bluuebunny/crossref_metadata_2025 huggingface dataset:
414 Housing and Environmental Exposures: A Systematic Literature Review on Research and Policy Implications
Authors: Bhat Aarti C. , Fenelon Andrew
Published: April 2023

OBJECTIVES/GOALS: Poor housing conditions and quality can be linked with residents’environmental exposures, which may contribute to a variety of adverse health outcomes. This systematic literature review will examine literature around housing, environmental exposure, and health; and policy implications to reduce the impact of housing on environmental exposures. METHODS/STUDY POPULATION: This systematic literature review will identify and evaluate published peer-reviewed articles as well as governmental and NGO policy briefs relating to connections between housing quality and condition, neighborhood characteristics, and environmental exposures (e.g., lead poisoning, secondhand smoke, PFAS chemicals) in the United States; and will particularly focus on health implications of such environmental exposures, racial/ethnic and socioeconomic disparities in exposure, and current and future policy recommendations to alleviate the association between housing and environmental risk. A computerized literature search of relevant electronic databases (e.g., PubMed, Sociological Abstracts, EPA database, Congressional database) for literature published after 2000 will be conducted. RESULTS/ANTICIPATED RESULTS: The findings from this literature review will be split up into categorizations around (1) the contribution of housing/neighborhoods on resident environmental exposure; (2) geospatial and demographic inequality (historic and current) around housing/neighborhood conditions contributing to disproportionate environmental exposures for low-income and minoritized residents; (3) health implications of environmental exposures; (4) prior policy addressing the connections between housing/neighborhoods and environmental risk; and (5) future policy recommendations to improve housing/neighborhood quality and minimize environmental exposures for residents. DISCUSSION/SIGNIFICANCE: This project will illuminate connections between housing conditions and environmental exposures, health implications of these exposures, and contribute to advancing understanding of potential policies to reduce adverse environmental health impacts of poor housing conditions for residents (particularly for low-income, minoritized groups).
419 A CTS team approach to identifying thematic constructs related to kratom use during pregnancy and breastfeeding: A qualitative analysis of social media posts
Authors: Hoeflich Carolin C. , Kuntz Michelle A. , McCurdy Christopher R. , Striley Catherine W.
Published: April 2023

OBJECTIVES/GOALS: Research on the safety of perinatal kratom use - an herb that acts on opioid receptors - is scarce. Our transdisciplinary clinical and translational science (CTS) team is conducting parallel qualitative analyses of subreddit posts related to kratom use during (1) pregnancy and (2) breastfeeding. METHODS/STUDY POPULATION: Pregnancy- and breastfeeding-related keywords are being used to extract posts and selected metadata from the following subreddit communities: r/kratom, r/quittingkratom, r/pregnant, and/or r/breastfeeding. After the removal of duplicate posts, posts written in a non-English language and those that state in the post text and/or title that they were published by minors ( RESULTS/ANTICIPATED RESULTS: Among the eligible posts, the number of unique usernames of the sources publishing the posts; the range of publication dates; and the mean, median, & range of the number of comments per post will be presented. Inter-rater concordance in thematic coding will be computed. A word cloud will be created with the most used nouns from the eligible posts. Verbatim quotes will be shown to illustrate themes depicted in the sample. The quantitative and qualitative analyses will be conducted separately for the posts related to kratom use during pregnancy and breastfeeding. DISCUSSION/SIGNIFICANCE: These findings could assist clinicians in identifying questions that obstetric patients may have regarding the perinatal use of this emerging substance of concern. Further research is needed to validate these findings using other social media data, such as Twitter.
424 Clinical Translational Approach to Targeted Therapy in SLC6A1-related Neurodevelopmental Disorder
Authors: Goodspeed Kimberly , Sirsi Deepa , Gray Steven , Rioux Matthew , Guo WeiRui , Iannaccone Susan
Published: April 2023

OBJECTIVES/GOALS: SLC6A1-Related Neurodevelopmental Disorder (SLC6A1-NDD) is a leading genetic cause of epilepsy and autism. Haploinsufficiency of SLC6A1 leads to reduced uptake of GABA from the synaptic cleft, and increased extracellular GABA in mice. It is a candidate for gene transfer therapy, but translational read outs are needed. EEG is a promising biomarker. METHODS/STUDY POPULATION: The SLC6A1-NDD program includes a specialty clinic and prospective cohort study run in parallel with pre-clinical gene therapy development. Characterization and pre-clinical testing of a homozygous knock-out, heterozygous knock-out, and two humanized knock-in models are on-going, including EEG analyses before and after treatment. Patients with a confirmed diagnosis of SLC6A1-NDD are seen annually in a specialty clinic and a subset participate in the cohort study which collects standardized questionnaires, EEGs, and MR Spectroscopy to measure glutamate and GABA. Gene Therapy Program investigators meet weekly to discuss progress on pre-clinical and clinical trial readiness on SLC6A1-NDD and to align efforts on translational read outs, including EEG, in both humans and the pre-clinical models. RESULTS/ANTICIPATED RESULTS: We have enrolled the full cohort of 20 participants in the prospective SLC6A1-NDD cohort study. Preliminary results have shown that all but 1 individual has a history of developmental delay, and 8 of the 24 individuals in our clinical cohort had at least one episode of developmental regression. Over 90% have epilepsy, and 17/20 in the cohort study have intermittent rhythmic delta activity on EEG. The full knock out mice have behavioral and learning deficits and abnormal electrical brain activity on telemetry, including bursts of spike trains, analogous to epileptiform activity seen in humans. Next steps include quantitative analysis of both mouse and human EEG to develop a translational brain-based biomarker. We plan to assess delta power and investigate genotype-phenotype correlations in mice and humans. DISCUSSION/SIGNIFICANCE: With targeted therapies in development for SLC6A1-NDD, translational biomarkers that demonstrate engagement with the brain are critical. With clinical heterogeneity in SLC6A1-NDD, biomarkers can objectively capture change. Collaborative translational projects may improve efficiency in rare disease research to facilitate early phase trials.
426 Datathon Revisited: Implementation of Lesson Learned
Authors: Zimolzak Andrew J. , Sippel Katherine , Davila Jessica A. , DeBakey Michael E. , Punugoti Vamshi , Klotman Paul E. , Petersen Laura A. , DeBakey Michael E. , Liao Gloria , Leiber Lee , Amos Christopher I.
Published: April 2023

OBJECTIVES/GOALS: In 2020, Baylor College of Medicine held a datathon to introduce a data warehouse, identify its capabilities/limitations, foster collaborations, and engage trainees. The event was held again in 2022, and lessons learned (e.g., tools for data self-service or team communication) were applied. METHODS/STUDY POPULATION: Senior faculty reviewed proposals with an emphasis on feasibility, impact, and relevance to quality improvement or population health. Selected teams worked with Information Technology (IT) for 2 months and presented findings at a 1-day event. Surveys were administered to participants before and after the event to evaluate their background, team characteristics, collaborations, knowledge before and after the datathon, perceived value of the datathon, and plans for future work. Descriptive statistics of respondents’ self-reports were tabulated. RESULTS/ANTICIPATED RESULTS: In 2022, 19 of 36 projects were accepted (13/33 in 2020). At both events, most projects studied quality improvement or clinical outcomes. Of 82 participants in 2022, 54 completed surveys. In 2022, 72% had no datathon experience (48% in 2020). Median effort was 10 person-hours; median IT time was 20% (20 and 10%, in 2020). Seven respondents finished and 21 partially finished their projects (1 and 11, in 2020); 92% made new collaborations (91% in 2020). Respondents strongly agreed that: the experience was valuable (n=28), they would participate in future datathons (n=30), and they would use the warehouse for future work (n=25). Twenty-seven have planned abstracts; 25 have planned manuscripts. DISCUSSION/SIGNIFICANCE: The 2022 datathon had more participants with less experience, potentially due to improved promotion and training opportunities. Fewer person-hours and a higher percentage of IT time were required as compared to 2020, and more projects were completed, possibly due to increased IT efficiency.
430 Etiology of Hepatocellular Carcinoma in the 27-County Rochester Epidemiology Project Catchment Area, 2010-2021
Authors: VanLith Caitlin , Uwilingiyimana Aimee , Roberts Lewis R
Published: April 2023

OBJECTIVES/GOALS: The goal of this study is to examine the incidence, etiology, and outcomes of hepatocellular carcinoma (HCC) in a 27-county region in SE Minnesota and W Wisconsin between 2010 and 2021. A comparison of the first to second half of the period will be made to look for possible trends. METHODS/STUDY POPULATION: The Rochester Epidemiology Project (REP) is a database of patient records across SE Minnesota and W Wisconsin. Starting in 2010, the REP opened to a 27-county catchment area, which includes over 1.3 million patients with a population coverage of approximately 64%. This study will use the expanded REP data to collect data on patients 20 years of age and older with a new diagnosis of HCC between Jan 1, 2010 and Dec 31, 2021â€”an estimated 1000 cases. Patients with a record of less than one year of residence in the catchment area will be excluded. Data on etiology, comorbidities, and outcomes of HCC will be extracted from medical records and analyzed for risk factors and changes over time. RESULTS/ANTICIPATED RESULTS: We anticipate that the overall incidence of HCC in the REP geographic area has increased over the period of 2010 to 2021. We anticipate that the prevalence of hepatitis C virus infection in patients with HCC has between 2010 and 2021, due to the widespread use and accessibility of hepatitis C-specific antiviral treatment over the past decade. We anticipate that the prevalence of NAFLD in patients with HCC has increased between 2010 and 2021. We do not anticipate significant changes in treatment modality or survival outcomes over this period. DISCUSSION/SIGNIFICANCE: This study will provide a comprehensive update on the state, etiology, and outcomes of HCC in the area surrounding Rochester, MN. We will be able to track changes in risk factors over time and work to enhance screening protocols to target the most vulnerable populations.
439 Research Dynamics within a New Multi-Institutional Cross-Disciplinary Translational Team (MCTT): A Formative Study
Authors: Kotarba Joseph A. , Molldrem Stephen , Smith Elise , Spratt Heidi , Bhavnani Suresh K. , Wooten Kevin
Published: April 2023

OBJECTIVES/GOALS: This report evaluates participants’experiences from three universities who assembled a complex grant proposal related to research on post-acute sequala of COVID-19 (PASC), also called long COVID. Activities reviewed ranged from the assembly of the team to responses to reviews by the National Center for Advancing Translational Sciences (NCATS). METHODS/STUDY POPULATION: Data were collected by means of semi-structured interviews, conducted and recorded on Zoom, with a sample of 15 scientists and staff both during proposal assembly and following proposal review. The sample comprised 40% of the total team equally selected from the 3 universities, The interview protocol was reviewed by the IRB at UTMB and the interviews were recorded on Zoom, and analyzed by means of the constant comparative strategy in the grounded theory method of qualitative research. Given the relatively small number of interviews in this project, we paid special attention to preserving the confidentiality of respondents. Only the verbal tracks of the interviews were professionally transcribed. Respondents were asked to suggest changes for future inter-organizational proposals. RESULTS/ANTICIPATED RESULTS: FIRST INTERVIEWS *LEADERSHIP: The scope of leadership opportunities was expanded as sub-teams in specific areas such as community engagement were formed. *TEAM: Each university’s community engagement team specializes in a different ethnic clientele, precluding a singular statement for the proposal. SECOND INTERVIEWS *LEADERSHIP: Staff members noted that the team concept too easily evolved into a bureaucratic format, resulting in less negotiation and more direction. *ASSEMBLY TASKS: The Writing Team turned out to be one of the most critical staff teams. *COMMUNICATION: The behavioral scientists in community engagement do not necessarily share paradigms (e.g., public health, psychology, and social work). They had difficulty generating productive communication and a unified statement for the proposal. DISCUSSION/SIGNIFICANCE: The scientists, as a group, suggested that future proposals should focus on one general topic, such as the microbiome, as opposed to attempting to integrate widely divergent interests. The scientists as a group should decide a priori whether to treat innovative ideas such as machine learning science as a science or a service.
449 Progression of silica-induced pulmonary fibrosis is arrested after selective ablation of Col1a1+ fibroblasts
Authors: Foster Daniel G , Javkhlan Nomin , Wilson Jasmine , Edelman Benjamin L. , Riches David W. H. , Redente Elizabeth F.
Published: April 2023

OBJECTIVES/GOALS: Silicosis is a highly fatal progressive fibrotic disease of the lungs characterized by accumulation and persistence of fibroblasts that excessively deposit Collagen1a1. We sought to eliminate Collagen1a1-expressing fibroblasts through a targeted genetic ablation strategy and hypothesized that this would arrest the progression of Silicosis. METHODS/STUDY POPULATION: Silicosis was induced with a single intratracheal (i.t.) instillation of silica particles ( RESULTS/ANTICIPATED RESULTS: Targeted ablation of Col1a1+ fibroblast in established Silicosis resulted in a decrease in: 1) Col1a1+ fibroblasts by flow cytometry and within fibrotic nodules by immunofluorescent staining, 2) total lung collagen content by histology and hydroxyproline assay, 3) tissue-associated disease by microCT and an increase in arterial oxygen saturation by pulse oximetry. Cessation of targeted Col1a1+ fibroblast ablation resulted in a rebound effect in Silicosis disease progression. Following ablation, Col1a1+ fibroblasts expanded by proliferation (Ki67+) and total lung collagen levels returned to pre-ablation levels. DISCUSSION/SIGNIFICANCE: Silicosis is a often fatal disease with no FDA approved therapies. These results suggest that targeted loss of Col1a1+ fibroblasts in Silicosis is sufficient to arrest disease progression. Thus, it is essential to understand how targeted loss of pro-fibrotic fibroblasts can alter disease progression as a tool to develop novel therapeutic strategies.
454 A Human 3D Model of Duchenne Muscular Dystrophy Cardiomyopathy to Investigate Calcium Regulation and Mitochondrial Dysfunction
Authors: Ernst Patrick , Dora Michaela , Zhou Lufang , Ogle Brenda , Kamdar Forum
Published: April 2023

OBJECTIVES/GOALS: We will use control- and DMD-engineered heart tissues to better model and investigate DMD cardiomyopathy. We will primarily assess cardiac calcium handling, mitochondrial function, and mitochondrial calcium handling, as calcium regulation and mitochondrial function are known to be affected in DMD. METHODS/STUDY POPULATION: We will use patient-derived stem cells, differentiated into cardiomyocytes in bioprinted 3D heart tissue muscle chambers to better model DMD cardiomyopathy. We will look at calcium handling and general mitochondrial function, as well as mitochondrial calcium handling, using a novel multifunctional genetic probe I previously developed allowing for simultaneous observation of cytosolic and mitochondrial calcium in real time. Optical mapping will also be used for tissue-level analysis. We will establish the functional differences at baseline, and then progress heart failure in the tissues to see how the abnormalities seen in the DMD tissues may get worse. Finally, we will investigate the effects of early restoration of dystrophin function on the effects of DMD cardiomyopathy development. RESULTS/ANTICIPATED RESULTS: We anticipate that DMD tissues will show more irregular/abnormal calcium handling, as seen in 2D hiPSC-CMs, as well as disruptions to mitochondrial function and ultrastructural development, as well as a decreased synchronization between cytosolic and mitochondrial calcium dynamics. We anticipate that these abnormalities will be exacerbated as the disease state progresses, but at least partially ameliorated with the restoration of dystrophin function. DISCUSSION/SIGNIFICANCE: DMD is a fatal disease with no known cure. Patients develop heart failure in their teens and die in their 20s, so any new insight that may prolong life and improve quality of life for patients is drastically needed. This would be the most accurate preclinical model of DMD cardiomyopathy to date and would investigate yet-untapped aspects of the disease state.
456 Analysis of Clinical, Histologic, and Molecular Characteristics of Proliferative Verrucous Leukoplakia
Authors: Weikel Dana R. , Isaacs Anne , Basile John , Weikel Dianna S. , Meiller Timothy F.
Published: April 2023

OBJECTIVES/GOALS: This study aims to develop objectively scored histological characteristics of early oral leukoplakia, which may be correlated with molecular pathways predictive of progression into proliferative verrucous leukoplakia (PVL). The secondary aim is to develop a biomarker profile to be used in diagnosis, staging, and management of PVL. METHODS/STUDY POPULATION: Clinical and pathology records of 120 patients with oral leukoplakia and/or PVL were reviewed. Eight patients were selectedâ€”all had serial biopsies over time leading to PVL suspicion. Specimens were deidentified and subjected to blinded examination by a board certified oral pathologist, then scored relative to the extent of each of the commonly accepted histologic characteristics of PVL: hyperkeratosis, acanthosis, blunt rete ridges, hyperchromatic nuclei, increased nuclear-cytoplasmic ratio, dyskeratosis, and surface corrugation. Given these results, a larger subset of patient samples will be labeled and assayed for expression of epidermal growth factor receptor tyrosine kinases and downstream pro-oncogenic signaling mediators. Expression of these factors will be tested against progression to PVL. RESULTS/ANTICIPATED RESULTS: Histologically, in scoring the specimens from eight subjects, the characteristics of acanthosis, dyskeratosis, and blunted rete ridges had the strongest correlation with eventual progression to PVL. These criteria will therefore be recommended as an objective histopathologic method of identification of patients with high risk of development of PVL, and therefore malignant potential. We expect the results of the biomarker assay to provide a molecular basis for predicting PVL pathogenesis. Particularly, we anticipate pro-oncogenic targets such as EGFR, PI3K, Akt, and mTOR pathways will show increased expression as leukoplakic lesions progress. These results would then provide the basis for testing patient samples for expression of these markers in a longitudinal study of PVL emergence and progression. DISCUSSION/SIGNIFICANCE: The aggressive nature of PVL, with a rate of malignant transformation of 61% and mortality rate of 40%, requires close clinical monitoring in order to improve patient outcomes. Therefore, well defined objective clinical, histologic, and molecular criteria are critical for early detection of sites likely to progress to PVL and subsequent malignancy.
473 Exploring gastrointestinal bacterial colonization in rosacea as a biomarker for systemic abnormalities in innate immunity
Authors: Nelson Jessie M , Nakamura Mio
Published: April 2023

OBJECTIVES/GOALS: To investigate the relationship between abnormal bacterial colonization of the gastrointestinal (GI) tract and systemic abnormalities in innate immunity as it contributes to the pathogenesis of rosacea. METHODS/STUDY POPULATION: This is a prospective observational study of patients with erythematotelangiectatic or papulopustular rosacea. The study participants will undergo urea breath testing for Helicobacter pylori (Hp) and hydrogen-methane breath testing for small intestinal bacterial overgrowth (SIBO). Colonic microbiome analysis will be performed using 16S rRNA sequencing of fecal samples. Further, key pro-inflammatory cytokines will be quantified from serum samples. Markers for rosacea subjects and subgroups will be compared by standard analysis of variance methods where appropriate, and Tukey studentized range tests will be done for specific comparisons. Chi-square tests will be used to assess group differences in categorical data. At least 42 subjects will be studied to provide 80% power atÎ±-0.05. RESULTS/ANTICIPATED RESULTS: We hypothesize that the results of this study will support an observed relationship between abnormal GI bacterial colonization and systemic innate immunity abnormalities in rosacea as determined by three primary endpoints: a significantly greater prevalence of Hp and SIBO in rosacea participants, presence of pro-inflammatory cytokines linked to rosacea pathogenesis including interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor (TNF)-Î±, and Granulocyte-macrophage colony-stimulating factor (GM-CSF), and observation of distinct, metabolically active colonic bacterial communities specific to rosacea participants. DISCUSSION/SIGNIFICANCE: By identifying rosacea as a cutaneous manifestation of a more systemic inflammatory disease, the results of this study will have implications for the development of important pharmacological interventions targeting key inflammatory pathways in rosacea pathogenesis.
479 Insomnia and Depression Trajectories in Women with and without Breast Cancer: Protective Effects of Satisfying Relationships
Authors: Shrout Rosie , Renna Megan E. , Madison Annelise , Kiecolt-Glaser Janice K.
Published: April 2023

OBJECTIVES/GOALS: Breast cancer survivors have a high risk for chronic disease and early mortality, especially if their psychological and physical symptoms persist beyond treatment. We compared survivors’and noncancer patient controls’health trajectories. We also examined how their relationship satisfactionâ€”a key health determinantâ€”impacted their health. METHODS/STUDY POPULATION: In this longitudinal study, participants were women who were married/domestic partners with an initial suggestive test of cancer identified at cancer clinics. After follow-up testing, women received either a malignant diagnosis (cancer survivors; n=139, stages 0–IIIC) or benign diagnosis (noncancer patient controls; n=69). Breast cancer survivors completed a baseline visit prior to beginning cancer treatment and two follow-up visits 6 and 18 months after treatment ended (surgery, radiation, or chemotherapy, whichever came last); noncancer patient controls completed visits within a comparable timeframe. At each visit, all women completed self-report questionnaires assessing their relationship satisfaction, insomnia, and depressive symptoms. RESULTS/ANTICIPATED RESULTS: We used mixed models and adjusted for participant age, comorbidities, cancer treatment and stage, BMI, and menopause status. At the pre-treatment visit, cancer survivors reported greater depressive symptoms than noncancer patient controls. Cancer survivors’depressive symptoms also decreased over time and were higher before treatment than at the 6- and 18-month post-treatment visits. Insomnia in cancer survivors, but not noncancer patient controls, decreased over time: insomnia was higher at the pre-treatment and 6-months post-treatment visits relative to the 18-month post-treatment visit. Survivors, but not noncancer patient controls, had lower depressive symptoms and insomnia at visits when they reported higher satisfaction than at visits when they reported lower satisfaction. DISCUSSION/SIGNIFICANCE: Cancer survivors had poorer psychological health than those without cancer before treatment, but survivors’psychological and physical health improved after finishing treatment. Survivors’satisfying relationships predicted better psychological and physical health, demonstrating the notable health benefits of survivors’relationships.
480 Integrating a Research Ethics Program within an Academic Health Science Center
Authors: Farroni Jeffrey S. , McNamara Victoria H. , Smith Elise
Published: April 2023

OBJECTIVES/GOALS: Research ethics services are critical to the clinical, research, and educational missions of an academic health science center. Our ethics program aims to develop a culture where investigators are as intellectually engaged in ethical issues of scientific integrity as they are in study design, data collection, and implementation. METHODS/STUDY POPULATION: This descriptive analysis depicts the historical development, from 2010 to 2022, of our research ethics program as an exemplar of ethics integration into the research enterprise of an academic health science center that engages in translational research. In this culture, clinicians, translational researchers and their scientific peers, research participants, and community members become involved in ethics investigation, deliberation, and innovation. RESULTS/ANTICIPATED RESULTS: There are four pillars to our research ethics program: 1) research ethics consultation service, which fosters the development of ethical best practices and standards for the practice of translational research; 2) education, which provides customized training and educational opportunities in research ethics to diverse stakeholders; 3) leadership, through collaboration and partnerships; 4) scholarly engagement, in the pursuit of innovative ethics research and professional development. Through these initiatives we can engage a broad constituency of stakeholders, become an integral component of research oversight, engage as active participants in the research enterprise, and have a critical role in guiding institutional culture. DISCUSSION/SIGNIFICANCE: The integration of our ethics program mirrors the translational science continuum which promotes the multidirectional flow of ideas among ethics consultants, laboratory/clinical scientists, implementation researchers and the community.
481 Interactions between buprenorphine and norbuprenorphine in neonatal opioid withdrawal syndrome
Authors: Tobacyk Julia , Parks Brian J. , Coward Lori , Berquist Michael D. , Gorman Gregory S. , Brents Lisa K.
Published: April 2023

OBJECTIVES/GOALS: Buprenorphine (BUP) is used for opioid use disorder during pregnancy but causes neonatal opioid withdrawal syndrome (NOWS). The goal of this study was to determine the contribution of the active metabolite, norbuprenorphine (NorBUP), to the development of NOWS when the parent drug, BUP, is administered during pregnancy. METHODS/STUDY POPULATION: Subcutaneously implanted osmotic minipumps delivered BUP (0, 0.01, 0.1 or 1 mg/kg/day) ± NorBUP (1 mg/kg/day) to pregnant Long-Evans rats from gestation day 9 until after delivery. NOWS was measured between 3 and 12 hours after delivery. Withdrawal was precipitated by an intraperitoneal injection of a mu opioid receptor antagonist naltrexone (NTX; 0, 1 or 10 mg/kg), and movement duration (MD; a validated proxy for NOWS) was measured using Noldus Ethovision. Concentrations of BUP, NorBUP, and their glucuronide conjugates in the brains of neonatal littermates not undergoing withdrawal testing were determined using LC/MS/MS. Two-way ANOVA and multiple linear regression analyses tested for interactions between BUP and NorBUP on MD and related brain concentrations to MD, respectively. RESULTS/ANTICIPATED RESULTS: There was no interaction effect between BUP and NorBUP on MD for either sex or at any dose of naltrexone. In females, but not males, BUP (1 mg/kg/day) significantly increased NorBUP-induced MD by 58% following an injection with 1 mg/kg NTX. A multiple linear regression model that included BUP and NorBUP brain concentrations as predictors of MD was significant and well-fitting [FEMALES: F (2, 40) = 23.97, P < .0001, adj R2 = 0.52; MALES: F (2, 40) = 5.84, P = .0059, adj R2 = 0.19]. There was a differential contribution of NorBUP brain concentrations to MD based on sex. The partial regression coefficient for NorBUP was 51.34 (p < .0001) for females and 19.21 (p = 0.093) for males. The partial regression coefficient for BUP was similar for females and males (FEMALES:βBUP = 10.62, p = .0017; MALES:βBUP = 11.38, p = .009). DISCUSSION/SIGNIFICANCE: We show for the first time a differential contribution of NorBUP to BUP-associated NOWS in each sex, suggesting sex differences in NorBUP susceptibility and implicating that treatment strategies reducing prenatal NorBUP exposure may be more effective for females than males.
486 Molecular Mechanisms of Type II Spiral Ganglion Neuron Development
Authors: George Deborah Jane , Mejia Juliet , Thiru Shankar , Deans Michael , Coate Thomas
Published: April 2023

OBJECTIVES/GOALS: 30,000,000 people in the U.S. have hearing loss, negatively impacting quality of life and work. Understanding auditory axon guidance for spiral ganglia neurons (SGNs) will aid development of new therapies. I study role of Eph/Ephrin signaling in mediating type II SGN turning events, and how planar cell polarity (PCP) signaling modulates this process. METHODS/STUDY POPULATION: This quantitative study was conducted on Efna3 and Vangl2 null mice possessing Neurog1CreERT2 and R26RtdTomato mutations. Spontaneous Cre activity within the Neurogenin 1 CreERT2 line causes recombination and expression of fluorescent Rosa26 Reporter (R26R)tdTomato in a restricted number of SGNs, including type IIs. Together these lines permit SGN sparse labeling. Bulk-labeling was used for Efna3;Vangl2 double knockout (DKO) mutants. Immunostaining and confocal imaging was used to analyze dsRed in Efna3; Vangl2 and NF-200 in DKOs to quantify type II SGN turning. In combination, 3D rendering in Imaris software was used to quantify type II SGN turning, branching and other growth and navigation characteristics. 5-6 cochleae per genotype were analyzed and compared by t-test to wildtype controls. RESULTS/ANTICIPATED RESULTS: EPHRIN-A3 is expressed on the membranes of outer pillar and Deiters’cells of the cochlear epithelium. Efna3 nulls showed a small rise in type II SGNs incorrectly turning toward the apex at an error frequency of 16.9% compared to controls (n=6; p=0.05). Efna3 nulls had reduced branch number/fiber compared to controls, 4.14 and 7.22, respectively (n=129; p DISCUSSION/SIGNIFICANCE: Our results suggest that Eph/Ephrin signaling acts parallel of PCP signaling to mediate type II SGN guidance during development. The clinical implications of these findings are that therapeutics targeting EPHRIN-A3 and/or VANGL2 in this pathway could stimulate new outer hair cell innervation by type II SGNs following auditory damage.
502 The Prospective Geriatric Patient Reported Outcomes (GERI-PRO) Study: Understanding Post- Traumatic Injury Recovery from the Patient’s Perspective
Authors: Ghneim Mira , Stein Deborah
Published: April 2023

OBJECTIVES/GOALS: Patient reported outcomes (PROs) provide unique insight to the patients experience with their healthcare related quality of life QoL. This study aims to 1. Characterize geriatric trauma patients’(GTPs) perceived QoL, at time of injury vs. 3- and 6-months post-injury. 2. Introduce and validate a PROs tool, known as the Five Favorite Activities. METHODS/STUDY POPULATION: This is a prospective cohort study of older adults (≥65) presenting to our trauma center with mild traumatic brain injury and/or mild spine, thoracic or extremity fractures. Participants will be asked to complete the NIH-validated Patient-Reported Outcome Measure Information System (PROMIS)-29, PROMIS Cognitive and Functional Abilities, Life-Space Levels and Five Favorite Activities assessment (a list of the five favorite overall and daily activities) tools. Cognitive function will be measured using Montreal Cognitive Assessment tool. Physical function will be evaluated using the Activity Measure for Post-Acute Care 6-click tool. Patients will be contacted at 3- and 6- months post discharge and asked to complete the assessment tools listed above to evaluate changes in QoL during the recovery process. RESULTS/ANTICIPATED RESULTS: We hypothesize that geriatric trauma patients will experience a decline in QoL, physical and cognitive function post-injury. This decline will be associated with a decrease in return to the ability to participate in their pre-injury Five Favorite Activities . DISCUSSION/SIGNIFICANCE: First, this study is one of the first to evaluate PROMs in GTPs. Second, the Five Favorite Activities PROM, will provide a unique, direct and individualized characterization of what GTPs find important to their recovery post injury compared to the current generic PROMs. This information can be utilized in the future to align goal of care with expectations
511 Eliminating System xc- Signaling Between Astrocytes and Neurons Selectively Impairs Complex Cognition
Authors: Simandl Gregory , Simandl Gregory J. , Hess Evan , Kong Linghai , Raddatz Nicholas J. , Hurley Matthew M. , Maunze Brian , Choi SuJean , Geurts Aaron M. , Baker David A.
Published: April 2023

OBJECTIVES/GOALS: We aim to discover safer and more effective therapeutics for CNS disorders. Current therapeutic development is hindered by dosing out drugs for safe consumption. By identifying proteins with narrow functional roles in the brain (i.e., behavioral control), we can develop drugs targeting these proteins for improved treatment safety and efficacy. METHODS/STUDY POPULATION: We focused on an evolutionarily new, non-neuronal, non-synaptic glutamate signaling mechanism, system xc- (Sxc). Sxc activity was eliminated by mutating the gene Slc7a11 through pronuclear injection of zinc-finger nucleases into Sprague Dawley rat embryos to create a line of rats lacking Sxc (MSxc). To confirm Sxc mutation, we verified that tissue from MSxc rats had a complete lack of xCT, which is the regulatory subunit of Sxc that is encoded by Slc7a11. We also verified that astrocyte cultures generated from MSxc tissue lacked cystine-evoked glutamate release. Next, we measured development (body weight), CNS regulation of metabolism, and other indicators of generalized, non-specific brain function as well as behaviors that are reliant on behavioral control, such as impulse control and response inhibition. RESULTS/ANTICIPATED RESULTS: Eliminating Sxc was not lethal and did not impair development or produce widespread changes in brain function as is commonly observed when deleting other glutamate mechanisms. MSxc rats did not differ from wildtype in growth rate, central regulation of metabolism as reflected by absolute or diurnal changes in core body temperature, locomotor activity in a familiar or novel environment, or simple forms of cognition such as novel object recognition, or operant responding (food and cocaine-reinforced). In contrast, behaviors that rely on behavioral control were impaired. MSxc rats displayed deficits in impulse control and behavioral flexibility. We hypothesize that MSxc rats will also show deficits in response inhibition using the stop signal reaction time task, a common metric used in clinical populations. DISCUSSION/SIGNIFICANCE: Eliminating Sxc activity in rats produced deficits in behaviors reliant on impulse control, without impacting development or simple brain function. These results show the potential of targeting Sxc to restore behavioral control without generating therapeutically limiting adverse effects resulting from non-specific changes in brain function.
514 Understanding Structural and Dynamic Effects of the EWS-FLI1 interactome on the EWS Low Complexity Domain Function
Authors: Parra George Louis , Selig Emily , Baudin Antoine , Weintraub Susan , Fongang Bernard , Libich David
Published: April 2023

OBJECTIVES/GOALS: The EWSR1-FLI1 gene fusion is implicated as a source of oncogenic activity in the majority of Ewing sarcoma (EwS) cases (>70%). Our studies will provide unparalleled insight into the transformative mechanics of EWS-FLI1 METHODS/STUDY POPULATION: EWS-FLI1 is an intrinsically disordered protein (IDP). IDPs do not form stable secondary or tertiary folds in biological conditions and ofter contain proline-rich regions and other multivalent binding regions. These regions interact with numerous partners resulting in highly dynamic and complex protein-protein interactions. Recent advances in proximity labelling techniques, such as the use of a biotin ligase fused to a protein of interest are exceptionally well suited to identifying IDP interactomes since they do not rely on the binding affinities but rather the distance between interacting proteins. Combining novel discovery proteomics with Nuclear Magnetic Resonance (NMR) approaches will provide unparalleled insight into the transformative mechanics of EWS-FLI1. RESULTS/ANTICIPATED RESULTS: Using the proximity labeling technique TurboID, which limits the number of false-positive interactions, we have shown that EWSR1 and EWS-FLI1 act within the spliceosome (responsible for mRNA splicing and processing). Using bioinformatics techniques, we show EWS-FLI1 interacts with peptidyl-prolyl isomerase (PPI) proteins, specifically PPIL1, through the EWS-FLI1 N-terminal region (EWS-LCD). We used NMR to provide insight into the interaction between PPIL1 and EWS-LCD, showing that EWS-LCD interacts with the catalytic region of PPIL1. We anticipate that PPIL1 isomerizes EWS-FLI1 to modulate its activity, and that EWS-FLI1 interacts with the spliceosome through formation of a biological condensate. However, future proximity labeling and NMR studies are needed to verify this activity. DISCUSSION/SIGNIFICANCE: Our studies will yield actionable insights regarding the protein-protein interfaces in EWS-FLI1 that can be targeted to attenuate the oncogenic activity of EWS-FLI1. More broadly, our results will be applicable toward understanding the etiology of other pediatric cancers and for guiding the development of novel targeted treatments.
Open data as an anticorruption tool? Using distributed cognition to understand breakdowns in the creation of transparency data
Authors: Martinez Tatiana M. , Whitley Edgar A.
Published: April 2023

One of the drivers for pushing for open data as a form of corruption control stems from the belief that in making government operations more transparent, it would be possible to hold public officials accountable for how public resources are spent. These large datasets would then be open to the public for scrutiny and analysis, resulting in lower levels of corruption. Though data quality has been largely studied and many advancements have been made, it has not been extensively applied to open data, with some aspects of data quality receiving more attention than others. One key aspect however—accuracy—seems to have been overlooked. This gap resulted in our inquiry: how is accurate open data produced and how might breakdowns in this process introduce opportunities for corruption? We study a government agency situated within the Brazilian Federal Government in order to understand in what ways is accuracy compromised. Adopting a distributed cognition (DCog) theoretical framework, we found that the production of open data is not a neutral activity, instead it is a distributed process performed by individuals and artifacts. This distributed cognitive process creates opportunities for data to be concealed and misrepresented. Two models mapping data production were generated, the combination of which provided an insight into how cognitive processes are distributed, how data flow, are transformed, stored, and processed, and what instances provide opportunities for data inaccuracies and misrepresentations to occur. The results obtained have the potential to aid policymakers in improving data accuracy.
Religious Exemption, LGBT Rights, and the Social Construction of Harm and Freedom
Authors: Kazyak Emily , Burke Kelsy , Behrendt Maia , Oliver Marissa
Published: April 2023

In this article, we examine how courts make decisions in religious exemption cases that implicate LGBT rights in a wide range of contexts including education, employment, and medical care. Through an in-depth qualitative analysis of 50 federal cases decided between 1990 and 2020, we demonstrate a shift in how anti-LGBT sentiment is expressed by parties bringing religion-based claims—from a broad condemnation of LGBT identity to a narrow condemnation of same-sex marriage—and find that courts are more likely to rule in favor of the latter. We show how courts construct competing understandings of harm and religious freedom depending on the context of the case and whether the setting is deemed public or private. Our analyses shed light on the shifting and competing meanings about religion, sexuality, and public life in the United States.
“Not Even the Highest Wall Can Stop AIDS”: Expertise and Viral Politics at the German-German Border
Authors: Folland Johanna
Published: April 2023

This article explores East German responses to HIV/AIDS and the emergence of sex as a site of border insecurity in the imagination of the East German state in the mid-1980s. Existing histories often dismiss the East German response to HIV/AIDS as ineffective or negligible on account of its illiberalism and insularity. These narratives, however, ignore the tense debates and wide variety of state and activist responses to the AIDS epidemic that developed within the GDR over the course of its final decade. I argue that as scientists and health officials sought to integrate East German institutions into the “global AIDS community,” the specter of African sexuality loomed larger in their characterizations of this epidemiological threat (notably, in ways that do not neatly correlate with rates of HIV prevalence in the GDR). Explanations of East German AIDS policy should therefore focus less on the GDR's illiberalism and more on its liberalization—that is, its entrance in the mid-1980s into a global moral economy of AIDS that elided and disincentivized socialist commitments to the Global South.
Obsessive–compulsive disorder (OCD) is associated with increased engagement of frontal brain regions across multiple event-related potentials
Authors: Perera M. Prabhavi N. , Mallawaarachchi Sudaraka , Bailey Neil W. , Murphy Oscar W. , Fitzgerald Paul B.
Published: April 2023

Background

Obsessive–compulsive disorder (OCD) is a psychiatric condition leading to significant distress and poor quality of life. Successful treatment of OCD is restricted by the limited knowledge about its pathophysiology. This study aimed to investigate the pathophysiology of OCD using electroencephalographic (EEG) event-related potentials (ERPs), elicited from multiple tasks to characterise disorder-related differences in underlying brain activity across multiple neural processes.

Methods

ERP data were obtained from 25 OCD patients and 27 age- and sex-matched healthy controls (HCs) by recording EEG during flanker and go/nogo tasks. Error-related negativity (ERN) was elicited by the flanker task, while N200 and P300 were generated using the go/nogo task. Primary comparisons of the neural response amplitudes and the topographical distribution of neural activity were conducted using scalp field differences across all time points and electrodes.

Results

Compared to HCs, the OCD group showed altered ERP distributions. Contrasting with the previous literature on ERN and N200 topographies in OCD where fronto-central negative voltages were reported, we detected positive voltages. Additionally, the P300 was found to be less negative in the frontal regions. None of these ERP findings were associated with OCD symptom severity.

Conclusions

These results indicate that individuals with OCD show altered frontal neural activity across multiple executive function-related processes, supporting the frontal dysfunction theory of OCD. Furthermore, due to the lack of association between altered ERPs and OCD symptom severity, they may be considered potential candidate endophenotypes for OCD.
Critical junctures as complex processes: examining mechanisms of policy change and path dependence in the Canadian pandemic response to homelessness
Authors: Kopec Anna
Published: April 2023

Policy change is not an instantaneous or linear process. In fact, change includes several mechanisms working in tandem and even against one another. This article examines the impacts of the COVID-19 pandemic on homelessness policy in Canada. In a sector that is already plagued with emergency responses – rather than long-term solutions – the pandemic has initiated a critical juncture where policy change is possible, but not guaranteed. Although the existing failures to alleviate homelessness in Canada make policy failings even more obvious, aspects of the pre-existing Canadian response to homelessness negate change. The pandemic, however, has led to temporary solutions and created a setting where long-term change is possible. Using over 150 primary sources, this article analyses mechanisms of change and path dependence in the pandemic response to homelessness. The presence of such mechanisms is tested in three major Canadian cities.
Inequities in COVID-19 Omicron infections and hospitalisations for Māori and Pacific people in Te Manawa Taki Midland region, New Zealand
Authors: Whitehead Jesse , Gan Han , Heerikhuisen Jacob , Gray George , Richardson Trevor , Brown Paul , Lawrenson Ross
Published: April 2023

COVID-19 impacts population health equity. While mRNA vaccines protect against serious illness and death, little New Zealand (NZ) data exist about the impact of Omicron – and the effectiveness of vaccination – on different population groups. We aim to examine the impact of Omicron on Māori, Pacific, and Other ethnicities and how this interacts with age and vaccination status in the Te Manawa Taki Midland region of NZ. Daily COVID-19 infection and hospitalisation rates (1 February 2022 to 29 June 2022) were calculated for Māori, Pacific, and Other ethnicities for six age bands. A multivariate logistic regression model quantified the effects of ethnicity, age, and vaccination on hospitalisation rates. Per-capita Omicron cases were highest and occurred earliest among Pacific (9 per 1,000) and Māori (5 per 1,000) people and were highest among 12–24-year-olds (7 per 1,000). Hospitalisation was significantly more likely for Māori people (odds ratio (OR) = 2.03), Pacific people (OR = 1.75), over 75-year-olds (OR = 39.22), and unvaccinated people (OR = 4.64). Length of hospitalisation is strongly related to age. COVID-19 vaccination reduces hospitalisations for older individuals and Māori and Pacific populations. Omicron inequitably impacted Māori and Pacific people through higher per-capita infection and hospitalisation rates. Older people are more likely to be hospitalised and for longer.