Department of Medicine

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    1-Alpha, 25-dihydroxyvitamin D3 alters the pharmacokinetics of mycophenolic acid in renal transplant recipients by regulating two extrahepatic UDP-glucuronosyltransferases 1A8 and 1A10
    (Elsevier, 2016-12) Wang, Xiaoliang; Wang, Hongwei; Shen, Bing; Overholser, Brian R.; Cooper, Bruce R.; Lu, Yinghao; Tang, Huamei; Zhou, Chongzhi; Sun, Xing; Zhong, Lin; Favus, Murray J.; Decker, Brian S.; Liu, Wanqing; Peng, Zhihai; Department of Medicine, IU School of Medicine
    Mycophenolic acid (MPA) is an important immunosuppressant broadly used in renal transplantation. However, the large inter-patient variability in mycophenolic acid (MPA) pharmacokinetics (PK) limits its use. We hypothesize that extrahepatic metabolism of MPA may have significant impact on MPA PK variability. Two intestinal UDP-glucuronosyltransferases 1A8 and 1A10 plays critical role in MPA metabolism. Both in silico and previous genome-wide analyses suggested that vitamin D (VD) may regulate intestinal UGT1A expression. We validated the VD response elements (VDREs) across the UGT1A locus with chromatin immunoprecipitation (ChIP) and luciferase reporter assays. The impact of 1-alpha,25-dihydroxyvitamin D3 (D3) on UGT1A8 and UGT1A10 transcription and on MPA glucuronidation was tested in human intestinal cell lines LS180, Caco-2 and HCT-116. The correlation between transcription levels of VD receptor (VDR) and the two UGT genes were examined in human normal colorectal tissue samples (n = 73). PK alterations of MPA following the parent drug, mycophenolate mofetil (MMF), and D3 treatment was assessed among renal transplant recipients (n = 10). Our ChIP assay validate three VDREs which were further demonstrated as transcriptional enhancers with the luciferase assays. D3 treatment significantly increased transcription of both UGT genes as well as MPA glucuronidation in cells. The VDR mRNA level was highly correlated with that of both UGT1A8 and UGT1A10 in human colorectal tissue. D3 treatment in patients led to about 40% reduction in both AUC0-12 and Cmax while over 70% elevation of total clearance of MPA. Our study suggested a significant regulatory role of VD on MPA metabolism and PK via modulating extrahepatic UGT activity.
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    1082. Real-World Experience with Omadacycline for Nontuberculous Mycobacterial Infections: A Multicenter Evaluation
    (Oxford University Press, 2021-12-04) Morrisette, Taylor; Alosaimy, Sara; Lagnf, Abdalhamid M.; Philley, Julie V.; Sigler, Carly; Butt, Saira; Kaip, Emily A.; MacDougall, Conan; Mejia-Chew, Carlos; Bouchard, Jeannette; Frens, Jeremy J.; Gore, Tristan; Hamad, Yasir; Howard, Catessa; Barger, Melissa; Cabanilla, M. Gabriela; Ong, Aaron; Veve, Michael P.; Webb, Andrew J.; Stevens, Ryan W.; Cohen, Keira A.; Rybak, Michael J.; Medicine, School of Medicine
    Background: Nontuberculous mycobacteria (NTM) are resistant to numerous antibiotics and lead to significant morbidity and mortality. Omadacycline (OMC) is an aminomethylcycline antibiotic that is Food and Drug Administration-approved for acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia. Furthermore, OMC has shown in vitro activity against NTM. Given that real-world evidence is lacking, our primary objective was to evaluate the clinical success and tolerability of OMC when used for a variety of NTM infections. Methods: This was a multicenter, retrospective, observational study conducted from January 2020 to June 2021. We included all patients ≥ 18 years of age that received OMC of any indication for Mycobacterium spp. The primary outcome was clinical success, defined as a lack of all-cause mortality, lack of persistence or re-emergence of infection during or after therapy, and lack of alteration of OMC. Incidence of adverse effects potentially attributable to OMC and reasons for OMC utilization were also analyzed. Results: A total of 31 patients were included from 12 geographically distinct academic health systems (median age: 57 (IQR, 45-63) years; 45% male; 81% Caucasian). The majority of isolated pathogens were Mycobacterium abscessus complex (84%) and of those with subspeciation performed (54%), the majority (86%) were subsp. abscessus. The primary infections were of pulmonary origin (67%) and the median (IQR) duration of OMC therapy was 5.3 (3.2-9.4) months. Most isolates did not have OMC susceptibility conducted (87%), while the majority did for tigecycline (90%). Clinical success was reported in 81% of the population. Most patients were on combination antimicrobial therapy, and 39% of patients reported an adverse effect while on OMC (58% gastrointestinal distress). The majority of patients were prescribed OMC due to ease of administration (61%) and antimicrobial resistance to previous antibiotics (42%). Conclusion: OMC may be a potential option for the therapy of NTM infections. Prospective, randomized clinical trials are needed to confirm our preliminary findings.
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    15. Augmentation of homing of cord blood stem cells
    (Elsevier, 2005-11) Broxmeyer, H.E.; Christopherson, K.W.; Hangoc, G.; Campbell, T.B.; Medicine, School of Medicine
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    1581. Weight and Metabolic Changes with Long-Acting Lenacapavir in a Combination Regimen in Treatment-Naïve People with HIV-1 at Week 80
    (Oxford University Press, 2023-11-27) Kumar, Princy N.; Goldstein, Deborah A.; Hengel, Richard L.; Gaur, Aditya H.; Wurapa, Anson K.; Khalsa, Ann M.; Newman, Cheryl L.; Saunders, Gary; Liu, Shan-Yu; Dvory-Sobol, Hadas; Rhee, Martin; Gupta, Samir K.; Medicine, School of Medicine
    Background: Lenacapavir (LEN) is a highly potent, long-acting, first-in-class inhibitor of HIV-1 capsid protein approved for the treatment of HIV-1 infection in adults with multidrug resistance in combination with other antiretrovirals. CALIBRATE is an ongoing phase 2 study in people with HIV-1 (PWH) who are newly initiating treatment. At Week 80 (W80), subcutaneous (SC) and oral LEN, in combination with other antiretrovirals, maintained high rates of virologic suppression. In PWH initiating treatment, weight increases associated with a return to health effect have been observed. This analysis examined weight and metabolic changes to the W80 timepoint. Methods: Participants were randomized (2:2:2:1) to 1 of 4 treatment groups (TG). TG1 and TG2 both received SC LEN (927 mg) every 6 months + oral once daily (QD) emtricitabine/tenofovir alafenamide (F/TAF) for 28 weeks, after which virologically suppressed participants continued a 2-drug maintenance regimen: SC LEN (927 mg) with oral QD TAF (TG1) or oral QD bictegravir (BIC) (TG2). TG3 received oral QD LEN + F/TAF, and TG4 received oral QD BIC/F/TAF throughout. The metabolic profile of LEN was assessed from baseline to W28 and after initiating the 2-drug maintenance regimen to W80. Due to the small sample size, no statistical testing was performed. Results: 182 participants (7% female, 52% Black) were randomized and dosed (n=52, 53, 52, 25 in TG1 to TG4, respectively). Baseline median age was 29 years; 15% had baseline viral load >100,000 c/mL. Baseline median weight and body mass index (BMI) were 78.2 kg and 25.8 kg/m2, respectively. Weight, BMI, and fasting lipid profiles for each treatment group through W80 are presented. Conclusion: In this phase 2 study of treatment-naïve PWH, treatment regimens that included SC or oral LEN in combination with other antiretroviral agents led to expected weight gain and increase in BMI, consistent with the return to health phenomenon, and were not associated with clinically relevant increases in lipids.
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    16.3 Are Visual Motion Perception and Detection of Animacy Critical to Higher-Order Social Cognitive Function in Schizophrenia?
    (Oxford University Press, 2019-04) Johannesen, Jason; Lysaker, Paul; James, Alison; Kenney, Joshua; Bell, Morris; Medicine, School of Medicine
    Background The observation that individuals with schizophrenia tend to misinterpret subtle social cues is often attributed to deficit in Theory of Mind (ToM). While ToM is commonly assessed using videos portraying interaction between actors, recent work in vision science shows that stimuli with no innate animate features can also convey similar social information through motion alone. These simplified stimuli are advantageous for experimental purposes and may provide further insights into perceptual mechanisms supporting social cognitive function. The Social Attribution Task-Multiple Choice (SAT-MC), based on the classic Hieder and Simmel (1944) stimuli, tells a story using three geometric shapes moving about a centrally fixed figure, followed by questions about what the viewer observed. Although there are no explicit social cues, viewers typically detect actions suggestive of relationships between objects, their intentions, and emotions. This talk will present findings from three studies examining psychometric, functional, and neurophysiological aspects on SAT -MC performance in schizophrenia. Methods Study 1 examined psychometric properties of two forms of the SAT-MC in comparison to video-based social cognitive tests using human actors in 32 schizophrenia (SZ) and 30 substance use disorder (SUD) participants. Study 2 examined functional relationships of the SAT-MC and affect recognition (BLERT) performance across neurocognitive, metacognitive, ToM, and symptom domains in 72 adults with SZ. Study 3 is an in-progress investigation of neurophysiological mechanisms of social cognition using test versions adapted for EEG recording. Chronic SZ, clinical high-risk (CHR), and healthy age-matched community samples are being collected. Results SZ scored significantly lower than SUD on two versions of the SAT-MC, each classifying ~60% of SZ as impaired, compared with ~30% of SUD. The two SAT-MC forms demonstrated good test-retest and parallel form reliability, minimal practice effect, high internal consistency, similar patterns of correlation with social cognitive test performance, and compared favorably to social cognitive tests across psychometric features. When examining functional correlates of SAT -MC performance, impairment is found to co-occur with deficits in affect recognition in the majority of cases but relates uniquely to reductions in verbal memory and emotional intelligence measures. Finally, a preliminary analysis (n=8 SZ, n=2 CHR) of EEG collected during SAT-MC video presentation finds significant correlations (r=.66-.72) between occipito-parietal gamma desynchronization and task performance. Additional analyses find task-related EEG during SAT to be predictive of affect recognition (BLERT) and ToM (TASIT) performance, with correlates including alpha desynchronization in frontal, occipital, and temporal regions, and synchronization of temporal theta and occipital gamma (all r > .5). Conclusions SAT-MC performance is found to be reliable using different stimuli, related to affect recognition and ToM in three independent samples, and shows high diagnostic specificity in classifying SZ against a SUD sample. Functional correlates also involve encoding and emotional intelligence abilities tested outside the visual modality. Analysis of neural oscillatory activity related SAT-MC performance to visual and attention processes, as well as engagement of a broader social cognitive network applied to affect recognition and ToM tasks. Impairment in visual motion processing appears integral to schizophrenia pathophysiology and a critical factor influencing social cognitive abilities attributed to higher-order ToM ability.
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    17β-Estradiol and estrogen receptor α protect right ventricular function in pulmonary hypertension via BMPR2 and apelin
    (American Society for Clinical Investigation, 2021-03-15) Frump, Andrea L.; Albrecht, Marjorie; Yakubov, Bakhtiyor; Breuils-Bonnet, Sandra; Nadeau, Valérie; Tremblay, Eve; Potus, Francois; Omura, Junichi; Cook, Todd; Fisher, Amanda; Rodriguez, Brooke; Brown, R. Dale; Stenmark, Kurt R.; Rubinstein, C. Dustin; Krentz, Kathy; Tabima, Diana M.; Li, Rongbo; Sun, Xin; Chesler, Naomi C.; Provencher, Steeve; Bonnet, Sebastien; Lahm, Tim; Medicine, School of Medicine
    Women with pulmonary arterial hypertension (PAH) exhibit better right ventricular (RV) function and survival than men; however, the underlying mechanisms are unknown. We hypothesized that 17β-estradiol (E2), through estrogen receptor α (ER-α), attenuates PAH-induced RV failure (RVF) by upregulating the procontractile and prosurvival peptide apelin via a BMPR2-dependent mechanism. We found that ER-α and apelin expression were decreased in RV homogenates from patients with RVF and from rats with maladaptive (but not adaptive) RV remodeling. RV cardiomyocyte apelin abundance increased in vivo or in vitro after treatment with E2 or ER-α agonist. Studies employing ER-α–null or ER-β–null mice, ER-α loss-of-function mutant rats, or siRNA demonstrated that ER-α is necessary for E2 to upregulate RV apelin. E2 and ER-α increased BMPR2 in pulmonary hypertension RVs and in isolated RV cardiomyocytes, associated with ER-α binding to the Bmpr2 promoter. BMPR2 is required for E2-mediated increases in apelin abundance, and both BMPR2 and apelin are necessary for E2 to exert RV-protective effects. E2 or ER-α agonist rescued monocrotaline pulmonary hypertension and restored RV apelin and BMPR2. We identified what we believe to be a novel cardioprotective E2/ER-α/BMPR2/apelin axis in the RV. Harnessing this axis may lead to novel RV-targeted therapies for PAH patients of either sex.
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    17β-Estradiol mediates superior adaptation of right ventricular function to acute strenuous exercise in female rats with severe pulmonary hypertension
    (APS Journals, 2016-08-01) Lahm, Tim; Frump, Andrea L.; Albrecht, Marjorie E.; Fisher, Amanda J.; Cook, Todd G.; Jones, Thomas J.; Yakubov, Bakhtiyor; Whitson, Jordan; Fuchs, Robyn K.; Liu, Aiping; Chesler, Naomi C.; Brown, M. Beth; Medicine, School of Medicine
    17β-Estradiol (E2) exerts protective effects on right ventricular (RV) function in pulmonary arterial hypertension (PAH). Since acute exercise-induced increases in afterload may lead to RV dysfunction in PAH, we sought to determine whether E2 allows for superior RV adaptation after an acute exercise challenge. We studied echocardiographic, hemodynamic, structural, and biochemical markers of RV function in male and female rats with sugen/hypoxia (SuHx)-induced pulmonary hypertension, as well as in ovariectomized (OVX) SuHx females, with or without concomitant E2 repletion (75 μg·kg−1·day−1) immediately after 45 min of treadmill running at 75% of individually determined maximal aerobic capacity (75% aerobic capacity reserve). Compared with males, intact female rats exhibited higher stroke volume and cardiac indexes, a strong trend for better RV compliance, and less pronounced increases in indexed total pulmonary resistance. OVX abrogated favorable RV adaptations, whereas E2 repletion after OVX markedly improved RV function. E2's effects on pulmonary vascular remodeling were complex and less robust than its RV effects. Postexercise hemodynamics in females with endogenous or exogenous E2 were similar to hemodynamics in nonexercised controls, whereas OVX rats exhibited more severely altered postexercise hemodynamics. E2 mediated inhibitory effects on RV fibrosis and attenuated increases in RV collagen I/III ratio. Proapoptotic signaling, endothelial nitric oxide synthase phosphorylation, and autophagic flux markers were affected by E2 depletion and/or repletion. Markers of impaired autophagic flux correlated with endpoints of RV structure and function. Endogenous and exogenous E2 exerts protective effects on RV function measured immediately after an acute exercise challenge. Harnessing E2's mechanisms may lead to novel RV-directed therapies.
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    192. Health Equity Starts with Us: Recommendations from the Indiana Clinical and Translational Sciences Institute Racial Justice and Health Equity Task Force
    (Cambridge University Press, 2022) Sotto-Santiago, Sylk; Tucker Edmonds, Brownsyne; Wiehe, Sarah; Moe, Sharon
    OBJECTIVES/GOALS: The Indiana CTSI Strategy Committee charged the Racial Justice and Health Equity Taskforce to identify priorities with short-term and long-term goals consistent with the I-CTSI mission. In addition, I-CTSI leadership asked for a general description of current state and the resources necessary to achieve the proposed goals. METHODS/STUDY POPULATION: The Taskforce applied an inclusive excellence model to the way we look at the I-CTSI structure, policies, and programs while performing an environmental scan within and across I-CTSI partner institutions. In order to reach equitable solutions and consensus, listening tours were held with partner stakeholders guided by the SOAR framework for strategic planning. This approach allowed us to assess current resources, needs, and gaps across the system, along with a baseline of measures currently monitored. Taskforce members openly discussed strengths and opportunities for enhancement of current programs and services. In addition, these conversations offered an opportunity to disrupt existing practices and through collective agency we identified priority areas that promote equity, diversity and inclusion. RESULTS/ANTICIPATED RESULTS: The Taskforce identified recurring themes in conversations with all partners, which led to the formation of three working groups that examined recruitment broadly: workforce, staffing, and research participation; professional development across all stakeholders from community members to I-CTSI staff; and data-centered metrics informing current state, decision-making, and accountability. Recommendations included these priorities, content, and implementation strategies. The Taskforce delivered a report to the I-CTSI leadership fostering the promotion of diversity, equity and inclusion along with a systematic collection of gender, race, and ethnicity data for individuals utilizing I-CTSI services and resources requiring additional metrics and tracking. DISCUSSION/SIGNIFICANCE: The pandemic shed light on the manner in which marginalized groups are rendered particularly vulnerable to death and disease by systemic and structural racism. The I-CTSI recognized that we cannot advance population health without attending to root causes of inequity and that includes our internal structure. We offer a potential model for other CTSAs.
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    196 Measuring the Impact of Community Engagement Brokers through Qualitative Interviews
    (Cambridge University Press, 2023-04-24) Piechowski, Patricia; Claxton, Gina; Spencer, Nicola 'Nicki'; Vasile, Elizabeth; Zender, Robynn; Medicine, School of Medicine
    OBJECTIVES/GOALS: As the clinical and translational research enterprise evolves toward addressing health equity and the science of translational science, the CE Brokers are exploring new avenues for impacting the CTSA consortium. METHODS/STUDY POPULATION: Since 2013, managers of Community Engagement (CE) programs across the NCATS CTSA institutes have met monthly to build connections, share knowledge, and advocate for the boundary spanner role. As the clinical and translational research enterprise evolves toward addressing health equity and the science of translational science, the CE Brokers are exploring new avenues for impacting the CTSA consortium. The CE Brokers are composed of 140 individuals from 58 CTSA-associated institutions, and have a long history that has fostered rich, trusting relationships. The growth and strength of this group has primed it to pivot with the new NCATS direction to contribute meaningfully to the science of community engagement and continue the work of improving health equity within the communities we serve. RESULTS/ANTICIPATED RESULTS: In 2022; we surveyed its members about their roles and responsibilities; the ways the network has contributed to their hub’s adoption and development of best practices and innovations; resources and lessons learned; the creation of opportunities for members to collaboratively conduct and disseminate original research; and research on the science of CE. Grounding ourselves in this initial data, we have developed interview questions to take the inquiry further, by gathering qualitative data on the impact of the group: How the Brokers group impacted them personally and professionally; How the Brokers impacted the work of their CTSA; In three words, describe the group; How could the CE Brokers contribute to the science of community engagement? DISCUSSION/SIGNIFICANCE: Together, we will identify themes supported by quotes to inform how the CE Broker group is most effectively moving the CTSAs’ mission forward and how it can be improved. These will be shared at the Translational Science Meeting, 2023.