bluuebunny/crossref_metadata_2025 huggingface dataset:
4573 Characterization of vascular disease in an Acta2 mutant mouse model
Authors: Kaw Anita , Kwartler Callie , Chattopadhyay Abhijnan , Milewicz Dianna M.
Published: July 2020

OBJECTIVES/GOALS: ACTA2 R179 carriers present with early-onset stroke; occlusive lesions of the distal internal carotid artery and branches are filled with cells staining positive for smooth muscle cell (SMC) markers. We will identify pathways leading to increased SMC proliferation and migration and thus occlusion. METHODS/STUDY POPULATION: We generated an Acta2SMC-R179C/+ mouse model, which expresses the Acta2 R179C mutation in SMCs via the SM22a-Cre-Lox system. rt-PCR performed in aortic tissue confirms the presence of the mutation in the mutant mice and absence in mice with only the floxed allele (WT). We will determine phenotypic differences between mutant and WT brains using micro CT, vascular casting, histology, and immunostaining. We will characterize mutant SMC phenotype in culture by assessing expression of contractile genes and stem cell markers, proliferation, and migration. Single cell RNA (scRNA) sequencing of the brain will assess differential gene expression and cell populations between mutant and WT mice. RESULTS/ANTICIPATED RESULTS: Mutant mice have decreased blood pressure compared to WT mice from 8-24 weeks old, consistent with the phenotype seen in ACTA2 R179 patients. We expect to see occluded and straighter cerebrovascular arteries and white matter changes in the Acta2SMC-R179C/+ mice. iPSC-derived SMCs from patients show de-differentiation, continued expression of stem cell markers, and increased proliferation and migration. We expect to see a similar phenotype in Acta2SMC-R179C/+ mouse SMCs in culture. Via scRNA sequencing, we expect to see altered transcriptional profiles in mutant mice brains including upregulated proliferative pathways in SMCs, glial cell activation, and gene expression changes in neurons. DISCUSSION/SIGNIFICANCE OF IMPACT: These studies will contribute important information on the pathogenesis of the cerebrovascular disease in ACTA2 R179 patients. These results may aid in identifying treatments to prevent or decrease risk of developing strokes in those with known predisposition to cerebrovascular occlusive disease.
4421 Exposure to topical antimicrobials reduces inflammatory gene expression in keratinocytes
Authors: Sirobhushanam Sirisha , Billi Allison C , Berthier Celine C , Tsoi Lam C , Gudjonsson Johann E , Kahlenberg J Michelle
Published: July 2020

OBJECTIVES/GOALS: Lupus lesional skin has elevated interferon expression, is highly colonized with Staphylococcus aureus (50%) and has no FDA-approved treatment options. We decided to investigate the effect of topical antibiotics on lupus lesional skin to determine whether it affects inflammatory gene expression. METHODS/STUDY POPULATION: Adult Systemic Lupus Erythematosus (SLE) patients with skin inflammation were recruited for this study from the Michigan Lupus cohort. All patients gave informed consent approved by the University of Michigan IRB. Lesions were swabbed for S. aureus colonization and then skin biopsies were collected from the affected area. Patients were then randomized for either mupirocin treatment or VaselineTM as the control. Product was applied to the lesion thrice daily for 7 days and swab samples and biopsies were collected again. Biopsies were saved at −80 °C. RNA was isolated from the biopsies, checked for quality and RNA-sequencing was performed to determine transcriptomic changes. RESULTS/ANTICIPATED RESULTS: Our preliminary results indicate that a higher number of genes are differentially expressed (DEGs) following treatment with mupirocin (184) than VaselineTM (133). Interestingly the DEGs from the two treatments were almost completely independent with only a few that were DE in both treatments when the data were fitted to a scatter plot. Functional enrichment analysis of the data showed significant downregulation of cytokine and chemokine pathways in the mupirocin but not the VaselineTM treatment group. DISCUSSION/SIGNIFICANCE OF IMPACT: Our preliminary data suggests that inflammatory signaling can be reduced in lesional skin by reducing bacterial load by topical antibiotic treatment in lupus patients. This can be particularly helpful in patients who are recalcitrant to typical treatment protocols for skin inflammation. CONFLICT OF INTEREST DESCRIPTION: J.M.K. received research funding from Celgene and serves on advisory boards for AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, and Eli Lilly and J.E.G. received research funding from AbbVie, SunPharma, Celgene, and Genentech and serves on advisory boards for Novartis, AbbVie, and MiRagen. The other authors have no financial conflicts of interest.
4031 Heart Transplant Candidates Listed at Low First-Offer Organ Acceptance Rate Centers are More Likely to Die Waiting
Authors: Choi Ashley Y , Mulvihill Michael S. , Lee Hui-Jie , Zhao Congwen , Kuchibhatla Maragatha , Schroder Jacob N. , Patel Chetan B. , Granger Christopher B. , Hartwig Matthew G.
Published: July 2020

OBJECTIVES/GOALS: We sought to examine: 1) variability in center acceptance patterns for heart allografts offered to the highest-priority candidates, 2) impact of this acceptance behavior on candidate survival, and 3) post-transplantation outcomes in candidates who accepted first rank offer vs. previously declined offer. METHODS/STUDY POPULATION: In this retrospective cohort study, the US national transplant registry was queried for all match runs of adult candidates listed for isolated heart transplantation between 2007-2017. We examined center acceptance rates for heart allografts offered to the highest-priority candidates and accounted for covariates in multivariable logistic regression. Competing risks analysis was performed to assess the relationship between center acceptance rate and waitlist mortality. Post-transplantation outcomes (patient survival and graft failure) between candidates who accepted their first-rank offers vs those who accepted previously declined offers were compared using Fine-Gray subdistribution hazards model. RESULTS/ANTICIPATED RESULTS: Among 19,703 unique organ offers, 6,302 (32%) were accepted for first-ranked candidates. After adjustment for donor, recipient, and geographic covariates, transplant centers varied markedly in acceptance rates (12%-62%) of offers made to first-ranked candidates. Lowest acceptance rate centers (<25%) associated with highest cumulative incidence of waitlist mortality. For every 10% increase in adjusted center acceptance rate, waitlist mortality risk decreased by 27% (SHR 0.73, 95% CI 0.67-0.80). No significant difference was observed in 5-year adjusted post-Tx survival and graft failure between hearts accepted at the first-rank vs lower-rank positions. DISCUSSION/SIGNIFICANCE OF IMPACT: Wide variability in heart acceptance rates exists among centers, with candidates listed at low acceptance rate centers more likely to die waiting. Similar post-Tx survival suggests previously declined allografts function as well as those accepted at first offer. Center-level decision is a modifiable behavior associated with waitlist mortality.
4144 Identifying the needs of family caregivers of people with dementia to improve service delivery: Bridging a research-practice gap
Authors: Moss Sara A. , Gebhardt-Kram Lauren E. , Dabelko-Schoeny Holly , Cheavens Jennifer
Published: July 2020

OBJECTIVES/GOALS: The goal of this mixed methods project is to develop a comprehensive framework of the personal and care-related needs of informal caregivers of people with dementia. This model can be used to enhance targeted delivery of evidence-based services to caregivers in need. METHODS/STUDY POPULATION: To create a model of the personal and care-related needs of family caregivers of people with dementia, we conducted semi-structured in-depth interviews with current caregivers (N = 12) and conducted a content analysis of materials related to government reports and evidence-based interventions (N = 28) and existing measures of dementia caregiver needs (N = 54). Content analysis is a systematic qualitative methodology that is used to distill complex source material into content-related categories and is well-suited for both interview data and document data (Elo & Kyngäs, 2008). We identified themes related to caregiver needs through examination of materials within and across source categories. RESULTS/ANTICIPATED RESULTS: We propose a framework of five inter-related need categories: Environmental needs (e.g., transportation, health-care access, financial resources, time), psychological needs (e.g., emotional wellbeing, identity/autonomy, perceived preparedness), social needs (e.g., social support, family dynamics), health-related needs (e.g., health behaviors, sleep), and needs related to the care and functioning of the person with dementia. We also consider how needs and background characteristics transact to influence which services may be of greatest use. In the future, we plan to test this model empirically with a nationally representative sample of caregivers. DISCUSSION/SIGNIFICANCE OF IMPACT: Evidence-based services exist to meet the needs of dementia caregivers. A dearth of models clearly defining caregiver needs limits empirically-based plans for dissemination of services. We have identified a framework of the needs of family caregivers from which to create targeted dissemination plans.
4473 Immune control of plasma cell disorders – in-depth analysis of Sox2 immunity in MGUS
Authors: Susanibar Adaniya Sandra Patricia , Cummins Casey L. , Baroja Miren L. , Carreno Beatriz , Linette Gerald P. , Garfall Alfred L. , Robnett Maya G.
Published: July 2020

OBJECTIVES/GOALS: We aim to identify and characterize anti-Sox2-specific CD8+ T cell responses in stable MUGS patients expressing HLA class I alleles-A*02:01 and /or -B*07:02. METHODS/STUDY POPULATION: Cross sectional study of patients with stable MGUS defined as stable serum paraprotein for ≥ 12 months from the MM Research Clinic at the Abramson Cancer Institute. Sox2 T cell reactivity will be assessed by IFN-γ ELISPOT assays. Rested PBMC will be pulsed with candidate Sox2-derived peptides predicted to display high affinity to HLA class I alleles and known to be processed and presented as determined by “targeted MS/MS” (mass spectrometry). The presence of anti-Sox2-specific CD8+ T cells will be confirmed in peptide/HLA multimer assays using flow cytometry. Anti-Sox2-specific CD8+ T cells will be characterized for HLA restriction and TCR αβ composition. RESULTS/ANTICIPATED RESULTS: Our work is still in progress. From Aug to Dec 2019, 22 MGUS subjects have been analyzed, 11 of which were found to have the HLA of interest. Positive Sox-2 reactivity by ELISpot was found in 3 subjects. DISCUSSION/SIGNIFICANCE OF IMPACT: Anti-Sox2 immune responses may maintain MGUS in a clinical indolent state by eliminating Sox2-expressing clonogenic MM cells. A detailed characterization of anti-Sox2 T cells followed by in-vivo assessment of their anti-myeloma activity could provide the foundation for a Sox2 based immunotherapy approach in MM.
4304 Immune markers in tumor immune microenvironment of neuroblastoma correlate with risk groups
Authors: Gartrell Robyn Denise , Moisander-Joyce Hanna M. , Silverman Andrew M. , Remotti Helen E. , Yamashiro Darrell J
Published: July 2020

OBJECTIVES/GOALS: Neuroblastoma (NB) is the most common extra-cranial solid tumor with outcomes varying from spontaneous regression to metastatic with high mortality rates. The tumor immune microenvironment (TIME) may play a significant role in this disease. In this study we analyze the TIME comparing high-risk (HR) and low-risk (LR) NBs using multiplex platforms. METHODS/STUDY POPULATION: Two tissue microarrays (TMAs) with 2mm cores were created from 41 patients treated at Columbia University Irving Medical Center. Five micron TMA slides were stained for Digital Spatial Profiling (DSP, nanoString) and multiplex immunofluorescence (mIF). For DSP, a 24-patient subset including 11 HR, 8 LR and 4 intermediate risk patients was analyzed for 34 proteins. Protein expression among risk groups was compared using Mann-Whitney t-test. For mIF, TMA FFPE slides were stained for DAPI, CD3, CD8, CD68, HLA-DR, PDL1 and Chromogranin A. Whole TMA cores were captured as 9 -20X multispectral images (MSIs) stitched into a 3x3 MSI using Vectra (Akoya). MSIs were processed with inForm and qualitative analysis performed comparing HR and LR tumors. RESULTS/ANTICIPATED RESULTS: With DSP, we find significantly more HLA-DR in HR compared to LR tumors (p = 0.016). When controlling for immune cells with CD45 we find HLA-DR/CD45 to be higher in HR than LR tumors (p = 0.026). We found increased PD1 and PDL1 expression in all groups without significant difference between LR and HR (p = 0.778 and p = 0.310, respectively). Preliminary analysis of mIF on 9 patients (4 HR and 5 LR) finds HR tumors appear to have more immune cells than LR tumors, specifically more CD3+CD8- T cells while total CD8+ cells may be similar. There may be less macrophages in the HR compared to LR tumors. Completion of image processing and quantitative analysis of mIF data is underway. DISCUSSION/SIGNIFICANCE OF IMPACT: Increased expression of immune markers in NB TIME correlates with higher risk, which is unlike many other tumors. We compared TIME in HR and LR NB using multiplex platforms, DSP and mIF. We find that HLA-DR is more expressed in HR NB while PD1 and PDL1 expression is consistently high and not different between risk groups. Further analysis is underway. CONFLICT OF INTEREST DESCRIPTION: Robyn D. Gartrell-Corrado received grant support from nanoString for Digital Spatial Profiling and received honoraria and travel support from Northwest Biotherapeutics and PerkinElmer, respectively.
4020 Impact of Patients’ Health Literacy Level on Patients’ Health Outcomes
Authors: Kim Dae Hyun , Hearld Larry , Opoku-Aygeman William
Published: July 2020

OBJECTIVES/GOALS: The objective of this study is to examine the relationship between gastro-intestinal (GI) patients’ health literacy levels and patients’ health outcomes (length of stay, readmission, complication). METHODS/STUDY POPULATION: A research team at the University of Alabama at Birmingham (UAB) ‘s Gastro-Intestinal (GI) surgical department collected inpatient GI patients’ health literacy data by distributing the Brief Health Literacy Screen (BRIEF) survey to patients are about to be discharged. Patients’ health outcomes data were gathered through Business Objects, an online platform that allows physicians and researchers to access and gather patients’ medical information with an IRB approval. After accounting for necessary control variables, logistic regression and multiple linear regression models will be run to assess whether there is a significant relationship between patients’ health literacy levels and patients’ health outcomes. RESULTS/ANTICIPATED RESULTS: Three specific hypotheses are proposed in this study. H1: GI patients’ health literacy levels will be negatively associated with their lengths of stay H2: GI patients’ health literacy levels will be negatively associated with their readmission status to the hospital H3: GI patients’ health literacy levels will be negatively associated with their complication status to the hospital DISCUSSION/SIGNIFICANCE OF IMPACT: This study allows us to further our understanding of patients’ health literacy level and its’ relationship with important health outcomes. By looking at a variety of diverse health outcomes, the impact of a patients’ health literacy level on that patients’ health outcomes will be observed more clearly.
4021 Learning from Patient Experience to Improve Diagnosis: a Pilot Study
Authors: Gleason Kelly , Himmelfarb Cheryl Dennison , Peterson Susan , Wynn Taylor , Villanueva Mariel , Bondal Paula , Newman-Toker David
Published: July 2020

OBJECTIVES/GOALS: Leveraging Patient’s Experience to improve Diagnosis (LEAPED) is our proposed method of measuring diagnostic error through seeking patient feedback on their understanding of their diagnosis and health status following emergency department discharge. To pilot test LEAPED’s feasibility, we deployed and determined patient uptake of LEAPED. METHODS/STUDY POPULATION: To test LEAPED, we employed a longitudinal cohort study design at emergency departments across one academic health system in the Mid-Atlantic region. Patients consented to complete questionnaires regarding their understanding of their diagnosis and/or follow-up steps and their health status at 2 weeks, 1 month, and 3 months following emergency department discharge. People aged 18 and older who were seen at the emergency department within the past 7 days with at least one chronic condition (hypertension, diabetes, history of stroke, arthritis, cancer, heart disease, osteoporosis, depression, and/or chronic obstructive lung disease) and one or more of the following common chief complaints: chest pain, upper back pain, abdominal pain, shortness of breath/cough, dizziness, and headache were eligible to join the study. RESULTS/ANTICIPATED RESULTS: Of those enrolled (n = 59), 95% (n = 53) responded to the two week post-ED discharge questionnaire (1 and 3-month ongoing). Of the 6 non-responders, 1 had died and 3 were hospitalized at two weeks. The average age was 50 years (SD 16) and 64% were female. Over half of participants (53%) were white and 41% were black. Almost one-third (27%) reported they were not given an explanation of their health problem on leaving the ED, and of those, a third did not have an understanding of what steps to take after leaving the ED. Participants reported a new health problem was identified after ED discharge (19%), worsening health status (12%), and health status stayed the same (16%). DISCUSSION/SIGNIFICANCE OF IMPACT: Patient uptake of LEAPED was high, which suggests that patient-report is a feasible method of evaluating diagnostic decision making and delivery to patients and yields insightful information beyond administrative data. The next steps are to validate the accuracy of patient-reported diagnostic error by comparing with administrative data.
4341 Neuroclinical fingerprints of risk for psychosis: Profiles of neurophysiology, symptom severity, and cognitive function
Authors: Novak Keisha , Buck Sam , Kotov Roman , Foti Dan
Published: July 2020

OBJECTIVES/GOALS: The study aims to utilize event-related potentials (ERPs) coupled with observable reports of symptoms to comprehensively understand neurological and symptomatic profile of individuals at risk for developing psychosis. The study is a short-term longitudinal design which allows for examination of course as well as structure of illness. METHODS/STUDY POPULATION: This study uses a combination of well-validated ERPs (P300, N400, ERN) and symptom data to predict variation in symptoms over time. We parse heterogeneity within a high-risk group to create innovative profiles and predict variation in course of symptoms. Data collection is ongoing (n = 35; target N = 100). Methods include a battery of ERP tasks tracking neural processes associated with attention, language processing, and executive function (P300, N400, ERN), along with assessment of symptom type and severity. Analyses include how ERPs correlate with severity of risk and symptom dimensions (positive, negative, disorganized). We examine whether individual versus global ERP aberrations (P300, N400, ERN) predict individual versus global symptom domain severity (positive, negative, disorganized), or vice versa. RESULTS/ANTICIPATED RESULTS: Symptom domain scores were elevated compared to general population on positive (M = 1.65, SD = .36), negative (M = 1.9 SD = .42), and depressive (M = 1.94, SD = .40) domains. Small to medium effect sizes emerged for P300 profile (r’s = −.001 to −.41) and ERN profile (r’s = −.03 to −.37), though small effect sizes for N400 profile (r’s = −.06 to .29). Analyses were run to determine the degree to which profiles of risk were similar: P300/ERN (r = −.09), ERN/N400 (r = −.39), and N400/P3 (r = −.20). Additional analyses suggest potential mediating effects of cognition on neural activity and symptoms. DISCUSSION/SIGNIFICANCE OF IMPACT: We use a combination of well-validated ERPs (i.e. P300, N400, ERN) with behavioral and symptom data to predict variation in symptoms over time. A “fingerprint” physiologic aberration may be exhibited within high-risk individuals and can be used as biomarkers to identify those at risk even before onset of observable symptoms.
4238 Racial/ethnic variation in the relation between diabetes control and healthy eating, food security, exercise, and access to health care
Authors: Shaheen Magda , Sanderlin Quanincia , Schrode Katrina
Published: July 2020

OBJECTIVES/GOALS: Diabetes mellitus is a common metabolic disease. Uncontrolled diabetes can lead to complications. The objective of this study is to examine the racial/ethnic variation in the relation between diabetes control and healthy eating, food security, exercise, and access to health care. METHODS/STUDY POPULATION: We analyzed data related to diabetes control, demographics, insurance, healthy eating, food security and physical activity for 949 diabetics from the National Health and Nutrition Examination Survey (NHANES). The population examined was adults with diabetes mellitus. Diabetes control was classified as fair control [HbA1c 7-<8 and fasting glucose <126 mg/dL], good control [HbA1c<7 and fasting glucose <110 mg/dL] or uncontrolled [HbA1c8 and fasting glucose <110 mg/dL]. We used multinomial logistic regression controlling for confounders to analyze the data overall and for each racial/ethnic group and report adjusted odds ratios (AOR) and 95% confidence limits (CL). RESULTS/ANTICIPATED RESULTS: Of the 949 diabetics, 14.7% were Blacks, 15.9% were Hispanics, 11.0% had fair control, 61.0% had good control, 14.2% were uninsured, 18.1% had low/very low food security, and 39.7% were inactive. Overall, uninsured subjects had a lower chance of fair diabetes control (AOR = 0.2, 95% CL = 0.1-0.9, p = 0.04), but this relationship was significant only for Hispanics and Blacks (p<0.05). Whites with low/very low food security were less likely to have fair control (AOR = 0.2, 95% CI = 0.001-0.9, p = 0.04). Blacks who were inactive, and insufficiently active Hispanics had a lower chance of good/excellent diabetes control (AOR = 0.5, 95% CI = 0.2-0.9, p = 0.03; AOR = 0.3, 95% CI = 0.1-0.7, p = 0.007 respectively). DISCUSSION/SIGNIFICANCE OF IMPACT: The results show the importance of insurance coverage, food security and physical activity in diabetes control among different racial/ethnic groups. They indicate a need for affordable health care and for culturally-relevant interventions that include physical activity and food security.
4139 Risk Aversion in Lung Transplantation: Organ Procurement Organizations Differ in Willingness to Pursue Non-ideal Donor Organs
Authors: Halpern Samantha Ellen , McConnell Alec , Peskoe Sarah , Raman Vignesh , Jawitz Oliver K , Choi Ashley Y , Haney John C , Klapper Jacob A , Hartwig Matthew G
Published: July 2020

OBJECTIVES/GOALS: Lung transplant (LTx) candidates benefit from use of non-ideal donor organs. Each organ procurement organization (OPO) defines “acceptable” donor organs introducing unmeasured variation in donor pursuit. We characterized non-ideal donor pursuit among OPOs to identify drivers of risk aversion in LTx. METHODS/STUDY POPULATION: We queried the UNOS registry for adult donors who donated ≥1 organ for transplantation from 12/2007-12/2018. Non-ideal donors were those with any of age>50, smoking history ≥20 pack-years, PaO2/FiO2 (P/F) ratio<350, donation after cardiac death (DCD) status, or CDC increased risk (IRD) status. Non-ideal donor pursuit rate was defined as the proportion of non-ideal donors at each OPO from whom consent for lung donation was requested with lower numbers indicating increased risk aversion. We estimated the correlation between non-ideal and overall donor pursuit using a Spearman correlation coefficient. Adjusted non-ideal donor pursuit rates were estimated using multivariable logistic regression. RESULTS/ANTICIPATED RESULTS: Overall, 18,333 deceased donors were included and classified as ideal or non-ideal. Among 58 OPOs, rates of non-ideal donor pursuit ranged from 0.24-1.00 Figure). Of 5 non-ideal characteristics, DCD and IRD status were associated with the most and least risk aversion, respectively. Non-ideal donor pursuit was strongly correlated with overall donor pursuit (r = 0.99). On adjusted analysis, older age (OR 0.15, 95% CI 0.13-0.16), smoking history (OR 0.38, 95% CI 0.34-0.44), low P/F ratio (OR 0.12, 95% CI 0.11-0.14), and DCD status (OR 0.04, 95% CI 0.03-0.04) were all independently associated with significant risk aversion, corresponding to decreased rates of donor pursuit. DISCUSSION/SIGNIFICANCE OF IMPACT: OPOs differ in their levels of risk aversion in LTx and risk aversion is not uniform across selected categories of non-ideal lung donor. Consideration of new OPO performance metrics that encourage the pursuit of non-ideal lung donors is warranted.
4145 Stepping Stones for Success in T3-T4 Translation: Building Collective Impact
Authors: Athreya Kishore , Nakazono Terry , Morrison Jim , Davidson Pamela
Published: July 2020

OBJECTIVES/GOALS: We will investigate the influence of multisector partnerships in T3-T4 research associated with advances in delivery systems, patient/population outcomes and health policy and the translational processes linked to these improvements. METHODS/STUDY POPULATION: We are using both quantitative and qualitative data to measure and analyze partnership characteristics linked to successful translation into practice & policy. We aim to complete 100 surveys of investigators who have conducted CTSA-supported T3-T4 research to examine partnerships, conditions of collective impact, and quantifiable changes in delivery systems, health outcomes, and policy. Using rigorous criteria, we will select projects for more in-depth interviews to understand the practices of successful translation and roadblocks and barriers that challenge translation. RESULTS/ANTICIPATED RESULTS: The anticipated research products include: (i) an analytic report on partnership structure and processes and the statistical associations to stages of change outcomes, (ii) a series of vignettes to describe the impact stories and translational processes, (iii) cross-project analysis of the data and vignettes to produce generalizable information to improve T3-T4 translation, and (iv) peer-reviewed manuscript(s) for publication. DISCUSSION/SIGNIFICANCE OF IMPACT: The study will inform and improve researcher competencies and accelerate translation in CTSA hubs that emphasize T3-T4 research. We will develop novel definitions of the T3-T4 research impact. Ultimately, the results will inform research training to better address real-world priorities and needs.
4498 The Effect of the Affordable Care Act on the Stage at Diagnosis in Low income Privately Insured Cancer Patients, including those with Marketplace coverage
Authors: Kim Uriel , Koroukian Siran , Rose Johnie
Published: July 2020

OBJECTIVES/GOALS: The goal of this study was to examine the change in the odds of being diagnosed with metastatic cancer after the Affordable Care Act (ACA) among low-income, privately insured, nonelderly patients with newly diagnosed cancer. Low-income was defined as having income<250% FPL (federal poverty level). METHODS/STUDY POPULATION: Using Ohio cancer registry data linked with census tract-level income data, individuals aged 18-64 years diagnosed with one of the 15 leading cancers and reported being privately insured or uninsured were identified. Low-income patients were isolated using probability weighting, a process in which each observation was assigned a weight equal to the probability of a patient having an income <250% FPL based on the patient’s census tract of residence. Then, a multivariable logistic model was fitted to examine the independent association between the exposure (Post-ACA, years 2015-2016 versus Pre-ACA, years 2012-2013) and the outcome (metastatic versus non-metastatic disease at diagnosis). RESULTS/ANTICIPATED RESULTS: Between the Pre-ACA and Post-ACA periods, the percent uninsured in the low-income study population decreased from 14.1% to 4.5% (p <0.01). In the Post-ACA period, among those with insurance coverage, an estimated 11.7% of individuals had Marketplace coverage. After adjusting for potential confounders (sex, age, race-ethnicity, marital status, community-level income, rurality, and cancer type), individuals diagnosed Post-ACA had 5% lower odds of having metastatic disease relative to Pre-ACA (Adjusted Odds Ratio: 0.95, 95% Confidence Interval: 0.91 - 0.99, p = 0.04). DISCUSSION/SIGNIFICANCE OF IMPACT: The shift towards non-metastatic disease likely reflects increases to coverage brought on by the marketplaces. However, the shift is smaller than those observed in Medicaid enrollees, suggesting that policy refinements in the marketplaces can further improve outcomes in low-income cancer patients.
4354 The Impact of the 2014 Kidney Allocation System on Waitlisting Rates at the Dialysis Facility Level
Authors: Melanson Taylor Andrew , Gander Jennifer , Patzer Rachel
Published: July 2020

OBJECTIVES/GOALS: The new Kidney Allocation System (KAS) was implemented in 2014 and it is not fully understood how its changes to patient incentives may have impacted dialysis facility waitlisting rates. We examine differences in facility performance and how such differences may have been impacted by this policy change. METHODS/STUDY POPULATION: We used Dialysis Facility Report data from 2011 to 2017 to study waitlisting rates at 3,392 dialysis facilities in the US, using waitlisting counts in the numerator, and the total number of ESRD patients in a facility as the denominator. We examined changes in waitlisting rates over by year at the facility, regional, and national level, and report national trends in waitlisting pre- and post-KAS. Facilities were stratified based on waitlisting rate in 2011 and then we examined whether each facility moved into a higher or lower quartile or stayed in the same quartile in 2017. RESULTS/ANTICIPATED RESULTS: Among n = 3,392 dialysis facilities, the average change in dialysis facility waitlisting rates from 2011 to 2017 was −4.74 percentage points (range -54.4% to 42.3%). Average change in dialysis facility waitlisting rates from 2011 to 2014 was −0.57 percentage points while the average change in dialysis facility waitlisting rates from 2014 to 2017 was −4.17 percentage points. Half of facilities in the 2011 lowest quartile remained in the lowest quartile in 2017; 45% of facilities in the top 2011 quartile dropped into a lower quartile. The middle 2 quartiles were fairly evenly split between worsening, improving, and not changing. DISCUSSION/SIGNIFICANCE OF IMPACT: Average waitlisting rates have declined since KAS implementation. Many facilities switched quartiles from 2011-17 suggesting that facility waitlisting rates are unstable over time. The decline in waitlisting rates post-KAS suggests that new allocation rules may be discouraging patients and/or providers from getting ESRD patients waitlisted.
4191 The Role of Suggestibility and Trait Anxiety in Young Adult Alcohol Use
Authors: Cowand Alexandra , Schwandt Melanie , Schneider Alyssa , Gilman Jodi M. , Diazgranados Nancy , Ramchandani Vijay A. , Stangl Bethany L.
Published: July 2020

OBJECTIVES/GOALS: The purpose of this study was to investigate how suggestibility and social susceptibility relate to alcohol use in young adult non-dependent alcohol users, and the role of trait anxiety in this relationship. We hypothesized that greater trait anxiety would be associated with higher levels of alcohol misuse, and this would be mediated by suggestibility. METHODS/STUDY POPULATION: Study participants enrolled in the NIAAA screening and assessment protocol completed questionnaires on suggestibility, anxiety, and alcohol use. The Multidimensional Iowa Suggestibility Scale (MISS) is a 95-question self-report assessment of suggestibility. Trait anxiety is assessed with the State Trait Anxiety Inventory-Trait (STAI-T). Alcohol measures included the Alcohol Use Disorder Identification Test (AUDIT). Structured Clinical Interviews for DSM-IV or DSM-5 disorders were conducted, and non-dependent participants (N = 113) were considered. A median split was conducted (median age = 35.1 years), with the focus of this study on the younger individuals (N = 55). RESULTS/ANTICIPATED RESULTS: Initial analyses showed that suggestibility, alcohol misuse, and trait anxiety all had significant positive correlations with one another. To better understand the relationship of peer influence, specifically, with drinking and anxiety, MISS subscale of Peer Conformity was analyzed. MISS total score and Peer Conformity were positively correlated with AUDIT Total as well as STAI-T Score. STAI-T Score was additionally positively correlated with AUDIT Total (all p2 = 0.222). We also looked at Peer Conformity in place of MISS Total (R2 = 0.213). In both models, only suggestibility measures were significant predictors of harmful alcohol use (p<0.01). DISCUSSION/SIGNIFICANCE OF IMPACT: In young social drinkers, there were significant positive associations between suggestibility, risky alcohol use, and trait anxiety. These results suggest that suggestibility may be a modifiable risk factor for risky alcohol consumption. Future directions include using mediation models to explore the associations between suggestibility, anxiety, and alcohol misuse.
4308 DEEP-PRIMED IL-15 SUPERAGONIST IMPROVES ANTIVIRAL EFFICACY OF HIV-SPECIFIC CD8+ T-CELLS IN HUMANIZED MOUSE MODEL
Authors: McCann Chase Daniel , Zale Elizabeth , Ward Adam , Dilling Thomas , Danesh Ali , Stevenson Eva , Mota Talia , Boesch Austin , Andresen Thomas , Irvine Darrell , Jones R. Brad
Published: July 2020

OBJECTIVES/GOALS: HIV-specific CD8+ T-cells play a critical role in partially controlling viral replication in infected-individuals, but ultimately fail to eliminate infection. Enhancing these T-cell responses through lymphocyte engineering approaches has the potential as a novel therapy capable of achieving durable control or eradication of infection. METHODS/STUDY POPULATION: IL-15 Superagonist (IL-15SA) potently supports the in vivo persistence and antiviral activity of adoptively transferred CD8+ T-cells. The Deep-PrimingTM technology platform, developed by Torque, allows for loading of immunomodulators onto the surface of T-cells via electrostatic ‘nanogels’, which slowly release to deliver sustained autocrine immune stimulation without the harmful effects of systemic exposure. Here, we investigate the impact of IL-15SA Deep-Priming on HIV-specific CD8+ T-cells in a humanized mouse model of HIV infection. Humanized mice were generated by engrafting NOD-scid-IL2Rgnull mice with memory CD4+ T-cells isolated from an ARV-suppressed HIV+ donor. An autologous HIV-specific Cytotoxic T-Lymphocyte (CTL) clone was isolated, and killing potential confirmed. Four weeks post humanization, mice were infected with HIV and received an infusion of unmodified HIV-Specific CTLs, or IL-15SA Deep-Primed HIV-specific CTLs (CTL-DP). T-cell numbers and plasma viral loads were quantified weekly by flow cytometry and qRT-PCR. RESULTS/ANTICIPATED RESULTS: Mice receiving unmodified CTLs trended toward reduced viral loads compared to the No Treatment condition, while mice receiving CTL-DP saw significant, 2-Log10 reductions in VL (p < 0.01). At 41 days post-infection 100% (5/5) of the No Treatment, 66.7% (4/6) of the CTL treatment, and 16.7% (1/6) of CTL-DP treatment mice had detectable viremia. IL-15SA Deep-Priming increased CTL expansion and persistence in peripheral blood which correlated with improved CD4+T-cell preservation. DISCUSSION/SIGNIFICANCE OF IMPACT: Here we demonstrate the first in vivo analysis of IL-15SA Deep-Priming of HIV-Specific CTLs. These data suggest that Deep-Priming of patient T-cells can enhance in vivo function and persistence, leading to improved viral suppression; a significant advancement in the field of HIV cure research. CONFLICT OF INTEREST DESCRIPTION: Austin Boesch, Thomas Andresen, and Douglas Jones are employees of Torque. Darrell Irvine is a co-founder of Torque and Chairman of Torque’s Scientific Advisory Board.
4313 Impaired Natural Killer Cell Function May Be Associated with Cancer-related Fatigue
Authors: Regan Jeniece , Feng Rebekah , Saligan Leorey
Published: July 2020

OBJECTIVES/GOALS: During and after cancer treatment, cancer-related fatigue (CRF) is a debilitating symptom reported by up to 80% of cancer patients Our understanding of the pathology underlying CRF is limited. Preliminary RNA sequencing data suggest that increased levels of KIR3DL1, the natural killer cell (NK) immunoglobulin-like receptor 3DL1a, may be associated with CRF. METHODS/STUDY POPULATION: Fatigue was measured using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACT-F). Functional validation of the NK cell finding was performed from whole blood obtained from fatigued and non-fatigued subjects. NK cells were isolated from freshly collected whole blood using a human NK cell isolation kit based on CD56 microbead positive selection. NK cell function was assessed using the NK cell direct cytotoxicity assay. Briefly, isolated NK cells were co-cultured in a 2:1 ratio with calcein AM-labelled K562 cells, which are NK cell-sensitive due to the very low MHCI expression. NK cell-mediated cytotoxicity was assessed with Cytation 1 Cell Imaging Multi-Mode reader. Flow cytometric protocols were used to examine NK subset differences between the fatigued and non-fatigued groups. RESULTS/ANTICIPATED RESULTS: NK cells isolated from the fatigued group exhibited decreased cytotoxicity at 12.28% compared to NK cells isolated from non-fatigued controls at a mean of 40.6% cytotoxicity. Flow cytometry analysis revealed a decrease in the CD56dim CD16bright population in the fatigued group (87.1% of CD56+CD4- cells) compared to the control (91.4% of CD56+CD4- cells). Furthermore, there was a decrease in NKG2A expression in mature NK cells (CD56dim CD16bright) isolated from the fatigued group compared to the non-fatigued group. DISCUSSION/SIGNIFICANCE OF IMPACT: Results from the pilot study suggest that there was a decrease in NK cell cytotoxicity in the fatigued group. In addition, there may be a shift in NK cell subpopulations associated with fatigue. Findings from this pilot study suggest that impaired NK cell function may be associated with CRF pathogenesis.
4126 Intermuscular adipose tissue secretes pro-inflammatory, extracellular matrix, and lipid signals related to insulin resistance and type 2 diabetes
Authors: Kahn Darcy , Zarini Simona , Macias Emily , Garfield Amanda , Harrison Kathleen , Cree-Green Melanie , Schoen Jonathan , Bergman Bryan
Published: July 2020

OBJECTIVES/GOALS: Intermuscular adipose tissue (IMAT) has been associated with insulin resistance and type 2 diabetes, yet mechanistic studies addressing the functional role of IMAT are lacking. The aim of this work was to identify novel mechanisms by which IMAT may directly impact skeletal muscle metabolism. METHODS/STUDY POPULATION: We quantified the secretome of IMAT, subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) to determine if there are differences between depots in the secretion of cytokines, eicosanoids, FFAs and proteins that influence metabolic function. SAT and VAT biopsies from patients undergoing laparoscopic bariatric surgery and IMAT extracted from vastus lateralis biopsies of individuals with Obesity were cultured for 48 hours in DMEM, and the conditioned media was analyzed using nanoflow HPLC-MS, multiplex ELISAs and LC/MS/MS for proteins, cytokines and eicosanoids/FFA, respectively. RESULTS/ANTICIPATED RESULTS: IMAT secretion of various extracellular matrix proteins (fibrinogen-β, collagenV1a3, fibronectin) was significantly different than VAT and SAT. Pro-inflammatory cytokine secretion of IFNg, TNFa, IL-8 and IL-13 from IMAT was higher than VAT and significantly higher than SAT (p < 0.05). IMAT secretes significantly more pro-inflammatory eicosanoids TXB2 and PGE2 than VAT (p = 0.02, 0.05) and SAT (p = 0.01, 0.04). IMAT and VAT have significantly greater basal lipolysis assessed by FFA release rates compared to SAT (p = 0.01, 0.04). DISCUSSION/SIGNIFICANCE OF IMPACT: These data begin to characterize the disparate secretory properties of SAT, VAT and IMAT and suggest a metabolically adverse secretome of IMAT, that due to its proximity to skeletal muscle may play an important functional role in the pathogenesis of insulin resistance and type 2 diabetes.
4040 Investigation of a Series of 1,4-diaryl-pyrazolo-pyridinones as Anti-Leishmanial Agents
Authors: Corman Hannah Noel , Shoue Douglas A. , Melancon Bruce J. , McDowell Mary Ann
Published: July 2020

OBJECTIVES/GOALS: This study was conducted in order to identify novel chemical compounds that exhibit anti-leishmanial activity and to further characterize their efficacy and toxicity in in vitro and in vivo systems in the hopes of future chemotherapeutic developments. METHODS/STUDY POPULATION: We developed a novel, target-free fluorometric high-throughput screen (HTS) to identify small molecules with anti-leishmanial activity. Screening of 10,000 small molecules from the ChemBridge DIVERset-EXP library cassette #5 yielded 210 compounds that killed 80% of parasites. One hundred nine (109) molecular scaffolds were represented within the hit compounds, including the 1,4-diaryl-pyrazolo-pyridinone (1,4-DAPP). A total of 27 novel 1,4-DAPP compounds were synthesized and anti-leishmanial efficacy and host cell toxicity was determined using L. donovani mCherry expressing amastigotes and THP-1 macrophages. Additional pharmacokinetic analyses of a potent 1,4-DAPP compound were conducted. RESULTS/ANTICIPATED RESULTS: Four experimental compounds had IC50 values less than 5μM, providing similar anti-leishmanial activity to miltefosine. Compound 9279817 had a clearance almost twice the rate of normal hepatic blood flow and had a relatively high volume of distribution, indicating this compound is rapidly cleared and distributes into tissues. in vitro rat liver microsome assays suggest a rapid metabolism of 9279817, and MS/MS results suggest this metabolite is most likely formed via oxidation of the sulfur on the lower aromatic ring. DISCUSSION/SIGNIFICANCE OF IMPACT: This study revealed a novel structural class of compounds that have anti-leishmanial activity. in vitro experiments show compounds with similar efficacy as miltefosine while having significantly less toxicity, suggesting that this class could be further developed as a potential chemotherapeutic.
4400 Low CD4 nadir linked to widespread cortical thinning in adults with HIV
Authors: Hassanzadeh-Behbahani Shiva , Shattuck Kyle F. , Bronshteyn Margarita , Dawson Matthew , Diaz Monica , Kumar Princy , Moore David J. , Ellis Ronald J. , Jiang Xiong
Published: July 2020

OBJECTIVES/GOALS: The history of immune suppression, especially CD4 nadir, has been shown to be a strong predictor of HIV-associated neurocognitive disorders (HAND). However, the potential mechanism of this association is not well understood. This study examined the relationship between CD4 nadir and brain atrophy. METHODS/STUDY POPULATION: Fifty-nine people with HIV participated in the cross-sectional study (mean age, 56.5 ± 5.8; age range, 41-69; 15 females; 46 African-Americans). High resolution structural MRI images were obtained using a 3T Siemens scanner. From a comprehensive 7-domain neuropsychological test battery, a global deficit score (GDS) and HAND diagnoses were determined for each participant. The correlation between CD4 nadir (the lowest ever lymphocyte CD4 count) and cortical thickness was investigated using a vertex-wise non-parametric approach with a conservative statistical threshold of p < 0.05 (FWE-corrected). RESULTS/ANTICIPATED RESULTS: Out of the 59 participants, 12 met standard Frascati criteria for asymptomatic neurocognitive impairment (ANI) and two met the criteria for mild neurocognitive disorder (MND). Across all participants, low CD4 nadir was associated with widespread cortical thinning, especially in the frontal and temporal regions. Higher GDS (indicating worse global neurocognitive function) was associated with bilateral frontal cortical thinning, and the association largely persisted in the subset of participants who did not meet HAND criteria. DISCUSSION/SIGNIFICANCE OF IMPACT: These results suggest that the low CD4 nadir may be associated with widespread neural injury in the brain, especially in the frontal and temporal regions. This spatial profile might contribute to the prevalence/phenotypes of HAND in the cART era, such as the frequently observed deficits in the executive domain.
4006 Methionine Dependence in Cancer: From Metabolic Phenotype to Therapy
Authors: Miousse Isabelle
Published: July 2020

OBJECTIVES/GOALS: Methionine dependence was described 45 years ago as an increased reliance on an exogenous supply of the essential amino acid methionine in most cancer cells compared to normal cells. Methionine depletion, using either synthetic diets or the enzyme methioninase, potentiates the effects of chemotherapy and radiotherapy in tumor-bearing animal models. Two main obstacles prevent methionine dependence from integrating the clinical treatment of cancer. The first is the weight loss associated with methionine depletion therapy, increasing the risk of cachexia in patients. The second is the stubborn absence of a mechanism to explain the inability of cancer cells to adapt to low methionine levels. METHODS/STUDY POPULATION: To address these two obstacles, we are using an immunocompetent murine model of metastatic melanoma to compare the effects of complete methionine deprivation with a moderate, 75-80% methionine restriction similar to the one used to increase lifespan in animal models. In an effort to identify a mechanism of action, we also performed a proteomic screen of two melanoma cell lines divergent for methionine dependence under methionine stress. RESULTS/ANTICIPATED RESULTS: We recently showed that methionine restriction is sufficient to provide gains in treating local and metastatic lesions in vivo, without weight loss. We observed few differences in pathway activation between the two cell lines in response to methionine stress, despite proliferation being cut by half in the methionine dependent cell line. We expect that subcellular translocation events may provide further information on the molecular bases of methionine dependence. DISCUSSION/SIGNIFICANCE OF IMPACT: A moderate restriction in methionine is sufficient to recapitulate the benefits of methionine depletion in cancer, without weight loss. The mechanism behind this effect remains unknown. This work contributes towards the integration of methionine dependence into clinical practice and the discovery of novel drug targets.