Objectives/Goals: Team science (TS) competency is important for translational science team collaboration. However, there are few educators available to assist teams. Asynchronous learning is an effective strategy for delivering TS content. The goal of this project is to expand TS education by providing online access to our learners using online modules. Methods/Study Population: The Collaboration and Team Science (CaTS) team at the University of Cincinnati provides a robust TS education and training program. As the need for team science gains recognition, CaTS has received increased requests for services, leading to a need to broaden TS offerings. To address this demand, the CaTS team created “Team Science 101,” an online, asynchronous, series of 15 modules covering basic team science concepts. Each module consists of an educational recording lasting an average of 20 minutes, optional topic resources, pre- and post-module surveys assessing learners’ confidence and satisfaction, post-module knowledge checks, and evaluation questions. Upon completing all modules, participants receive a completion certificate. Results/Anticipated Results: TS 101 will be piloted with a group of participants who expressed interest in asynchronous TS content and will be adjusted based on the feedback received. The associated pre- and post-module survey, post-module knowledge check, and evaluation questions will be monitored to determine learning levels and improve TS 101 overall. Canvas is the educational platform that houses these modules, allowing for participant follow-up and scalable dissemination. The CaTS team plans to disseminate TS 101 nationally and internationally for anyone interested in this resource. Discussion/Significance of Impact: There is a national effort to collect and curate TS education, training, and toolkits. TS 101 will be a useful educational tool that will expand the reach of team science educators, provide the foundation for educators to explore topics more deeply by building on the module topics, and provide education to broader audiences who lack access to TS experts.

Objectives/Goals: Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system that affects 2 million people worldwide causing severe disability. This study uses the Gamt-GFP transgenic mouse line as a novel approach to track oligodendrocyte lineage cell regeneration in inflammatory demyelination for identifying potential therapies. Methods/Study Population: We previously showed that Gamt, an enzyme required for creatine synthesis, is essential for oligodendrocyte (OL) maturation and survival using the Gamt-Green Fluorescent Protein (Gamt-GFP) reporter line. In this study, we capitalize on this finding and track OL lineage cells in an experimental autoimmune encephalomyelitis (EAE) mouse model by inducing immune-mediated demyelination in the Gamt-GFP reporter line. At 7 days postimmunization (dpi), both control and EAE mice receive 4 mg/kg tamoxifen for 4 consecutive days to induce GFP expression. GFP+ cells and those also expressing OL lineage markers [Olig2 (pan-OL lineage cell marker), NG2 (OL precursor cells; OPCs), and CC1 (mature OL)] are quantitated by immunofluorescent staining of spinal cord sections collected at 28 dpi. Results/Anticipated Results: Preliminary data using immunofluorescent staining demonstrated GFP was expressed in Olig2+ cells in the inflammatory ventral white matter lesions of mice with EAE, whereas no GFP labeling was present in the control mice. Moreover, GFP+ cells also expressed NG2+. In contrast, few CC1+ cells were detected in the inflammatory lesions. The low number of dual labeled GFP+CC1+ cells in these lesions suggests OPCs under the EAE environment are unable to efficiently differentiate into mature OL. Therefore, the Gamt-GFP reporter mouse can be used to identify and track activated OL lineage cell populations (i.e., GFP+CC1) in inflammatory lesions in the EAE mouse model. Discussion/Significance of Impact: The Gamt-GFP reporter line identifies activated OL lineage cells responding to inflammatory demyelination, making it a valuable tool for testing potential therapeutics aimed at enhancing remyelination. This model helps bridge the gap between preclinical and clinical research to guide MS therapy development.

Objectives/Goals: Our study team won a Public Health Answers to Speed Tractable Results (PHASTR) contract to conduct a target trial emulation to answer “Does metformin show a reduction of severe outcomes of COVID-19 or of Long COVID in the N3C Data Enclave?” We quickly delivered an answer due to productive technical and collaboration support in the N3C. Methods/Study Population: Our analytic plan was updated based on helpful feedback from the PHASTR program. We performed a trial emulation analysis using the N3C data, comparing adult new users of metformin to controls prescribed fluvoxamine, fluticasone, ivermectin, or montelukast. The composite outcome was Long COVID or Death (LC/D) within 180 days of COVID infection. We used entropy balancing to estimate the average treatment effect with a weighted log-linear model. Productivity was enhanced by reusing code workbooks and validated codesets from related N3C projects. The team of 4 (physician, informaticist, data programmer, and statistician) and key unpaid advisors spent 10 weeks developing and analyzing the data. Results/Anticipated Results: Totally, 9,660 patients were identified for analysis. After weighting, there were 248 in the metformin and control groups. In the metformin group, 4.0% developed LC/D vs. 8.5% in the control group, with an adjusted risk ratio (aRR) of 0.47 (95% CI 0.25 to 0.89). Results were consistent across subgroups and sensitivity analyses. The PHASTR contract structure helped produce high-quality results quickly by not only providing funding but also requiring a compressed timeline for a small team to focus on the study. The most time was spent on contract execution, enclave provisioning, and too many last-minute download requests. A project final report was submitted in March and a full manuscript was submitted in September. Discussion/Significance of Impact: The analysis was productive because the environment made reuse easy and supported rich collaborations among clinicians, informaticists, epidemiologists, statisticians, and data developers. Advice from PHASTR advisors (Axel) and N3C diabetes domain team members was also key to a faster completion.

Objectives/Goals: Understanding cognitive habits and values of individuals or groups, and providing tools to apply them to collaborative, interdisciplinary endeavors to better communicate between different industries, functions, and cultures. Methods/Study Population: Using literary research to establish groupings of common core values in interpersonal communications, applying established 5 patterns of “thought languages” to scale to group communications. Accepted psychological personality inventories for individuals will overlay into cognitive values, primarily using the current big five OCEAN model. Demonstrating these values to find common goals among interdisciplinary collaborations can identify prospective members, cultural differences in industry, patient communication, and public messaging in STEM. Integrating these tools into research groups to establish more efficacious communication between teams, governing bodies, and patient communication can be sampled via pre and post research surveys of feeling understood. Results/Anticipated Results: The results of feeling understood by various parties in collaborative research would be a measure of not just effective expressed communication, but received communication. Feeling understood is a current metric of communication that is correlated with satisfaction, trust, and interdependence. All of these results are integral to the successful operations of collaborative projects. Demonstrating a positive correlation between applying the 5 thought languages and better-surveyed outcomes of understanding will guide the effectiveness of this as a future collaborative tool for translational sciences. Discussion/Significance of Impact: The significance of effective communication based on positive reception will foster future collaborations. Encouraging familiarity between differing individuals, groups, and industries, even between subjects and researchers, patients and healthcare. More satisfaction, more trust, and more interdependence will propagate between these groups.

Objectives/Goals: Primary sclerosing cholangitis (PSC) manifests with an inflammatory milieu that leads to fibrotic scarring of the liver. Human PSC liver bile ducts are enriched with neutrophils; however, their infiltration and functional role is unexplored. Our goal is to investigate the mechanism and impact of peribiliary neutrophil infiltration observed in PSC. Methods/Study Population: Primary cholangiocytes (bile duct cells) isolated from WT and mouse models of PSC (3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-fed mice and Mdr2-/- mice) were analyzed by RNA-sequencing. Immunofluorescence (IF) was performed on liver tissues from PSC patients and mouse models of PSC for markers of bile ducts and neutrophils (KRT19 and MPO). Intrahepatic leukocytes (IHL) isolated from mice livers were evaluated for neutrophil abundance and activation state. Anti-Ly6G antibody-mediated neutrophil depletion in Mdr2-/- mice was analyzed by IF, histology, and cytometry by time-of-flight (CyTOF). Cholangiocytes stimulated with TNFα (to induce an inflammatory phenotype) were analyzed for neutrophil chemoattractants with genetic and pharmacological interventions. Results/Anticipated Results: RNA-seq analysis of primary cholangiocytes from PSC mouse models revealed enrichment in inflammatory and neutrophil degranulation pathways. Flow cytometry and RT-PCR analysis revealed an increase in the neutrophil population in PSC mice with activated phenotype. Peripheral depletion of neutrophils in Mdr2-/- mice alleviated liver injury and inflammation, along with a reduction in peribiliary neutrophil infiltration and attenuated bridging fibrosis. CyTOF analysis showed a significant reduction in CD8+ T cells upon neutrophil depletion, implying neutrophils sustain CD8+ T cells in PSC liver. Mechanistically in cholangiocytes, TNFα mediates expression of neutrophil chemoattractants, CXCL1 and CXCL8, through the cyclic GMP-AMP synthase stimulator of interferon genes (cGAS-STING) pathway. Discussion/Significance of Impact: Our findings suggest that activation of the STING pathway in cholangiocytes in cholestatic liver disease triggers an immune response resulting in peri-portal neutrophil infiltration via CXC chemokines. The sustained presence of these activated neutrophils engages the adaptive immune system to perpetuate the inflammation and fibrosis seen in PSC.

Learning Health Systems (LHS) iteratively implement and evaluate health improvement projects. Dissemination and implementation (D&I) science is the study of evidence-based practices in real-world settings, a critical tool for LHS. This paper explores intersections between LHS and D&I science in Clinical and Translational Science Awards (CTSAs) institutions and identifies critical components of collaboration. We conducted website scans of 34 CTSAs and their home institutions that had Dissemination, Implementation, and Knowledge Translation (DIKT) Workgroup members. We identified linkages between CTSAs and their institutions’ LHS. We interviewed six CTSA leaders experienced in LHS and D&I sciences. Nearly half of CTSAs identified an LHS structure on their websites, but only one-third indicates CTSA involvement in these efforts. Interviewees identified key components for successful integration of LHS and D&I sciences: leadership, infrastructure, balance between rigor and efficiency, and aligned incentives. The need for research integration in LHS, to improve evaluation and increase knowledge, is an emerging opportunity for D&I scientists and CTSAs. CTSAs that are engaged in D&I science can introduce and/or expand the role of D&I science in LHS. Collaboration between CTSAs and clinical leaders could result in strengthened relationships between clinical and research enterprises, effective and efficient health care delivery, and improved health.

Advances in translational science require innovative solutions, and engagement of productive transdisciplinary teams play a critical role. While various forms of scientific meetings have long provided venues for sharing scientific findings and generating new collaborations, many conferences lack opportunities for active discussions. We describe the use of an Un-Meeting to foster innovative translational science teams through engaged discussions across multidisciplinary groups addressing a shared theme. The Un-Meeting was delivered by the University of Rochester Center for Leading Innovation and Collaboration, the national coordinating center for the National Institutes of Health Clinical and Translational Science Awards (CTSA) program. This pilot CTSA program Un-Meeting focused on engaging translational scientists, policy-makers, community members, advocates, and public health professionals to address the opioid crisis. The participant-driven format leveraged lightning talks, attendee-led idea generation, and extensive breakout discussions to foster multidisciplinary networking. Results indicated participation by a broad set of attendees and a high level of networking during the meeting. These results, coupled with the growth of the Un-Meeting across the CTSA Consortium, provide practices and models to potentially advance team and translational science. While future work will further assess the impact of Un-Meetings, this format presents a promising approach to enhance translational science.

The NIH Center for Accelerated Innovations at Cleveland Clinic (NCAI-CC) was funded by the National Heart Lung and Blood Institute (NHLBI) to support academic investigators in technology development and commercialization. NCAI-CC was one of three multi-institutional Centers established in the fall of 2013. The goal of each Center was to catalyze the growth of an ecosystem of commercialization within their affiliated institutions and regions by managing a program of funding and guiding translational project development and by delivering commercialization education programs to participating investigators. NCAI-CC created and managed such a funding program, ultimately supporting 75 different projects across seven separate academic institutions and developed tailored educational content following the National Science Foundation I-Corps™ curriculum and delivered the program to 79 teams from 12 institutions. We determined early on that in establishment and implementation of projects, it is important to support the teams and principal investigators throughout the program. The support includes a change in principal investigator mindset from specific aims orientation to goals and deliverables on projects. Our skills development efforts emphasized commercialization and a deep understanding of customer needs for new technology adoption. Here, we review our experiences, outcomes, and insights, including the challenges identified in program implementation.

Objectives/Goals: Depression is common among people living with HIV (PLWH). This study explored the link between reduced metacognitive awareness and depression in PLWH. It utilized a positive emotion regulation task to compare brain activation during viewing versus upregulating positive emotions. Methods/Study Population: Depressed PLWH (N = 24; mean age  =  53; HAM-D mean  =  19) participated in an emotion regulation task while blood oxygen-level-dependent (BOLD) responses were recorded. In the emotional regulation task, participants were shown the International Affective Picture System (IAPS) a series of positive, negative, and neutral images. Participants were asked to view these images and given instructions to either negatively reappraise (RN) or positively reappraise (RP). In the RP condition, participants were no longer shown the image and asked to upregulate their positive emotional responses associated with it. Ten onset times were included for each trial. Results/Anticipated Results: A one-sample t-test was conducted to analyze contrasts between reappraisal of positive images and viewing positive images (RP > VP). Results showed significantly greater activation in the posterior cingulate and angular gyrus during the RP condition (peak MNI: 18, -52, 34; p < 0.001, uncorrected, k > 10 voxels). In comparing the reappraisal of negative images to viewing negative images (RN > VN), there was increased activation in the right supramarginal gyrus (peak MNI: 50, -28, 22; p < 0.001, uncorrected, k > 10 voxels). When contrasting the reappraisal of positive to negative images (RP > RN), BOLD signals were higher in the left dorsolateral prefrontal cortex (peak MNI: 40, -38, 32; p < 0.001, uncorrected, k > 10 voxels). Discussion/Significance of Impact: Findings underscore that depressed PLWH demonstrates BOLD responses in brain regions linked to appetitive motivation and meta-cognitive awareness during the RP condition which demands more executive resources among those with depression, highlighting the complexity of emotional regulation in this population.

Rapid whole genome sequencing (rapid WGS) is a powerful diagnostic tool that is becoming increasingly practical for widespread clinical use. However, protocols for its use are challenging to implement. A significant obstacle to clinical adoption is that laboratory certification requires an initial research development phase, which is constrained by regulations from returning results. Regulations preventing return of results have ethical implications in cases which might impact patient outcomes. Here, we describe our experience with the development of a rapid WGS research protocol, that balanced the requirements for laboratory-validated test development with the ethical needs of clinically relevant return of results.

The Community Research Advisory Council (C-RAC) of the Johns Hopkins Institute for Clinical and Translational Research was established in 2009 to provide community-engaged research consultation services. In 2016–2017, C-RAC members and researchers were surveyed on their consultation experiences. Survey results and a 2019 stakeholder meeting proceeding helped redesign the consultation services. Transitioning to virtual consultations during COVID-19, the redesigning involved increasing visibility, providing consultation materials in advance, expanding member training, and effective communications. An increase in consultations from 28 (2009–2017) to 114 (2020–2022) was observed. Implementing stakeholder-researcher inputs is critical to holistic and sustained community-engaged research.