bluuebunny/crossref_metadata_2025 huggingface dataset:
420 Computable Phenotyping with “Big Data” as a Foundation for Artificial Intelligence Algorithm Construction: Puberty as a Transdisciplinary Case Example
Authors: Schnabel David (DJ) , Dorn Lorah D.
Published: April 2024

OBJECTIVES/GOALS: Artificial intelligence (AI) depends on quality machine learning (ML) algorithms constructed with high-quality training data. This TL1 trainee project develops a disease-agnostic computable phenotype framework for ML algorithm construction, modeling male puberty as a case example. METHODS/STUDY POPULATION: A computable phenotype of male puberty was constructed to answer the question: “Does early pubertal timing increase the risk of developing type II diabetes (T2D) in males?” A computable phenotype of males < 18 years old was created in the TriNetX© Diamond Network utilizing Boolean operator data queries. TriNetX© contains patient electronic health record information (ICD-10 diagnoses, anthropometric measures). An exploratory analysis of patient counts reflecting various computable phenotypes allowed for outcome (T2D) comparison of males diagnosed with precocious puberty (E30.1, ICD code for early pubertal timing) to those without, controlling for body mass index (BMI). RESULTS/ANTICIPATED RESULTS: Subjects (n=12,996,132) displayed the following computable phenotype: Male, < 18 years old, without ever having a BMI documented >85th percentile. Males diagnosed with precocious puberty (E30.1) were 6.89 times more likely to develop T2D when aged 14-18 years old than those without (OR 6.89, 95% CI: 5.17-9.19, p<0.0001). Next steps involve training a ML model on each computable phenotype groupings’ health data, with anticipated results identifying underlying salient pathophysiologic variables. A generalized computable phenotype approach is further developed to: 1) explore clinical questions in large databases like TriNetX©, and 2) model disease development with AI/ML algorithm construction. DISCUSSION/SIGNIFICANCE: Computed phenotypes reveal males with precocious puberty may have increased T2D risk. Next steps utilize subject data to train an AI/ML algorithm, model development to identify salient pathophysiologic variables, and synthesize a generalized AI/ML developmental research framework for dissemination.
424 Deciphering the Immune Landscape in Benign Breast Disease: Implications for Risk Stratification and Breast Cancer Prevention
Authors: Rossi Matilde , Cruz-Reyes Nicole , Vierkant Rob , Degnim Amy , Sherman Mark , Radisky Derek
Published: April 2024

OBJECTIVES/GOALS: The objective of our research is to define unique molecular and immune markers in benign breast tissue to better identify women at risk of node-positive breast cancer (BC). The goal of the work is to improve individualized risk assessment, to guide targeted prevention and screening recommendations, and to reduce disease incidence and mortality. METHODS/STUDY POPULATION: From the Mayo Clinic’s Benign Breast Disease (BBD) cohort, we matched women who developed node-positive breast cancer after a BBD biopsy (cases; n=42) with women who remained cancer-free (controls; n=37), considering patient age and biopsy date. We used NanoString gene expression profiling to identify differentially expressed genes (DEGs) between cases and controls. We optimized a multiplex immunofluorescence (mIF) approach to simultaneously detect multiple markers within single FFPE tissue slides to correlate cells expressing DEGs in relation to innate and adaptive immune effectors. We used tissue segmentation, cell phenotyping, and spatial relationships to define molecular and immune differences between cases and controls. RESULTS/ANTICIPATED RESULTS: We discovered higher gene expression levels of IRF8 (interferon regulatory factor 8, a factor involved in immune cell differentiation) in controls as compared to cases (p = 0.0024) and found that IRF8 expression is also associated with longer cancer onset times among cases (p = 0.0012). Our pilot mIF experiments revealed higher frequencies of CD4+, CD8+, CD68+, CD20+ and CD11c+ cells in controls compared to cases. We predict that higher IRF8 expression and increased frequencies of immune cells in BBD biopsies indicate a proactive immune environment that may act to prevent cancer development. Furthermore, we predict that our analyses of the spatial localization of these markers by mIF may offer further predictive insight. DISCUSSION/SIGNIFICANCE: Deciphering the relationship between immune alterations in BBD and risk of node positive BC has the potential to improve individualized risk prediction. These insights will foster improved surveillance and informed screening and prevention, ultimately reducing BC incidence and mortality.
430 Genome-wide meta-analysis identifies novel risk loci for uterine fibroids across multiple ancestry groups
Authors: Kim Jeewoo , Williams Ariel , Noh Hannah , Shuey Megan M. , Edwards Todd L. , Velez Edwards Digna R. , Hellwege Jacklyn N.
Published: April 2024

OBJECTIVES/GOALS: Uterine fibroids are benign tumors of the uterus with a high disease prevalence and burden, yet there are few multi-ancestry genetic studies. This is the largest and most diverse fibroid GWAS to-date. Our goal is to identify novel genetic variants and gene expression pathways associated with fibroids and characterize their biological relevance. METHODS/STUDY POPULATION: We performed a cross-ancestry meta-analysis of GWAS summary statistics from eight datasets. The total sample size was 74,294 cases and 465,810 controls with participants of European (80% of sample), African (4%), East Asian, and Central South Asian (16%) ancestry. We mapped variants to genes with OpenTarget Genetics and used Functional Mapping and Annotation to conduct tissue expression gene-set enrichment and identify lead variants. We used S-PrediXcan to estimate genetically predicted gene expression (GPGE) associated with fibroid risk. This was with models that predicted gene expression across 49 different tissue types. Ingenuity Pathway Analysis compiled significant GPGE genes and their weights with a scientific literature database to identify overlapping pathways. RESULTS/ANTICIPATED RESULTS: We identified 370 independent significant variants. Among these, we identified variants mapped to three novel genes (PAX2, VIP, FOXO3) and eight genes not previously validated (TEKT1, SLC16A11, RPEL1, RASL11B, ASGR1, SLC12A7, TTC28, POLR2A). Many loci have roles in cell cycle regulation or are associated with fibroid risk factors like blood pressure, BMI, and vitamin D levels. Loci were significantly enriched in DNA damage and cell cycle pathways. Of 588 significant predicted expression gene-tissue pairs, 173 unique genes were novel fibroid associations. These genes are also associated with cancers, estradiol, and endometriosis. Top enriched pathways included p53 signaling, HOTAIR, BRCA1DNA damage response, and pulmonary fibrosis signaling. In uterine tissue there were 15 novel GPGE associations. DISCUSSION/SIGNIFICANCE: Using this large and diverse data, we identified novel loci associated with fibroids that are enriched in hormone-response, DNA damage, and cell-cycle pathways. GPGE loci were in tumorigenesis and fibrosis pathways. These novel genetic loci and uterine gene expression findings may provide translational opportunities for novel fibroid treatments.
434 Investigating the metabolic-inflammatory mechanisms of cachexia symptoms in head and neck cancer patient plasma via multiomics integration of the metabolome, lipidome, and inflammation cytokines
Authors: Eldridge Ronald C. , Saba Nabil F. , Miller Andrew H. , Wommack Evanthia C. , Felger Jennifer , Bruner Deborah W. , Xiao Canhua
Published: April 2024

OBJECTIVES/GOALS: Cachexia is the involuntary and irreversible loss of muscle and fat and is a major cause of morbidity and mortality in head and neck cancer (HNC). It remains a poorly understood disease diagnosed by weight loss and a confluence of symptoms. We explored the metabolic and inflammatory mechanisms of cachexia symptoms via an multiomics network algorithm. METHODS/STUDY POPULATION: Prior to chemoradiotherapy, HNC subjects completed questionnaires and donated blood for untargeted (metabolites) and targeted (lipids and cytokines) assays. Metabolites and lipids were measured by liquid chromatography mass spectrometry. Cytokines were measured by multiplex assays. We plotted a multiomics network graph by estimating partial least squares correlations amongst metabolites, lipids, cytokines, and common cachexia symptoms—max percent weight loss over 1 year, baseline BMI, fatigue, performance, albumin, hemoglobin, and white blood cell count. To interpret the network, an algorithm identified highly correlated clusters of metabolites-lipids-cytokines-symptoms representing possible biological relatedness, which were functionally annotated via metabolic enrichment analysis. RESULTS/ANTICIPATED RESULTS: In 123 subjects (59 years of age, 72% male, 84% white, avg weight loss of 13%), we analyzed 186 metabolites, 54 lipids, 7 cytokines and 7 cachexia symptoms. We required a correlation >0.25 and P-value <.05 to be included in the network graph, resulting in 323 connections and 3 identified clusters. Max weight loss and baseline BMI were in a cluster enriched by unsaturated fatty acid biosynthesis (P<.0001) and arachidonic acid (P=.01) metabolic pathways but not linked to inflammation cytokines. The five other cachexia symptoms were in a cluster with 4 cytokines (C-reactive protein, interleukin 6, IL10, IL1, Tumor necrosis factor receptor 2) and enriched by aminoacyl tRNA (P<.01) and valine biosynthesis (P=.02). We observed no meaningful differences when we stratified the analysis by human papillomavirus. DISCUSSION/SIGNIFICANCE: Cachexia symptoms in head and neck cancer may be linked to specific metabolic dysregulation—weight loss and BMI were linked to fatty acids; fatigue, anemia and others were linked to amino acids and inflammation. This information may allow for the recognition of a cachexic-metabolic subtype or provide novel targets for metabolic intervention.
440 Muscle Protein Synthesis and Whole-Body Protein Balance Following Ingestion of Beef or a Soy Protein Based Meat Alternative
Authors: Church David D. , Hirsch Katie R. , Kviatkovsky Shiloah A. , Ferrando Arny A. , Azhar Gohar , Wolfe Robert R
Published: April 2024

OBJECTIVES/GOALS: We endeavor to investigated the hypothesis that muscle protein synthesis (MPS) is stimulated more after consumption of a 4-ounce beef patty as compared to 4- and 8-ounces of a soy protein based meat alternative (SPBMA) and if a greater stimulation is related to differences in the responses of plasma essential amino acid (EAA) concentrations. METHODS/STUDY POPULATION: Participants were aged 18 to 40 years of age with a BMI between 20 and 32 kg/m2. Written informed consent was obtained from all participants, and approved by UAMS IRB. Participants were assigned to one of three intervention groups via a single-blinded permuted block randomization, stratified for sex: 4 oz beef patty; 4 oz SPBMA; 2 x 4 oz (8oz) SPBMA. The impossible burgerTM was selected as it is primarily soy protein, a high-quality plant protein, and specifically designed to mimic a beef burger. Stable isotope were infused to assess protein metabolism. Appropriate muscle and blood samples were obtained. Enrichment and plasma EAA concentrations were measured with mass spectrometry. ANOVA’s on the change from basal to postprandial were used to identify group difference, significance was accepted at p < 0.05. RESULTS/ANTICIPATED RESULTS: The MPS increase from basal to postprandial indicated a significant main effect of group (p = 0.026), with the beef group (0.020 ± 0.016%/hour) being significantly greater than the 4oz SPBMA (0.003 ± 0.010%/hour; p = 0.021) but not the 8oz PBMA group (0.013 ± 0.016%/hour; p = 0.454). Similar results were observed for whole-body protein synthesis, where the beef group (p = 0.042) and 8oz SPBMA (p = 0.033) were significantly greater than the 4oz SPBMA (p = 0.021). Whole-body protein balance was significantly greater in the 8oz SPBMA as compared to 4oz of beef and SPBMA. Lastly, we observed a significantly relationship (p = 0.046; r = 0.411) between the maximal plasma EAA concentration and change in MPS, indicating the greater rate of MPS following 4oz of beef is mediated by an higher increase in plasma EAA concentrations. DISCUSSION/SIGNIFICANCE: In conclusion, 4oz of beef stimulates muscle protein FSR more than 4oz of a SPBMA. A common SPBMA can stimulate increase in protein metabolism, however, greater amounts are required as compared to beef protein. Further, the change in the muscle protein FSR response was significantly correlated with the maximal EAA concentration.
448 Deformable Medial Modeling to Generate Novel Shape Features of the Placenta Using Automated versus Manual Segmentations
Authors: Arenas Gabriel , Pouch Alison , Oguz Ipek , Oguz Baris , Byram Brett , Yao Xing , Schwartz Nadav
Published: April 2024

OBJECTIVES/GOALS: In this study, we implemented deformable medial modeling as a morphometric approach in first trimester placentas to characterize morphometric differences between fully automated and manual segmentations. METHODS/STUDY POPULATION: Twenty placentas from singleton pregnancies between 11-14 weeks’ gestation were manually and automatically segmented from 3D ultrasound volumes. Automated segmentations were produced by a trained convolutional neural network pipeline. Dice overlap scores and volumes were computed between manual and automated segmentations. Deformable medial modeling was applied to both manual and automated segmentations to produce the following metrics: maternal and chorionic surface areas (SA), thickness, circumference, and diameter along the generated medial surface. Placental non-planarity was also determined as the greatest medial surface height difference. A paired t-test and simple linear regression was performed between manual and automated segmentations for each shape metric. RESULTS/ANTICIPATED RESULTS: Mean placental volume measurements between manual and automated segmentations were similar, with a percent difference of 3.28% and a mean Dice overlap score of 0.85 ± 0.07. There were strong, statistically significant (p <0.01) linear correlations with chorionic and maternal SA, SA difference, thickness, circumference, medial surface diameter, and medial surface height difference. No significant differences were noted with chorionic SA, thickness, circumference, maximum medial surface diameter, or medial surface height difference. However, statistically significant differences (p <0.01-0.03) were noted in maternal SA, SA difference, and mean medial surface diameter. Despite these differences, mean percent difference for all morphometric parameters was less than or equal to 10%. DISCUSSION/SIGNIFICANCE: A deformable medial model evaluate unique global and regional shape placental features with highly correlated values between manual versus automated placental segmentations. However, clinical studies are needed to determine if minor differences would impact the clinical utility of these features as potential indicators of placental function.
460 Changes in Lipid Profiles with Progression of Pregnancy in Black Women
Authors: Saadat Nadia , Aguate Fernando , Nowak Alexandra , Hyer Suzanne , Lydic Todd , de los Campos Gustavo , Padmanabhan Vasantha , Misra Dawn , Giurgescu Carmen
Published: April 2024

OBJECTIVES/GOALS: Pregnant African American (Black women) have higher rates of adverse pregnancy outcomes compared to other races and routine monitoring of lipid levels is not currently in practice in prenatal care. We hypothesized that lipid profiles would show variation across pregnancy indicative of specific requirements during gestation and fetal development. METHODS/STUDY POPULATION: We used an untargeted lipidome analysis approach to investigate lipid metabolism with the progression of pregnancy. Pregnant Black women were recruited at prenatal clinics in Midwest (Metro Detroit, Michigan and Columbus, Ohio), women under 18 or above 45 years of age were not enrolled due to metabolic changes associated with these age groups. Women signed the consent forms and plasma samples were collected at 8-18 weeks at (T1), 22-29 weeks (T2) and 30-36 weeks (T3) of pregnancy. Samples from sixty-three women (mean age 27.41 ± 5.61 years) who had term birth (completed 37 weeks of pregnancy) were subjected to “shotgun” Orbitrap high resolution/ accurate mass spectrometry. Mixed-effects models were used to quantify systematic changes in relative lipid abundances over time using R lme4 and ggplot2 packages. RESULTS/ANTICIPATED RESULTS: Total lipids and some major lipid classes showed a significant increase with the progression of pregnancy. Phospholipids and glycerolipids exhibited a gradual increase throughout pregnancy, while sphingolipids and total sterol lipids displayed a more pronounced increase at the T3 timepoint. Acylcarnitines, hydroxy acylcarnitines and Lyso phospholipids levels significantly decrease from T1 to T3. One of the interesting finding was that non-esterified fatty acids decreased from T1 to T2 and increased again from T2 to T3, suggesting a possible role for these lipids during the later stages of pregnancy. The fatty acids showing this trend included key fatty acids- Linoleic Acid, Arachidonic Acid, Alpha-linolenic acid, Eicosapentaenoic acid, Docosapentaenoic acid, Docosahexaenoic acid. DISCUSSION/SIGNIFICANCE: Mapping lipid trends during pregnancy could lend support to a precision health approach to reduce perinatal health disparities among pregnant Black women. The findings from this study will be used to identify biomarkers and study associations with social and environmental factors responsible for adverse perinatal outcome in pregnant Black women.
467 Enhancing Cell Infiltration and Controlled Growth Factor Release for a Customized 3D-Printed Bone Graft Composite
Authors: Alston Claudia Benito , Chadwick Madelyn , Rupani Saaniya , Moldovan Nicanor , Barco Clark , Solorio Luis
Published: April 2024

OBJECTIVES/GOALS: Annually, 1.5 million global patients receive maxillofacial reconstruction. The gold standard, involving bone particulate, lacks reproducibility. To improve this, we have developed a custom 3D-printable, porous cover-core design. This study optimizes the hydrogel core properties and growth factor (GF) release for enhanced bone regeneration. METHODS/STUDY POPULATION: Different ratios of Methacrylated Gelatin (GelMa), Methacrylated Alginate (AlgMa) and tricalcium phosphate (α²-TCP) were combined to optimize cell viability, GF sequestration and mechanical stability. Material characterization was performed using a rheometer to determine the viscoelastic properties of the blends. Release from disks loaded with FGF-containing PLGA microparticles was quantified with an ELISA kit. Furthermore, scanning electron microscopy (SEM) was conducted to quantify hydrogel porosity. In vitro studies were performed using NIH 3T3 murine fibroblasts in Corning Transwells while immunofluorescent, metabolic and osteogenic studies were performed in 96 well plates to investigate cell infiltration, cell adhesion, viability and differentiation, respectively. RESULTS/ANTICIPATED RESULTS: By adjusting the AlgGelMa ratio, we manipulated matrix properties. GelMa possesses excellent durability and cell adhesion due to intrinsic RGD-binding motifs. AlgMa enhanced swelling by 30%, growth factor sequestration by 50% in 24hrs, and matrix storage modulus without increasing the loss modulus which could cause cell migration away from the hydrogel. Varying the AlgGelMa ratio lowered pH, promoted cell infiltration, and reduced fibronectin accumulation. The addition of β-TCP is anticipated to improve cell differentiation towards an osteogenic lineage due to improved elastic modulus, calcium and phosphate ion concentration improving mineral deposition. DISCUSSION/SIGNIFICANCE: These findings suggest through the use of this composite, early cell infiltration can be increased and promoted due to FGF release, leading to increased osteointegration. Our porous cover-core design ensures efficient clot integration and early cell infiltration, enhancing osteointegration through FGF release.
469 Diverse Role of blaCTX-M and Porins in Mediating Ertapenem Resistance Among Carbapenem Resistant Enterobacterales
Authors: Black Cody , Black Cody A. , Benavides Raymond , Bandy Sarah M. , Dallas Steven S. , Gawrys Gerard , So Wonhee , Moreira Alvaro G. , Aguilar Samantha , Quidilla Kevin , Smelter Dan F. , Reveles Kelly R. , Frei Christopher R. , Koeller Jim M. , Lee Grace C.
Published: April 2024

OBJECTIVES/GOALS: In this study, we aim to report the role of porins and blaCTX-M β-lactamases among Escherichia coli and Klebsiella pneumoniae, focusing on emerging carbapenem resistant Enterobacterales (CRE) subtypes, including non-carbapenemase producing Enterobacterales (NCPE) and ertapenem-resistant but meropenem-susceptible (ErMs) strains. METHODS/STUDY POPULATION: Whole genome sequencing was conducted on 76 carbapenem-resistant isolates across 5 hospitals in San Antonio, U.S. Among these, NCP isolates accounted for the majority of CRE (41/76). Identification and antimicrobial susceptibility testing (AST) results were collected from the clinical charts. Repeat speciation was determined through whole genome sequencing (WGS) analysis and repeat AST, performed with microdilution or ETEST®. Minimum inhibitory concentrations (MIC) were consistent with Clinical and Laboratory Standards Institute (CLSI M100, ED33). WGS and qPCR were used to characterize the resistome of all clinical CRE subtypes, while western blotting and liquid chromatography with tandem mass spectrometry (LC-MS-MS) were used to determine porin expression and carbapenem hydrolysis, respectively. RESULTS/ANTICIPATED RESULTS: blaCTX-Mwas found to be most prevalent among NCP isolates (p = 0.02). LC-MS/MS analysis of carbapenem hydrolysis revealed that blaCTX-M-mediated carbapenem hydrolysis, indicating the need to reappraise the term, “non-carbapenemase (NCP)®” for quantitatively uncharacterized CRE strains harboring blaCTX-M. Susceptibility results showed that 56% of all NCPE isolates had an ErMs phenotype (NCPE vs. CPE, p < 0.001), with E. coli driving the phenotype (E. coli vs. K. pneumoniae, p < 0.001). ErMs strains carrying blaCTX-M, had 4-fold more copies of blaCTX-M than ceftriaxone-resistant but ertapenem-susceptible isolates (3.7 v. 0.9, p < 0.001). Immunoblot analysis demonstrated the absence of OmpC expression in NCP-ErMs E. coli, with 92% of strains lacking full contig coverage ofompC. DISCUSSION/SIGNIFICANCE: Overall, this work provides evidence of a collaborative effort between blaCTX-M and OmpC in NCP strains that confer resistance to ertapenem but not meropenem. Clinically, CRE subtypes are not readily appreciated, potentially leading to mismanagement of CRE infected patients. A greater focus on optimal treatments for CRE subtypes is needed.
470 Associations with gene-transcript expressions in cocaine use disorder reveal genetic predispositions with other substance use and cardio-neurovascular disease.
Authors: Nwaneshiudu Chinwe , Girdhar Kiran , Goldstein Rita Z. , Butelman Eduardo , Alia-Klein Nelly , Roussos Panos , Peters James J.
Published: April 2024

OBJECTIVES/GOALS: Using biomarkers to identify vulnerabilities from cocaine use disorder (CUD) is a focus of recent investigations. Current clinical efforts focus on psychiatric recovery in CUD, however other body systems are missed. Applying blood-based transcriptomics to investigate how clinical conditions relate to CUD can alter current treatment approaches. METHODS/STUDY POPULATION: We conducted a comprehensive longitudinal study of 12 individuals (mean 53 yrs.; M/F ratio 9: 3) with CUD abstinent from cocaine. 44 blood samples collected repeatedly every 3 months for 9 months were bulk RNA sequenced. We began with phenotype harmonization grouping individuals with the following metrics; cocaine withdrawal, cue craving, generalized craving, perceived stress, and days of abstinence. We ran differential gene and transcript expression with time across grouping of metrics using the dream software and used the multivariate test to examine their associations. We used the association of gene-transcripts to determine genetic predispositions with clinical traits using the Multi-marker Analysis of GenoMic Annotation assessing their overlap to a reference GWAS database. RESULTS/ANTICIPATED RESULTS: Individuals were grouped in 2 clusters based on scores of cue craving, generalized craving, cocaine withdrawal, and 3 clusters based on days of abstinence from cocaine use. Gene-transcript(s) associationsrevealed genetic predisposition towards certain clinical conditions and substance use traits. Cannabis use disorder showed significant enrichment between the greater vs. lesser abstinent days, and lesser vs. least abstinent days at 9 months. The “drinks per week” trait showed significant gene enrichment between greater vs. lesser abstinent days at 9 months. Coronary artery disease was also enriched with greater vs. least abstinent days at 3 months. Lastly, significant baseline differences in predisposition to small vessel ischemic stroke were seen in responders with high vs low perceived stress. DISCUSSION/SIGNIFICANCE: These results from a robust and feasible pipeline suggest genetic predisposition in CUD for other substances and cardio-neurovascular diseases. This pilot study may lead to larger studies into whole genome-based blood biomarker approaches for monitoring abstinence and other clinical co-morbidities to be addressed in cocaine addiction recovery.
494 Expert group decision making for pharmacogenomic testing in Ontario
Authors: Neumark Samuel , Schmitz Mary , Mohiuddin Ayeshah G. , Gillespie Daniel , Austin Zubin , Foty Richard , Ferenbok Joseph
Published: April 2024

OBJECTIVES/GOALS: There is a need to better understand how governments develop strategies to adopt, evaluate, and implement novel health technologies in a public healthcare system. The goal of this project is to understand this strategy development process for the translation of pharmacogenomic (PGx) testing in Ontario, Canada. METHODS/STUDY POPULATION: This observational case study of the Ontario Health PGx Working Group focused on developing recommendations for a PGx testing implementation strategy in the province. The group included 9 individuals affiliated with Ontario Health and 13 healthcare experts from multiple clinical fields. Ontario Health is the government agency that oversees provincial healthcare planning and service delivery. Guided by the Translational Thinking Framework and qualitative research methods, we observed the working group’s activities for eight months. We collected meeting recordings, slideshow decks, emails, and group characteristics. We used descriptive statistics and a nine-step inductive approach to analyze the data to create process maps, a case report, and key decision summaries. RESULTS/ANTICIPATED RESULTS: There were 19 meetings conducted remotely with videoconferencing technology. Throughout the working group’s activities, we identified 15 key decisions related to either administrative processes or PGx scientific content. We further stratified these two categories into four main themes relating to decisions about 1) membership involvement, 2) logistical management, 3) discussion and recommendation scope, and 4) information dissemination. These four decision themes represent tools by which Ontario Health guided the expert group activities and achieved their goal of generating a strategic roadmap for PGx testing implementation in Ontario. DISCUSSION/SIGNIFICANCE: The Ontario government makes decisions about how expert groups function by monitoring and controlling the group’s activities to ensure efficiency, standardization, and practicality. Describing expert group decision-making increases transparency and highlights the critical role they play in the translational pathway of health technologies.
498 Bruton’s tyrosine kinase (BTK) inhibitors impede platelet aggregation but not adhesion to collagen.
Authors: Kartika Thomas , Buitrago Lorena , Li Jihong , Coller Barry S.
Published: April 2024

OBJECTIVES/GOALS: The research objectives of this project are to elucidate the effects of Bruton’s tyrosine kinase inhibitors (BTKi) of varying target specificity on platelet function with regard to platelet aggregation, adhesion, spreading, and intracellular signaling as measured by kinase phosphorylation. METHODS/STUDY POPULATION: Blood from healthy volunteers was obtained and processed to obtain both washed platelets and platelet-rich plasma. The samples were then treated with one of the BTKi drugs or with vehicle (DMSO) at concentrations matching patient blood concentrations derived from clinical trials and pharmacokinetic studies. The incubated samples were then analyzed in an aggregometer using one of several agonists. Aggregation was stopped after five minutes with a perchloric acid-based lysis buffer. The samples were then analyzed by SDS-PAGE and immunoblotting to quantify BTK protein and BTK phosphorylation. Adhesion was assessed by incubating washed platelets treated with BTKi on microtiter wells coated with fibrinogen or collagen and quantifying adherent platelets by their endogenous acid phosphatase activity. RESULTS/ANTICIPATED RESULTS: We found that ibrutinib, zanubrutinib, and pirtobrutinib all completely inhibited collagen-induced platelet aggregation, whereas they did not inhibit aggregation induced by thrombin, ristocetin, arachidonic acid, or the PAR1 activator peptide SFLLRN (T6). Acalabrutinib inhibited collagen-induced platelet aggregation only at high concentrations (1-2 micromolar). At the lower concentration of 200 nanomolar, comparable to the concentration required for the other BTK inhibitors to completely inhibit platelet aggregation, acalabrutinib failed to inhibit aggregation but did inhibit auto-phosphorylation, indicating an impact on signaling. None of the BTKi drugs inhibited adhesion of platelets to collagen-coated surfaces. DISCUSSION/SIGNIFICANCE: Our data show the inhibitory effect of BTKi on collagen-induced platelet aggregation and signaling. However, it remains unclear whether the inhibition is due to an effect on BTK itself or other related kinases. Better insight into the mechanisms of platelet inhibition by BTKi may help guide the development of BTKi with a lower risk of hemorrhage.
510 Addressing the Regulatory Needs and Challenges of Academic Researchers by Creating a One-Stop Shop Web Portal
Authors: Manrique Karen , Pacifici Eunjoo
Published: April 2024

OBJECTIVES/GOALS: To identify challenges faced by academic researchers in accessing online regulatory information and/or tools to advance their research work to develop a free, publicly accessible, interactive web portal that provides regulatory support. METHODS/STUDY POPULATION: The Regulatory Knowledge and Support core of the Southern California Clinical and Translational Science Institute interviewed five local research professionals. These interviews guided the development of a Qualtrics survey, consisting of multiple responses and open-ended questions, submitted to our local institutional review board (IRB). After receiving IRB approval, the survey was disseminated via email, newsletters, flyers, and presentations targeting researchers at academic institutions and members of clinical and translational science hubs. Survey data will be used to identify the challenges academic researchers face in finding regulatory resources and to compile the types of regulatory information or tools they would find helpful for their research. RESULTS/ANTICIPATED RESULTS: According to the interviews, researchers with extensive involvement in clinical trials found regulatory resources easily accessible compared to those with less experience. Additionally, they all stated having a colleague or regulatory specialist whom they can consult about regulatory requirements. Insights from these initial interviews confirmed the need to obtain a comprehensive view across research professionals. Anticipated results will show the challenges in accessibility, source, and type of regulatory resources researchers typically encounter. It is also anticipated that researchers will share what kinds of resources they would find most useful for their work. Ultimately, the information and tools identified as essential by survey takers will be collected and incorporated into the web portal. DISCUSSION/SIGNIFICANCE: Academic researchers find navigating through regulatory hurdles persistently challenging when translating their work from bench to clinic, especially since academia is typically resource-constrained. Findings from this study will allow the creation of a web portal for researchers that is broadly accessible and meets their regulatory needs.
518 Improving Clinical Trial Activation Timelines through Parallel Processing and Key Stakeholder Involvement
Authors: Monosmith Michelle , White Cierra , Byrne Julie , Mangold Aaron , Avery Kelly , Pereira Naveen , Chokkalingam Audi
Published: April 2024

OBJECTIVES/GOALS: A strategic initiative of Mayo Clinic is to decrease clinical trial activation timelines by 25% from 2022 levels. The team’s goal is to streamline activation via parallel processing, improved collaboration with business units, project manager facilitation, and early study coordinator involvement. METHODS/STUDY POPULATION: The workgroup targeted industry trials, focusing on key financial, regulatory, and operational elements. Current state process workflows and pain points were prepared and opportunities for concurrent activities or automation identified. The scope of the project manager role from the Office of Clinical Trials was extended to guide each activation team, who have varying levels of experience, to maintain timelines until the trial is opened. Coordinators responsible for study conduct engaged in key operational discussions earlier to ensure the trial will be run successfully. A Pilot program is utilizing the identified concurrent activities, project manager support, and earlier coordinator involvement to gauge effectiveness of the proposed solutions. RESULTS/ANTICIPATED RESULTS: The goal is for 120 industry clinical trials to join the Pilot program and to open enrollment in less than 30 weeks from being document ready. As of Q3 2023, 109 clinical trials across multiple Mayo sites have enrolled in the pilot. Thirty-five (85 percent) of 41 Pilot trials have opened to enrollment and have met the goal, with a median timeline of 24 weeks. Twenty-one (21) trials opened to enrollment in Q3 2023 with a median timeline of 23 weeks, representing 24% of all industry clinical trials opened that quarter. Opening trials and monitoring is ongoing and PI and study team feedback is positive. DISCUSSION/SIGNIFICANCE: Using a team-based approach, we identified key areas for optimization and parallel processing. The solution reduces trial activation timelines, increases patient access to experimental therapies, and has been positively received by study staff. Future projects will focus on enterprise implementation, optimization, and automation.
520 Johns Hopkins Institute for Clinical and Translational Research (ICTR) - Research Personnel Onboarding Program
Authors: Hamdawi Mais , Keyes Anthony
Published: April 2024

OBJECTIVES/GOALS: In Sep 2022, Johns Hopkins Research Coordinator Support Service launched Research Personnel Onboarding Program. The program on board in experienced individuals in 6-8 weeks, tailoring training plans to Investigator and study needs. It also offers Ongoing Support to enhance sustainability and adaptability. METHODS/STUDY POPULATION: * Assess Principal Investigator (PI)’s need Evaluate study’s need Understand trainee’s background Develop a personalized training plan (∼6-8 weeks) Weekly updates Ongoing mentorship Research staff spend 200+ training hours, depending on their need. Training encompasses various modalities: Interactive 1:1 onboarding sessions, Online, and Instructor-led trainings and sessions cover a wide range of topics, including: * Mandatory JHU/Institutional Review Board trainings * Good Clinical Practice * Regulatory submissions * Screening/Consenting * Monitoring/Auditing * Visit conduct * Clinical skills * Soft Skills Figure 1. Chart shows cumulative onboarding hours that focus on “How” to do tasks Figure 2. Chart shows cumulative training hours that focus on regulations, ethics and “Why” for tasks RESULTS/ANTICIPATED RESULTS: * The program contributed nearly 4000 hrs. of research staff training in the past 1 year * The program received 26 requests from investigators; 14 Completed the onboarding program, 1 Active, 5 Projected (Future start date), and 6 Cancelled (HR issues, lack of fund, or hired a trained staff) * 22 requests opted in the “Ongoing Support” * Ongoing Support, is averaged at 1 hr./month for the first 3-6 months. This indicates program success in empowering independent task performance * Developing REDCap request had significantly reduced meetings and paperwork * Web-Based Clockify invoicing has drastically reduced monthly manually invoicing processing time DISCUSSION/SIGNIFICANCE: * Grow the next generation of clinical research professionals * Centralize and standardize expert onboarding throughout the University * Improve outcomes, enhanced productivity, knowledge sharing, collaboration, and innovation * Decrease frustration and enhance satisfaction of trainees and departments
525 A Library-CTSI Collaboration to Support Researcher Compliance with the 2023 NIH Policy for Data Management and Sharing
Authors: Ragon Bart , Jones Lucy Carr , Burks Sandra G. , Denton Andrea H.
Published: April 2024

OBJECTIVES/GOALS: Seeking ways to support teams in the preparation for and the implementation of the new National Institutes of Health (NIH) Policy for Data Management and Sharing (DMSP), the integrated Translational Health Research Institute of Virginia (iTHRIV) partnered with the UVA Health Sciences Library to develop training and resources for researchers. METHODS/STUDY POPULATION: Health sciences librarians and iTHRIV (an NIH-NCATS supported Clinical Translational Research Institute) convened a Working Group, inviting representatives from central and unit-specific research support offices (e.g. the Comprehensive Cancer Center), research compliance, regulatory affairs, sponsored programs, institutional review boards, libraries, and data science to review and discuss the DMSP requirements. After an initial orientation to the policy, the group reviewed existing public resources and solicited feedback about steps to best support UVA researchers in compliance. Leveraging the broad expertise of the group, the team provides guidance to researchers on writing the DMS plan and choosing a data repository, and provides tools and templates to support implementation of the policy. RESULTS/ANTICIPATED RESULTS: A library-created website provided policy guidance, including links to NIH-hosted information, resources created by other institutions, and new UVA-specific templates and suggested proposal language. Librarians led a webinar on the new policy and UVA resources which included a speaker from UVA regulatory affairs to describe the new DMSP requirements, and a tour of the new guide. The guide has been viewed over 5000 times to date and librarians have provided consultations and training to individuals and departments. Current plans include developing a user satisfaction survey, reviewing DMSP feedback from submitted proposals, and incorporating lessons learned into the website and future training. DISCUSSION/SIGNIFICANCE: The collaboration between iTHRIV and the Health Sciences Library to support the NIH Data Management and Sharing Policy was a successful partnership that provided leadership at the institutional level to communicate with and engage researchers and utilized the library’s web presence, expertise, and service model to provide direct support.
526 Administrative Simplification of Committee Reviews through REDCap
Authors: Galloway Taylor , Hanson Laura , Elsner Lysette , Wrenn Margot , Griffin Carol , Day Gregory S
Published: April 2024

OBJECTIVES/GOALS: A Mayo Clinic in Florida committee completes 100+ Scientific Reviews annually through manual e-mail and Excel tracking, placing a manual burden on reviewers and coordinators. REDCap, an electronic data capture system, was leveraged to reduce the administrative burden.#_ftn1 #_ftnref2 METHODS/STUDY POPULATION: Historically, emails were sent by a coordinator to physicians, requesting their initial review and following up with reminders. This process was tracked using Excel, presenting a need to make this process more efficient, so a workgroup was created. To ensure all perspectives were accounted for, the workgroup included the review coordinator, a physician reviewer, and study team members who submit development requests for studies. The process was mapped using the existing Excel spreadsheet, and email templates. Critical data elements were identified, ensuring the database would identify bottlenecks. Two REDCap instruments were then created: one to outline the coordinator workflow and a survey for physician reviewers to complete the scientific reviews. #_ftn2#_ftnref1 RESULTS/ANTICIPATED RESULTS: The workflow is live in REDCap and has effectively processed over 100 scientific reviews in <1 year. The system captures the review status and guides the coordinator through the workflow, capturing dates when tasks are completed. When review criteria are met, the database sends an email to the assigned reviewer. The email includes a link to a REDCap survey, containing all pertinent documents. The reviewer uploads their completed review form within the survey, if this is not completed within a given period, the database sends email reminders. Once the review is complete, a notification is sent to the review coordinator. The review workflow is accessible to the study team who requested scientific review, making them aware of their request status ad giving them access to the review the moment it is completed. DISCUSSION/SIGNIFICANCE: Leveraging REDCap has increased visibility, reduced overall manual processes, and simplified the reviewer burden by providing all the information needed in a single notification. REDCap is a cost-effective, impactful solution to simplifying administrative burden in managing committee reviews.
533 Student Undergrad Researchers’ Race, Ethnicity, And Language in a Student-Run Free Clinic (SURREAL)
Authors: Lee Gabriel , Shihabuddin Courtney , Shihabuddin Bashar
Published: April 2024

OBJECTIVES/GOALS: Our primary objective is to determine the demographic and linguistic characteristics of student research assistants (SRAs) in a large student-run free clinic associated with a mid-western university. Our secondary objective was to determine if the SRAs perceived any impact of those characteristics on their duties and ability to conduct research. METHODS/STUDY POPULATION: We plan to conduct a 15-question electronic survey of Student Research Assistants at the student run free clinic. There are a variety of projects that require varying levels of commitment from researchers, which will be aggregated. This survey has been modified from a previously validated survey that focused on the demographic and linguistic characteristics of pediatric research coordinators. This survey will be emailed out to student research assistants and will be done over a period of 3 months. The study population will be predominantly undergraduate students who are all interested in a career in healthcare, ages expected to range from 18-25. RESULTS/ANTICIPATED RESULTS: We anticipate that the majority of student research assistants will be older students and will be students who identify as non-white/caucasian, as the majority of students volunteering at this free clinic do not identify as white. Additionally, we anticipate that students will feel that their racial/ethnic identity will positively impact their recruitment efforts. We also anticipate that the ability of a student research assistant to speak another language is expected to positively affect their perceived recruitment efforts. We also anticipate that gender will influence the student researchers’ perceptions of their recruitment efforts. DISCUSSION/SIGNIFICANCE: An individual’s background can directly impact how they perceive their contributions towards research. Considering the paucity in research for underinsured and uninsured and the rise in undergraduate student research assistants, optimizing research efforts and SRA confidence is essential to increase the accuracy and efficiency of research.
535 Translational science vs. translational research in CTSA pilot projects: characteristics and perceptions
Authors: Sparks Crystal , Dillon Pamela , Ghanem Eman , Neal Jasmine , Ranu Hardeep , Schneider Margaret
Published: April 2024

OBJECTIVES/GOALS: NCATS requires that CTSA-funded pilot projects focus on translational science (TS) and evaluate the translational process. However, a consistent understanding of TS remains elusive. This gap is being addressed by a consortium of 12 CTSA hubs aimed at identifying distinctive features of TS and translational research (TR) proposals. METHODS/STUDY POPULATION: CTSA External Review Exchange Consortium (CEREC) is a reciprocal review collaboration among CTSA hubs. Reviewers were CEREC members from hubs that submitted CTSA applications (PAR-21-293); read the Notice of Funding Opportunity (NOFO) Clinical and Translations Science Pilot Module; and discussed TS with their hubs “a fair amount” or “quite a bit” and then they independently categorized proposals. Proposals were labeled TS or TR if reviewers reached a consensus on category assignment; without consensus, proposals were labeled unclassified. In addition to category assignment, reviewers commented about their classifications. R was used to evaluate the comments and create word clouds with phrases/themes that distinguished between the categories of proposals. RESULTS/ANTICIPATED RESULTS: Twelve CEREC participating hubs submitted 26 proposals, which were funded prior to the new NCATS TS requirements. Eight reviewers from distinct CEREC hubs evaluated and classified each proposal as TS or TR. Consensus (at least 87% agreement) was reached for 12 proposals, 6 TS and 6 TR. Reviewers provided comments describing the rationale for their classifications for 70% of the proposals. Qualitative analysis of the reviewers’ comments and rationale by classification (TS, TR, or unclassified) revealed common themes within and differences between groups and shed light on what defines TS and TR. The most frequent themes that distinguished TS from TR were generalizability across multiple diseases and a focus on increasing research efficiency. DISCUSSION/SIGNIFICANCE: NIH is focused on research that meets the new definition of TS. Investigators seeking to address this funding priority should explicitly state the relevance of their research to multiple diseases and to the acceleration of future research. Programs seeking to attract TS projects should instruct applicants to include this information.