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.indianapolis.iu.edu/). 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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Cardiac outcomes of subjects on adjuvant trastuzumab emtansine vs paclitaxel in combination with trastuzumab for stage I HER2-positive breast cancer (ATEMPT) study (TBCRC033): a randomized controlled trial
(Springer Nature, 2022-02-16) Barroso-Sousa, Romualdo; Tarantino, Paolo; Tayob, Nabihah; Dang, Chau; Yardley, Denise A.; Isakoff, Steven J.; Valero, Vicente; Faggen, Meredith; Mulvey, Therese; Bose, Ron; Hu, Jiani; Weckstein, Douglas; Wolff, Antonio C.; Reeder-Hayes, Katherine; Rugo, Hope S.; Ramaswamy, Bhuvaneswari; Zuckerman, Dan; Hart, Lowell; Gadi, Vijayakrishna K.; Constantine, Michael; Cheng, Kit; Briccetti, Frederick; Schneider, Bryan; Merrill Garrett, Audrey; Marcom, Kelly; Albain, Kathy; DeFusco, Patricia; Tung, Nadine; Ardman, Blair; Nanda, Rita; Jankowitz, Rachel C.; Rimawi, Mothaffar; Abramson, Vandana; Pohlmann, Paula R.; Van Poznak, Catherine; Forero-Torres, Andres; Liu, Minetta; Ruddy, Kathryn J.; Zheng, Yue; Rosenberg, Shoshana M.; Gelber, Richard D.; Trippa, Lorenzo; Barry, William; DeMeo, Michelle; Burstein, Harold; Partridge, Ann; Winer, Eric P.; Krop, Ian; Tolaney, Sara M.; Medicine, School of Medicine
The excellent outcomes seen in patients treated with adjuvant trastuzumab emtansine (T-DM1) in the ATEMPT trial and the favorable toxicity profile associated with this agent make T-DM1 a potential therapeutic option for select patients with stage I HER2-positive breast cancer. Moreover, T-DM1 is an established adjuvant treatment for patients with HER2-positive breast cancer with the residual invasive disease after neoadjuvant therapy. Given that cardiotoxicity is the most significant adverse event of trastuzumab, which is a main molecular component of T-DM1, we conducted a sub-analysis of the ATEMPT trial to determine the cardiac safety of adjuvant T-DM1. In this analysis, the incidence of grade 3-4 left ventricular systolic dysfunction (LVSD) in T-DM1 or trastuzumab plus paclitaxel arms were respectively 0.8 and 1.8%. In addition, three (0.8%) patients in the T-DM1 arm and six (5.3%) patients in the adjuvant paclitaxel with trastuzumab (TH) arm experienced a significant asymptomatic left ventricular ejection fraction (LVEF) decline that per-protocol required holding T-DM1 or trastuzumab. All patients with available follow-up data experienced full resolution of cardiac symptoms and LVEF normalization. Furthermore, we performed an exploratory analysis to assess the relationship between age, baseline LVEF, and body mass index with cardiac outcomes. No significant association between these baseline characteristics and the incidence of significant asymptomatic LVEF decline or symptomatic LVSD was identified. The low incidence of significant cardiac adverse events in this population during therapy with adjuvant T-DM1 suggests that studies on the cost-effectiveness of cardiac monitoring during adjuvant therapy using anthracycline-free regimens are needed.
OMRT-9. Effect of Pre-Operative Stereotactic Radiosurgery on Brain Metastasis: Analysis of DNA and RNA Genomic Profiles from Phase-II Clinical Trial NCT03398694
(Oxford University Press, 2021-07) Shireman, Jack; Huff, Wei; Monaco, Gina; Agrawal, Namita; Watson, Gordon; Dey, Mahua; Neurological Surgery, School of Medicine
Background: With improved systemic therapy that has limited impact on the intracranial compartment, the incidence of brain metastasis (BM) from solid cancers is rising and negatively impacting patient’s overall survival (OS). Treatment varies based on presentation, however, for patients with <4 symptomatic BMs current clinical practice involves surgical resection followed by stereotactic radiosurgery (SRS) to the resection cavity. Post-operative SRS is associated with increased risk of leptomeningeal disease (LMD) and local recurrence in the follow-up period. We hypothesize that pre-operative SRS will decrease the incidence of LMD as well as local recurrence and increase patient’s OS by delivering a lethal dose of radiation to tumor cells before they are disturbed by surgical resection. In a Phase II clinical trial (NCT03398694) we are treating patients with 1–4 symptomatic BMs with pre-operative SRS while collecting DNA and RNA sequencing data from core and peripheral edges of the resected tumor to examine the genomic effects of SRS on tumor. Methods: Post-SRS resected tumor specimens were divided into two groups: ‘center’ and ‘periphery’ with respect to the center of SRS treatment with periphery within 50% isodose line. Previously resected untreated BMs were used as control. DNA and RNA were isolated from all samples for sequencing. Conclusions: Our initial analyses show that pre-treatment with SRS, results in significant genomic changes at DNA and RNA levels throughout the tumor, in both center as well as periphery. Furthermore, significant transcriptomic differences were noted among matched samples between the central and peripheral SRS locations implicating differential effect of SRS dosing within a tumor. Initial gene ontological analysis on non-small cell lung cancer samples demonstrated an overexpression of WNT and BMP signaling pathways (p <.001, p<.01). These pathways are typically involved in neuronal development, hinting that adaptation to the brain microenvironment was occurring post SRS treatment.
U.S. Montmorency Tart Cherry Juice Decreases Bone Resorption in Women Aged 65–80 Years
(MDPI, 2021) Dodier, Tiffany; Anderson, Kendall L.; Bothwell, James; Hermann, Janice; Lucas, Edralin A.; Smith, Brenda J.; Obstetrics and Gynecology, School of Medicine
Pre-clinical studies have demonstrated that tart cherries, rich in hydroxycinnamic acids and anthocyanins, protect against age-related and inflammation-induced bone loss. This study examined how daily consumption of Montmorency tart cherry juice (TC) alters biomarkers of bone metabolism in older women. Healthy women, aged 65–80 years (n = 27), were randomly assigned to consume ~240 mL (8 fl. oz.) of juice once (TC1X) or twice (TC2X) per day for 90 d. Dual-energy x-ray absorptiometry (DXA) scans were performed to determine bone density at baseline, and pre- and post-treatment serum biomarkers of bone formation and resorption, vitamin D, inflammation, and oxidative stress were assessed. Irrespective of osteoporosis risk, the bone resorption marker, tartrate resistant acid phosphatase type 5b, was significantly reduced with the TC2X dose compared to baseline, but not with the TC1X dose. In terms of indicators of bone formation and turnover, neither serum bone-specific alkaline phosphatase nor osteocalcin were altered. No changes in thiobarbituric acid reactive substances or high sensitivity C-reactive protein were observed in response to either TC1X or TC2X. We conclude that short-term supplementation with the higher dose of tart cherry juice decreased bone resorption from baseline without altering bone formation and turnover biomarkers in this cohort.
The Musculoskeletal Knowledge Portal: improving access to multi-omics data
(Springer Nature, 2022) Westendorf, Jennifer J.; Bonewald, Lynda F.; Kiel, Douglas P.; Burtt, Noël P.; Anatomy, Cell Biology and Physiology, School of Medicine
Patients with Mood Disorders Require Higher Doses of Buprenorphine for Management of Opioid Use Disorder But Have No Increased Risk of Neonatal Abstinence Syndrome
(Metrodora, 2021) Tonismae, Tiffany; McDowell, Misty; Torres, Loraine; Slaven, James E.; Quinney, Sara K.; Schubert, Frank; Pell Abernathy, Mary; Obstetrics and Gynecology, School of Medicine
Objective: This study compared differences in buprenorphine doses needed to treat opioid use disorder in pregnant women with and without mood disorders and to compare the development of neonatal abstinence syndrome in infants delivered to mothers treated with buprenorphine in patients with history of mood disorders versus those without mood disorder. Methods: This retrospective cohort study included women with opioid use disorder prescribed buprenorphine who had at least one outpatient visit at with the Indiana University Department of Maternal Fetal Medicine during pregnancy and delivered within the Indiana University Health system. Charts were reviewed for maternal demographics, medical history and medication use, and neonatal outcomes. Cases included those patients with history of mood disorder including depression, anxiety, or post-traumatic stress disorder based on initial appointment intake forms. Starting and maximum doses of buprenorphine during pregnancy were recorded. Outcomes were compared using Student’s t-tests and Analysis of Variance models for continuous variables and chi-square tests for categorical variables. All analytic assumptions were verified, with non-parametric tests being performed where necessary. Results: A total of 266 women were treated with opioids, of which 171 were diagnosed with a mood disorder: 148 depression, 130 anxiety, and 19 post-traumatic stress disorder. Over 40% of the patients had a history of dual diagnoses. Patients with a history of depression or anxiety required a higher dose of buprenorphine during pregnancy (p=0.0217, p=0.0165) compared to those without a history of mood disorder. There was no significant difference in the doses in patients with post-traumatic stress disorder versus controls. In those with a diagnosis of mood disorder, there was no difference in buprenorphine dose between women on medication versus those not on medication for depression, anxiety, and Post Traumatic Stress Disorder. There was no statistical difference between patients with or without mood disorder and the development of neonatal abstinence syndrome. For those that developed neonatal abstinence syndrome, infants whose mothers had anxiety or post-traumatic stress disorder required 2-6 extra days of morphine treatment compared to those infants of mothers without mood disorder (p=0.0088, p=0.0291), no difference seen for depression or a combination of mood disorders. Development of neonatal abstinence syndrome or length of treatment did not vary if the mother was on medication for treatment of her mood disorder. Conclusion: Pregnant women with a mood disorder require higher doses of buprenorphine compared to patients without a mood disorder. In women with mood disorders, there was no difference in buprenorphine dose in women treated with medication compared to those not taking medication for mood disorders. While, there was no difference in the incidence of neonatal abstinence syndrome in infants whose mothers also had a mood disorder, infants born of women with anxiety or post-traumatic stress disorder had longer stays at the Neonatal Intensive Care Unit as they needed 2-6 extra days of morphine treatment. These findings may help guide provider counseling of these women in discussion of post-delivery expectations.
A reimbursement framework for artificial intelligence in healthcare
(Springer Nature, 2022-06-09) Abràmoff, Michael D.; Roehrenbeck, Cybil; Trujillo, Sylvia; Goldstein, Juli; Graves, Anitra S.; Repka, Michael X.; Silva, Ezequiel, III; Medicine, School of Medicine
Responsible adoption of healthcare artificial intelligence (AI) requires that AI systems which benefit patients and populations, including autonomous AI systems, are incentivized financially at a consistent and sustainable level. We present a framework for analytically determining value and cost of each unique AI service. The framework’s processes involve affected stakeholders, including patients, providers, legislators, payors, and AI creators, in order to find an optimum balance among ethics, workflow, cost, and value as identified by each of these stakeholders. We use a real world, completed, an example of a specific autonomous AI service, to show how multiple “guardrails” for the AI system implementation enforce ethical principles. It can guide the development of sustainable reimbursement for future AI services, ensuring the quality of care, healthcare equity, and mitigation of potential bias, and thereby contribute to realize the potential of AI to improve clinical outcomes for patients and populations, improve access, remove disparities, and reduce cost.
Atlanto-axial rotary instability (Fielding type 1): characteristic clinical and radiological findings, and treatment outcomes following alignment, fusion, and stabilization
(Springer, 2021) Henderson, Fraser C.; Rosenbaum, Robert; Narayanan, Malini; Koby, Myles; Tuchman, Kelly; Rowe, Peter C.; Francomano, Clair; Medical and Molecular Genetics, School of Medicine
Atlanto-axial instability (AAI) is common in the connective tissue disorders, such as rheumatoid arthritis, and increasingly recognized in the heritable disorders of Stickler, Loeys-Dietz, Marfan, Morquio, and Ehlers-Danlos (EDS) syndromes, where it typically presents as a rotary subluxation due to incompetence of the alar ligament. This retrospective, IRB-approved study examines 20 subjects with Fielding type 1 rotary subluxation, characterized by anterior subluxation of the facet on one side, with a normal atlanto-dental interval. Subjects diagnosed with a heritable connective tissue disorder, and AAI had failed non-operative treatment and presented with severe headache, neck pain, and characteristic neurological findings. Subjects underwent a modified Goel-Harms posterior C1-C2 screw fixation and fusion without complication. At 15 months, two subjects underwent reoperation following a fall (one) and occipito-atlantal instability (one). Patients reported improvement in the frequency or severity of neck pain (P < 0.001), numbness in the hands and lower extremities (P = 0.001), headaches, pre-syncope, and lightheadedness (all P < 0.01), vertigo and arm weakness (both P = 0.01), and syncope, nausea, joint pain, and exercise tolerance (all P < 0.05). The diagnosis of Fielding type 1 AAI requires directed investigation with dynamic imaging. Alignment and stabilization is associated with improvement of pain, syncopal and near-syncopal episodes, sensorimotor function, and exercise tolerance.
Spironolactone and chlorthalidone—old drugs, new uses—but approach with caution
(Oxford University Press, 2022) Agarwal, Rajiv; Medicine, School of Medicine
Racial and Ethnic Differences in Bystander CPR for Witnessed Cardiac Arrest
(Massachusetts Medical Society, 2022) Garcia, R. Angel; Spertus, John A.; Girotra, Saket; Nallamothu, Brahmajee K.; Kennedy, Kevin F.; McNally, Bryan F.; Breathett, Khadijah; Del Rios, Marina; Sasson, Comilla; Chan, Paul S.; Medicine, School of Medicine
Background: Differences in the incidence of cardiopulmonary resuscitation (CPR) provided by bystanders contribute to survival disparities among persons with out-of-hospital cardiac arrest. It is critical to understand whether the incidence of bystander CPR in witnessed out-of-hospital cardiac arrests at home and in public settings differs according to the race or ethnic group of the person with cardiac arrest in order to inform interventions. Methods: Within a large U.S. registry, we identified 110,054 witnessed out-of-hospital cardiac arrests during the period from 2013 through 2019. We used a hierarchical logistic regression model to analyze the incidence of bystander CPR in Black or Hispanic persons as compared with White persons with witnessed cardiac arrests at home and in public locations. We analyzed the overall incidence as well as the incidence according to neighborhood racial or ethnic makeup and income strata. Neighborhoods were classified as predominantly White (>80% of residents), majority Black or Hispanic (>50% of residents), or integrated, and as high income (an annual median household income of >$80,000), middle income ($40,000-$80,000), or low income (<$40,000). Results: Overall, 35,469 of the witnessed out-of-hospital cardiac arrests (32.2%) occurred in Black or Hispanic persons. Black and Hispanic persons were less likely to receive bystander CPR at home (38.5%) than White persons (47.4%) (adjusted odds ratio, 0.74; 95% confidence interval [CI], 0.72 to 0.76) and less likely to receive bystander CPR in public locations than White persons (45.6% vs. 60.0%) (adjusted odds ratio, 0.63; 95% CI, 0.60 to 0.66). The incidence of bystander CPR among Black and Hispanic persons was less than that among White persons not only in predominantly White neighborhoods at home (adjusted odds ratio, 0.82; 95% CI, 0.74 to 0.90) and in public locations (adjusted odds ratio, 0.68; 95% CI, 0.60 to 0.75) but also in majority Black or Hispanic neighborhoods at home (adjusted odds ratio, 0.79; 95% CI, 0.75 to 0.83) and in public locations (adjusted odds ratio, 0.63; 95% CI, 0.59 to 0.68) and in integrated neighborhoods at home (adjusted odds ratio, 0.78; 95% CI, 0.74 to 0.81) and in public locations (adjusted odds ratio, 0.73; 95% CI, 0.68 to 0.77). Similarly, across all neighborhood income strata, the frequency of bystander CPR at home and in public locations was lower among Black and Hispanic persons with out-of-hospital cardiac arrest than among White persons. Conclusions: In witnessed out-of-hospital cardiac arrest, Black and Hispanic persons were less likely than White persons to receive potentially lifesaving bystander CPR at home and in public locations, regardless of the racial or ethnic makeup or income level of the neighborhood where the cardiac arrest occurred.
Neurocognitive Features of Motor Premanifest Individuals With Myotonic Dystrophy Type 1
(Wolters Kluwer, 2021-03-18) van der Plas, Ellen; Koscik, Timothy R.; Magnotta, Vincent; Cumming, Sarah A.; Monckton, Darren; Gutmann, Laurie; Nopoulos, Peggy; Neurology, School of Medicine
Objective: The goal of the study was to identify brain and functional features associated with premanifest phases of adult-onset myotonic dystrophy type 1 (i.e., PreDM1). Methods: This cross-sectional study included 68 healthy adults (mean age = 43.4 years, SD = 12.9), 13 individuals with PreDM1 (mean age: 47.4 years, SD = 16.3), and 37 individuals with manifest DM1 (mean age = 45.2 years, SD = 9.3). The primary outcome measures included fractional anisotropy (FA), motor measures (Muscle Impairment Rating Scale, Grooved Pegboard, Finger-Tapping Test, and grip force), general cognitive abilities (Wechsler Adult Intelligence Scales), sleep quality (Scales for Outcomes in Parkinson's Disease-Sleep), and apathy (Apathy Evaluation Scale). Results: Individuals with PreDM1 exhibited an intermediate level of white matter FA abnormality, where whole-brain FA was lower relative to healthy controls (difference of the estimated marginal mean [EMMdifference] = 0.02, 95% confidence interval (CI) 0.01-0.03, p < 0.001), but the PreDM1 group had significantly higher FA than did individuals with manifest DM1 (EMMdifference = 0.02, 95% CI 0.009-0.03, p < 0.001). Individuals with PreDM1 exhibited reduced performance on the finger-tapping task relative to control peers (EMMdifference = 5.70, 95% CI 0.51-11.00, p = 0.03), but performance of the PreDM1 group was better than that of the manifest DM1 group (EMMdifference = 5.60, 95% CI 0.11-11.00, p = 0.05). Hypersomnolence in PreDM1 was intermediate between controls (EMMdifference = -1.70, 95% CI -3.10-0.35, p = 0.01) and manifest DM1 (EMMdifference = -2.10, 95% CI -3.50-0.60, p = 0.006). Conclusions: Our findings highlight key CNS and functional deficits associated with PreDM1, offering insight in early disease course.

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