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Dentists as Primary Care Providers: Expert Opinion on Predoctoral Competencies
(Frontiers Media, 2021) Gordon, Sara C.; Kaste, Linda M.; Mouradian, Wendy E.; Beemsterboer, Phyllis L.; Berg, Joel H.; Murdoch-Kinch, Carol Anne; School of Dentistry
Dentistry and medicine traditionally practice as separate professions despite sharing goals for optimal patient health. Many US residents experience both poor oral and general health, with difficulty accessing care. More efficient collaboration between these professions could enhance health. The COVID-19 pandemic disclosed further disparities while underscoring concerns that physician supply is inadequate for population needs. Hence, enhancing healthcare provider education to better meet the public's health needs is critical. The proposed titles “Oral Physician” or “Oral Health Primary Care Provider” (OP-PCP) acknowledge dentist's capacity to diagnose and manage diseases of the orofacial complex and provide some basic primary healthcare. The US Surgeon General's National Prevention Council and others recommend such models. Medical and dental education already overlap considerably, thus it is plausible that dental graduates could be trained as OP-PCPs to provide primary healthcare such as basic screening and preventive services within existing dental education standards. In 2018, 23 dental and medical educators participated in an expert-opinion elicitation process to review educational competencies for this model. They demonstrated consensus on educational expansion and agreed that the proposed OP-PCP model could work within existing US Commission on Dental Accreditation (CODA) standards for predoctoral education. However, there were broader opinions on scope of practice details. Existing CODA standards could allow interested dental programs to educate OP-PCPs as a highly-skilled workforce assisting with care of medically-complex patients and to helping to reduce health disparities. Next steps include broader stakeholder discussion of OC-PCP competencies and applied studies including patient outcome assessments.
IL-6 receptor blockade does not slow β cell loss in new-onset type 1 diabetes
(American Society for Clinical Investigation, 2021) Greenbaum, Carla J.; Serti, Elisavet; Lambert, Katharina; Weiner, Lia J.; Kanaparthi, Sai; Lord, Sandra; Gitelman, Stephen E.; Wilson, Darrell M.; Gaglia, Jason L.; Griffin, Kurt J.; Russell, William E.; Raskin, Philip; Moran, Antoinette; Willi, Steven M.; Tsalikian, Eva; DiMeglio, Linda A.; Herold, Kevan C.; Moore, Wayne V.; Goland, Robin; Harris, Mark; Craig, Maria E.; Schatz, Desmond A.; Baidal, David A.; Rodriguez, Henry; Utzschneider, Kristina M.; Nel, Hendrik J.; Soppe, Carol L.; Boyle, Karen D.; Cerosaletti, Karen; Keyes-Elstein, Lynette; Long, S. Alice; Thomas, Ranjeny; McNamara, James G.; Buckner, Jane H.; Sanda, Srinath; ITN058AI EXTEND Study Team; Pediatrics, School of Medicine
Background:
IL-6 receptor (IL-6R) signaling drives development of T cell populations important to type 1 diabetes pathogenesis. We evaluated whether blockade of IL-6R with monoclonal antibody tocilizumab would slow loss of residual β cell function in newly diagnosed type 1 diabetes patients.
Methods:
We conducted a multicenter, randomized, placebo-controlled, double-blind trial with tocilizumab in new-onset type 1 diabetes. Participants were screened within 100 days of diagnosis. Eligible participants were randomized 2:1 to receive 7 monthly doses of tocilizumab or placebo. The primary outcome was the change from screening in the mean AUC of C-peptide collected during the first 2 hours of a mixed meal tolerance test at week 52 in pediatric participants (ages 6–17 years).
Results:
There was no statistical difference in the primary outcome between tocilizumab and placebo. Immunophenotyping showed reductions in downstream signaling of the IL-6R in T cells but no changes in CD4 memory subsets, Th17 cells, Tregs, or CD4+ T effector cell resistance to Treg suppression. A DC subset decreased during therapy but regressed to baseline once therapy stopped. Tocilizumab was well tolerated.
Conclusion:
Tocilizumab reduced T cell IL-6R signaling but did not modulate CD4+ T cell phenotypes or slow loss of residual β cell function in newly diagnosed individuals with type 1 diabetes.
A 12-Year Retrospective Study of the Prevalence of Anticholinergic Polypharmacy and Associated Outcomes Among Medicare Patients with Overactive Bladder in the USA
(Springer, 2021) Campbell, Noll L.; Hines, Lisa; Epstein, Andrew J.; Walker, David; Lockefeer, Amy; Shiozawa, Aki; Medicine, School of Medicine
Background and objective: Antimuscarinics, drugs with anticholinergic properties, are frequently prescribed for overactive bladder, and anticholinergic burden is associated with adverse events. The "Polypharmacy: Use of Multiple Anticholinergic Medications in Older Adults" (Poly-ACH) measure was developed by the Pharmacy Quality Alliance and is used by the Centers for Medicare and Medicaid Services. Using the Poly-ACH measure, we assessed the prevalence of anticholinergic polypharmacy among Medicare patients in the USA with overactive bladder and determined associations between polypharmacy and medical conditions, care, and spending.
Methods: This was a retrospective cohort study of Medicare beneficiaries with overactive bladder (coverage period: 2006-2017). Anticholinergic polypharmacy, measured by the Poly-ACH, was defined as concurrent use of two or more anticholinergics, each with two or more prescription claims on different dates of service for ≥ 30 cumulative days. Change in annual frequency of anticholinergic polypharmacy was assessed using logistic regression. Associations between anticholinergic polypharmacy over 3 years and falls, fractures, mental status, and medical care spending were assessed with longitudinal regression models.
Results: In total, 226,712 patients contributed 940,201 person-years of follow-up after overactive bladder diagnosis. The share of patients meeting the Poly-ACH definition was 3.3% in 2006 and 1.7% in 2017. Women and nursing home residents had higher risks of anticholinergic polypharmacy. Having 1 year or more of positive Poly-ACH status in the 3 years prior was associated with higher rates of all outcomes.
Conclusions: Anticholinergic polypharmacy was uncommon among older adults with overactive bladder. Prevalence was higher among women and nursing home residents, and it was associated with negative outcomes, highlighting potential longitudinal implications of anticholinergic burden.
Cas9-specific immune responses compromise local and systemic AAV CRISPR therapy in multiple dystrophic canine models
(Springer Nature, 2021-11-24) Hakim, Chady H.; Kumar, Sandeep R. P.; Pérez-López, Dennis O.; Wasala, Nalinda B.; Zhang, Dong; Yue, Yongping; Teixeira, James; Zhang, Keqing; Million, Emily D.; Nelson, Christopher E.; Metzger, Samantha; Han, Jin; Louderman, Jacqueline A.; Schmidt, Florian; Feng, Feng; Grimm, Dirk; Smith, Bruce F.; Yao, Gang; Yang, N. Nora; Gersbach, Charles A.; Chen, Shi-jie; Herzog, Roland W.; Duan, Dongsheng; Pediatrics, School of Medicine
Adeno-associated virus (AAV)-mediated CRISPR-Cas9 editing holds promise to treat many diseases. The immune response to bacterial-derived Cas9 has been speculated as a hurdle for AAV-CRISPR therapy. However, immunological consequences of AAV-mediated Cas9 expression have thus far not been thoroughly investigated in large mammals. We evaluate Cas9-specific immune responses in canine models of Duchenne muscular dystrophy (DMD) following intramuscular and intravenous AAV-CRISPR therapy. Treatment results initially in robust dystrophin restoration in affected dogs but also induces muscle inflammation, and Cas9-specific humoral and cytotoxic T-lymphocyte (CTL) responses that are not prevented by the muscle-specific promoter and transient prednisolone immune suppression. In normal dogs, AAV-mediated Cas9 expression induces similar, though milder, immune responses. In contrast, other therapeutic (micro-dystrophin and SERCA2a) and reporter (alkaline phosphatase, AP) vectors result in persistent expression without inducing muscle inflammation. Our results suggest Cas9 immunity may represent a critical barrier for AAV-CRISPR therapy in large mammals.
Loss of proximal tubular transcription factor Krüppel-like factor 15 exacerbates kidney injury through loss of fatty acid oxidation
(Elsevier, 2021) Piret, Sian E.; Attallah, Ahmed A.; Gu, Xiangchen; Guo, Yiqing; Gujarati, Nehaben A.; Henein, Justina; Zollman, Amy; Hato, Takashi; Ma’ayan, Avi; Revelo, Monica P.; Dickman, Kathleen G.; Chen, Chung-Hsin; Shun, Chia-Tung; Rosenquist, Thomas A.; He, John C.; Mallipattu, Sandeep K.; Medicine, School of Medicine
Loss of fatty acid β-oxidation (FAO) in the proximal tubule is a critical mediator of acute kidney injury and eventual fibrosis. However, transcriptional mediators of FAO in proximal tubule injury remain understudied. Krüppel-like factor 15 (KLF15), a highly enriched zinc-finger transcription factor in the proximal tubule, was significantly reduced in proximal tubule cells after aristolochic acid I (AAI) treatment, a proximal tubule-specific injury model. Proximal tubule specific knockout of Klf15 exacerbated proximal tubule injury and kidney function decline compared to control mice during the active phase of AAI treatment, and after ischemia-reperfusion injury. Furthermore, along with worsening proximal tubule injury and kidney function decline, knockout mice exhibited increased kidney fibrosis as compared to control mice during the remodeling phase after AAI treatment. RNA-sequencing of kidney cortex demonstrated increased transcripts involved in immune system and integrin signaling pathways and decreased transcripts encompassing metabolic pathways, specifically FAO, and PPARα signaling, in knockout versus control mice after AAI treatment. In silico and experimental chromatin immunoprecipitation studies collectively demonstrated that KLF15 occupied the promoter region of key FAO genes, CPT1A and ACAA2, in close proximity to transcription factor PPARα binding sites. While the loss of Klf15 reduced the expression of Cpt1a and Acaa2 and led to compromised FAO, induction of KLF15 partially rescued loss of FAO in AAI-treated cells. Klf15, Ppara, Cpt1a, and Acaa2 expression was also decreased in other mouse kidney injury models. Tubulointerstitial KLF15 independently correlated with eGFR, PPARA and CPT1A appearance in expression arrays from human kidney biopsies. Thus, proximal tubule-specific loss of Klf15 exacerbates acute kidney injury and fibrosis, likely due to loss of interaction with PPARα leading to loss of FAO gene transcription.