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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APOE, TOMM40, and Sex Interactions on Neural Network Connectivity
(Elsevier, 2022) Li, Tianqi; Pappas, Colleen; Le, Scott T.; Wang, Qian; Klinedinst, Brandon S.; Larsen, Brittany; Pollpeter, Amy; Lee, Ling Yi; Lutz, Mike W.; Gottschalk, William K.; Swerdlow, Russell H.; Nho, Kwangsik; Willette, Auriel A.; Radiology and Imaging Sciences, School of Medicine
The Apolipoprotein E ε4 (APOE ε4) haplotype is the strongest genetic risk factor for late-onset Alzheimer‟s disease (AD). The Translocase of Outer Mitochondrial Membrane-40 (TOMM40) gene maintains cellular bioenergetics, which is disrupted in AD. TOMM40 rs2075650 (‘650) G vs. A carriage is consistently related to neural and cognitive outcomes, but it is unclear if and how it interacts with APOE. We examined 21 orthogonal neural networks among 8,222 middle-aged to aged participants in the UK Biobank cohort. ANOVA and multiple linear regression tested main effects and interactions with APOE and TOMM40 ‘650 genotypes, and if age and sex acted as moderators. APOE ε4 was associated with less strength in multiple networks, while ‘650 G vs. A carriage was related to more language comprehension network strength. In APOE ε4 carriers, ‘650 G-carriage led to less network strength with increasing age, while in non G-carriers this was only seen in women but not men. TOMM40 may shift what happens to network activity in aging APOE ε4 carriers depending on sex.
Tlr2/4‐Mediated Hyperinflammation Promotes Cherubism‐Like Jawbone Expansion in Sh3bp2 (P416R) Knockin Mice
(Wiley, 2021-10-30) Fujii, Yasuyuki; Monteiro, Nelson; Sah, Shyam Kishor; Javaheri, Homan; Ueki, Yasuyoshi; Fan, Zhichao; Reichenberger, Ernst J.; Chen, I-Ping; Biomedical Sciences and Comprehensive Care, School of Dentistry
Cherubism (CBM), characterized by expansile jawbones with multilocular fibrocystic lesions, is caused by gain-of-function mutations in SH3 domain-binding protein 2 (SH3BP2; mouse orthologue Sh3bp2). Loss of jawbone and dental integrity significantly decrease the quality of life for affected children. Treatment for CBM is limited to multiple surgeries to correct facial deformities. Despite significant advances made with CBM knockin (KI) mouse models (Sh3bp2 KI/KI ), the activation mechanisms of CBM lesions remain unknown because mutant mice do not spontaneously develop expansile jawbones. We hypothesize that bony inflammation of an unknown cause triggers jawbone expansion in CBM. To introduce jawbone inflammation in a spatiotemporally controlled manner, we exposed pulp of the first right mandibular molar of 6-week-old Sh3bp2 +/+ , Sh3bp2 KI/+ , and Sh3bp2 KI/KI mice. Bacterial invasion from the exposed pulp into root canals led to apical periodontitis in wild-type and mutant mice. The pathogen-associated molecular patterns (PAMPs)-induced inflammation of alveolar bone resulted in jawbone expansion in Sh3bp2 KI/+ and Sh3bp2 KI/KI mice. CBM-like lesions developed exacerbated inflammation with increased neutrophil, macrophage, and osteoclast numbers. These lesions displayed excessive neutrophil extracellular traps (NETs) compared to Sh3bp2 +/+ mice. Expression levels of IL-1β, IL-6, and TNF-α were increased in periapical lesions of Sh3bp2 +/+ , Sh3bp2 KI/+ , and Sh3bp2 KI/KI mice and also in plasma and the left untreated mandibles (with no pulp exposure) of Sh3bp2 KI/KI mice, suggesting a systemic upregulation. Ablation of Tlr2/4 signaling or depletion of neutrophils by Ly6G antibodies ameliorated jawbone expansion induced by PAMPs in Sh3bp2 KI/KI mice. In summary, successful induction of CBM-like lesions in jaws of CBM mice is important for studying initiating mechanisms of CBM and for testing potential therapies. Our findings further emphasize a critical role of host immunity in the development of apical periodontitis and the importance of maintaining oral health in CBM patients.
Antigen-specific T cell responses correlate with decreased occurrence of acute GVHD in a multicenter contemporary cohort
(Springer Nature, 2022) Cruz, Conrad Russell Y.; Bo, Na; Bakoyannis, Giorgos; Wright, Kaylor E.; Chorvinsky, Elizabeth A.; Powell, Allison; Bollard, Catherine M.; Jacobsohn, David; Cooke, Kenneth R.; Duncan, Christine; Krance, Robert M.; Carpenter, Paul A.; Rowan, Courtney M.; Paczesny, Sophie; Biostatistics and Health Data Science, School of Medicine
Nomogram for prediction of portal vein system thrombosis after splenectomy for hypersplenism in patients with Wilson disease
(APM, 2022-12-28) Yao, Yu; Zhang, Juan; Jiang, Huaizhou; Li, Rui; Xie, Daojun; Jiang, Feng; Zhang, Wanqiu; Ma, Min; Biology, School of Science
Background: The occurrence of portal vein system thrombosis (PVST) after splenectomy in patients with Wilson disease (WD) can lead to serious complications. The early identification of high-risk patients can help improve patient prognosis. This study aimed to establish and validate a personalized nomogram for assessing the risk of PVST after splenectomy in patients with WD and hypersplenism. Methods: We retrospectively collected the data from 81 patients with WD and hypersplenism who underwent splenectomy. Based on whether PVST occurred within a month after the operation, they were divided into the PVST group and the non-PVST group. The clinical data of the 2 groups were compared, and univariate analysis was used to select the statistically significant features and incorporated into the least absolute shrinkage and selection operator (LASSO) regression model for optimization. Multivariate logistic regression analysis was used to determine the independent risk factors for PVST after splenectomy, which were then applied to establish a personalized nomogram. We calculated the concordance (C)-index and drew the receiver operating characteristic (ROC) curve, the model calibration curve, and the clinical decision analysis (DCA) curve to evaluate the accuracy, calibration, and clinical applicability of the model, respectively. We used bootstrapping for internal validation of the model. Results: Univariate analysis showed that the differences in preoperative portal vein diameter and velocity of portal blood flow, postoperative mean platelet volume (MPV), mean platelet distribution width (PDW), D-dimer, prothrombin time (PT), and the increase of platelet count (PLT) were of statistical significance (P<0.05). According to the results of the LASSO and multivariate logistic regression analyses, a model including preoperative portal vein diameter, preoperative portal blood flow velocity, postoperative D-dimer, and the increase of PLT was established to predict the risk of PVST after splenectomy. The model showed good accuracy with a C-index of 0.838 (95% CI: 0.750–0.926) and had a well-fitted calibration curve. Furthermore, internal validation showed it achieved a moderate C-index of 0.805. The DCA curve indicated that the model has clinical applicability when patients are treated at thresholds of 2–100%. Conclusions: Establishing a predictive model for the risk of PVST in patients with WD and hypersplenism after splenectomy can help clinicians identify patients at high risk of PVST who require intervention measures.
Process research: compare and contrast the recovery-orientated strengths model of case management and usual community mental health care
(Springer Nature, 2021-10-28) Tse, Samson; Ng, Catalina S. M.; Yuen, Winnie W. Y.; Lo, Iris W. K.; Fukui, Sadaaki; Goscha, Richard J.; Wan, Eppie; Wong, Stephen; Chan, Sau-Kam; School of Social Work
Background: The strengths model of case management (SMCM), which was developed by Rapp and Goscha through collaborative efforts at the University of Kansas, assists individuals with mental illness in their recovery by mobilizing individual and environmental resources. Increasing evidence has shown that the utilization of the SMCM improves outcomes, including increased employment/educational attainment, reduced hospitalization rates, higher self-efficacy, and hope. However, little is known about the processes through which the SMCM improves outcomes for mental health service users. This study explores the views of case workers and service users on their experience of providing or receiving the SMCM intervention. Methods: A qualitative design was employed using individual interviews with service users and case workers drawn from two study conditions: the SMCM group and the control group (treatment as usual). For both study conditions, service users were recruited by either centres-in-charge or case workers from integrated community centres for mental wellness (ICCMWs) operated by three non-governmental organizations (NGOs) in different districts of Hong Kong. Through purposeful sampling, 24 service users and 14 case workers from the SMCM and control groups joined the study. We used an inductive approach to analyse the qualitative data. Results: We identified two overarching themes: service users' and case workers' (1) perceptions of the impacts of the interventions (SMCM and control group) and (2) experiences of the interventions, such as features of the interventions and the factors that facilitated the outcomes. The results showed that there were improvements in the functional recovery of the SMCM group in areas such as employment and family relationships, how self-identified goals were achieved, and how service users gained a better understanding of their own strengths and weaknesses. Regarding their experience of the interventions, participants in both the SMCM group and the control group reported that a good relationship between service users and case workers was vital. However, some concerns were raised about the use of SMCM tools, including the strengths assessment and the personal recovery plan (PRP) and the risk of case workers being subjective in the presentation of cases in group supervision sessions. Conclusion: The results were promising in terms of supporting the use of the SMCM, with some refinements, in mental health services for Chinese clients.
Haptoglobin 1 allele predicts higher serum haptoglobin concentration and lower multiorgan failure risk in sickle cell disease
(ASH Publications, 2022-12-22) Ruiz, Maria A.; Shah, Binal N.; Ren, Guohui; Hussain, Faiz; Njoku, Franklin; Machado, Roberto F.; Gordeuk, Victor R.; Saraf, Santosh L.; Medicine, School of Medicine
Haptoglobin (HP) is an acute-phase protein and the main scavenger of cell-free hemoglobin. When HP is depleted, as observed in hemolytic conditions such as sickle cell disease (SCD), cell-free hemoglobin can lead to acute organ damage. The impact of the HP 1-1, 2-1, and 2-2 isoforms on HP and cell-free hemoglobin concentrations and SCD-related complications is unclear. In a longitudinal cohort of patients with SCD, the HP 1 allele was associated with higher HP and lower cell-free hemoglobin concentrations at a routine clinic visit as well as during hospitalization for a vaso-occlusive episode or acute chest syndrome. With a median follow-up of 6.8 years, acute chest syndrome occurred in 42% (n = 163) and multiorgan failure in 14% (n = 53) of 391 patients with SCD with a minimum follow-up of 6 months. The HP 1 allele was independently associated with lower risk of developing multiorgan failure during acute chest syndrome (additive model hazard ratio, 0.5; P < .001). Future studies assessing the regulation of HP concentrations and ability to bind cell-free hemoglobin according to the HP genotype may help to identify patients with SCD at high risk for multiorgan failure and to guide interventions, such as rapid initiation of exchange transfusion or HP replacement therapy.
Increasing Readiness for Early Integrated Palliative Oncology Care: Development and Initial Evaluation of the EMPOWER 2 Intervention
(Elsevier, 2021) Perry, Laura M.; Sartor, Oliver; Malhotra, Sonia; Alonzi, Sarah; Kim, Seowoo; Voss, Hallie M.; Rogers, James L.; Robinson, William; Harris, Kendra; Shank, Jessica; Morrison, David G.; Lewson, Ashley B.; Fuloria, Jyotsna; Miele, Lucio; Lewis, Brian; Mossman, Brenna; Hoerger, Michael; Psychology, School of Science
Context: Early integrated palliative care improves quality of life, but palliative care programs are underutilized. Psychoeducational interventions explaining palliative care may increase patients' readiness for palliative care. Objectives: To 1) collaborate with stakeholders to develop the EMPOWER 2 intervention explaining palliative care, 2) examine acceptability, 3) evaluate feasibility and preliminary efficacy. Methods: The research was conducted at a North American cancer center and involved 21 stakeholders and 10 patient-participants. Investigators and stakeholders iteratively developed the intervention. Stakeholders rated acceptability of the final intervention. Investigators implemented a pre-post trial to examine the feasibility of recruiting 10 patients with metastatic cancer within one month and with a ≥50% consent rate. Preliminary efficacy outcomes were changes in palliative care knowledge and attitudes. Results: Using feedback from four stakeholder meetings, we developed a multimedia intervention tailored to three levels of health-literacy. The intervention provides knowledge and reassurance about the purpose and nature of palliative care, addressing cognitive and emotional barriers to utilization. Stakeholders rated the intervention and design process highly acceptable (3.78/4.00). The pilot met a priori feasibility criteria (10 patients enrolled in 14 days; 83.3% consent rate). The intervention increased palliative care knowledge by 83.1% and improved attitudes by 18.9 points on a 0 to 51 scale (Ps < 0.00001). Conclusions: This formative research outlines the development of a psychoeducational intervention about palliative care. The intervention is acceptable, feasible, and demonstrated promising pilot test results. This study will guide clinical teams in improving patients' readiness for palliative care and inform the forthcoming EMPOWER 3 randomized clinical trial.
Adjusting ventilator settings to avoid air trapping in extremely premature infants reduces the need for tracheostomy and length of stay
(Frontiers, 2022-12-30) Sammour, Ibrahim; Conlon, Steven M.; Bauer, Sarah E.; Montgomery, Gregory S.; Cristea, A. Ioana; Rose, Rebecca S.; Pediatrics, School of Medicine
Despite the improving understanding of how lung mechanics and tidal volume requirements evolve during the evolution of bronchopulmonary dysplasia (BPD), clinical management continues to be heterogeneous and inconsistent at many institutions. Recent reports have examined the use of high tidal-volume low respiratory rate strategies in these patients once disease has been well established to help facilitate their eventual extubation and improve their long-term neurodevelopmental outcomes. In this retrospective observational research study, we describe how intentional adjustment of ventilator settings based on patient lung mechanics by an interdisciplinary BPD team improved the care of the at-risk population of infants, reduced the need for tracheostomies, as well as length of stay over a period of over 3 years. The team aimed to establish consistency in the management of these children using a high tidal volume, low-rate approach, and titrating PEEP to address the autoPEEP and bronchomalacia that is frequently observed in this patient population.
Frontotemporal-Orbitozygomatic Approach and Its Variants: Technical Nuances and Video Illustration
(Wolters Kluwer, 2022-12) El Ahmadieh, Tarek Y.; Nuñez, Maximiliano; Vigo, Vera; Abou-Al-Shaar, Hussam; Fernandez-Miranda, Juan C.; Cohen-Gadol, Aaron A.; Neurological Surgery, School of Medicine
The frontotemporal-orbitozygomatic (FTOz) approach is an extension of the traditional pterional approach. It provides the neurosurgeon with a wide access to the skull base with minimal or no brain retraction needed; it also offers a panoramic view that enables various trajectories toward the anterior, middle, and central cranial fossae as well as the upper segment of the posterior cranial fossa. Intracranial lesions that can be addressed using the FTOz approach include large medial sphenoid wing and spheno-orbital meningiomas; suprasellar and parasellar tumors; lesions of the orbital apex, interpeduncular cistern, third ventricle, and upper paraclival regions; and anterior communicating artery and basilar-tip aneurysms. In this article, we discuss the advantages and disadvantages of the FTOz approach and describe related technical nuances and common pitfalls. Our goal was to provide an up-to-date report of this time-tested surgical approach using original high-quality dissections, 3-dimensional models, and 2-dimensional 4K videos to serve as a reliable and practical educational resource for neurosurgery trainees and junior neurosurgeons. A case example is also provided to show the 1-piece orbitozygomatic approach.
Associating Persistent Self-Reported Cognitive Decline with Neurocognitive Decline in Older Breast Cancer Survivors Using Machine Learning: The Thinking and Living with Cancer Study
(Elsevier, 2022) Van Dyk, Kathleen; Ahn, Jaeil; Zhou, Xingtao; Zhai, Wanting; Ahles, Tim A.; Bethea, Traci N.; Carroll, Judith E.; Cohen, Harvey Jay; Dilawari, Asma A.; Graham, Deena; Jacobsen, Paul B.; Jim, Heather; McDonald, Brenna C.; Nakamura, Zev M.; Patel, Sunita K.; Rentscher, Kelly E.; Saykin, Andrew J.; Small, Brent J.; Mandelblatt, Jeanne S.; Root, James C.; Radiology and Imaging Sciences, School of Medicine
Introduction: Many cancer survivors report cognitive problems following diagnosis and treatment. However, the clinical significance of patient-reported cognitive symptoms early in survivorship can be unclear. We used a machine learning approach to determine the association of persistent self-reported cognitive symptoms two years after diagnosis and neurocognitive test performance in a prospective cohort of older breast cancer survivors. Materials and methods: We enrolled breast cancer survivors with non-metastatic disease (n = 435) and age- and education-matched non-cancer controls (n = 441) between August 2010 and December 2017 and followed until January 2020; we excluded women with neurological disease and all women passed a cognitive screen at enrollment. Women completed the FACT-Cog Perceived Cognitive Impairment (PCI) scale and neurocognitive tests of attention, processing speed, executive function, learning, memory and visuospatial ability, and timed activities of daily living assessments at enrollment (pre-systemic treatment) and annually to 24 months, for a total of 59 individual neurocognitive measures. We defined persistent self-reported cognitive decline as clinically meaningful decline (3.7+ points) on the PCI scale from enrollment to twelve months with persistence to 24 months. Analysis used four machine learning models based on data for change scores (baseline to twelve months) on the 59 neurocognitive measures and measures of depression, anxiety, and fatigue to determine a set of variables that distinguished the 24-month persistent cognitive decline group from non-cancer controls or from survivors without decline. Results: The sample of survivors and controls ranged in age from were ages 60-89. Thirty-three percent of survivors had self-reported cognitive decline at twelve months and two-thirds continued to have persistent decline to 24 months (n = 60). Least Absolute Shrinkage and Selection Operator (LASSO) models distinguished survivors with persistent self-reported declines from controls (AUC = 0.736) and survivors without decline (n = 147; AUC = 0.744). The variables that separated groups were predominantly neurocognitive test performance change scores, including declines in list learning, verbal fluency, and attention measures. Discussion: Machine learning may be useful to further our understanding of cancer-related cognitive decline. Our results suggest that persistent self-reported cognitive problems among older women with breast cancer are associated with a constellation of mild neurocognitive changes warranting clinical attention.

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