OBJECTIVES/GOALS: We are investigating the role of IL-6 in regulating renal function by measuring mean arterial pressure (MAP), renal plasma flow (RPF) and glomerular filtration rate (GFR) in wild type (WT) and IL-6-knockout (KO) mice in established mouse models of angiotensin II (AII)-dependent- hypertension and -salt-sensitive hypertension. METHODS/STUDY POPULATION: Twelve-week-old male WT and KO mice on the C57BL6 background strain were infused with vehicle (V; saline) or angiotensin II (AII; 200 ng/kg/min) for 12-14 days. Half of the AII-treatment groups were maintained on a high salt (HS; 6% NaCl) diet for the duration of the experiment, while the other half of the AII treatment groups and both vehicle groups were fed normal rat chow. MAP was continuously measured by a fluid filled catheter in conscious mice for the duration of the experiment. RPF and GFR were measured on days 12-14 in anesthetized mice by the para-aminohippurate, and fluorescein isothiocynate-Inulin techniques, respectively. All data were analyzed by 2-way ANOVA; *p<0.05 vs. WT, same treatment; #p<0.05 vs.V, same genotype; ^p<0.05, AII vs. AII+HS, same genotype. RESULTS/ANTICIPATED RESULTS: MAP was 31% lower in KO vs WT mice. AII increased MAP (1.2-fold) in WT but not KO mice. HS diet magnified AII-induced increases in MAP in WT and moderately increased MAP in AII-KO mice: [MAP (mmHg): WT+V, 130±7.0; KO+V, 91.0+4.0*; WT+AII, 153±5.0#; KO+AII, 83.0±4.0*; WT+AII+HS, 150±11#; KO+AII+HS, 93.0±4.0#]. AII infusion reduced RPF in the KO but not WT mice. Addition of HS reduced RPF in WT and exacerbated AII-induced reductions in RPF in KO mice [RPF (ml/min/g): WT+V, 1.82±0.23; KO+V, 1.91+0.40; WT+AII, 3.16±0.75#; KO+AII, 1.65±0.42*; WT+AII+HS, 1.10±0.31#^; KO+AII+HS, 1.13±0.XX#^]. The HS diet reduced GFR in AII-infused KO but not WT mice [GFR (µl/min/g): WT+V, 756±XX; KO+V, 788±XX; WT+AII, 1010±63*#; KO+AII, 756±23*; WT+AII+HS, 1100±150#; KO+AII+HS: 540±210*#^]. DISCUSSION/SIGNIFICANCE: The absence of IL-6 in male mice attenuated AII- and/or AII+HS-induced increases in MAP; however, it exacerbated HS-induced reductions in RPF and GFR. These findings suggest inhibiting IL-6 has therapeutic potential as an antihypertensive but not as a renal protective agent in hypertension and salt-sensitive hypertension disease states.

OBJECTIVES/GOALS: Involving community partners in translational research improves impact. Yet, community-engaged research is challenging, and teams vary in their success. This study builds the evidence of key barriers and facilitators to effective community-engaged team science by drawing on the perspectives of seasoned researchers and community partners. METHODS/STUDY POPULATION: We conducted 3 focus groups with academic researchers (n=9) and 2 focus groups with community research partners (n=8). All participants were adults from the Southern California area, and had experience working on research teams that included academics and community partners. The focus group guide included questions about the participant’s experience with community-engaged research, including the value of these partnerships, examples of success and challenges, and opportunities for improvement. Transcriptions of the focus group recordings were analyzed to identify key themes and insights, and to explore similarities and differences between academic and community participant perspectives. RESULTS/ANTICIPATED RESULTS: Both researchers and community partners saw the potential value of participating in community-engaged research. However, they identified challenges to address, including: 1) Community partners should be invited to participate in early stages of the research process as equal partners to help frame the objectives. 2) Community partner’s knowledge should be valued through the use of their ideas and input, and providing monetary compensation for their time. 3) Academic researchers should aim to build long-term meaningful relationships with the community and build cultural competency (language, culture, and trust). 4) Community partners should be closely involved with the interpretation of results to confirm accuracy and identify valuable insights, and these contributions should be acknowledged. DISCUSSION/SIGNIFICANCE: Community partners being undervalued is a central challenge of community-engaged research teams. Greater adoption of best practices in team science could empower community partners and increase the value of this research. Structural barriers related to research funding and academic promotion should align to support these efforts.

We used a Zoom Un-meeting as an educational approach to provide experienced clinical research professional (CRP) adult learners a collaborative learning space to learn more about current issues for academic medical center (AMC) clinical research workforce development and collaborate on solution finding. CRPs operationalize the conduct of clinical trials and represent a significant brain trust for the Clinical and Translational Science (CTSA) consortium hubs with their vast knowledge base, extensive experience, understanding of relevant institutional policy, organizational culture, and clinical research operations. Un-meetings are an intentionally organized and coordinated group activity that encourages participants to focus on a topic and incorporate an open flow of ideas through brainstorming and an open discussion format, setting the stage for future collaborative action. We divided topics into a series of six consecutive monthly Un-meeting Zoom workshops. Ultimately, one resulting output from the meeting was the Center for Leading Innovation and Collaborations (CLIC) synergy paper award to support continued collaborative work. Currently, work teams have emerged to analyze qualitative data from brainstorming and breakout session recordings and to identify small-group activities. We describe this adult learning tool as valuable for exploring issues of AMC CRP professional development. This approach encouraged creative/critical thinking and opportunities for leadership, team science, and problem-solving among participants.

External advisory committees (EACs) are critical peer-review meetings that drive improvement at Clinical and Translational Science Award Program Hubs. Despite their ubiquity, evaluations of EAC optimization and effective implementation remain scarce. We present a two-tiered approach to optimizing EAC meetings through (1) in-depth, topically focused “pre-review” meetings comprised of external topic experts and at least one standing “full-board” EAC member, followed by (2) a traditional “full-board” EAC meeting. This approach allowed pre-review discussion of program-focused topics and specific recommendations, later delivered to the full-board for review and direction. To evaluate this approach, we interviewed 18 people who planned, administered, or attended pre-review and/or full-board meetings, including internal Hub staff, external topic experts, and standing EAC members. Thematic analysis was used to explore planning, implementation, and value of our two-tiered approach versus the traditional single full-board approach. Interviewees preferred the two-tiered approach, noting benefits including additional time to reflect, shared identification of strengths and challenges, and discussion of solutions to share later with the full-board. Those who attended pre-review meetings described building “transformational,” rather than “transactional,” relationships with invitees through more discussion and inter-hub sharing. That increased sharing invited more exploration, discussion, and planning of next steps toward innovation.

OBJECTIVES/GOALS: Contingency management (CM) procedures yield measurable reductions in cocaine use. This poster describes a trial aimed at using CM as a vehicle to show the biopsychosocial health benefits of reduced use, rather than total abstinence, the currently accepted metric for treatment efficacy. METHODS/STUDY POPULATION: In this 12-week, randomized controlled trial, CM was used to reduce cocaine use and evaluate associated improvements in cardiovascular, immune, and psychosocial well-being. Adults aged 18 and older who sought treatment for cocaine use (N=127) were randomized into three groups in a 1:1:1 ratio: High Value ($55) or Low Value ($13) CM incentives for cocaine-negative urine samples or a non-contingent control group. They completed outpatient sessions three days per week across the 12-week intervention period, totaling 36 clinic visits and four post-treatment follow-up visits. During each visit, participants provided observed urine samples and completed several assays of biopsychosocial health. RESULTS/ANTICIPATED RESULTS: Preliminary findings from generalized linear mixed effect modeling demonstrate the feasibility of the CM platform. Abstinence rates from cocaine use were significantly greater in the High Value group (47% negative; OR = 2.80; p = 0.01) relative to the Low Value (23% negative) and Control groups (24% negative;). In the planned primary analysis, the level of cocaine use reduction based on cocaine-negative urine samples will serve as the primary predictor of cardiovascular (e.g., endothelin-1 levels), immune (e.g., IL-10 levels) and psychosocial (e.g., Addiction Severity Index) outcomes using results from the fitted models. DISCUSSION/SIGNIFICANCE: This research will advance the field by prospectively and comprehensively demonstrating the beneficial effects of reduced cocaine use. These outcomes can, in turn, support the adoption of reduced cocaine use as a viable alternative endpoint in cocaine treatment trials.

OBJECTIVES/GOALS: Dietary fiber has been used in other clinical populations to improve mineral disorders, but there is limited data in chronic kidney disease, despite the high prevalence of mineral and bone disorder (known as CKD-MBD). Our objective was to evaluate the effect of dietary fiber based on viscosity and fermentability on CKD-MBD outcomes. METHODS/STUDY POPULATION: 22-week-old male CKD rats (mild-to-moderate CKD) were randomly assigned to receive one of four fiber treatments (10% w/w each) based on fermentability and viscosity: 1) Cellulose (-fermentability, -viscosity), 2) Inulin (+fermentability, -viscosity), 3) Psyllium husk (-fermentability, +viscosity), or 4) Pectin (+ fermentability, +viscosity). Treatments lasted 10 weeks, and rats were euthanized at 32 weeks of age (kidney failure). Rats were placed in metabolic cages for 3 consecutive days the last week before euthanasia for mineral balance. At euthanasia, blood, tibia, heart, and aorta were collected for CKD-MBD assessment. Additional tissues collected included kidneys and all intestinal segments. RESULTS/ANTICIPATED RESULTS: Our preliminary data indicates that weight trajectories and survival were similar between treatment groups. At 33 weeks of age, kidney weight index (an indirect measurement of kidney function as this animal model develops polycystic kidneys) was lower in the psyllium-treated rats compared to all of the other treatments. Plasma phosphorus was lower with Psyllium and Pectin compared to Cellulose-treated rats. Left ventricular mass index was lower in the Inulin, Psyllium, and Pectin-treated rats compared to the Cellulose-treated rats. Ongoing tissue analyses include biochemical markers of mineral and bone metabolism (parathyroid hormone, fibroblast growth factor-23, and phosphorus balance), bone parameters (dynamic histomorphometry and microCT), and cardiovascular calcification. DISCUSSION/SIGNIFICANCE: Our preliminary data indicate that dietary fiber based on fermentability and viscosity impacts CKD-MBD outcomes and may be an innovative, low-cost intervention that can be trialed in people with CKD for the prevention and treatment of CKD-MBD.

The internal research program of the National Center for Advancing Translational Sciences (NCATS) at the National Institutes of Health aims to fundamentally transform the preclinical translational research process to get more treatments to more people more quickly. The program develops and implements innovative scientific and operational approaches that accelerate and enhance translation across many diverse projects. Cross-disciplinary team science is a defining feature of our organization, with scientists at all levels engaged in multiple research teams. Here, we share our systems approach to nurturing cross-disciplinary team science, which leverages organizational policies, structures, and processes. Policies including the organizational mission statement, principles for ethical conduct of research, performance review criteria, and training program objectives and approaches reinforce the value of team science to achieve the program’s scientific goals. Structures including an organizational structure designed around solving translational problems, co-location of employees in a single state-of-the-art scientific facility, and shared-use laboratories, expertise and instrumentation facilitate collaboration. Processes including fluid team assembly, specialized project management, cross-agency partnerships, and decision making based on clear screening criteria and milestones enable effective team assembly and functioning. We share evidence of the impact of these approaches on the science and commercialization of findings and discuss pathways to broad adoption of similar approaches.

Clinical trials conducted with incarcerated populations are rare. We present a case example of one such jail-based cancer prevention clinical trial to demonstrate the importance of including a theory-driven approach to intervention framing, novel experimental designs to boost access to low-risk trials, and retention strategies for long-term follow-up of hard-to-reach populations. As such we offer a social determinant of health framework to ensure cancer prevention research is conducted through the lenses of health promotion and health equity. Deviations from the gold-standard randomized control design, transparent systematic allotment, and street-based outreach retention strategies contribute to the feasibility of conducting clinical trials in carceral settings and after people leave jail. Best practices presented can be used in design and conduct of future clinical trials with criminal legal system-involved populations.

OBJECTIVES/GOALS: In the U.S., over 4 million people including children experience transient periods of undernutrition annually. Cardio-metabolic and renal diseases are more prevalent in this population. We are investigating therapeutic strategies to reverse the long-term risk of these diseases in a rat model of transient undernutrition followed by refeeding. METHODS/STUDY POPULATION: Thirty six female Fischer rats (3-months of age) were initially divided into 2 groups. Half were fed regular chow (CT) while the other half were severely food restricted (sFR) by 60% from 0-2 weeks (wks) followed by refeeding from 2-14 wks (sFR-Refed). These 2 groups were then subdivided and treated ± metformin (Met) from wk 7 to wk 12 (n=9/group). High precision ultrasound was conducted on live rats to assess heart and kidney function immediately after the sFR period ended (wk 2) and at the end of the study (wk 14). At the conclusion of the experiment, the rats were sacrificed and the histology of the kidney and heart tissues were analyzed in hematoxylin and eosin-stained sections. The protein to DNA ratio was also calculated in homogenates from these tissues. RESULTS/ANTICIPATED RESULTS: In sFR-Refed rats, cardiac output (CO), heart rate (HR) and renal artery blood flow (RBF) were decreased by 11 ± 1.5%#, 7.0 ± 6.0% and 22 ± 0.6%#, respectively, compared to control (CT) rats; #p<0.05. Mean glomerular diameter was reduced in the kidneys of sFR-refed rats compared to CT and this effect was attenuated by metformin treatment [(µm): CT, 406 ± 31; sFR-Refed, 383 ± 11, p<0.06; CT+Met, 393 ± 18; sFR-Refed+Met, 407 ± 18*]. Furthermore, the mean cardiomyocyte thickness was reduced in sFR-Refed rats compared to controls while metformin treatment prevented this effect [(µm): CT, 16.4 ± 3.6; sFR-Refed, 11.5 ± 2.3#; CT+Met, 16.4 ± 3.6; sFR-Refed+Met, 15.9 ± 3.2*]. #p<0.05 vs. CT, same treatment; *p<0.05 vs. Met, same diet; two-way ANOVA. DISCUSSION/SIGNIFICANCE: These findings have promising implications for metformin use to mitigate long-term impairments in heart and kidney structure and function in individuals who have experienced bouts of undernutrition earlier in life for either voluntarily (e.g., very low calorie dieting) or involuntary (e.g., very low food security) reasons.

OBJECTIVES/GOALS: Cognitive decline is associated with obesity, stress, poor sleep, and circadian rhythm misalignment, which are themselves functionally intertwined. Irregular food intake timing exacerbates these all. Prolonged nightly fasting (PNF) aligns food intake with innate circadian rhythms. METHODS/STUDY POPULATION: A nationwide, remotely-delivered, 2-arm randomized controlled trial was conducted to assess feasibility and 8-week outcomes of cognition, stress, sleep, eating behaviors, and general eating habits, after a PNF intervention (14-hr nightly fast, 6 nights/week, no calories after 8pm) compared to a health education control (HEC) condition. Eligible participants were living with obesity, stress (Perceived stress scale-4 (PSS-4) total score ≥5), and memory “not as good as it used to be.” Data were collected via Zoom meetings with participants and trained staff and entered into REDCap. All participants had weekly staff check-in calls to report fasting times (PNF group only) and feedback. RESULTS/ANTICIPATED RESULTS: Eligible participants were enrolled from 37 of 50 US states; N=58, 86% women, 71% white, 93% non-Latinx, mean (SD) 50.1 (5.1) years of age, BMI 35.6 (3.6) kg/m^2. No group differences existed at baseline. Linear mixed-effects models were used to compare group differences across all outcome changes. Compared to the HEC condition, the PNF intervention was associated with improved sleep quality (Pittsburgh Sleep Quality Index; B = -2.52; SE = 0.90; 95% CI-4.30 to -0.74; p=0.006). Stress, everyday cognition, and emotional eating behavior significantly changed over time (p<0.02), but there were no group differences. Analysis of feasibility outcomes are on-going. DISCUSSION/SIGNIFICANCE: Changing food intake timing 6 days per week, to exclude nighttime eating without mandating food quality/quantity change, may benefit many individuals living with obesity, stress and memory decline to improve their sleep. Improved sleep quality may lead to more health benefits over time.

OBJECTIVES/GOALS: To present Substance Abuse Research: Bench to Community (SARB2C) as a model for team science both within and between institutions. Emerging from targeted efforts by the NIH to engage translational scientists in prominent public health issues, the initiative illustrates the benefits of bringing together researchers and trainees to share ideas. METHODS/STUDY POPULATION: In 2019 a group was formed at University of Florida to discuss ongoing translational research in the area of substance abuse, including faculty, staff, and trainees from across the campus. The group was expanded in February 2022 to include domestic colleagues at the University of Kentucky as well as international collaborators at Chulalongkorn University in Bangkok, Thailand. One-hour monthly meetings began in person but now take place virtually. Larger projects are discussed individually, focusing on opportunities for collaboration. Attendees also provide updates on their work, including proposals in development and manuscripts in process. This facilitates dialogue around the science, from the bench to the community, and connects people to advance team science. RESULTS/ANTICIPATED RESULTS: In light of the ongoing opioid epidemic and the public health threat of other emerging substances, collaboration among researchers in this area is essential to advance the science and explore real-world solutions. SARB2C demonstrates the benefit of connecting researchers across T0 to T4, and that of including trainees for invaluable experience. This environment fosters open discussion and creativity and helps break down the silos that impede science. A highlight from early in the group’s history was a visit from the Program Officer for the UF Clinical and Translational Science Institute in February 2020. Since that time, multiple collaborations have resulted in grants submitted, such as P30 center grants and an innovative R61/R33, as well as numerous publications. DISCUSSION/SIGNIFICANCE: A complex public health emergency like the opioid epidemic requires creativity and collaboration, from laboratory science to interventions in the community, putting it squarely within the sights of translational research. SARB2C will soon enter its fifth year of linking researchers and training the next generation of scientists.

In a prospective, remote natural history study of 277 individuals with (60) and genetically at risk for (217) Parkinson’s disease (PD), we examined interest in the return of individual research results (IRRs) and compared characteristics of those who opted for versus against the return of IRRs. Most (n = 180, 65%) requested sharing of IRRs with either a primary care provider, neurologist, or themselves. Among individuals without PD, those who requested sharing of IRRs with a clinician reported more motor symptoms than those who did not request any sharing (mean (SD) 2.2 (4.0) versus 0.7 (1.5)). Participant interest in the return of IRRs is strong.

OBJECTIVES/GOALS: A barrier to the proliferation of team science is that academicians are often trained in disciplinary silos where “independent” research contributions are lauded. To tackle some of the most pressing scientific challenges, dismantling silos and increasing team science training efforts that focus on early career investigators is a must. METHODS/STUDY POPULATION: A team science training workshop for early career investigators from varied disciplinary backgrounds was informed by a 20-item needs assessment that addressed essential team science competencies and was completed by early career investigators participating in federally funded professional development programs on our campus. During the workshop, the benefits of cross-disciplinary teaming was discussed. Strategies including team formation, team effectiveness and/or dysfunction, diagnosing team strengths and weaknesses, and teaming in community settings were discussed. Instructional methods included short presentations, video clips, case studies, group discussions, pair and share activities, and panel discussions with expert role models encouraged active learning. RESULTS/ANTICIPATED RESULTS: The impact and value of the workshop series to participant’s professional development and knowledge of team science concepts will be evaluated before and after the workshop. Multiple Likert-scale items focused on team science competencies (e.g., confidence in your ability to carry out responsibilities specific to your role on a team, recognize when the team is not functioning well; engage team science practices in on-going research), and open-ended questions (e.g., importance of engaging community partners in academic research teams, vision of what factors contribute to an effective team science collaboration) will be completed by program participants before and after completing the workshop. DISCUSSION/SIGNIFICANCE: Effective collaboration among scientists with expertise in different disciplines is needed to address and solve complex scientific problems. We believe our interactive approach to team competency training sessions would work in a variety of settings and improve team skills.

OBJECTIVES/GOALS: Since 2017, we have used the Design Lab methodology to support investigators taking innovative approaches to clinical effectiveness trial design. To date we have held 12 Design Labs and this year we are creating a handbook that will support dissemination of this approach across the Clinical and Translational Science Award consortium. METHODS/STUDY POPULATION: The Clinical Trial Design Lab brings together a multi-stakeholder group to consider innovative and impactful clinical trial designs. An investigative team is selected from a competitive pool of applicants, after which expert-led consultations support the investigator team to think about evidence generation in the context of the full treatment development pathway. Teams map the stakeholders at each step of this pathway (e.g. clinicians, patients, researchers, funders, industry experts, policy experts, regulatory experts, payers) and consider innovative design solutions. These consultations prepare investigators for an event that involves all stakeholders in a structured and facilitated discussion about trial designs that generate the best evidence and increase potential for health impact. RESULTS/ANTICIPATED RESULTS: The result of our work will be a set of Design Lab principles, a handbook with templates that support stakeholder mapping and structured discussions, and educational resources to accompany the handbook. The work is supported by a literature review that characterizes the multi-component processes included in the Design Lab, situates them within the larger context of team science interventions, and lays groundwork for the development of process metrics and impact evaluation criteria to assess the Design Lab method. In this poster presentation, we will share our multi-component broadly engaged team science approach, provide a brief outline of the principles and educational resources, and include an early version of the evaluation criteria. DISCUSSION/SIGNIFICANCE: Broadly engaged team science supports innovative thinking about study design and is especially important in the development of clinical trials. We have grown the Design Lab program of work over the past seven years and are now able to characterize our team science methodology and support others to use this approach to innovate for health impact.

OBJECTIVES/GOALS: Maternal opioid use disorder (OUD) is linked to poor fetal outcomes. While it has been established that opioids can cross from maternal to fetal circulation, the mechanisms underlying these adverse outcomes remain poorly defined. This study aims to uncover OUD-associated immunological changes in maternal and fetal circulation. METHODS/STUDY POPULATION: To study the effect of maternal OUD on the maternal immune system at delivery, we collected maternal blood samples at delivery from healthy pregnant women (controls) and pregnant women with a diagnosis of severe OUD. To study the impact of maternal OUD on newborn immunity, we also collected umbilical cord blood (UCB) at delivery. Flow cytometry was used to determine the frequency and phenotype of circulating immune cell subsets and responses to stimulation. Isolated monocytes were stimulated with bacterial/viral agonist cocktails, while T and NK cells were stimulated with PMA/ionomycin. The impact of maternal OUD on circulating immune mediators was determined by Luminex and on monocyte activation markers sCD14 and CRP by ELISA. RESULTS/ANTICIPATED RESULTS: In maternal circulation, OUD was associated with a significant decrease in markers of inflammation, cell proliferation, and activation. Frequencies of immune cell subsets were impacted by OUD, shown by an expansion of CD8+ EMRA T cells, marginal-zone B cells, mDCs, non-classical monocytes, and CD16low NK cells. While no differences were seen in T and NK cell responses to stimulation, monocytes and pDCs had significantly lower responses to bacterial and viral agonist stimulation. Analysis of UCB revealed increased levels of pro-apoptotic/T cell exhaustion mediators and pro-inflammatory cytokines, albeit decreased levels of several chemokines and growth factors. The UCB immune landscape is altered with maternal OUD, as demonstrated by a shift from naive to memory CD8+ T cells and a decrease in pDC frequency. DISCUSSION/SIGNIFICANCE: OUD dampens maternal peripheral immunity, possibly contributing to poor placental function or premature/delayed labor. Monocytes and pDCs lack antimicrobial functionality, suggesting increased infection susceptibility with OUD. Finally, these implications extend to the fetal compartment, shown by heightened immune activation in UCB.