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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Age‐dependent white matter disruptions after military traumatic brain injury: Multivariate analysis results from ENIGMA brain injury
(Wiley, 2022) Bouchard, Heather C.; Sun, Delin; Dennis, Emily L.; Newsome, Mary R.; Disner, Seth G.; Elman, Jeremy; Silva, Annelise; Velez, Carmen; Irimia, Andrei; Davenport, Nicholas D.; Sponheim, Scott R.; Franz, Carol E.; Kremen, William S.; Coleman, Michael J.; Williams, M. Wright; Geuze, Elbert; Koerte, Inga K.; Shenton, Martha E.; Adamson, Maheen M.; Coimbra, Raul; Grant, Gerald; Shutter, Lori; George, Mark S.; Zafonte, Ross D.; McAllister, Thomas W.; Stein, Murray B.; Thompson, Paul M.; Wilde, Elisabeth A.; Tate, David F.; Sotiras, Aristeidis; Morey, Rajendra A.; Psychiatry, School of Medicine
Mild Traumatic brain injury (mTBI) is a signature wound in military personnel, and repetitive mTBI has been linked to age‐related neurogenerative disorders that affect white matter (WM) in the brain. However, findings of injury to specific WM tracts have been variable and inconsistent. This may be due to the heterogeneity of mechanisms, etiology, and comorbid disorders related to mTBI. Non‐negative matrix factorization (NMF) is a data‐driven approach that detects covarying patterns (components) within high‐dimensional data. We applied NMF to diffusion imaging data from military Veterans with and without a self‐reported TBI history. NMF identified 12 independent components derived from fractional anisotropy (FA) in a large dataset (n = 1,475) gathered through the ENIGMA (Enhancing Neuroimaging Genetics through Meta‐Analysis) Military Brain Injury working group. Regressions were used to examine TBI‐ and mTBI‐related associations in NMF‐derived components while adjusting for age, sex, post‐traumatic stress disorder, depression, and data acquisition site/scanner. We found significantly stronger age‐dependent effects of lower FA in Veterans with TBI than Veterans without in four components (q < 0.05), which are spatially unconstrained by traditionally defined WM tracts. One component, occupying the most peripheral location, exhibited significantly stronger age‐dependent differences in Veterans with mTBI. We found NMF to be powerful and effective in detecting covarying patterns of FA associated with mTBI by applying standard parametric regression modeling. Our results highlight patterns of WM alteration that are differentially affected by TBI and mTBI in younger compared to older military Veterans.
An Adaptive Human-Robotic Interaction Architecture for Augmenting Surgery Performance Using Real-Time Workload Sensing—Demonstration of a Semi-autonomous Suction Tool
(Sage, 2024) Yang, Jing; Barragan, Juan Antonio; Farrow, Jason Michael; Sundaram, Chandru P.; Wachs, Juan P.; Yu, Denny; Urology, School of Medicine
Objective: This study developed and evaluated a mental workload-based adaptive automation (MWL-AA) that monitors surgeon cognitive load and assist during cognitively demanding tasks and assists surgeons in robotic-assisted surgery (RAS). Background: The introduction of RAS makes operators overwhelmed. The need for precise, continuous assessment of human mental workload (MWL) states is important to identify when the interventions should be delivered to moderate operators' MWL. Method: The MWL-AA presented in this study was a semi-autonomous suction tool. The first experiment recruited ten participants to perform surgical tasks under different MWL levels. The physiological responses were captured and used to develop a real-time multi-sensing model for MWL detection. The second experiment evaluated the effectiveness of the MWL-AA, where nine brand-new surgical trainees performed the surgical task with and without the MWL-AA. Mixed effect models were used to compare task performance, objective- and subjective-measured MWL. Results: The proposed system predicted high MWL hemorrhage conditions with an accuracy of 77.9%. For the MWL-AA evaluation, the surgeons' gaze behaviors and brain activities suggested lower perceived MWL with MWL-AA than without. This was further supported by lower self-reported MWL and better task performance in the task condition with MWL-AA. Conclusion: A MWL-AA systems can reduce surgeons' workload and improve performance in a high-stress hemorrhaging scenario. Findings highlight the potential of utilizing MWL-AA to enhance the collaboration between the autonomous system and surgeons. Developing a robust and personalized MWL-AA is the first step that can be used do develop additional use cases in future studies. Application: The proposed framework can be expanded and applied to more complex environments to improve human-robot collaboration.
Deficient functional wound closure as measured by elevated trans-epidermal water loss predicts chronic wound recurrence: An exploratory observational study
(Springer Nature, 2024-10-09) Chattopadhyay, Debarati; Sinha, Mithun; Kapoor, Akshay; Kumar, Manoj; Singh, Kanhaiya; Mathew-Steiner, Shomita S.; Sen, Chandan K.; Surgery, School of Medicine
A single-center, prospective, observational pilot study was performed to evaluate wound healing endpoint and recurrence by measuring transepidermal water loss (TEWL) post-closure at the site of wound repair. Patients with clinically-defined chronic wounds (such as pressure ulcers, diabetic ulcers, and trauma wounds) who visited the Plastic Surgery outpatient department or were in-patients at the All India Institute of Medical Sciences, Rishikesh, India, and were referred for chronic wound management, were enrolled. Non-invasive point-of-care TEWL measurements were obtained, from closed wound-site and contralateral healthy skin site, starting from confirmation of closure (post-closure, V0) continuing every 2 weeks for a maximum of five visits or until the wound recurred. Statistical analyses of the data involved logistic regression and likelihood ratio chi-square tests to assess differences in TEWL at visit 0 (V0) between the closed wound site and reference skin, with the TEWL score as the sole predictor of recurrence. Of the 72 subjects that completed the study, 44 (61%) showed no recurrence and 28 (39%) had wounds that recurred over a period of 12 weeks. A significant association was found between the V0 (post-closure) TEWL score and the odds of wound recurrence, both in univariate analysis (OR [95%CI] = 1.26[1.14,1.42] (p < 0.001) and after adjusting for covariates in multivariable analysis (OR [95%CI] = 1.34[1.19,1.61] (p < 0.001). The likelihood ratio chi-square analysis demonstrated that the V0 TEWL score is a significant universal predictor of recurrence across all wound types studied. Cases of closed wounds with subsequent recurrence showed an overall higher post-closure V0 TEWL score, compared to those who did not have a wound recurrence, across visits. The TEWL score cut-off value predictive of recurrence was 24.1 g.m-2.h-1 (AUC = 0.967). The outcome of this pilot study on a wide range of chronic wounds leads to the hypothesis that post-closure TEWL at the site of wound healing is a reliable biomarker of wound recurrence. It also raises the question whether the clinical endpoint of wound closure should include re-establishment of skin barrier function as additional criterion. The current standard of care wound closure endpoint calls for re-epithelialization of the wound with no discharge for two consecutive weeks disregarding the functional parameter of restoration of skin barrier function at the wound-site.
Prevalence of Obesity and Metabolic Syndrome in the High Cardiovascular Risk Setting of Rural Western Honduras
(Ethnicity & Disease, 2024-04-10) Montalvan-Sanchez, Eleazar E.; Rodriguez-Murillo, Aida; Carrasco-Stoval, Tiffani; Carrera, Keila; Beas, Renato; Giron, Roberto; Jerez-Moreno, Valeria; Soriano-Turcios, Roque Antonio; Reyes-Guerra, Orlando; Torres, Karla; Izquierdo-Veraza, Diego; Torres, Tatiana; Beran, Azizullah A.; Montalvan-Sanchez, Daniela; Norwood, Dalton A.; Medicine, School of Medicine
Objective: To determine the prevalence of obesity and metabolic syndrome (MS) in the population older than 45 years in rural Western Honduras and contribute to the limited literature on MS in Central America. Methods: Descriptive cross-sectional study conducted in the District of Copan. The study includes 382 men and women aged 45 to 75 years. With proper consent, anthropometric parameters, blood pressure, blood sugar, and lipid profile were evaluated. MS was diagnosed by using the National Cholesterol Education Program Criteria - Adult Panel Treatment III (NCEP-ATP III). Data were stored in REDCap (Research Electronic Data Capture) and analyzed with STATA14. Results: Data were collected on 382 patients; of these, 38% were male and 62% female. The prevalence of obesity was 24.1% for both sexes. The prevalence of MS was 64.9%. Prevalence in males and females was 54% and 71%, respectively. Notable parameters were elevated triglycerides (71%), low High-density lipoprotein cholesterol (HDL-C) (63.4%), and abdominal obesity (56.8%). In men, the distribution of MS was more homogeneous, with a mean result of 80% amongst all ages. Conclusions: The overall prevalence of obesity and MS is severely underestimated in rural Honduras. The most remarkable parameter for MS was high triglycerides (71%). Sixty-nine percent of the population has above-normal Body Mass Index (BMI). Public health efforts to control comorbidities and tackle risk factors in this population should take utmost priority.
Pediatric Drug-Associated Pancreatitis Reveals Concomitant Risk Factors and Poor Reliability of Causality Scoring: Report From INSPPIRE
(Wiley, 2023) Morinville, Veronique D.; Husain, Sohail Z.; Wang, Fuchenchu; Cress, Gretchen A.; Abu-El-Haija, Maisam; Chugh, Ankur; Downs, Elissa; Ellery, Kate; Fishman, Douglas S.; Freeman, Alvin Jay; Gariepy, Cheryl E.; Giefer, Matthew; Gonska, Tanja; Liu, Quin; Maqbool, Asim; Mark, Jacob; Mcferron, Brian Arthur; Mehta, Megha; Nathan, Jaimie D.; Ng, Ken; Ooi, Chee Y.; Perito, Emily; Ruan, Wenly; Schwarzenberg, Sarah Jane; Sellers, Zachary M.; Serrano, Jose; Troendle, David M.; Wilschanski, Michael; Zheng, Yuhua; Yuan, Ying; Lowe, Mark; Uc, Aliye; Consortium for the Study of Chronic Pancreatitis, Diabetes and Pancreatic Cancer (CPDPC); Pediatrics, School of Medicine
Objectives: Drug-associated acute pancreatitis (DAP) studies typically focus on single acute pancreatitis (AP) cases. We aimed to analyze the (1) characteristics, (2) co-risk factors, and (3) reliability of the Naranjo scoring system for DAP using INSPPIRE-2 (the INternational Study group of Pediatric Pancreatitis: In search for a cuRE-2) cohort study of acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP) in children. Methods: Data were obtained from ARP group with ≥1 episode of DAP and CP group with medication exposure ± DAP. Physicians could report multiple risk factors. Pancreatitis associated with Medication (Med) (ARP+CP) was compared to Non-Medication cases, and ARP-Med vs CP-Med groups. Naranjo score was calculated for each DAP episode. Results: Of 726 children, 392 had ARP and 334 had CP; 51 children (39 ARP and 12 CP) had ≥1 AP associated with a medication; 61% had ≥1 AP without concurrent medication exposure. The Med group had other risk factors present (where tested): 10 of 35 (28.6%) genetic, 1 of 48 (2.1%) autoimmune pancreatitis, 13 of 51 (25.5%) immune-mediated conditions, 11 of 50 (22.0%) obstructive/anatomic, and 28 of 51 (54.9%) systemic risk factors. In Med group, 24 of 51 (47%) had involvement of >1 medication, simultaneously or over different AP episodes. There were 20 ARP and 4 CP cases in "probable" category and 19 ARP and 7 CP in "possible" category by Naranjo scores. Conclusions: Medications were involved in 51 of 726 (7%) of ARP or CP patients in INSPPIRE-2 cohort; other pancreatitis risk factors were present in most, suggesting a potential additive role of different risks. The Naranjo scoring system failed to identify any cases as "definitive," raising questions about its reliability for DAP.
Computational Mechanobiology Model Evaluating Healing of Postoperative Cavities Following Breast-Conserving Surgery
(Elsevier, 2023) Harbin, Zachary; Sohutskay, David; Vanderlaan, Emma; Fontaine, Muira; Mendenhall, Carly; Fisher, Carla; Voytik-Harbin, Sherry; Buganza Tepole, Adrian; Surgery, School of Medicine
Breast cancer is the most commonly diagnosed cancer type worldwide. Given high survivorship, increased focus has been placed on long-term treatment outcomes and patient quality of life. While breast-conserving surgery (BCS) is the preferred treatment strategy for early-stage breast cancer, anticipated healing and breast deformation (cosmetic) outcomes weigh heavily on surgeon and patient selection between BCS and more aggressive mastectomy procedures. Unfortunately, surgical outcomes following BCS are difficult to predict, owing to the complexity of the tissue repair process and significant patient-to-patient variability. To overcome this challenge, we developed a predictive computational mechanobiological model that simulates breast healing and deformation following BCS. The coupled biochemical-biomechanical model incorporates multi-scale cell and tissue mechanics, including collagen deposition and remodeling, collagen-dependent cell migration and contractility, and tissue plastic deformation. Available human clinical data evaluating cavity contraction and histopathological data from an experimental porcine lumpectomy study were used for model calibration. The computational model was successfully fit to data by optimizing biochemical and mechanobiological parameters through Gaussian process surrogates. The calibrated model was then applied to define key mechanobiological parameters and relationships influencing healing and breast deformation outcomes. Variability in patient characteristics including cavity-to-breast volume percentage and breast composition were further evaluated to determine effects on cavity contraction and breast cosmetic outcomes, with simulation outcomes aligning well with previously reported human studies. The proposed model has the potential to assist surgeons and their patients in developing and discussing individualized treatment plans that lead to more satisfying post-surgical outcomes and improved quality of life.
8669 Characteristics Of Adults with Autosomal Dominant Hypocalcemia Type 1 (ADH1) Enrolled In The CLARIFY Disease Monitoring Study
(Oxford University Press, 2024-10-05) Ing, S. W.; Harmatz, P.; Mora, S.; Imel, E. A.; Tebben, P. J.; Warren, M. L.; Ma, N.; Khan, A. A.; Palermo, A.; Decallonne, B.; Lemoine, S.; Mantovani, G.; Linglart, A.; Wasserman, H.; Barbosa, A. P.; Cardot-Bauters, C.; Roberts, M.; Mathew, A.; Adler, S.; Zillikens, M. C.; Clifton-Bligh, R. J.; Rejnmark, L.; Medicine, School of Medicine
Autosomal dominant hypocalcemia type 1 (ADH1), caused by gain-of-function calcium-sensing receptor gene (CASR) variants, is characterized by low parathyroid hormone (PTH) concentrations, hypocalcemia, hypercalciuria, hyperphosphatemia and hypomagnesemia. While a rare disease, ADH1 is one of the more frequently identified causes of genetic hypoparathyroidism. Conventional therapy includes calcium (Ca) and/or active vitamin D, but this regimen incompletely corrects the hypocalcemia and is associated with persistent hypercalciuria, which may result in renal complications including nephrocalcinosis (NC), nephrolithiasis (NL), and chronic kidney disease (CKD). The CLARIFY disease monitoring study [NCT05227287] is a global, multicenter, longitudinal study to understand disease burden, management, and progression in children and adults with ADH1 over a 5-year period. Here we report data on the characteristics of adult participants at study entry. As of November 2023, 45 adults (≥18 years) with ADH1 were enrolled, with a mean±SD age of 42.1±16.5 years (range 18-80). The mean±SD age of a hypocalcemia diagnosis was 19.1±19.1 years, while the mean±SD age for a diagnosis of ADH1 was 28.2±20.6 years. As reported on medical history, in decreasing order of prevalence, 36% (16) had NC, 22% (10) had intracranial calcifications, 11% (5) had history of seizures, 11% (5) had CKD, 9% (4) had cataracts, 7% (3) had NL, and 4% (2) had undergone renal transplant. Treatment data were available for 43 participants and included the following: 74% (32) Ca and active vitamin D, 9% (4) Ca alone, 9% (4) active vitamin D alone, 37% (16) magnesium, 33% (14) thiazide diuretics, 26% (11) potassium, 7% (3) phosphate binder, 7% (3) PTH, and 5% (2) no treatment. Mean±SD fasting values collected prior to conventional therapy dose are presented. PTH concentrations (10.1±8.2 pg/mL [nl 15-65]) and albumin-corrected calcium ([cCa]=7.5±1.0 mg/dL [nl 8.5-10.5]) were low. Despite the low mean cCa, the mean 24-hr urine calcium was elevated (268±183 mg/d, [nl <250 women, <300 men]). Blood phosphate was 4.8±0.8 mg/dL [nl 2.5-4.8] while blood magnesium was 1.8±0.2 mg/dL [nl 1.8-2.4]. 25-OH vitamin D was 35.0±13.5 ng/mL [nl 30-80]. Renal function as assessed by CKD-EPIcr_R showed eGFR of 86±23 mL/min/1.73m² (range 36-123). This study represents the largest cohort of adults with ADH1 described to date. These data highlight variability in therapeutic approaches in a real-world setting with some participants receiving up to 6 different medications/supplements. Despite being followed in expert centers, and treated with available therapies, patients on average have low cCa with relatively high 24-hr urine calcium excretion. The CLARIFY study provides an opportunity to better understand the progression and burden of disease in participants with ADH1.
Advancing Public Health Surveillance in Child Care Centers: Stakeholder-Informed Redesign and User Satisfaction Evaluation of the MCRISP Network
(JMIR, 2024-09-24) Gribbin, William; Dejonge, Peter; Rodseth, Jakob; Hashikawa, Andrew; Medicine, School of Medicine
Leveraging user feedback, we redesigned a novel disease monitoring utility to allow for bidirectional data flow and in this letter offer insights into that process as well as lessons learned.
Correction: Whole-genome sequencing analysis reveals new susceptibility loci and structural variants associated with progressive supranuclear palsy
(Springer Nature, 2024-10-14) Wang, Hui; Chang, Timothy S.; Dombroski, Beth A.; Cheng, Po-Liang; Patil, Vishakha; Valiente-Banuet, Leopoldo; Farrell, Kurt; Mclean, Catriona; Molina-Porcel, Laura; Rajput, Alex; De Deyn, Peter Paul; Le Bastard, Nathalie; Gearing, Marla; Donker Kaat, Laura; Van Swieten, John C.; Dopper, Elise; Ghetti, Bernardino F.; Newell, Kathy L.; Troakes, Claire; de Yébenes, Justo G.; Rábano-Gutierrez, Alberto; Meller, Tina; Oertel, Wolfgang H.; Respondek, Gesine; Stamelou, Maria; Arzberger, Thomas; Roeber, Sigrun; Müller, Ulrich; Hopfner, Franziska; Pastor, Pau; Brice, Alexis; Durr, Alexandra; Le Ber, Isabelle; Beach, Thomas G.; Serrano, Geidy E.; Hazrati, Lili-Naz; Litvan, Irene; Rademakers, Rosa; Ross, Owen A.; Galasko, Douglas; Boxer, Adam L.; Miller, Bruce L.; Seeley, Willian W.; Van Deerlin, Vivanna M.; Lee, Edward B.; White, Charles L., III; Morris, Huw; de Silva, Rohan; Crary, John F.; Goate, Alison M.; Friedman, Jeffrey S.; Leung, Yuk Yee; Coppola, Giovanni; Naj, Adam C.; Wang, Li-San; P. S. P. genetics study group; Dalgard, Clifton; Dickson, Dennis W.; Höglinger, Günter U.; Schellenberg, Gerard D.; Geschwind, Daniel H.; Lee, Wan-Ping; Pathology and Laboratory Medicine, School of Medicine
Correction : Mol Neurodegeneration 19, 61 (2024) https://doi.org/10.1186/s13024-024-00747-3 The original article [1] erroneously gives a wrong affiliation for Ulrich Müller. His correct affiliation is Institute of Human Genetics, Justus-Liebig University Giessen, 35392 Giessen, Germany.
Gemcitabine plus nab-paclitaxel preserves skeletal and cardiac mass and function in a murine model of pancreatic cancer cachexia
(bioRxiv, 2023-04-18) Narasimhan, Ashok; Jengelley, Daenique H. A.; Huot, Joshua R.; Umberger, Tara S.; Doud, Emma H.; Mosley, Amber L.; Wang, Meijing; Zhong, Xiaoling; Counts, Brittany R.; Rupert, Joseph E.; Young, Andrew R.; Bonetto, Andrea; Horan, Daniel J.; Robling, Alexander G.; Fishel, Melissa L.; Kelley, Mark R.; Koniaris, Leonidas G.; Zimmers, Teresa A.; Surgery, School of Medicine
More than 85% of patients with pancreatic ductal adenocarcinoma (PDAC) suffer from cachexia, a debilitating syndrome characterized by the loss of muscle and fat and remains an unmet medical need. While chemotherapy remains an effective treatment option, it can also induce weight and muscle loss in patients with cancer. Gemcitabine combined with nab paclitaxel (GnP) is a first line treatment option for patients with PDAC but GnP’s effect on cachexia has not been comprehensively investigated. We interrogated the effects of GnP in a murine model of pancreatic cancer cachexia. Mice were orthotopically implanted with the cachexia inducing pancreatic cell line (KPC) and were administered GnP or vehicle. The controls underwent sham surgery. We defined GnP effects on cachexia and tumor burden by evaluating muscle and cardiac mass and function, fat mass, bone morphometry, and hematology measurements. We completed RNA sequencing and deep proteome profiling in skeletal and cardiac muscle. KPC+GnP reduced tumor burden over 50% and increased survival compared to KPC. KPC vehicle group had more than 15% muscle mass loss and decreased left ventricular mass, this was not present in KPC+GnP when compared to controls. RNA Seq and deep proteomics analyses suggested that muscle and cardiac dysfunction pathways activated in KPC group were either reversed or decreased in KPC+GnP. In all, our data suggests that GnP protects against muscle and cardiac wasting in an experimental model of PDAC cachexia.

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