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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Quantifying Ventricular CSF Clearance in the Human Brain Using Dynamic 18F-FDG PET: Insights into Age-Related Glymphatic Impairment
(medRxiv, 2025-04-09) Zhou, Zeyu; Zhao, Tianyun; Gardus, John I.; Wen, Qiuting; Feng, Yang; DeLorenzo, Christine; Parsey, Ramin; Huang, Chuan; Radiology and Imaging Sciences, School of Medicine
Purpose: The glymphatic system facilitates brain waste clearance via cerebrospinal fluid (CSF) flow, and its dysfunction has been linked to aging and neurodegeneration. However, clinically accessible methods to quantify glymphatic function in humans remain limited. This study aimed to examine the potential of dynamic 18F-FDG PET for measuring ventricular CSF clearance - as a surrogate marker of glymphatic function. Specifically, we evaluated its association with age, its test–retest reliability, and the feasibility of reduced scan durations for clinical applicability. Methods: We analyzed 72 baseline 18F-FDG PET scans from participants enrolled in a prior depression trial. Time–activity curves (TACs) were extracted from the lateral ventricles and fitted with a γ-variate model to estimate influx (𝜇𝑖𝑛) and clearance (𝜇𝑜𝑢𝑡) parameters. Associations with age and clinical factors were examined using correlation and multiple linear regression. Test–retest reliability was assessed in 11 placebo-treated participants who underwent repeat scans eight weeks apart. A feasibility analysis tested whether shorter scan windows could yield comparable clearance estimates. Results: 𝜇𝑜𝑢𝑡 showed a strong negative correlation with age (r = −0.680, p < 0.001), while 𝜇𝑖𝑛 was not significantly age-related. Age remained a significant predictor of 𝜇𝑜𝑢𝑡 after adjusting for sex, ventricle size, and depression severity. A positive association between 𝜇𝑜𝑢𝑡 and depression severity was observed after covariate adjustment. Test–retest analysis yielded an intraclass correlation coefficient of 0.702 for 𝜇𝑜𝑢𝑡, indicating moderate-to-good reproducibility. A shortened 30-minute scan window (starting 30 minutes post injection) preserved strong correlations with both 𝜇𝑜𝑢𝑡 and age, supporting the potential for abbreviated imaging protocols. Conclusion: Dynamic 18F-FDG PET provides a reliable and noninvasive method to quantify ventricular CSF clearance, revealing age-related decline indicative of glymphatic impairment. The method demonstrates reproducibility over time and retains key clearance metrics even with shortened scan durations. These findings establish a clinically feasible 18F-FDG PET-based approach for studying brain clearance and glymphatic function in aging and disease.
Care guided by tissue oxygenation and haemodynamic monitoring in off-pump coronary artery bypass grafting (Bottomline-CS): assessor blind, single centre, randomised controlled trial
(BMJ, 2025-03-24) Han, Jiange; Zhai, Wenqian; Wu, Zhenhua; Zhang, Zhao; Wang, Tao; Ren, Min; Liu, Ziyue; Sessler, Daniel I.; Guo, Zhigang; Meng, Lingzhong; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public Health
Objective: To assess whether perioperative management guided by near-infrared spectroscopy to determine tissue oxygen saturation and haemodynamic monitoring reduces postoperative complications after off-pump coronary artery bypass grafting. Design: Assessor blinded, single centre, randomised controlled trial (Bottomline-CS trial). Setting: A tertiary teaching hospital in China. Participants: 1960 patients aged 60 years or older who were scheduled for elective off-pump coronary artery bypass grafting. Interventions: All patients had multisite monitoring of tissue oxygen saturation (bilateral forehead and unilateral forearm brachioradialis) and haemodynamic monitoring. Both groups received usual care, including arterial blood pressure, central venous pressure, electrocardiography, and transoesophageal echocardiography when indicated. Guided care aimed to maintain tissue oxygenation within 10% above or below preoperative baseline values, established 24-48 hours before surgery, from the start of anaesthesia until extubation or for up to 24 hours postoperatively. In the usual care group, tissue oximetry and haemodynamic data were concealed, and care was routine. Main outcome measures: The primary outcome was the incidence of a composite of 30 day postoperative complications, which were cerebral, cardiac, respiratory, renal, infectious, and mortality complications. Secondary outcomes included the individual components of the composite outcome, new-onset atrial fibrillation, and hospital length of stay. Results: Of 1960 patients randomly assigned, data from 967 guided care and 974 usual care patients were analysed. During anaesthesia, the area under the curve for tissue oxygen saturation measurements outside the plus and minus 10% baseline range was significantly smaller with guided care than only usual care: left forehead 32.4 versus 57.6 (%×min, P<0.001), right forehead 37.9 versus 62.6 (P<0.001), and forearm 14.8 versus 44.7 (P<0.001). The primary composite outcome occurred in 457/967 (47.3%) patients in the guided care group and 466/974 (47.8%) patients in the usual care group (unadjusted risk ratio 0.99 (95% confidence interval 0.90 to 1.08), P=0.83). No secondary outcomes differed significantly between groups. The largest observed difference was in incidence of pneumonia, which was less frequent in the guided care group (88/967, 9.1%) than in the usual care group (121/974, 12.4%) and not statistically significant after adjusting for multiple comparisons. Conclusions: Guided care by use of multisite near-infrared spectroscopy and haemodynamic monitoring effectively maintained tissue oxygenation near baseline levels compared with usual care. However, no clear evidence was noted that this approach reduced the incidence of major postoperative complications. These findings do not support the routine use of near-infrared spectroscopy and haemodynamic monitoring to maintain tissue oxygenation during off-pump coronary artery bypass grafting.
Sex differences in the clinical manifestation of autosomal dominant frontotemporal dementia
(Wiley, 2025) Memel, Molly; Staffaroni, Adam M.; Ilan-Gala, Ignacio; Garcia Castro, Jesús; Kornak, John; Tartaglia, Carmela M.; Saloner, Rowan; VandeBunte, Anna M.; Paolillo, Emily W.; Cadwallader, Claire J.; Chen, Coty; Gorno-Tempini, Maria Luisa; Mandelli, Malu; Apostolova, Liana; Graff-Radford, Neil; Litvan, Irene; Bayram, Ece; Pressman, Peter S.; Miyagawa, Toji; Mackenzie, Ian; Goldman, Jill; Darby, Richard R.; Appleby, Brian S.; Petrucelli, Len; Gendron, Tania; Heuer, Hilary W.; Forseberg, Leah K.; Rojas, Julio C.; Boeve, Brad F.; Brushaber, Nellie; Domoto-Reilly, Kimiko; Ghoshal, Nupur; Lapid, Maria; Pascual, Belen; Lee, Suzee; Ramos, Eliana Marisa; Ramanan, Vijay; Rademakers, Rosa; Rascovsky, Katya; Pantelyat, Alex; Masdeu, Joseph C.; Snyder, Allison; Boxer, Adam L.; Rosen, Howard J.; Casaletto, Kaitlin; ALLFTD Consortium; Neurology, School of Medicine
Introduction: Sex differences are apparent in neurodegenerative diseases but have not been comprehensively characterized in frontotemporal dementia (FTD). Methods: Participants included 337 adults with autosomal dominant FTD enrolled in the ALLFTD Consortium. Clinical assessments and plasma were collected annually for up to 6 years. Linear mixed-effects models investigated how sex and disease stage are associated with longitudinal trajectories of cognition, function, and neurofilament light chain (NfL). Results: While sex differences were not apparent at asymptomatic stages, females showed more rapid declines across all outcomes in symptomatic stages compared to males. In asymptomatic participants, the association between baseline NfL and clinical trajectories was weaker in females versus males, a difference that was not present in symptomatic participants. Discussion: In genetic FTD, females show cognitive resilience in early disease stages followed by steeper clinical declines later in the disease. Baseline NfL may be a less sensitive prognostic tool for clinical progression in females with FTD-causing mutations. Highlights: Females with genetic FTD exhibit overall steeper increases in plasma neurofilament light chain (NfL) than males. Females with genetic FTD outperform NfL levels in asymptomatic stages compared to males. Once symptomatic, females with genetic FTD decline more rapidly than males. Plasma NfL is a stronger prognostic marker in asymptomatic males than females.
Lumbar Fusion and Decompression in American Indian, Alaskan Native, Native Hawaiian, and Pacific Islander Populations: Healthcare Disparities in Spine Surgery
(Springer Nature, 2025-03-29) Khan, Mohammad F.; Patel, Saarang; Putzler, Dillon H.; Albert, Avi N.; Khan, Hibbah I.; Gensler, Ryan T.; Abella, Maveric; Hayashi, Jeffrey; Paulo, Frishan O.; Gendreau, Julian L.; Bow-Keola, Janette; Finlay, Andrea; Amanatullah, Derek F.; Noh, Thomas; Neurological Surgery, School of Medicine
Introduction: Racial disparities in surgical outcomes are well documented, yet data on American Indian/Alaskan Native (AI/AN) and Native Hawaiian/Pacific Islander (NH/PI) populations remain limited. This study examines disparities in 30-day outcomes following lumbar decompression and fusion in these underrepresented groups. Materials and methods: A retrospective analysis was conducted using the American College of Surgeons National Surgical Quality Improvement Program database (2017-2020). Patients undergoing lumbar decompression and fusion were identified via current procedural terminology codes. Multivariable logistic regression models adjusted for demographic and clinical factors assessed associations between race/ethnicity and postoperative outcomes, including readmission, complications, reoperation, and non-home discharge. Adjusted odds ratios (AOR) with 95% confidence intervals (CI) were reported. Results: Among 113,340 patients, 0.38% (n=429) were AI/AN patients and 0.20% (n=229) were NH/PI patients. Compared to non-Hispanic White patients, AI/AN patients had higher odds of readmission (AOR: 1.023, 95% CI: 1.003-1.043, p=0.026) and complications (AOR: 1.030, 95% CI: 1.004-1.056, p=0.023). NH/PI patients had increased odds of readmission (AOR: 1.033, 95% CI: 1.006-1.062, p=0.018), major complications (AOR: 1.029, 95% CI: 1.007-1.051, p=0.009), and reoperation (AOR: 1.035, 95% CI: 1.014-1.057, p=0.001). Conclusions: AI/AN and NH/PI patients face higher risks of adverse postoperative outcomes following lumbar spine surgery. Targeted interventions and increased inclusion in surgical disparities research are needed to improve equity in spine care.
IA-2A positivity increases risk of progression within and across established stages of type 1 diabetes
(Springer, 2025) Sims, Emily K.; Cuthbertson, David; Ferrat, Lauric A.; Bosi, Emanuele; Evans‑Molina, Carmella; DiMeglio, Linda A.; Nathan, Brandon M.; Ismail, Heba M.; Jacobsen, Laura M.; Redondo, Maria J.; Oram, Richard A.; Sosenko, Jay M.; Pediatrics, School of Medicine
Aims/hypothesis: Accurate understanding of type 1 diabetes risk is critical for optimisation of counselling, monitoring and interventions, yet even within established staging classifications, individual time to clinical disease varies. Previous work has associated IA-2A positivity with increased type 1 diabetes progression but a comprehensive assessment of the impact of screening for IA-2A positivity across the natural history of autoantibody positivity has not been performed. We asked whether IA-2A would consistently be associated with higher risk of progression within and across established stages of type 1 diabetes in a large natural history study. Methods: Genetic, autoantibody and metabolic data from adult and paediatric autoantibody-negative (n=192) and autoantibody-positive (n=4577) relatives of individuals with type 1 diabetes followed longitudinally in the Type 1 Diabetes TrialNet Pathway to Prevention Study were analysed. Cox regression was used to compare cumulative incidences of clinical diabetes by autoantibody profiles and disease stages. Results: Compared with IA-2A- individuals, IA-2A+ individuals had higher genetic risk scores and clinical progression risk within single-autoantibody-positive (5.3-fold increased 5 year risk), stage 1 (2.2-fold increased 5 year risk) and stage 2 (1.3-fold increased 5 year risk) type 1 diabetes categories. Individuals with single-autoantibody positivity for IA-2A showed increased metabolic dysfunction and diabetes progression compared with people who were autoantibody negative, those positive for another single autoantibody, and IA-2A- stage 1 individuals. Individuals at highest risk within the single-IA-2A+ category included children (HR 14.2 [95% CI 1.9, 103.1], p=0.009), individuals with IA-2A titres above the median (HR 3.5 [95% CI 1.9, 6.6], p<0.001), individuals with high genetic risk scores (HR 1.4 [95% CI 1.2,1.6], p<0.001) and individuals with HLA DR4-positive status (HR 3.7 [95% CI 1.6, 8.3], p=0.002). When considering all autoantibody-positive individuals, progression risk was similar for euglycaemic IA-2A+ individuals and dysglycaemic IA-2A- individuals. Conclusions/interpretation: IA-2A positivity is consistently associated with increased progression risk throughout the natural history of type 1 diabetes development. Individuals with single-autoantibody positivity for IA-2A have a greater risk of disease progression than those who meet stage 1 criteria but who are IA-2A-. Approaches to incorporate IA-2A+ status into monitoring strategies for autoantibody-positive individuals should be considered.
Social and Behavior Factors of Alzheimer’s Disease and Related Dementias: A National Study in the U.S.
(Elsevier, 2024) Ciciora, David; Vásquez, Elizabeth; Valachovic, Edward; Hou, Lifang; Zheng, Yinan; Xu, Hua; Jiang, Xiaoqian; Huang, Kun; Gabriel, Kelley Pettee; Deng, Hong-Wen; Gallant, Mary P.; Zhang, Kai; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public Health
Introduction: Considerable research has linked many risk factors to Alzheimer's Disease and Related Dementias (ADRD). Without a clear etiology of ADRD, it is advantageous to rank the known risk factors by their importance and determine if disparities exist. Statistical-based ranking can provide insight into which risk factors should be further evaluated. Methods: This observational, population-based study assessed 50 county-level measures and estimates related to ADRD in 3,155 counties in the U.S. using data from 2010 to 2021. Statistical analysis was performed in 2022-2023. The machine learning method, eXtreme Gradient Boosting, was utilized to rank the importance of these variables by their relative contribution to the model performance. Stratified ranking was also performed based on a county's level of disadvantage. Shapley Additive exPlanations (SHAP) provided marginal contributions for each variable. Results: The top three ranked predictors at the county level were insufficient sleep, consuming less than one serving of fruits/vegetables per day among adults, and having less than a high school diploma. In both disadvantaged and non-disadvantaged counties, demographic variables such as sex and race were important in predicting ADRD. Lifestyle factors ranked highly in non-disadvantaged counties compared to more environmental factors in disadvantaged counties. Conclusions: This ranked list of factors can provide a guided approach to ADRD primary prevention strategies in the U.S., as the effects of sleep, diet, and education on ADRD can be further developed. While sleep, diet, and education are important nationally, differing prevention strategies could be employed based on a county's level of disadvantage.
Comparing adolescent glomerular disease clinical outcomes to the clinical outcomes in childhood, young adult, and adult-onset glomerular disease in the CureGN database
(Springer, 2025) Garrity, Kelly; Putnam, Nathaniel; Kamil, Elaine S.; Massengill, Susan; Khalid, Myda; Srivastava, Rachana; Isaacs, Jaya; Salmon, Eloise; Pediatrics, School of Medicine
Background: There is a lack of evidence to suggest that outcomes of adolescent and adult-onset glomerular disease differ. Still, most glomerular disease trials include adults but exclude adolescents. Methods: We designed a retrospective study using the CureGN database to compare individuals with adolescent-onset glomerular disease relative to individuals with older and younger age at onset. The two main outcomes were sustained proteinuria remission off immunosuppression treatment and composite eGFR decline. Results: Our data did not show a significant difference in sustained proteinuria remission off treatment or composite eGFR decline between adolescent onset glomerular disease and either childhood (age 5-12), young adult (age 20-29), or adult (age 30-39) onset glomerular disease. Having high-risk APOL1 alleles and hypertension at the time of study enrollment decreased the likelihood of achieving sustained proteinuria remission off treatment. While participants with minimal change disease and IgA nephropathy were similarly likely to achieve sustained proteinuria remission off treatment, participants with focal segmental glomerulosclerosis and membranous nephropathy were less likely to achieve sustained proteinuria remission off treatment compared to participants with minimal change disease. CKD stage, high-risk APOL1 alleles, hypertension stage, and education all significantly impacted the likelihood of progression to the composite eGFR decline outcome. Conclusions: Approximately 25% of each age cohort reached the composite eGFR decline outcome within 5 years. As more glomerular disease clinical trials become available, we must consider opening these trials to people with childhood and adolescent onset disease since like adults they are at high risk of progressive kidney function decline.
High Glucose-induced transcriptomic changes in human trabecular meshwork cells
(Springer, 2025-04-25) Singh, Shivendra; Raghavan, Srimathi; Patel, Niketa A.; Soundararajan, Avinash; Pattabiraman, Padmanabhan P.; Ophthalmology, School of Medicine
Glaucoma is a leading cause of irreversible blindness, often associated with elevated intraocular pressure (IOP) due to trabecular meshwork (TM) dysfunction. Diabetes mellitus (DM) is recognized as a significant risk factor for glaucoma; however, the molecular mechanisms through which hyperglycemia affects TM function remain unclear. This study investigated the impact of high glucose on gene expression in human TM (HTM) cells to uncover pathways that contribute to TM dysfunction and glaucoma pathogenesis under diabetic conditions. Primary HTM cells were cultured under normoglycemic (5.5 mM) and hyperglycemic (30 mM) conditions for seven days, followed by mRNA sequencing (mRNA-seq) to identify differentially expressed genes, with quantitative PCR (qPCR) used for confirmatory analysis. STRING network analysis was performed to predict potential interactions among upregulated and downregulated genes. mRNA-seq analysis revealed 25 significantly differentially expressed genes in high glucose conditions, including upregulated genes associated with oxidative stress, apoptosis, autophagy, immune response, and fibrosis. Notably, TXNIP gene was significantly upregulated, indicating increased oxidative stress and apoptosis in TM cells, while downregulation of autophagy-related genes, such as HSPA6 and LAMP3, suggests compromised protein quality control. Immune response genes, including CCL7 and CHI3L1, were upregulated, suggesting an inflammatory response to oxidative stress. Increased expression of fibrosis-related genes, such as SNAI1, FGF7, and KRT19, and an increase in ECM proteins like Collagen 1 and FN accumulation and fibril formation suggest increased fibrosis of TM in diabetic conditions, potentially elevating IOP. Metabolic changes in diabetic patients could therefore lead to TM dysfunction, impair aqueous humor outflow, and elevate IOP, thereby increasing glaucoma risk. Targeting oxidative stress and fibrosis pathways offers therapeutic strategies to mitigate glaucoma progression in diabetic populations.
Randomized Trial of Group Postpartum Care Model Improves Knowledge and Clinical Outcomes
(Wolters Kluwer, 2025) Adams, Yenupini Joyce; Agbenyo, John Stephen; Lau, Elizabeth; Young, Jessica; Haas, David; Obstetrics and Gynecology, School of Medicine
Background: In sub-Saharan Africa, the risk of obstetric complications remains high throughout the postpartum period. Objective: We developed and tested a novel, integrated model of group postpartum care titled Focused-Postpartum Care (Focused-PPC) to improve outcomes. In this paper, we report clinical outcomes of participants in the intervention arm and differences in knowledge of postbirth warning signs among those in the intervention and control arms. Methods: Focused-PPC encompassed recommended clinical assessments, targeted education, and peer support up to 1 year after birth. Focused-PPC was implemented as a parallel randomized controlled trial involving 192 postpartum women across four health centers in Tamale, Ghana, from February 2022 to August 2023. Eligible participants 18 years or older with a live birth were randomly assigned to either the Focused-PPC intervention arm or the control arm at a 1:1 allocation and were not blinded to their allocation. At each health center, 48 participants were allocated to either an intervention or control arm. Focused-PPC groups in the intervention arm consisted of eight participants per group. Participants in the intervention arm received the Focused-PPC integrated group model of care. Participants in the control arm received the standard of postnatal care already administered at each health center. Results: Baseline analysis included 96 participants from the control arm and 91 participants from the intervention arm. We found that vital signs and clinical outcomes were relatively stable; however, incidences of hypertension substantially decreased among participants in the intervention arm. By 3 months postbirth, most participants in the intervention arm were able to identify all postbirth warning signs and retain this knowledge compared to the control arm. Those in the intervention arm were also knowledgeable of more warning signs at each time point compared to the control arm. Discussion: An integrated, evidence-based approach to postpartum care, such as Focused-PPC, has potential to increase knowledge and improve clinical outcomes among mothers in Ghana.
Taking the Next Step in Neurologic Rehabilitation: Contributions of Intensity and Variability of Stepping Tasks During Locomotor Training
(Oxford University Press, 2025) Hornby, T. George; Moore, Jennifer; Holleran, Carey L.; Henderson, Christopher E.; Physical Medicine and Rehabilitation, School of Medicine
Research over the past 20 years indicates the amount of task-specific walking practice provided to individuals with stroke, brain injury, or incomplete spinal cord injury can strongly influence walking recovery. However, more recent data suggest that attention toward 2 other training parameters, including the intensity and variability of walking practice, may maximize walking recovery and facilitate gains in non-walking outcomes. The combination of these training parameters represents a stark contrast from traditional strategies, and confusion regarding the potential benefits and perceived risks may limit their implementation in clinical practice. The purpose of this perspective is to delineate the evidence regarding the contributions of intensity and variability of locomotor training to improve mobility outcomes in individuals with acute-onset brain and spinal cord injury. The rationale and evidence supporting the utility of these training parameters in controlled laboratory settings is first described by integrating concepts in the field of neuroscience, motor learning, biomechanics, and exercise physiology into a rehabilitation intervention. Subsequently, the evidence supporting the efficacy of this paradigm is addressed, including discussions of some of the misconceptions regarding perceived negative consequences of these strategies in an effort to mitigate common clinical concerns. Finally, the utility of these strategies implemented during inpatient rehabilitation is delineated to facilitate a more comprehensive understanding of the feasibility and potential benefits early following neurologic injury. A greater understanding of how and why to integrate higher intensity, variable stepping practice will support therapists to take the next step to maximize mobility in the patients they serve.

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