Clinical And Translational Science Research Articles

Informatics and Artificial Intelligence-Guided Assessment of the Regulatory and Translational Research Landscape of First-in-Class Oncology Drugs in the United States, 2018-2022.

Cancer drug development remains a critical but challenging process that affects millions of patients and their families. Using biomedical informatics and artificial intelligence (AI) approaches, we assessed the regulatory and translational research landscape defining successful first-in-class drugs for patients with cancer. This is a retrospective observational study of all novel first-in-class drugs approved by the US Food and Drug Administration (FDA) from 2018 to 2022, stratified by cancer versus noncancer drugs. A biomedical informatics pipeline leveraging interoperability standards and ChatGPT performed integration and analysis of public databases provided by the FDA, National Institutes of Health, and WHO. Between 2018 and 2022, the FDA approved a total of 247 novel drugs, of which 107 (43.3%) were first-in-class drugs involving a new biologic target. Of these first-in-class drugs, 30 (28%) treatments were indicated for patients with cancer, including 19 (63.3%) for solid tumors and the remaining 11 (36.7%) for hematologic cancers. A median of 68 publications of basic, clinical, and other relevant translational science preceded successful FDA approval of first-in-class cancer drugs, with oncology-related treatments involving fewer median years of target-based research than therapies not related to cancer (33 v 43 years; P < .05). Overall, 94.4% of first-in-class drugs had at least 25 years of target-related research papers, while 85.5% of first-in-class drugs had at least 10 years of translational research publications. Novel first-in-class cancer treatments are defined by diverse clinical indications, personalized molecular targets, dependence on expedited regulatory pathways, and translational research metrics reflecting this complex landscape. Biomedical informatics and AI provide scalable, data-driven ways to assess and even address important challenges in the drug development pipeline.

Considerations for reporting variants in novel candidate genes identified during clinical genomic testing

Since the first novel gene discovery for a Mendelian condition was made via exome sequencing, the rapid increase in the number of genes known to underlie Mendelian conditions coupled with the adoption of exome (and more recently, genome) sequencing by diagnostic testing labs has changed the landscape of genomic testing for rare diseases. Specifically, many individuals suspected to have a Mendelian condition are now routinely offered clinical ES. This commonly results in a precise genetic diagnosis but frequently overlooks the identification of novel candidate genes. Such candidates are also less likely to be identified in the absence of large-scale gene discovery research programs. Accordingly, clinical laboratories have both the opportunity, and some might argue a responsibility, to contribute to novel gene discovery, which should, in turn, increase the diagnostic yield for many conditions. However, clinical diagnostic laboratories must necessarily balance priorities for throughput, turnaround time, cost efficiency, clinician preferences, and regulatory constraints and often do not have the infrastructure or resources to effectively participate in either clinical translational or basic genome science research efforts. For these and other reasons, many laboratories have historically refrained from broadly sharing potentially pathogenic variants in novel genes via networks such as Matchmaker Exchange, much less reporting such results to ordering providers. Efforts to report such results are further complicated by a lack of guidelines for clinical reporting and interpretation of variants in novel candidate genes. Nevertheless, there are myriad benefits for many stakeholders, including patients/families, clinicians, and researchers, if clinical laboratories systematically and routinely identify, share, and report novel candidate genes. To facilitate this change in practice, we developed criteria for triaging, sharing, and reporting novel candidate genes that are most likely to be promptly validated as underlying a Mendelian condition and translated to use in clinical settings.

Considerations for reporting variants in novel candidate genes identified during clinical genomic testing.

Since the first novel gene discovery for a Mendelian condition was made via exome sequencing (ES), the rapid increase in the number of genes known to underlie Mendelian conditions coupled with the adoption of exome (and more recently, genome) sequencing by diagnostic testing labs has changed the landscape of genomic testing for rare disease. Specifically, many individuals suspected to have a Mendelian condition are now routinely offered clinical ES. This commonly results in a precise genetic diagnosis but frequently overlooks the identification of novel candidate genes. Such candidates are also less likely to be identified in the absence of large-scale gene discovery research programs. Accordingly, clinical laboratories have both the opportunity, and some might argue a responsibility, to contribute to novel gene discovery which should in turn increase the diagnostic yield for many conditions. However, clinical diagnostic laboratories must necessarily balance priorities for throughput, turnaround time, cost efficiency, clinician preferences, and regulatory constraints, and often do not have the infrastructure or resources to effectively participate in either clinical translational or basic genome science research efforts. For these and other reasons, many laboratories have historically refrained from broadly sharing potentially pathogenic variants in novel genes via networks like Matchmaker Exchange, much less reporting such results to ordering providers. Efforts to report such results are further complicated by a lack of guidelines for clinical reporting and interpretation of variants in novel candidate genes. Nevertheless, there are myriad benefits for many stakeholders, including patients/families, clinicians, researchers, if clinical laboratories systematically and routinely identify, share, and report novel candidate genes. To facilitate this change in practice, we developed criteria for triaging, sharing, and reporting novel candidate genes that are most likely to be promptly validated as underlying a Mendelian condition and translated to use in clinical settings.

Environmental pollutant risk factors for worse COVID-19 related clinical outcomes in predominately hispanic and latino populations

BackgroundPer- and poly-fluorinated compounds (PFAS) and heavy metals constitute two classes of environmental exposures with known immunotoxicant effects. In this pilot study, we aimed to evaluate the impact of exposure to heavy metals and PFAS on COVID-19 severity. We hypothesized that elevated plasma-PFAS concentrations and urinary heavy metal concentrations would be associated with increased odds of ICU admission in COVID-19 hospitalized individuals. MethodsUsing the University of Southern California Clinical Translational Sciences Institute (SC-CTSI) biorepository of hospitalized COVID-19 patients, urinary concentrations of 15 heavy metals and urinary creatinine were measured in n = 101 patients and plasma concentrations of 13 PFAS were measured in n = 126 patients. COVID-19 severity was determined based on whether a patient was admitted to the ICU during hospitalization. Associations of metals and PFAS with ICU admission were assessed using logistic regression models, controlling for age, sex, ethnicity, smoking status, and for metals, urinary dilution. ResultsThe average age of patients was 55 ± 14.2 years. Among SC-CTSI participants with urinary measurement of heavy metals and blood measures of PFAS, 54.5% (n = 61) and 54.8% (n = 80) were admitted to the ICU, respectively. For heavy metals, we observed higher levels of Cd, Cr, and Cu in ICU patients. The strongest associations were with Cadmium (Cd). After accounting for covariates, each 1 SD increase in Cd resulted in a 2.00 (95% CI: 1.10–3.60; p = 0.03) times higher odds of admission to the ICU. When including only Hispanic or Latino participants, the effect estimates between cadmium and ICU admission remained similar. Results for PFAS were less consistent, with perfluorodecanesulfonic acid (PFDS) exhibiting a positive but non-significant association with ICU admission (Odds ratio, 95% CI: 1.50, 0.97–2.20) and perfluorodecanoic acid (PFDA) exhibiting a negative association with ICU admission (0.53, 0.31–0.88). ConclusionsThis study supports the hypothesis that environmental exposures may impact COVID-19 severity.

Altered transcriptomic immune responses of maintenance hemodialysis patients to the COVID-19 mRNA vaccine.

End-stage renal disease (ESRD) patients experience immune compromise characterized by complex alterations of both innate and adaptive immunity, and results in higher susceptibility to infection and lower response to vaccination. This immune compromise, coupled with greater risk of exposure to infectious disease at hemodialysis (HD) centers, underscores the need for examination of the immune response to the COVID-19 mRNA-based vaccines. The immune response to the COVID-19 BNT162b2 mRNA vaccine was assessed in 20 HD patients and cohort-matched controls. RNA sequencing of peripheral blood mononuclear cells was performed longitudinally before and after each vaccination dose for a total of six time points per subject. Anti-spike antibody levels were quantified prior to the first vaccination dose (V1D0) and 7 d after the second dose (V2D7) using anti-spike IgG titers and antibody neutralization assays. Anti-spike IgG titers were additionally quantified 6 mo after initial vaccination. Clinical history and lab values in HD patients were obtained to identify predictors of vaccination response. Transcriptomic analyses demonstrated differing time courses of immune responses, with prolonged myeloid cell activity in HD at 1 wk after the first vaccination dose. HD also demonstrated decreased metabolic activity and decreased antigen presentation compared to controls after the second vaccination dose. Anti-spike IgG titers and neutralizing function were substantially elevated in both controls and HD at V2D7, with a small but significant reduction in titers in HD groups (p<0.05). Anti-spike IgG remained elevated above baseline at 6 mo in both subject groups. Anti-spike IgG titers at V2D7 were highly predictive of 6-month titer levels. Transcriptomic biomarkers after the second vaccination dose and clinical biomarkers including ferritin levels were found to be predictive of antibody development. Overall, we demonstrate differing time courses of immune responses to the BTN162b2 mRNA COVID-19 vaccination in maintenance HD subjects comparable to healthy controls and identify transcriptomic and clinical predictors of anti-spike IgG titers in HD. Analyzing vaccination as an in vivo perturbation, our results warrant further characterization of the immune dysregulation of ESRD. F30HD102093, F30HL151182, T32HL144909, R01HL138628. This research has been funded by the University of Illinois at Chicago Center for Clinical and Translational Science (CCTS) award UL1TR002003.

531 Transforming a Pilot Grant Program to Advance Clinical &amp; Translational Science

OBJECTIVES/GOALS: A new mandate for Clinical &amp; Translational Science Award (CTSA) Programs is for pilot grant funding to support clinical and translational science (CTS) projects that study challenges in the translational research pipeline. This pivot requires new structures and supports to help investigators design and implement high-quality CTS projects. METHODS/STUDY POPULATION: The Michigan Institute for Clinical &amp; Health Research (MICHR) at the University of Michigan (U-M) has launched two rounds of pilot funding since March 2023. Faculty and staff across U-M’s three campuses, community members, and those at collaborating institutions and hospitals were eligible to apply. New pre-award supports included a CTS project framework; a recorded webinar that educated about CTS and the funding opportunity; office hours to provide tailored project feedback; a letter of intent to screen for alignment with CTS; and reviewer training for academic and community reviewers. Funded projects operate like 'mini cooperative agreements”, with MICHR experts partnering with awardees to refine evaluation plans, prepare work products, advise on dissemination, and navigate emergent challenges. RESULTS/ANTICIPATED RESULTS: The first round of funding was launched in the absence of pre-award supports; ten applications we received from faculty proposing translational research rather than CTS. We quickly re-released the FOA, expanding eligibility to staff. We received nine applications, ultimately funding four staff and one faculty studying operational challenges in translation and helping them create robust evaluation plans. We piloted the pre-award supports in our second round, with 40 individuals viewing our webinar and 11 attending office hours. Those who watched the webinar before attending office hours better understood how to embed CTS questions within their programs of research. We recently received 19 letters of intent, addressing both operational and scientific challenges, with 16 eligible to submit applications. DISCUSSION/SIGNIFICANCE: Education and personalized feedback seem to elicit a higher yield of CTS projects. Staff are already adept at solving operational challenges, so the pre-award supports were most critical for faculty accustomed to writing traditional translational research proposals. Staff have most benefited from guidance in evaluation and dissemination.

156 Art as a Multiplier of Science Communication

OBJECTIVES/GOALS: Scientists are increasingly confronted with 'science critical' #_msocom_1 belief systems. The politicization of science fuels hesitancy towards evidence-based therapies. To overcome these barriers, we aim to devise strategies to communicate clinical translational science (CTS) through art. METHODS/STUDY POPULATION: A two-year pilot artist-in-residency (AIR) program embedded in the Translational Research Immersion Program (TRIP). Since 2009, TRIP contributes to CTS Workforce Development (WD) through a 10-week mentored, curriculum-rich summer undergraduate research experience. Students are recruited from 5 regional institutions, 6 HBCUs, and the University of Puerto Rico. AIR is composed of 3 phases: the “Immersive Phase” where the artist gains intensive exposure to the scientific process through the lived experience of TRIP students, the “Productive Phase” where the artist conceptualizes the process of CTS into works of art, and the “Engagement Phase” where the CTS workforce, artists, and community members coalesce around science-to-art materializations. RESULTS/ANTICIPATED RESULTS: In 2022 &amp; 2023 the AIR participated in ~35hrs of CTS research seminars, panel discussions, and professional skills workshops. Additional TRIP student-AIR interaction occurred in focus groups including visits to mentor’s labs. An AIR-led workshop culminated in an Empowering CTS Communication event where TRIP students engaged with community members through elevator pitches of their CTS summer project on a speed-rotating basis. A month-long art-CTS exhibition planned for 3/2024 will feature contributions from AIR, TRIP students, and ITMAT community members. Qualitative insights were that TRIP is an effective art-science incubator, students strengthened their CTS communication skills, art functions as an icebreaker between science and communities with an ocean of opportunities for science education. DISCUSSION/SIGNIFICANCE: AIR embedded into existing CTS WD programs is proposed as creative approach to strengthen the reputation of science in the public. CTS-informed art functions as connective tissue between public and CTS workforce. The hands-on experience to adopt art as a science communication tool is a powerful soft skill for the next generation of CTS investigators.

Strategies to promote language inclusion at 17 CTSA hubs.

The prioritization of English language in clinical research is a barrier to translational science. We explored promising practices to advance the inclusion of people who speak languages other than English in research conducted within and supported by NIH Clinical Translational Science Award (CTSA) hubs. Key informant interviews were conducted with representatives (n = 24) from CTSA hubs (n = 17). Purposive sampling was used to identify CTSA hubs focused on language inclusion. Hubs electing to participate were interviewed via Zoom. Thematic analysis was performed to analyze interview transcripts. We report on strategies employed by hubs to advance linguistic inclusion and influence institutional change that were identified. Strategies ranged from translations, development of culturally relevant materials and consultations to policies and procedural changes and workforce initiatives. An existing framework was adapted to conceptualize hub strategies. Language justice is paramount to bringing more effective treatments to all people more quickly. Inclusion will require institutional transformation and CTSA hubs are well positioned to catalyze change.

Development of an undergraduate certificate in clinical and translational science: improving competence of the clinical research workforce.

Introduction: Academic research centers often struggle to recruit and retain a well-trained and diverse clinical and translational science (CTS) workforce. In particular, the clinical research professional (CRP) career pathway is not well known to undergraduate students and other individuals outside of academic medicine despite being a potential career route. To address these workforce challenges, the CRP Task Force at the University of Cincinnati (UC) aims to train a competent and diverse CRP workforce through targeted educational programming in the UC undergraduate population. Methods: Using a six-step curriculum development process that included: 1) performing a needs assessment, 2) determining content, 3) writing goals and objectives, 4) selecting the educational strategies, 5) implementing the curriculum, and 6) evaluating the curriculum, we designed an undergraduate certificate program in CTS. Results: The needs assessment included both internal and external data gathering to inform curriculum development and program decisions. Content was determined using the Core Competency Framework for the Clinical Research Professional Version 3.1., and program learning outcomes were written with both the competency framework and local workforce needs in mind. Educational strategies were selected based on optimization of available resources and local expertise with an emphasis on interactive didactics complemented by experiential learning. Implementation is underway and evaluation will follow once students begin enrolling. Discussion: By educating an undergraduate student population about CTS methods and career opportunities, we anticipate increased numbers of well-qualified, diverse applicants who pursue CRP careers locally and regionally.

Building our research administrator workforce as our clinical and translational research programs become increasingly complex.

Introduction: Research administrators (RA's) are critical members of the research workforce. For purposes of this article, research administrators are personnel who support the development, compliance, management, and financial oversight of sponsored research. There are currently very few institutional career development and mentoring programs available to research administrators. Recruitment and retention of quality research administrators has been especially challenging across the country in recent years. Methods: In an effort to address this gap in training and to increase recruitment and retention, the integrated Translational Health Research Institute of Virginia (iTHRIV), a collaborative NIH-NCATS funded Clinical Translational Science Award (CTSA) hub, has developed an innovative program of workforce development and mentoring for research administrators. This article provides an overview of one institutional training and development initiative, the Research Administration Program for Training and Resources (RAPTR). RAPTR provides training, resources and mentoring to develop a Community of Practice. Results: The program provides a forum where research administrators can share ideas, practices, and challenges. Discussion: This manuscript describes the benefits and lessons learned from our early experience in this program. We highlight selected components that may be generalizable to other institutions and describe individualized components, which require local policies and processes.

Addressing Resistance to Therapy in Colorectal Cancer

Addressing Resistance to Therapy in Colorectal Cancer

262-LB: Fasting Intact Insulin by Liquid Chromatography–Tandem Mass Spectrometry (LC-MS/MS) as a Predictor of Nonalcoholic Fatty Liver Disease in Pediatric Patients

Background: Recent research in adults has shown fasting intact insulin levels measured by mass spectrometry can predict nonalcoholic fatty liver disease (NAFLD) in patients without diabetes; however, there is limited research in children. This study aimed to evaluate fasting intact insulin by LC-MS/MS as a predictive biomarker of NAFLD in adolescents. Methods: This retrospective, cross-sectional study was based on data from four previously conducted studies. Existing clinical laboratory values included fasting intact insulin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), C-peptide, and the insulin resistance (IR) score. Hepatic fat was assessed by magnetic resonance imaging proton density fat fraction (MRI-PDFF) or MR spectroscopy (MRS). NAFLD was defined as intrahepatic fat of ≥5%. Results: A total of 73 children were included in the analysis (64% male; 13.9 ± 2.8 years of age; body mass index (BMI) 29.1 ± 8.5 kg/m2; 56% with NAFLD). Intact fasting insulin, C-peptide, AST, ALT, and IR scores were higher in children with NAFLD compared to non-NAFLD children (P&amp;lt;0.05). Fasting intact insulin measurements predicted NAFLD (area under the receiver operating characteristic curve [AUROC] of 0.83 [95%CI, 0.73-0.93]). When combined with ALT (intact insulin (μU/mL) × ALT (× U/L)), the combined biomarker slightly improved the prediction of NAFLD (AUROC 0.89 [0.81-0.96]), with positive and negative predictive values of 79% and 100%, respectively. Based on maximizing Youden's index, the optimal cutoff points to predict NAFLD were 13.0 μU/mL for intact insulin and 380 μU/mL × U/L for intact insulin × ALT. Conclusion: Our findings support that fasting intact insulin alone, or combined with ALT (intact insulin × ALT), show promise as predictive biomarkers for pediatric NAFLD with high positive and negative predictive values. Additional studies are needed to validate these findings in other pediatric populations. Disclosure H. Huneault: None. D. Ayinde: None. Z. He: None. C. C. Cohen: None. M. J. McPhaul: Employee; Quest Diagnostics. M. B. Vos: Consultant; Boehringer Ingelheim International GmbH, BMS, Intercept Pharmaceuticals, Inc., Novo Nordisk, ProSciento, Eli Lilly and Company. Research Support; Quest Diagnostics, TARGET PharmaSolutions, Inc. Funding National Institutes of Health (R01DK125701); Georgia Clinical Translational Science Alliance (UL1TR002378)

To give or not to give: what is the evidence?

Social inequality is precipitated by insufficient access to resources such as money, education, jobs, growth opportunities, social connections, and networks, resulting in poverty. Under the effects of clusters of social and economic disadvantages, affected populations are unable to manage their health conditions. 1 McGrail K Morgan J Siddiqi A Looking back and moving forward: addressing health inequities after COVID-19. Lancet Reg Health Am. 2022; 9100232 Google Scholar Inequity transpired ruthlessly during the COVID-19 pandemic. 2 Nana-Sinkam P Kraschnewski J Sacco R et al. Health disparities and equity in the era of COVID-19. J Clin Transl Sci. 2021; 5: e99 Crossref PubMed Scopus (31) Google Scholar Millions of people in poverty lost their lives, although access to oxygen, timely testing, vaccines, and treatment could potentially have saved them. The effects of cash transfer programmes on HIV/AIDS prevention and care outcomes: a systematic review and meta-analysis of intervention studiesCash transfer programmes have a positive effect on mitigating HIV incidence for individuals who have to meet health-care conditionalities and on increasing retention in HIV care for pregnant women. These results show the potential of cash transfer programmes for HIV prevention and care, especially among people in extreme poverty, and highlight that cash transfer programmes must be considered when developing policies for HIV/AIDS control, as indicated by the UNAIDS 95-95-95 target of the HIV care continuum. Full-Text PDF

0367 Urban Stress and Sleep Health by Proximal Neighborhood Groups in Washington, DC

Abstract Introduction African Americans are disproportionately affected by environmental factors that increase the risk for negative health outcomes. Analyses from National Health Interview Survey (NHIS) data estimated 15 to 75 percent of the disparities between Black and White respondents being accounted for by residential context. Poor sleep health, particularly short sleep duration, has been linked to metabolic and cardiovascular disease. A population study indicated that sleep duration of less than 6 hours was more common among African Americans compared with other racial groups in the United States and this association was accounted for by African Americans living in high density urban environments. Threats of violence may engender feelings of vulnerability when sleeping and be an important determinant of sleep health though this relationship has not been adequately studied. The aim of this study is to determine how an individual’s sleep health relates to violent crime rates in their neighborhood of residence as well as indicators of neighborhood stress endorsed in a self-reported survey. Methods African- American men and women between the ages of 18-35 filled out the insomnia severity index (ISI) and city stress inventory (CSI). Sleep duration and sleep efficiency were obtained through home-based actigraphy. Participants were categorized as poor sleepers if two out of three criteria were met: sleep duration of less than six hours, ISI greater than 10, and sleep efficiency below 85%. Participants addresses were linked to one of the 51 proximal neighborhood groups (PNG) defined by the DC Department of Health and Office of Planning using MAR geocoder and QGIS mapping software. Violent death rates and other social health determinants are indicated by PNG in the DC DOH’s Health Equity Report (2019). Results Sleep measures were not correlated with neighborhood violent death rates (Pearson r’s: .05 - .17; all NS). SE and TST were weakly correlated with CSI scores (both r’s = -.22, NS). Conclusion The negative findings may be related to sample size, the presence of threat and crime in all of the locations, and the importance of individual coping. Support (if any) NIHLB grant R01HL136626 to Dr. Thomas A. Mellman and NCATS grant for a Clinical Translational Science Award UL1-TR001409.

0848 Total sleep time, wake after sleep onset, and inflammation predict obesity in young adult African Americans

Abstract Introduction Sleep is vital to maintaining psychological and physiological health. Poor sleep is associated with adverse health outcomes, including obesity. Studies have shown that African Americans disproportionately suffer from poor sleep and the adverse health outcome associated with obesity. We aimed to determine if sleep quality and peripheral inflammation are significant predictors of obesity in a young adult African American sample. Methods Participants were healthy adults with a body mass index of less than 40 between 18- 35 who self-identified as Black or African American and completed a protocol consisting of in-lab polysomnography, ambulatory monitoring and a morning blood draw. Height and weight were collected to derive body mass index (BMI). Total sleep time (TST), wake after sleep onset (WASO), sleep onset latency (SOL), and sleep efficiency (SE) were derived from in-home actigraphy. Venipuncture was used to collect blood samples within 15 minutes of awakening. Once samples were processed, interleukin-6 (IL-6) levels were detected and quantified using enzyme-linked immunosorbent assays (ELISA). Results Significant correlations were found between BMI, WASO, TST, SE, and IL-6. A forward stepwise linear regression was used to identify possible predictors of BMI out of the following candidate variables: TST, SE, WASO, and IL-6. At each step, variables were chosen according to their contribution to the model's R^2. The p-value threshold of 0.05 was used to set a limit on the total number of variables included in the final model. TST, WASO, and IL6 were the significant predictors in the final model that accounted for 26% of the variance in BMI (∆R2 = .260, p&amp;lt;.001). Regression coefficients suggest that IL-6 (β =.388), TST (β= -.234), and WASO (β=.205) predict obesity. Conclusion Total sleep time and wake after sleep onset are modifiable protective and risk factors that appear to be significant contributors to obesity in urban-residing young African Americans. Support (if any) This research was supported by the NIHLB grants R01HL087995 and R01HL136626 and to Dr. Thomas A. Mellman and NCATS grant for a Clinical Translational Science Award UL1-TR001409.

Female Recruitment Into Cardiovascular Disease Trials

Female Recruitment Into Cardiovascular Disease Trials

Clinical research resource support for off-site research coordinators in intensive and specialty care units.

Clinical Research Coordinators (CRCs) are vital collaborators in a clinical research project. They often are the primary liaisons between investigators and human participants in studies and are involved in every aspect of many protocols, including participant recruitment, care (both usual medical care and specific study-related monitoring and procedures), data collection, specimen processing, and follow-up. The Clinical Translational Science Award program, which was created by the National Institutes of Health in 2006, has significantly expanded the venues in which Clinical Research Resource (CRR) - based CRCs are embedded. CRCs functioning in these areas, outside of the research-focused in-patient environment of the CRR, are designated as "off-site" CRCs. Many of these locations, such as intensive care units and emergency departments, require that CRCs interact regularly with healthcare providers whose primary functions are focused on providing optimal patient care rather than research and often involving very complex patients. These off-site CRCs require additional training and support outside of the usual research-oriented environment of the CRR. They are required to function within the context of the patient-care team while fostering implementation of collaborative research. This is a description of such a program specifically geared to off-site CRCs with the goal of enhancing the quality of research and experiences of CRCs.

The catabolism of bilirubin to urobilin might be a leading factor in obesity-induced insulin resistance: New findings in human studies

For unknown reasons, plasma bilirubin levels are lower in obese humans and rodents. One possible explanation is that the hepatic expression of enzymes that regulate its half-life, such as the UGT1A1 UDP-glucuronosyltransferase, is higher in the obese compared to lean persons. Bilirubin is marked for excretion within the liver by the conjugation of two glucuronyl groups by UGT1A1, where it is then transported to the intestines by the biliary system. Once in the intestines, the gut microbiota containing bilirubin reductase remove the glucornyl groups and modify the structure to produce urobilin which can be absorbed via the hepatic portal vein and enter the systemic circulation. Previous correlation studies indicate that urobilin might be a factor that induces visceral obesity and cardiovascular disease. However, the physiological function of urobilin is unknown. The purpose of our study was to determine if there is a correlation between bilirubin and urobilin compared to adiposity and insulin resistance in lean and obese women and men. We hypothesized that bilirubin would be lower and urobilin higher in the plasma of obese humans compared to lean. We found that the plasma levels of urobilin and bilirubin are inversely correlated in women and men. Urobilin levels were positively associated with adiposity (BMI R 2 =0.29 and body fat percentage R 2 =0.25) and insulin resistance (blood glucose R 2 =0.05, insulin R 2 =0.22, and HOMA IR R 2 =0.18) in obese women. Urobilin was only correlated with adiposity in males (BMI R 2 =0.025 and body fat percentage R 2 =0.03). However, the males were not insulin resistant and had no significant difference in HOMA IR compared to lean men. In both women (BMI R 2 =0.065 and body fat percentage R 2 =0.05) and men (BMI R 2 =0.24 and body fat percentage R 2 =0.13), plasma bilirubin levels were negatively associated with adiposity. We observed that plasma bilirubin levels are negatively associated with adiposity, which has been previously reported. The new findings in our study indicate that urobilin is positively associated with adiposity and insulin resistance. Based on these data, we propose that bilirubin and urobilin are maintained at inverse levels in humans via the UGT1A1 axis and that activity is higher in the obese, reducing plasma bilirubin and providing more substrates to produce urobilin in the gut. These events cause an elevation in plasma urobilin levels that commence obesity-associated comorbidities. Future work to determine the role of urobilin in obesity-associated comorbidities such as insulin-resistant diabetes is warranted and may provide a biomarker for the early This work was supported by the National Institutes of Health R01DK121797 (T.D.H.J.). The sample collection was supported by the Center for Clinical and Translational Science (CCTS) grant UL1TR001998 at the University of Kentucky. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Weight cycling may induce lipid handling in mast cells

Abstract Weight cycling worsens diabetes risk in both humans and mice. We recently found that weight loss and weight cycling induce many immunological changes in the adipose tissue of mice by single cell RNA-sequencing. We also found a substantial increase in adipose mast cells with weight cycling, but not weight loss. The purpose of this study was to confirm and characterize the changes in mast cells with weight cycling. However, using flow cytometry (cKit+FcER1+) and Toluidine blue staining, we found that adipose mast cells are greatest in the weight loss group, in contrast to our prior study using single cell RNA-sequencing. Upon further analysis, we found two unique mast cell populations in our single cell sequencing dataset: one that we consider traditional mast cells and one with lower expression of mast cell surface and protease genes and elevated expression of lipid handling and antigen presentation genes. The second fraction appeared similar to lipid-associated macrophages and accounted for most of the mast cells in the weight cycled group. By flow cytometry, we confirmed the %CD9+, MHCII (I-A/I-E)+, and CD74+ mast cells were highest in weight cycled mice. We also found two mast cell populations in human subcutaneous adipose tissue that appear similar to the murine populations in our dataset, with one population significantly correlating with weight variability. Together, these data suggest that weight cycling may induce a population of lipid-associated mast cells. We next aim to to induce lipid handling in bone marrow derived mast cells by repeated exposure to adipose conditioned media in order to understand the mechanisms which induce lipid handling. This project was funded by a Veterans Affairs Merit Award 5I01BX002195 to AHH. AHH is also supported by a Career Scientist Award from the Veterans Affairs (IK6 BX005649). HLC was funded by an American Heart Association Postdoctoral Fellowship (20POST35120547), MAC was funded by an NIH F31 Predoctoral Fellowship (1F31DK123881), and both were previously supported by the Molecular Endocrinology Training Program (T32 DK07563). Additionally, the human mast cell work was funded by VICTR grants to HLC and MM. The Vanderbilt Institute for Clinical and Translational Research (VICTR) is funded by the National Center for Advancing Translational Sciences (NCATS) Clinical Translational Science Award (CTSA) Program, Award Number 5UL1TR002243-03.

Program Evaluation Standards for Utility Facilitate Stakeholder Internalization of Evaluative Thinking in the West Virginia Clinical Translational Science Institute.

The program evaluation standards (PES) can be considered established criteria for high-quality evaluations. We emphasize PES Utility standards and evaluation capacity building as we strive for meaningful application of our work in the real world. We focused our methodology on understanding how stakeholders discussed utility and how their perceptions related to our evaluation work aligned with the Utility domain of the program evaluation standards. The West Virginia Clinical Translational Science Institute (WVCTSI), a statewide multi-institutional entity for which we have conducted tracking and evaluation since 2012. Sustained collaborative engagement of evaluation stakeholders with the goal of increasing their utilization of evaluation products and evaluative thinking. Case study. We interviewed five key stakeholders. We used themes developed from coding of interview data to inform document analyses. We used interview and document analyses to develop additional themes and illustrative examples, as well as to develop and describe a five-level evaluation uptake scale. We describe shifts in initiation, use, and internalization of evaluative thinking by non-evaluation personnel. These shifts prompted our development and application of an evaluation uptake scale to capture increased evaluation capacity among stakeholders over time. We discuss how focus on the PES Utility standards and evaluation capacity building facilitated these shifts, and their implications for maximizing utility of evaluation activity in large, complex programmatic evaluations.