Open Access Policy Articles

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The IUPUI Faculty Council adopted an open access policy on October 7th, 2014 (available from: https://openaccess.iupui.edu/policy). This policy shows IUPUI's commitment to disseminating the fruits of research and scholarship as widely as possible. Open access policies increase authors’ rights, readership and citation rates for scholarly articles. The opt out provision ensures that all faculty authors have the freedom to publish in the journal of their choice.

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Now showing 1 - 10 of 23536

Evaluation of US Food and Drug Administration Drug Label Recommendations for Coadministration of Antivirals and Acid-Reducing Agents
(Wiley, 2022) Shugg, Tyler; Powell, Nicholas R.; Marroum, Patrick J.; Skaar, Todd C.; Younis, Islam R.; Medicine, School of Medicine
Coadministration with acid-reducing agents (ARAs), including proton pump inhibitors (PPIs), histamine H2 -receptor antagonists (H2 blockers), and antacids has been demonstrated to reduce antiviral exposure and efficacy. Therefore, it is essential that US Food and Drug Administration (FDA) drug labels include recommendations to manage these drug-drug interactions (DDIs). This investigation analyzed information in FDA drug labels to manage DDIs between ARAs and antivirals approved from 1998 to 2019. To ascertain clinical adoption, we assessed whether FDA label recommendations were incorporated into current antiviral clinical practice guidelines. We identified 82 label recommendations for 43 antiviral approvals. Overall, 56.1% of recommendations were deemed clinically actionable, with the most common actionable management strategies being dose adjustment during coadministration (40.2%) and coadministration not recommended (9.8%). The sources informing DDI recommendations were clinical DDI studies (59.8%) and predictions of altered exposure (40.2%). Antivirals with low aqueous solubility were more likely to have label recommendations and were more commonly investigated using clinical DDI studies (P < 0.01). For recommendations informed by clinical DDI studies, changes in drug exposure were associated with actionable label recommendations (P < 0.01). The frequency of exposure changes in clinical DDI studies was similar across antiviral indications, but exposure changes were numerically higher for antacids (71.4%) relative to PPIs (42.9%) and H2 blockers (28.6%). Of DDI pairs identified within drug labels, 76.8% were included in guidelines, and recommended management strategies were concordant in 90.5% of cases. Our findings demonstrate that current regulatory oversight mostly (but not completely) results in actionable label recommendations to manage DDIs for high-risk antivirals.
Understanding barriers to and facilitators of clinician-patient conversations about brain health and cognitive concerns in primary care: a systematic review and practical considerations for the clinician
(Springer Nature, 2023-11-06) Borson, Soo; Small, Gary W.; O’Brien, Quentin; Morrello, Andrea; Boustani, Malaz; Medicine, School of Medicine
Background: Primary care clinicians (PCCs) are typically the first practitioners to detect cognitive impairment in their patients, including those with Alzheimer's disease or related dementias (ADRD). However, conversations around cognitive changes can be challenging for patients, family members, and clinicians to initiate, with all groups reporting barriers to open dialogue. With the expanding array of evidence-based interventions for ADRD, from multidomain care management to novel biotherapeutics for early-stage AD, incorporating conversations about brain health into routine healthcare should become a standard of care. We conducted a systematic review to identify barriers to and facilitators of brain health conversations in primary care settings. Methods: We systematically searched PubMed, Scopus, Web of Science, and the Cochrane Library for qualitative or quantitative studies conducted in the US between January 2000 and October 2022 that evaluated perceptions of cognition and provider-patient brain health conversations prior to formal screening for, or diagnosis of, mild cognitive impairment or ADRD. We assessed the quality of the included studies using the Mixed Methods Appraisal Tool. Results: In total, 5547 unique abstracts were screened and 22 articles describing 19 studies were included. The studies explored perceptions of cognition among laypersons or clinicians, or provider-patient interactions in the context of a patient's cognitive concerns. We identified 4 main themes: (1) PCCs are hesitant to discuss brain health and cognitive concerns; (2) patients are hesitant to raise cognitive concerns; (3) evidence to guide clinicians in developing treatment plans that address cognitive decline is often poorly communicated; and (4) social and cultural context influence perceptions of brain health and cognition, and therefore affect clinical engagement. Conclusions: Early conversations about brain health between PCCs and their patients are rare, and effective tools, processes, and strategies are needed to make these vital conversations routine.
Analysis of INSPPIRE-2 Cohort: Risk Factors and Disease Burden in Children with Acute Recurrent or Chronic Pancreatitis
(Wiley, 2022) Uc, Aliye; Cress, Gretchen A.; Wang, Fuchenchu; Abu-El-Haija, Maisam; Ellery, Kate M.; Fishman, Douglas S.; Gariepy, Cheryl E.; Gonska, Tanja; Lin, Tom K.; Liu, Quin Y.; Mehta, Megha; Maqbool, Asim; McFerron, Brian A.; Morinville, Veronique D.; Ooi, Chee Y.; Perito, Emily R.; Schwarzenberg, Sarah Jane; Sellers, Zachary M.; Serrano, Jose; Shah, Uzma; Troendle, David M.; Wilschanski, Michael; Zheng, Yuhua; Yuan, Ying; Lowe, Mark E.; Pediatrics, School of Medicine
Objectives: The objective of this study is to investigate risk factors and disease burden in pediatric acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP). Methods: Data were obtained from INternational Study group of Pediatric Pancreatitis: In search for a cuRE-2 (INSPPIRE-2), the largest multi-center prospective cohort study in pediatric patients with ARP or CP. Results: Of 689 children, 365 had ARP (53%), 324 had CP (47%). CP was more commonly associated with female sex, younger age at first acute pancreatitis (AP) attack, Asian race, family history of CP, lower BMI%, genetic and obstructive factors, PRSS1 mutations and pancreas divisum. CFTR mutations, toxic-metabolic factors, medication use, hypertriglyceridemia, Crohn disease were more common in children with ARP. Constant or frequent abdominal pain, emergency room (ER) visits, hospitalizations, medical, endoscopic or surgical therapies were significantly more common in CP, episodic pain in ARP. A total of 33.1% of children with CP had exocrine pancreatic insufficiency (EPI), 8.7% had diabetes mellitus. Compared to boys, girls were more likely to report pain impacting socialization and school, medical therapies, cholecystectomy, but no increased opioid use. There was no difference in race, ethnicity, age at first AP episode, age at CP diagnosis, duration of disease, risk factors, prevalence of EPI or diabetes between boys and girls. Multivariate analysis revealed that family history of CP, constant pain, obstructive risk factors were predictors of CP. Conclusions: Children with family history of CP, constant pain, or obstructive risk factors should raise suspicion for CP.
The beta cell-immune cell interface in type 1 diabetes (T1D)
(Elsevier, 2023) James, Eddie A.; Joglekar, Alok V.; Linnemann, Amelia K.; Russ, Holger A.; Kent, Sally C.; Pediatrics, School of Medicine
Background: T1D is an autoimmune disease in which pancreatic islets of Langerhans are infiltrated by immune cells resulting in the specific destruction of insulin-producing islet beta cells. Our understanding of the factors leading to islet infiltration and the interplay of the immune cells with target beta cells is incomplete, especially in human disease. While murine models of T1D have provided crucial information for both beta cell and autoimmune cell function, the translation of successful therapies in the murine model to human disease has been a challenge. Scope of review: Here, we discuss current state of the art and consider knowledge gaps concerning the interface of the islet beta cell with immune infiltrates, with a focus on T cells. We discuss pancreatic and immune cell phenotypes and their impact on cell function in health and disease, which we deem important to investigate further to attain a more comprehensive understanding of human T1D disease etiology. Major conclusions: The last years have seen accelerated development of approaches that allow comprehensive study of human T1D. Critically, recent studies have contributed to our revised understanding that the pancreatic beta cell assumes an active role, rather than a passive position, during autoimmune disease progression. The T cell-beta cell interface is a critical axis that dictates beta cell fate and shapes autoimmune responses. This includes the state of the beta cell after processing internal and external cues (e.g., stress, inflammation, genetic risk) that that contributes to the breaking of tolerance by hyperexpression of human leukocyte antigen (HLA) class I with presentation of native and neoepitopes and secretion of chemotactic factors to attract immune cells. We anticipate that emerging insights about the molecular and cellular aspects of disease initiation and progression processes will catalyze the development of novel and innovative intervention points to provide additional therapies to individuals affected by T1D.
Evaluating the Impact of a Pilot Nationwide Webinar Series on National Med-Peds Residents' Association Membership
(Springer Nature, 2021-10-20) Cruz, Maximilian J.; Kapil, Sasha R.; Friedland, Allen R.; Magliola, Ronald J.; Pediatrics, School of Medicine
Background: As the COVID-19 pandemic significantly reduced the ability of medical students to travel and interact directly with combined Internal Medicine-Pediatrics (Med-Peds) residency programs, medical students desiring appropriate guidance and information about Med-Peds residency training needed a national forum for information during an unprecedented virtual recruitment year. Objective: To develop a nationally coordinated webinar series for medical students and student advisors to learn about the Med-Peds specialty for residency training to keep applicant numbers and applicant interest from significantly falling. Methods: A national webinar series focusing on general Med-Peds information, career interests, and tailored advising was created amongst the three national Med-Peds organizations over a three-month period in Spring 2020. Results: There was a 221% increase in medical student membership to the National Med-Peds Residents' Association (NMPRA) compared to the same months in 2017, 2018, and 2019 and no significant reduction in the Electronic Residency Application Service® applications to Med-Peds programs over that same time period. Conclusions: A national forum for medical students inquiring about the combined Med-Peds specialty can be effective in recruiting members to NMPRA and keeping interest high in Med-Peds.
Screening fructosamine-3-kinase (FN3K) inhibitors, a deglycating enzyme of oncogenic Nrf2: Human FN3K homology modelling, docking and molecular dynamics simulations
(Public Library of Science, 2023-11-01) Beeraka, Narasimha M.; Zhang, Jin; Mandal, Subhankar; Vikram P. R., Hemanth; Liu, Junqi; B. M., Namitha; Zhao, Di; Vishwanath, Prashanth; Gurupadayya, B. M.; Fan, Ruitai; Pediatrics, School of Medicine
Fructosamine-3-kinase (FN3K) is involved in the deglycation of Nrf2, a significant regulator of oxidative stress in cancer cells. However, the intricate functional aspects of FN3K and Nrf2 in breast cancers have not been explored vividly. The objectives of this study are to design the human FN3K protein using homology modeling followed by the screening of several anticancer molecules and examining their efficacy to modulate FN3K activity, Nrf2-mediated antioxidant signalling. Methods pertinent to homology modeling, virtual screening, molecular docking, molecular dynamics simulations, assessment of ADME properties, cytotoxicity assays for anticancer molecules of natural/synthetic origin in breast cancer cells (BT-474, T-47D), and Western blotting were used in this study. The screened anticancer molecules including kinase inhibitors of natural and synthetic origin interacted with the 3-dimensional structure of the catalytic domain in human FN3K protein designed through homology modeling by significant CDOCKER interaction energies. Subsequently, gefitinib, sorafenib, neratinib, tamoxifen citrate, and cyclosporine A enhanced the expression of FN3K in BT-474 cell lines with simultaneous alteration in Nrf2-driven antioxidant signalling. Oxaliplatin significantly downregulated FN3K expression and modulated Nrf2-driven antioxidant signalling when compared to cisplatin and other anticancer drugs. Hence, the study concluded the potential implications of existing anticancer drugs to modulate FN3K activity in breast cancers.
Single-chain insulin analogs threaded by the insulin receptor αCT domain
(Elsevier, 2022) Smith, Nicholas A.; Menting, John G.; Weiss, Michael A.; Lawrence, Michael C.; Smith, Brian J.; Biochemistry and Molecular Biology, School of Medicine
Insulin is a mainstay of therapy for diabetes mellitus, yet its thermal stability complicates global transportation and storage. Cold-chain transport, coupled with optimized formulation and materials, prevents to some degree nucleation of amyloid and hence inactivation of hormonal activity. These issues hence motivate the design of analogs with increased stability, with a promising approach being single-chain insulins (SCIs), whose C domains (foreshortened relative to proinsulin) resemble those of the single-chain growth factors (IGFs). We have previously demonstrated that optimized SCIs can exhibit native-like hormonal activity with enhanced thermal stability and marked resistance to fibrillation. Here, we describe the crystal structure of an ultrastable SCI (C-domain length 6; sequence EEGPRR) bound to modules of the insulin receptor (IR) ectodomain (N-terminal α-subunit domains L1-CR and C-terminal αCT peptide; "microreceptor" [μIR]). The structure of the SCI-μIR complex, stabilized by an Fv module, was determined using diffraction data to a resolution of 2.6 Å. Remarkably, the αCT peptide (IR-A isoform) "threads" through a gap between the flexible C domain and the insulin core. To explore such threading, we undertook molecular dynamics simulations to 1) compare threaded with unthreaded binding modes and 2) evaluate effects of C-domain length on these alternate modes. The simulations (employing both conventional and enhanced sampling simulations) provide evidence that very short linkers (C-domain length of -1) would limit gap opening in the SCI and so impair threading. We envisage that analogous threading occurs in the intact SCI-IR complex-rationalizing why minimal C-domain lengths block complete activity-and might be exploited to design novel receptor-isoform-specific analogs.
Evaluation of Point-of-Care Ultrasound Training for Family Physicians Using Teleultrasound
(Society of Teachers of Family Medicine, 2023) Russell, Frances M.; Herbert, Audrey; Lobo, Daniela; Ferre, Robinson; Nti, Benjamin K.; Emergency Medicine, School of Medicine
Background and objectives: The goal of this study was to assess family physicians' change in knowledge and ability to perform abdominal aorta ultrasound after implementation of a novel teleultrasound curriculum. Methods: This was a prospective, observational study conducted at a single academic institution. Family physicians completed a preassessment, test, and objective structured clinical evaluation (OSCE). Physicians then individually completed a standard curriculum consisting of online content and an hour-long, hands-on training session on abdominal aorta ultrasound using teleultrasound technology. Physicians then performed a minimum of 10 independent examinations over a period of 8 weeks. After physicians completed the training curriculum and 10 independent scans, we administered a postassessment, test, and OSCE. We analyzed differences between pre- and postcurriculum responses using Fisher exact and Wilcoxon signed rank tests. Results: Thirteen family physicians completed the curriculum. Comparing pre- to postcurriculum responses, we found significant reductions in barriers to using aorta POCUS and improved confidence in using, obtaining, and interpreting aorta POCUS (P<0.01). Knowledge improved from a median score of 70% to 90% (P<0.01), and OSCE scores improved from a median of 80% to 100% (P=0.012). Overall, 211 aorta ultrasound examinations were independently acquired with a median image quality of 4 (scale 1 to 4). Conclusions: After an 8-week teleultrasound curriculum, family physicians with minimal experience with POCUS showed improved knowledge and psychomotor skill in abdominal aorta POCUS.
Outcomes after Transcarotid Artery Revascularization Stratified by Pre-procedural Symptom Status
(Elsevier, 2022) Solomon, Yoel; Rastogi, Vinamr; Marcaccio, Christina L.; Patel, Priya B.; Wang, Grace J.; Malas, Mahmoud B.; Motaganahalli, Raghu L.; Nolan, Brian W.; Verhagen, Hence J. M.; de Borst, Gert J.; Schermerhorn, Marc L.; Surgery, School of Medicine
Objective: Previous studies on carotid endarterectomy and transfemoral carotid artery stenting demonstrated that perioperative outcomes differed according to preoperative neurologic injury severity, but this has not been assessed in transcarotid artery revascularization (TCAR). In this study, we examined contemporary perioperative outcomes in patients who underwent TCAR stratified by specific preprocedural symptom status. Methods: Patients who underwent TCAR between 2016 and 2021 in the Vascular Quality Initiative were included. We stratified patients into the following groups based on preprocedural symptoms: asymptomatic, recent (symptoms occurring <180 days before TCAR) ocular transient ischemic attack (TIA), recent hemispheric TIA, recent stroke, or formerly symptomatic (symptoms occurring >180 days before TCAR). First, we used trend tests to assess outcomes in asymptomatic patients versus those with an increasing severity of recent neurologic injury (recent ocular TIA vs recent hemispheric TIA vs recent stroke). Then, we compared outcomes between asymptomatic and formerly symptomatic patients. Our primary outcome was in-hospital stroke/death rates. Multivariable logistic regression was used to adjust for demographics and comorbidities across groups. Results: We identified 18,477 patients undergoing TCAR, of whom 62.0% were asymptomatic, 3.2% had a recent ocular TIA, 7.6a % had recent hemispheric TIA, 18.0% had a recent stroke, and 9.2% were formerly symptomatic. In patients with recent symptoms, we observed higher rates of stroke/death with increasing neurologic injury severity: asymptomatic 1.1% versus recent ocular TIA 0.8% versus recent hemispheric TIA 2.1% versus recent stroke 3.1% (Ptrend < .01). In formerly symptomatic patients, the rate of stroke/death was higher compared with asymptomatic patients, but this difference was not statistically significant (1.7% vs 1.1%; P = .06). After risk adjustment, compared with asymptomatic patients, there was a higher odds of stroke/death in patients with a recent stroke (odds ratio [OR], 2.8; 95% confidence interval [CI], 2.1-3.7; P < .01), a recent hemispheric TIA (OR, 2.0; 95% CI, 1.3-3.0; P < .01), and former symptoms (OR, 1.6; 95% CI, 1.1-2.5; P = .02), but there was no difference in stroke/death rates in patients with a recent ocular TIA (OR, 0.9; 95% CI, 0.4-2.2; P = .78). Conclusions: After TCAR, compared with asymptomatic status, a recent stroke and a recent hemispheric TIA were associated with higher stroke/death rates, whereas a recent ocular TIA was associated with similar stroke/death rates. In addition, a formerly symptomatic status was associated with higher stroke/death rates compared with an asymptomatic status. Overall, our findings suggest that classifying patients undergoing TCAR as symptomatic versus asymptomatic may be an oversimplification and that patients' specific preoperative neurologic symptoms should instead be used in risk assessment and outcome reporting for TCAR.
Cannabis Use and the Developing Brain: Highs and Lows
(Frontiers Media, 2023) Hurd, Yasmin L.; Ferland, Jacqueline-Marie N.; Nomura, Yoko; Hulvershorn, Leslie A.; Gray, Kevin M.; Thurstone, Christian; Psychiatry, School of Medicine
Although cannabis is a naturally occurring plant with a long history of use by humans, the chemicals it contains, called cannabinoids, can act on the human body in many ways. Use of cannabis during important periods of development, such as during pregnancy and adolescence, can have a long-lasting impact on the way the brain forms and develops its systems to control emotions and other functions. This article gives an overview of some of the effects of cannabinoids on the developing brain, before birth and as teenagers, and provides information about how young people can prevent or minimize the negative effects of cannabis on their brains.

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