Department of Medicine Works

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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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    11039 Indiana CTSI High-School STEM Summer Research Program: Future opportunities from a 2020 virtual program
    (Cambridge University Press, 2021) Sanders, Elmer; Cruz, Leigh-Ann; Speidell, Emily; Schnabel, Rose; Balaji, Adhitya; Hogarth, Elise; Miller, Jade; Vaides, Sofia; Allen, Matthew R.; Medicine, School of Medicine
    ABSTRACT IMPACT: The Indiana Clinical and Translational Sciences Institute K-12 STEM Outreach Program’s pivoted to a virtual program in summer 2020 which yielded novel approaches that could be retained in future years to extend the reach/impact of our pipeline program. OBJECTIVES/GOALS: Provide students with a meaningful and safe research experience during the COVID Pandemic. Develop new modules and approaches that could be delivered virtually. Engage students from communities that were not possible in previous years when in person meetings were required. METHODS/STUDY POPULATION: The program has historically supported over 100 high school students per year in a summer research internship for the last 5 years. Students are placed with academic research mentors in various Schools and Departments across the IUPUI campus, and also with industry laboratories. COVID-related restrictions required development of 100% virtual program. Key aspects of the virtual program included: cohort-based research mentor assignments with 1-4 mentees matched per research mentor, research projects that could be conducted virtually, heavy engagement of high-school teachers to facilitate the research experience with cohorts of mentees, a more rigorous virtual seminar series that included new modules such as COVID-specific programming and thus enhancing public education about COVID. RESULTS/ANTICIPATED RESULTS: The program served 130 students in summer 2020. We were able to recruit new faculty and industry mentors involved in data science research. As a result, we have now increased our mentor pool to serve more students in the future. Because student participation was virtual, we were able to accept students from further distances (up to 120 miles away) across the state. We were also able to accept local economically disadvantaged students that may have not been able to participate because of lack of reliable transportation. A positive unanticipated outcome was that mentees relationships with the mentors was established virtually thus increasing the potential for students to remain engaged in their research. DISCUSSION/SIGNIFICANCE OF FINDINGS: Adapting to a virtual platform provided research experience to high school students during a time when traditional approaches were not possible. Given some research experiences do not require in-person activities, this newly established model could be used moving forward to allow more statewide engagement in research experiences.
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    12589 Two Systematic Reviews Of Treatment Efficacy On Patient Important Outcomes In Adult X-linked Hypophosphatemia
    (Oxford University Press, 2024-10-05) Ali, Dalal S.; Mirza, Reza; Alsarraf, Farah; Hussein, Salma; Appelman-Dijkstra, Natasha; Beck-Nielsen, Signe Sparre; Biosse-Duplan, Martin; Brandi, Maria Luisa; Chaussain, Catherine; Cohen-Solal, Martine; Crowley, Rachel K.; Dandurand, Karel; Florenzano, Pablo F.; Fukumoto, Seiji; Gagnon, Claudia; Goodyer, Paul; Grasemann, Corinna; Imel, Erik Allen; De Beur, Suzanne Marie Jan; Lewiecki, E. Michael; Morgante, Emmett; Ward, Leanne; Aziz Khan, Aliya; Guyatt, Gordon; Medicine, School of Medicine
    Objective: Our objective was to examine the highest certainty evidence addressing the management of X-linked hypophosphatemia in adults, aiming to inform treatment recommendations. Eligibility criteria: We searched Embase, MEDLINE, Web of Science, and Cochrane from inception to March 2023 and included RCTs and observational studies enrolling individuals ≥ 18 years diagnosed with XLH on clinical grounds or with a confirmed pathogenic variant in PHEX. Manuscripts evaluating the effectiveness of burosumab compared to either no treatment or conventional therapy (phosphate salts and active vitamin D) or evaluating conventional therapy compared to no treatment were selected. Methods: Two reviewers independently determined eligibility, conducted data extraction, and assessed the risk of bias (RoB). GRADE was used to assess certainty of evidence. Results: After removing duplicates from 7,043 citations, we assessed 254 full texts. Of those, one RCT proved eligible. The RCT of burosumab versus no treatment was at low RoB with certainty of evidence on individual outcomes ranging from high to very low. Burosumab probably improves pain inferred from fracture and pseudofracture healing (moderate certainty); however, burosumab probably has little or no impact on direct pain measures (moderate certainty). While burosumab may reduce the need for parathyroidectomy, indicated by lowered PTH levels (low certainty), it has little or no impact on fatigue (high certainty), stiffness (moderate certainty), and mobility (low certainty) over 24 weeks. Burosumab may also increase dental abscesses (low certainty). No formal comparisons of burosumab and conventional therapy exist; therefore, our low certainty evidence inferences regarding burosumab versus conventional therapy were based on indirect evidence from comparisons of burosumab versus no treatment and from conventional therapy versus no treatment. Observational studies proved at high RoB providing very low certainty of evidence regarding the impact of conventional therapy versus no treatment. This evidence pertained to the reduction in the risk of parathyroidectomy, as well as the reduction in the burden of symptoms caused by chronic hypophosphatemia. Conclusion: Burosumab when compared to no treatment may improve pain through fracture healing and may reduce the need for parathyroidectomy, but it could also increase the risk of dental abscess. However, when using direct measures of pain and function, burosumab demonstrated probably little or no impact on pain and stiffness, little or no impact on fatigue, and may have had little to no impact on mobility. Very low certainty exists regarding conventional therapy versus no treatment in adults. Overall, our review highlights the need for more data to better understand the long-term impact of burosumab and conventional therapy on patient-important outcomes.
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    12605 Two Systematic Reviews Of Treatment Efficacy On Patient Important Outcomes In Children X-linked Hypophosphatemia
    (Oxford University Press, 2024-10-05) Ali, Dalal S.; Mirza, Reza; Hussein, Salma; Alsarraf, Farah; Alexander, R. Todd; AbuAlrob, Hajar; Brandi, Maria Luisa; Carpenter, Thomas O.; Dandurand, Karel; Filler, Guido; Florenzano, Pablo F.; Fukumoto, Seiji; Grasemann, Corinna; Imel, Erik A.; De Beur, Suzanne Marie Jan; Morgante, Emmett; Ward, Leanne M.; Aziz Khan, Aliya; Guyatt, Gordon; Medicine, School of Medicine
    Objective: We sought to examine the highest certainty evidence on managing X-linked hypophosphatemia (XLH) in children, aiming to inform treatment recommendations of XLH international guidelines. Data Sources: We searched Embase, MEDLINE, Web of Science, and Cochrane Central from inception to March 2023. We also reviewed reference lists of eligible studies and pertinent review articles. Study eligibility criteria: Eligible studies included randomized controlled trials (RCTs) and observational studies enrolling individuals younger than 18 years old with XLH diagnosed on clinical grounds or with a confirmed pathogenic variant in PHEX. Articles were selected according to specific criteria evaluating the effectiveness of burosumab compared to either no treatment or conventional therapy (phosphate salts and active vitamin D) or evaluating conventional therapy compared to no treatment. Methods: Two reviewers independently determined eligibility, conducted data extraction, and assessed the risk of bias (RoB) in eligible articles. We employed the GRADE methodology to evaluate the certainty of the evidence. Results: After removing duplicates from 7,043 citations, we screened 4,114 records and assessed 254 full texts, of which in the systematic review (SR) addressing burosumab one RCT and one post-Hoc study proved eligible. Being open-label design, the RoB was high, with certainty of evidence on individual outcomes ranging from moderate to very low. Burosumab, compared to conventional therapy, probably prevents lower limb deformity, and improves physical health quality of life (QoL) (moderate certainty). It might also increase height and possibly improve the burden of symptoms related to chronic hypophosphatemia (low certainty). Conversely, burosumab probably increases Treatment-Emergent adverse events after the first administration (moderate certainty), and it may increase dental abscesses (low certainty). In the second SR, one observational study assessing conventional therapy versus no treatment was at high RoB providing very low certainty of evidence regarding the impact of conventional therapy compared to no treatment on final height. Conclusion: Our review indicates that burosumab likely offers benefits in preventing lower limb deformity and improving physical health QoL, while potentially increasing height and improving the burden of symptoms related to chronic hypophosphatemia (low certainty). However, it may also increase adverse events, including dental abscesses. Additionally, our review found limited evidence regarding the impact of conventional therapy compared to no treatment on final height in children. These findings highlight the need for further research to better understand the long-term impact of conventional therapy and burosumab in children.
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    127 Reciprocal Innovation Workshops: Identify Shared Health Challenges for Mutual Benefit in Global Health
    (Cambridge University Press, 2022) Sors, Thomas; Wools-Kaloustian, Kara; O’Brien, Rishika Chauhan; Bermel, Luanne; Kiplagat, Jepchirchir; Lieberman, Marya; Morales-Soto, Nydia; Nyandiko, Winstone; Litzelman, Debra; Medicine, School of Medicine
    OBJECTIVES/GOALS: Our concept of reciprocal innovation (RI) supports global health (GH) research partnerships that address shared health challenges for mutual benefit in both high and low- and middle-income (LMIC) settings. To advance this GH approach, the Indiana CTSI launched a RI program building on longstanding global health partnerships in East Africa. METHODS/STUDY POPULATION: A core component of the program is annual RI workshops to promote reciprocal approaches in GH, identify priority areas for reciprocal research, and link investigators and stakeholders across settings. The first meeting in 2019 was in-person and focused on identifying health priority areas from the perspective of Indiana stakeholders. The second meeting was held virtually and focused on priority areas in East Africa. The third meeting focused on shared priority areas and discussing potential RI research projects. Agenda sessions include (1) presenting successful examples of funded RI projects; (2) breakout groups to share proposal ideas in preparation for the RI grants program; (3) building partnerships with colleagues in similar fields. RESULTS/ANTICIPATED RESULTS: As of 2021, three RI workshops have been held with an average of 60 attendees at each workshop. Participants identified several overlapping priority areas for research and RI in Indiana and East Africa, including research in chronic disease, substance abuse, infant and maternal health, and access to healthcare. A Global Health Innovation Exchange of RI projects was created to support connections between locally- and globally-focused investigators. The repository is used to share updates on project progress, outcomes, and published materials. Workshops have also been used to explore a reciprocal innovation virtual platform to facilitate and foster more regular collaborations between globally and locally-focused investigators and pursue research projects on shared health challenges for mutual benefit. DISCUSSION/SIGNIFICANCE: The collaboration at the stakeholder meetings set the foundation for continued partnership building, strong proposals for RI grants, and dissemination and translation of successful RI projects. To leverage momentum from the meetings, we are building a virtual RI platform to connect PIs across multiple CTSAs and increase the footprint of RI efforts
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    1270. HIV Drug Resistance and Viral Outcomes after 2nd-line Antiretroviral Failure in Kenya
    (Oxford University Press, 2022) Ali, Shamim M.; Humphrey, John; Novitsky, Vladimir; Sang, Edwin; DeLong, Allison; Jawed, Bilal; Kemboi, Emmanuel; Goodrich, Suzanne; Gardner, Adrian; Hogan, Joseph W.; Kantor, Rami; Medicine, School of Medicine
    Background: Program data on HIV drug resistance and clinical outcomes after 2nd-line antiretroviral therapy (ART) failure in resource-limited settings are limited, yet can inform care, particularly with better ART access and options. Methods: We examined resistance upon 2nd-line failure and subsequent viral outcomes at the Academic Model Providing Access to Healthcare (AMPATH) in Kenya. Charts of people with genotypes upon 2nd-line failure up to 6/2021 were reviewed; and associations with viral suppression (< 1000 copies/mL) closest to 12 months post-genotyping were determined using bi- and multivariate analyses, adjusting for age, sex, time on ART, switch to 3rd-line (darunavir-, dolutegravir-, and/or raltegravir-based ART), and any resistance to regimens upon viral load (VL) testing. Results: Of 194 participants (53% female; median age 41 years; median 3.3 and 4.1 years on 1st- and 2nd-line), 60% were on lopinavir/ritonavir and 40% on atazanavir/ritonavir-based regimens. Overall, 178 (92%) had any resistance: 19% mono-, 40% dual-, 41% triple-class; 79% to NRTIs; 81% NNRTIs; and 43% PIs - 33% of those on lopinavir/ritonavir; 58% on atazanavir/ritonavir (p< 0.001); 24% with intermediate-high predicted resistance to darunavir/ritonavir (12 upon LPV/ritonavir, and 8 upon atazanavir/ritonavir failure; p=0.98). Of 140/194 people with post-genotype VLs, 55% stayed on 2nd-line, and 45% switched to 3rd-line. Of those 140, 72% virally suppressed (89% who switched to 3rd-line; 58% who didn't), and 75% had any resistance to their regimen at post-genotype VL (90% who switched to 3rd-line; 62% who didn't). In bivariate analysis, suppression was associated with switching to 3rd-line, and with resistance upon VL testing (Table). In multivariate analysis, suppression remained more likely among those who switched to 3rd-line, and association with resistance was less pronounced. Conclusion: In a large Kenyan HIV program, high resistance upon 2nd-line failure, high failure rates, and suppression association with 3rd-line switch suggest the need for dedicated management of this vulnerable population. Potential association between resistance and better viral outcomes, similar to reports upon 1st-line failure, needs further data and suggests significance of inadequate adherence.
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    1288. US Healthcare Provider Perspectives on the initiation of cabotegravir and rilpivirine long-acting (CAB+RPV LA) in an observational real-world study (BEYOND)
    (Oxford University Press, 2022) Hsu, Ricky K.; Phoenix, John; Sinclair, Gary I.; Gupta, Samir K.; Puga, Ana; Nguyen, Kaitlin; Schubert, Catherine K.; Merrill, Deanna; Richardson, David; Nelson, Kate; Reynolds, Maria; Zografos, Laurie; Jean-Louis, Ashley; Garris, Cindy; Medicine, School of Medicine
    Background: CAB+RPV LA is a complete regimen for treatment of virologically suppressed people with HIV (PWH). As an injectable therapeutic administered by a healthcare provider (HCP), CAB+RPV LA may alleviate challenges with adherence to daily oral therapy and reduce fear of HIV status disclosure with oral treatment. Real world perspectives from HCPs and PWH are needed to enable successful delivery of this treatment in US healthcare settings. Methods: BEYOND is a 2 year prospective, observational, real-world study of utilization, outcomes, and experience of PWH initiating CAB+RPV LA across 30 US sites. HCPs at participating sites (treaters, injectors, drug acquisition/reimbursement staff) completed surveys at site activation (Sep 2021-Feb 2022; with follow-up surveys planned at 6, 12, 24 months) evaluating experiences to date with implementation of CAB+RPV LA at their sites. Results: HCPs from 24 sites responded to the initial survey (Table 1). 75% of HCPs estimated that ≥25% of their PWH are eligible for CAB+RPV LA, and 71% of sites are proactively discussing the regimen with ≥25% of PWH. The majority (79%) of treaters reported they were extremely/very positive about administering CAB+RPV LA. Over 90% of injectors reported a positive overall opinion about administering CAB+RPV LA, and 86% reported the injections were easy to administer. Most (87%) HCPs reported injection visits taking ≤45 minutes, including waiting time. Over 95% of sites have patient reminder systems; 86% will manually identify missed injections and all reported manual follow up by site staff. All sites utilizing the injection education video on the external HCP website (n=15/15) found it helpful and 94% (n=16/17) utilizing reimbursement specialists found them to be helpful. In their experience to date, most clinics reported only needing to increase coordination with the pharmacy team and add injection training to implement CAB+RPV LA. The most frequently reported benefits of implementing CAB+RPV LA by HCPs included assurance of patient adherence and patient engagement in their HIV treatment (Table 2). Conclusion: Early real-world data from US HCPs in this study indicates interest in and anticipated uptake of CAB+RPV LA at their sites, positive overall opinion, and multiple benefits of administering the CAB+RPV LA regimen to PWH.
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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