patients with plasma cell disorders and associated with significantly less than expected laboratory-confirmed influenza infections. The results suggest that this novel vaccination strategy may have a clinical benefit in reducing influenza infections in plasma cell disorder patients and thus may have practice changing implications. Final analyses of serologic responses, clinical correlates of response, and cell-mediated immune correlates may provide valuable insights into in vivo “immune-competence” in patients with plasma cell disorders.

OBJECTIVES/GOALS: This study aimed to investigate the mechanistic effects of fish oil (âμ-3 fatty acids) or evening primrose oil (âμ-6 fatty acids) supplementation on platelet reactivity in postmenopausal women. METHODS/STUDY POPULATION: Postmenopausal women were recruited from the Ann Arbor community and the University of Michigan Medicine Center. All subjects were recruited under study protocols approved by the University of Michigan IRB between November 2015 and March 2017. We conducted a randomized, double-blind, two-period crossover trial, consisting of a 60-day supplementation period followed by a 14-day washout period in between and at the end of the study. Subjects were treated daily in random order with 2g of fish oil supplement and 2g of evening primrose oil. Blood was drawn at baseline, post-supplementation, and after washout. The effects of fatty acid supplementation on platelet aggregation, dense granule secretion and activation of basal integrin âºIIbÎ23 were assessed following supplementation and washout period. RESULTS/ANTICIPATED RESULTS: The study started with 90 postmenopausal women. A total of 78 subjects completed the study, with 12 subjects dropping out due to non-compliance and medical reasons. Supplementation with fish oil attenuated the thrombin receptor PAR4-induced platelet aggregation, whereas primrose oil supplementation attenuated aggregation mediated by PAR4 or collagen. Supplementation with âμ-3 or âμ-6 fatty acids decreased platelet dense granule secretion and attenuated basal levels of integrin âºIIbÎ23 activation. Post-washout following supplementation with primrose oil, the thrombin receptor PAR1-induced platelet aggregation was similarly attenuated. For either treatment, the observed effects post supplementation on dense granule secretion and basal integrin activation were sustained after the washout. DISCUSSION/SIGNIFICANCE: Postmenopausal women are at increased risk for a cardiovascular event due to platelet hyperactivity. This study indicates that supplementation with âμ-3 and âμ-6 fatty acids may offer significant protection for postmenopausal women against cardiovascular diseases and occlusive thrombotic events by reducing platelet reactivity.

ABSTRACT IMPACT: This study establishes the association between childhood hypertension and health outcomes in early adulthood, identifying the need to understand blood pressure during early life for primary prevention of hypertension and cardiovascular disease. OBJECTIVES/GOALS: There is evidence that blood pressure level in early life can influence hypertension and other cardiovascular risk factors later in life. We examined whether hypertension before the age of 18 is associated with higher odds of obesity and hypertension after the age of 18. METHODS/STUDY POPULATION: We studied 19,367 children and adolescents from the Vanderbilt University Medical Center’s Synthetic Derivative, a de-identified version of the electronic medical record. Childhood hypertension was defined as systolic blood pressure (SBP) ≥130 mmHg or diastolic blood pressure (DBP) ≥80 mmHg at three or more outpatient visits before the age of 18. Obesity and hypertension in early adulthood were the primary outcomes. Obesity was defined as being above normal weight for adulthood height at age 30 based on the NIH’s body mass index tables. Hypertension was defined as SBP ≥130 mmHg or DBP ≥80 mmHg at three or more outpatient visits after the age of 18. Odds ratios and 95% confidence intervals (CIs) were computed from logistic regression models adjusted for demographics, medication use, and childhood weight. RESULTS/ANTICIPATED RESULTS: Most subjects were female (63%) and white (80%). During childhood, 17% of participants had hypertension. Approximately 58% of this group were obese at age 30, and 38% had hypertension as adults. Compared to females with no childhood hypertension, females with childhood hypertension had 1.35 times higher odds of being obese at age 30 (95% CI: 1.15, 1.58) and 3.56 times higher odds of having hypertension over the age of 18 (95% CI: 3.09, 4.09). Males with childhood hypertension, compared to males without, had 1.28 times higher odds of being obese at age 30 (95% CI: 1.08, 1.52) and 2.74 times higher odds of having hypertension over the age of 18 (95% CI: 2.35, 3.20). Associations between childhood hypertension, early adulthood obesity, and hypertension significantly differed by gender (p-for-interaction for both: <0.01). DISCUSSION/SIGNIFICANCE OF FINDINGS: Childhood hypertension is associated with obesity and hypertension in early adulthood. Understanding blood pressure levels in childhood and adolescence may help target efforts to reduce early adulthood cardiovascular risk factors.

OBJECTIVES/GOALS: Preterm birth is the most common birth complication in the United States. To date, there are no effective public health strategies to reduce the burden of prematurity. Using geospatial information system (GIS) mapping, we identified the most salient risk factors of preterm birth across US counties targetable for future interventions. METHODS/STUDY POPULATION: Risk factors of preterm birth were identified from the perinatal health nonprofit organization, March of Dimes, and included factors such as obesity, smoking, insurance coverage and poverty. US 2013 county-level data on sociodemographic characteristics, behavioral risk factors and preterm birth were extracted and combined from the American Census, Center for Disease Control, and US Health Resources and Services Administration. Spatial autocorrelation and multivariate spatial regression were used to determine the risk factors most strongly associated with preterm birth. These models were adjusted for race, given well-documented race disparities for preterm birth. As a case-study comparison, we mapped risk factors in the two states with the highest and lowest proportion of preterm births in 2013. RESULTS/ANTICIPATED RESULTS: In our preliminary analysis, obesity was the factor most strongly associated with preterm birth (ß = 7.32, SE: 1.13, p<0.001) at the US county-level. Surprisingly, smoking was not found to be significantly associated with preterm birth. In 2013, Vermont had the lowest prevalence of preterm birth at 7.6% and Mississippi had the highest prevalence of preterm birth at 13.1%. Health insurance coverage and obesity were the two risk factors that differed between Vermont and Mississippi. The median proportion of uninsured individuals in Mississippi counties was four times higher than that of Vermont counties (26.3% vs 10.9%, p<0.01). Similarly, the median obesity prevalence in Mississippi counties was significantly higher than the median obesity prevalence in Vermont counties (38.8% vs. 25.2%). DISCUSSION/SIGNIFICANCE OF IMPACT: Public health efforts aimed at reducing obesity and increasing health insurance coverage may have the greatest impact at addressing the US burden of preterm birth. Further, geospatial mapping is a powerful analytic tool to identify regions in the US where preterm birth interventions would be most beneficial.