bluuebunny/crossref_metadata_2025 huggingface dataset:
Silencing COQ8B in Aortic Smooth Muscle Cells Reveals Cellular Dysfunction Related to Changes in Cell Proliferation
Authors: Davis Joshua , Landis Benjamin
Published: January 2024

Background/Objective: Thoracic aortic aneurysm (TAA) is a prevalent disorder that predisposes to aortic dissection. Prior work identified the ubiquinone biosynthesis gene COQ8B as a genetic modifier of TAA progression. We sought to determine the impact of decreased COQ8B on global transcription in aortic smooth muscle cells (SMCs).
Methods: Primary human aortic SMCs from a healthy donor were seeded in 12-well plates. Six experimental conditions were created, each with 3 replicates: 1) siRNA targeting COQ8B (siCOQ8B); 2) siRNA targeting the dominant TAA gene SMAD3 (siSMAD3); 3) negative controlsiRNA (siNeg); 4) siCOQ8B and siSMAD3; 5) siCOQ8B with Angiotensin II (AngII) stimulation (siCOQ8B+AngII); 6) siNeg+AngII. RNA was extracted approximately 48 hours post-siRNA transfection and, for AngII conditions, after 1 hour of incubation with AngII (100 nM).  mRNAsequencing was performed and downstream analysis utilized R packages EdgeR and topGO.
Results: Multidimensional scaling identified distinct clustering of samples by experimental condition. Downregulated genes in siCOQ8B were enriched for Gene Ontology pathways related to cell proliferation including cell cycle regulators, DNA replication, and mitosis. MYOCD, a master regulator of SMC homeostasis, was downregulated. Similar proliferation-related pathways were enriched in siCOQ8B+siSMAD3 and siCOQ8B+AngII compared to siNeg. Pathways related to cell proliferation in siCOQ8B+AngII cells were downregulated when compared to siCOQ8B which indicates that AngII infusion in the context of COQ8B silencing may further dysregulate cell proliferation pathways.
Conclusion: The results indicate that COQ8B has an important role in cell cycle processes in aortic SMCs, including when SMCs are exposed to stressors associated with TAA development. Stimulation of angiotensin receptors may exacerbate the effects of decreased COQ8B in these processes. To investigate these experimental results in human pathology, bulk RNA samples and intact nuclei have been isolated from frozen human aortic specimens and prepared for transcriptomic analysis.
MicroRNA-150 (miR-150) as a Potential Biomarker for Diabetic Retinopathy
Authors: Smith Conner , Luo Qianyi , Mahajan Neha , Bhtwadekar Ashay
Published: January 2024

Diabetic retinopathy (DR) is a known chronic complication of diabetes mellitus and is one of the leading causes of visual impairment. The chronic inflammation associated with DR poses large risks not only for the vasculature but also for the surrounding neuronal tissue. Potential biomarkers, especially those surrounding microRNAs (miRNAs), have been proposed to indicate the progression of DR. Levels of certain miRNAs have been shown to be either down or upregulated in type 1 diabetes patients and have shown correlations with specific types of DR. MicroRNA-150 (miR-150) has also been shown to have protective effects on cells in hypoxic environments, but when downregulated, miR-150 actually induces apoptosis. And, it has been shown to be downregulated in patients with type 1 and type 2 diabetes as well as patients with obesity. We hypothesize then that the levels of miR-150 from a peripheral blood sample should be indicative of the progression of DR and may be used for potential early intervention. In this project, we assessed miR-150 levels in the peripheral blood mononuclear cells (MNCs) of individuals with different severities of DR by isolating mononuclear cells and extracting RNA. We then reverse-transcribed the RNA into cDNA and used RT-qPCR to measure the levels of miR-150 in individuals with varying DR severity. MiR-150 levels in the MNCS were decreased in individuals with diabetes with no retinopathy, moderate NPDR and severe NPDR groups when compared to control individuals; however, there was a marginal increase in the miR-150 mild NPDR group. The data could show evidence that a peripheral blood draw could be used as a less invasive approach to assessing the severity of diabetic retinopathy in patients. This would change the disease management and future treatments individually.
A Review of SNAP Nutritional Incentive Programs
Authors: Sogocio Dylan , Sawyer Antonia , Savaiano Dennis
Published: January 2024

There are over 40 million Americans in the Supplemental Nutrition Assistance Program (SNAP), formerly known as the Food Stamps Program. Despite this program attempting to eliminate food insecurity for people 130% below the poverty line, it does little to prevent nutrition related health disparities between SNAP participants and people who are more financially stable. Nearly every state has nutrition incentive programs attempting to address these nutritional health disparities that SNAP does not address. To synthesize a literature review of several of these programs, a search was conducted in PubMed, PubAg, and Google Scholar databases using terms such as “SNAP” and “nutritional incentive program,” along with date restrictions for 2013 or later. This search resulted in a total of 54 articles, however only 35 were used following screening. Included articles were screened first by abstract and then article content to determine relevancy. The literature suggests that programs address nutritional health disparities by providing financial interventions for SNAP participants to make nutritionally conscious decisions about the food they purchase and consume. There were three categories of interventions that were suggested by the literature: incentives, discounts, and restrictions. Regardless of the intervention, each of these categories of intervention were praised by SNAP participants. Participants were able to purchase and consume more fruits and vegetables, focus on nutrition, and financially support local farmers markets and supermarkets. This review discusses these different interventions to allow for new or existing programs to be developed to best address nutritional health disparities using scholarly evidence.
Induced Pluripotent Stem Cell-Derived Mesenchymal Stromal Cells Promote Muscle Regeneration in a Diabetic Mouse Model of Critical Limb Threatening Ischemia
Authors: Sualeh Ali , Doiron Theresa , Gil Chang-Hyun , Stashevsky Jennifer , Jimez Olivia , Chen Stone , Zhang Nancy , Samra Humraaz , Miller Steven J. , Murphy Michael P.
Published: January 2024

Critical limb threatening ischemia (CLTI), the end stage of peripheral arterial disease (PAD), is diagnosed in 500,000 patients each year, often results in amputation, and has a ~50% 5-year mortality rate. Diabetic CLTI patients experience especially high morbidity and mortality, and no effective non-surgical therapy exists for this population. Our Phase II MOBILE trial demonstrated that autologous bone marrow nucleated cells were unable to prevent amputations in diabetic patients; however, data from a Phase I trial shows that allogeneic bone marrow-derived mesenchymal stromal cells (BMD-MSC) stimulated angiogenesis in ischemic muscle, including diabetics. While allogeneic MSC may be an effective cell preparation to treat diabetic CLTI, passaging-related cell senescence prevents generation of sufficient cell numbers for therapeutic use. The development of induced pluripotent stem cell (iPSC)-derived MSC overcomes cell senescence issues and offers the possibility of genetic modifications to enhance cell function. The current study was designed to determine potential mechanisms by which iPSC-MSC stimulate muscle regeneration in a rodent CLTI model.
The CLTI mouse model was created by ligation/excision of the femoral artery in male polygenic diabetic TallyHo mice. Mice with intramuscular administration of iPSC-MSC displayed positive indicators of muscle regeneration compared to vehicle control mice. Real-time PCR performed with gastrocnemius muscle obtained 7- or 30-days post iPSC-MSC injection showed an increase in mRNA expression for MyH3, MyoD1, Mrc1, FoxP3, and VEGF-A vs. vehicle treated muscle, indicating promotion of muscle regeneration, M2-biased macrophage expression, T regulatory cell (Treg) expansion, and vascular proliferation. Downregulation of the NADPHoxidase subunit p47phox indicated a decrease in oxidative stress in the treated mice. The results are consistent with iPSC-MSC  promotion of muscle regeneration via a Treg mediated stimulation of the M1-M2 macrophage phenotypic shift. Thus, human iPSC-MSC could be an effective treatment to stimulate muscle regeneration and ameliorate CLTI in diabetic patients.
Parkinson’s Disease Progression: Exploring the Relationship between Motor Performance and Cognitive Function
Authors: Sullivan Megan E. , Shanghavi Aditya A. , Zauber Sarah Elizabeth , Sereno Anne B.
Published: January 2024

Background/Objective: Numerous studies have examined motor and cognitive decline in neurodegenerative diseases such as Parkinson’s Disease (PD) and results vary considerably. Studies also show that decline does not occur synchronously across all aspects of cognition or motor functions in PD. The goal was to examine if correlations exist between decline in specific motor and cognitive functions.
Experimental Design: A cohort of 15 PD patients (age 49-81;6 female) and 9 healthy controls (age 53-75;4 female) were enrolled and their motor and cognitive functions were assessed. Decline in motor function, covering tremor, rigidity and bradykinesia was evaluated using the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MS-UPDRS) scores. Cognition, covering attention, memory, language, and visuospatial functions, was assessed using the Montreal Cognitive Assessment (MoCA) test. Inertial measurement units (recording at 100 Hz), placed on both wrists, recorded linear acceleration and angular velocity while subjects performed the pronation/supination and kinetic tremor tasks of the MS-UPDRS. Using angular velocity, response time (RT) to initiate movement in each task was computed. Data analysis correlated MS-UPDRS scores with MoCA scores, and RTs.
Results: There were no significant correlations between MS-UPDRS and cognitive MoCA scores. There was a significant relationship between deficits in visuospatial function (MoCA) and increased RT in the pronation/supination task.
Conclusion/Potential Impact: Using correlation analyses, no correlation was found between MS-UPDRS and MoCA scores. However, RT on the pronation/supination task correlated positively with visuospatial deficits, suggesting a common voluntary attentional deficit. Although no relationship was found between a clinical score of bradykinesia and RT, measures of movement velocities (measured but not analyzed) may correlate better. Identification of interrelating factors between hard-to-measure cognitive and easy-to-measure motor changes in PD patients may aid clinicians in implementing simple and timely interventions to more easily track and ameliorate cognitive deficits and improve patients' overall functional status.
Social Determinants of Health Associated with Inpatient Admissions for Congestive Heart Failure, Diabetes, Chronic Obstructive Pulmonary Disease, and Asthma
Authors: Deckbar John , DeMichael Kelly , Gad Wael , Muvuka Baraka , Guerrero Jonathan
Published: January 2024

Introduction: The CDC and American Lung Association estimate that congestive heart failure (CHF), diabetes, chronic obstructive pulmonary disorder (COPD), and asthma (COPD/asthma) cost Americans $30.7 billion, $327 billion, and $50 billion respectively each year. They account for most inpatient readmissions at St. Mary Medical Center (SMMC), an urban hospital in Northwest Indiana. There is need for further research on the social, behavioral, and demographic determinants associated with these conditions. This study examined the social, behavioral, and demographic determinants associated with inpatient admission for CHF, diabetes, COPD/asthma in SMMC’s service area.
Methods: This retrospective study was part of a multi-phased Community-Based Participatory Research partnership between SMMC and Indiana University School of Medicine Northwest. SMMC implemented a pilot screening and referral program to assess social determinants of health in their service area as part of their Hospital Readmission Reduction Program. This study included data from 10,953 inpatient admissions between January 2021 to March 2023, majority of whom were transferred from the emergency department. Data analysis consisted ofunivariate, bivariate (Chi-square), and multivariate (binary logistic regression) analysis in SPSS 29.0.
Results: Bivariate analysis revealed a statistically significant association between CHF and smoking, age, insurance type, and income. Diabetes was significantly associated with smoking, smokeless tobacco use, age group, race, income, and sex. COPD/asthma was significantly associated with smoking, age group, transportation needs, stress, insurance, ethnicity, and sex. Multivariate analysis found the following significant associations: age group with both CHF (p<0.001) and diabetes (p<0.001), former smoking with both CHF (p = 0.007) and COPD/asthma (p = 0.049), current smoking with COPD/asthma (p = 0.016), and sex with diabetes (p <0.001).
Conclusions: These findings indicate significant associations between multiple sociobehavioral factors and admission for CHF, diabetes, COPD/asthma. Multi-risk-factor interventions may address these interactions and contribute to reducing readmission.
Osteoblast Transcriptome Changes During Iron Deficiency
Authors: Polaconda Shyam , Peng Gang , Clinkenbeard Erica
Published: January 2024

Introduction:Chronic kidney disease (CKD) often results in iron deficiency anemia and bone loss. Previously, iron deficiency was found to impede normal osteoblast differentiation. To investigate regulatory mechanisms elicited by iron deficiency we utilized unbiased RNA-sequencing to evaluate transcriptome-level changes over the course of differentiation.
Methods:Mouse progenitor clone 2 (MPC-2) cells were differentiated in osteogenic media with or without an iron chelator, deferoxamine (DFO; 5 μM). RNA was extracted at 3, 7, and 14 days after initiating differentiation. Library generation and sequence alignment was performed by the Center for Medical Genomics (CMG). Count-based algorithms implemented in R packages (edgeR and limma-voom; default parameters) identified differentially expressed genes between cells in the control and DFO treatment.
Results:RNA sequencing illustrated transcriptome changes due to iron deficiency including 63 upregulated/81 downregulated genes at day 3, 371 upregulated/780 downregulated genes at day 7, and 342 upregulated/739 downregulated genes at day 14. Importantly, day 14 controls clustered as transcriptional distinct whereas day 14 DFO treated cells clustered with early time points. As expected, genes involved in bone mineralization were suppressed with DFO including Dmp1 (logFC: -5.92, p= 5.7e-10) and Phex (logFC: -4.17, p= 5.5e-16). Interestingly, genes such as Ces2e, Gdf15, and Ano3, not previously found associated with osteoblasts, were significantly upregulated after 3 days with DFO (logFC: 5.14, 2.7, and 2.5 respectively).
Conclusions:Transcriptomic changes occur even within 3 days of exposure to iron deficiency. Next steps include performing functional enrichment analysis, and validating expression level changes in vitro as well as within in vivo models of CKD-mediated bone loss.
Scientific Impact and implications:Iron deficiency is intricately linked to impaired osteoblast function. Understanding the underlying molecular mechanisms could elucidate novel avenues for anabolic bone therapies in CKD.
Wearable Submental sEMG Sensors for the Treatment of Dysphagia; A Pilot Study
Authors: Zhang Albert Y , Hsuan Peng Ching , Berry Kevin , Malandraki Georgia A
Published: January 2024

Swallowing is a complex physiological process that is essential for survival and quality of life. When disrupted, it leads to oropharyngeal dysphagia. This is a common affliction which can have massive implications on health, including an increased risk for pneumonia and malnutrition.
Rehabilitative therapy is effective in improving swallowing function, but usually requires clinic visits with a speech language pathologist weekly or multiple times per week. Making treatment more accessible could improve follow-through among the disadvantaged patients with the greatest need for therapy.
To address this need, the Purdue I-EaT lab is developing a wearable submental surface electromyography (sEMG) sensor system (i-Phagia) for remote treatment of dysphagia. To evaluate the feasibility of using this device for a single-visit treatment, a pilot pre-post study is being conducted. Participants are evaluated with videofluoroscopic swallowing studies (VFSS) and sEMG before and after a 45-minute treatment session, involving two rehabilitative swallowing exercises, using i-Phagia. Following the post-treatment evaluation, feedback is collected regarding the tolerability of the sensor, including presence of any skin irritation. Outcome variables include normalized mean amplitude, time to peak amplitude of the sEMG signal, and patient satisfaction and safety.
As of now, five participants (ages 21, 21, 71, 69, 80) have participated. sEMG analysis was completed in four participants due to data loss for one. Pre-post sEMG analysis of neuromuscular activity showed an increase in normalized amplitude post-treatment in three of four analyzed participants. Four of five participants reported high satisfaction (average score 88/100) and one moderate, and all reported no pain (Wong-Baker pain scale).
These results show the feasibility and preliminary effectiveness of using the i-Phagia for in-clinic treatment visits in a small sample of healthy participants. Further research is ongoing to examine the feasibility for use in patients with Parkinson’s disease and for remote use outside of clinic.
Medicaid Reimbursement for Community Health Workers: A Comparative State Policy Analysis with Implications for Indiana
Authors: Wertz Kylie , Amstutz Julia , Scanlon Michael , Litzelman Debra K.
Published: January 2024

Background: Community health workers (CHWs) promote health education, address social determinants of health, and bridge the gap between healthcare systems and underserved populations, but the lack of sustainable funding remains a challenge to greater CHW utilization. Medicaid reimbursement has been identified as a promising mechanism to fund CHWs, however, state policies vary widely. A comparative policy analysis can guide future reimbursement strategies.
Methods: We conducted a comparative policy analysis of Medicaid reimbursement for CHWs. State government websites and legal databases were searched utilizing keyword search terms related to CHWs and Medicaid reimbursement. We identified and analyzed relevant statutes, regulations, and administrative codes for reimbursement mechanism, rates, supervision, certification, and scope of practice.
Results: 26 states currently reimburse CHWs through Medicaid; 3 states started reimbursement in the last six months. 16 states authorize payment through State Plan Amendments (SPAs), 3 use Section 1115 demonstration waivers, 10 use Medicaid managed care organization contracts, and 4 use blended strategies. 13 states require certification and supervision for reimbursement, although the supervising licensed professional can vary. The scope of practice of CHW also varies between states. There is a large range for reimbursement rates; for example, billing code 98960 currently used by 14 states varies from $9.70 in Indiana to $55.25 in Arizona for a 30 minute visit.
Policy Implications: This study can inform sustainable reimbursement models through Medicaid for CHWs in Indiana and other states. An SPA may be the most expedient way for Indiana to increase reimbursement for CHWs, but its narrowness and inflexibility could hinder CHWs' positive impact. The variety of strategies currently in use demonstrates that there is no single path to sustainable financing. Protocols for a set of scoping reviews will result from this comparative analysis for more in-depth investigations of key peer-reviewed and grey literature.
Investigating the Modulating Effects of Tirzepatide on NAFLD/NASH Progression Using 3D Human Liver Organoids
Authors: Wei Barry , Le Thi M.U. , `Catron Evan J. , Passarelli Robert P. , Li Ping , Zhang Wenjun , Ekser Burcin
Published: January 2024

Background: Nonalcoholic fatty liver disease (NAFLD) is a disease characterized by the accumulation of lipids in the liver that ultimately progresses to nonalcoholic steatohepatitis (NASH) and cirrhosis. Currently, there is no known FDA-approved treatment for NASH. Tirzepatide (brand name Mounjaro), a glucagon-like peptide 1 (GLP-1) agonist, has been hypothesized to have potential effects in reversing NAFLD/NASH progression and restoring liver function. However, this hypothesis remains untested in current literature. The aim of this study is to use 3D human liver organoids (3D-HLOs) as an ex vivo model system to determine the potential effects of tirzepatide on the progression of NAFLD/NASH.
 
Methods: 3D-HLOs were constructed by incorporating 5 major human hepatic cell types isolated from NAFLD livers, including hepatocytes, hepatic stellate cells, liver endothelial cells, cholangiocytes, and Kupffer cells. NAFLD 3D-HLOs were maintained in the hepatocyte medium supplemented with 50mM free fatty acid (FFA) only (control group) or FFA+tirzepatide (100nM, 200nM, or 500 nM) for 14 days. By the end of the treatment, 3D-HLOs were subjected to BODIPY493/503 staining to determine lipid droplet accumulation. Immunofluorescence staining and confocal microscopy analysis were performed to confirm hepatocyte function (ALBUMIN) and fibrosis (COL1A1). qPCR was performed to determine the relative expression markers of hepatocyte function (ALBUMIN, HNF4A), angiogenesis (PECAM-1, VCAM-1, ICAM-1), and fibrosis (ACTA2, COL1A1).
 
Results: BODIPY 493/503 revealed no significant difference in lipid deposition between 3D-HLOs in all treatment groups. Mean immunofluorescence staining intensity for albumin in controls, 100nM, 200nM, and 500nM tirzepatide were 154.4, 181.4, 221.1, and 236.4, respectively (p>0.05). Dose-dependent quadratic regression revealed a strong correlation between dose and albumin fluorescence intensity (R2 = 0.963). qRT-PCR analysis revealed that tirzepatide treatment did not significantly alter transcriptional levels of ALB, HNFA4, ACTA2, PECAM-1, VCAM-1, and ICAM-1 compared to the control group.
 
Conclusion: Although there is no statistically significant difference in liver cell function markers at different tirzepatide dosages in the setting of NAFLD/NASH, the highest dose of tirzepatide improved ALB expression despite ongoing FFA exposure, indicating a potential hyperbolic relationship between tirzepatide concentration and albumin production. Future investigation with altered treatment duration and dosage will elucidate whether there are any direct modulating effects of tirzepatide on NAFLD/NASH progression.
Factors Affecting General Surgery Intern Wellness: A Qualitative Study
Authors: Bear Payton , Blackwell Madeline , Stefanidis Dimitrios
Published: January 2024

Background:Surgical training is demanding and presents numerous challenges to new interns including long working hours that can threaten their well-being. The factors affecting their well-being as reported by interns themselves, are however, poorly understood. This qualitative study aimed to determine the factors contributing to the wellness of general surgery interns, and identify potential areas that could benefit from intervention and policy reform.
Methods:A comprehensive scoping review of the literature on resident wellness was initially performed, using "resident" and "wellness" as search criteria on PubMed, and encompassing articles published from 2013 onward. The results of this review were used for the development of an interview guide for in-person focus groups. General surgery interns at Indiana University participated in focus groups that were recorded and transcribed. Two coders coded the transcript independently to develop a code book. Thematic analysis was conducted using a constructivist grounded theory methodology to determine emergent themes.
Results:Ten surgical interns participated in the focus groups. Qualitative analysis revealed five predominant themes that impact intern wellness: Lack of respect, inadequate facilities and resources, lack of fulfillment, work overload, and poor communication.
Conclusions:The themes identified reveal numerous factors that impact intern wellness beyond working hours and pay and provide targets for interventions that can address them. Our results suggest that “one-size fits all” wellness solutions are unlikely to address the specific challenges faced by surgical trainees; multifaceted interventions are required to enhance intern well-being. Future research should focus on the development and implementation of targeted strategies to address these identified issues.
Neurovascular Conditions and Associated Socio-Demographic and Behavioral Factors in an Urban Hospital in Northwest Indiana
Authors: Jones Brendan , Chandler Brianna , DeMichael Kelly , Muvuka Baraka , Guerrero Jonathan , Gosporadek Kyle
Published: January 2024

Background: Brain health equity remains an underexplored research area despite high prevalence of neurovascular conditions and related health impacts. This study examined the associations between socio-demographic, behavioral factors, and hospital admissions for neurovascular-related morbidity in an urban underserved community. It is part of a multi-phased Community-Based Participatory Research (CBPR) partnership between Indiana University School of Medicine-Northwest and St. Mary Medical Center (SMMC) to examine the prevalence, distribution, and relationships between social determinants of health (SDOH), demographics, health behaviors, and health outcomes in Northwest Indiana.
Methods: This retrospective study analyzed a limited dataset generated by SMMC from EPIC™ with SDOH, demographic, behavioral and health outcomes data for adult inpatient visits from January 2021 to March 2023. Neurovascular admission was determined by ICD-10 Codes I67-69. Data analysis was conducted in SPSS 29.0 using descriptive statistics (i.e., frequencies and central tendency), bivariate analysis (Chi-square; p<0.05), and multivariate analysis (binary logistic regression; p<0.05). This study received exemption from Indiana University Human Research Protection Program (IRB #14040).
Results: There were 1,489 participants included in this study. The majority were white (77.7%), older adults (67 ± 21.5) and publicly insured (77.8%). The bivariate analysis demonstrated significant relationships between admission for neurovascular conditions and age group (p<0.001), veteran status (p<0.001), insurance type (p<0.037), and physical activity (p<0.001). After adjusting for these factors in multivariate analysis, age group (p< 0.003) and physical inactivity (p<0.008) were significantly associated with admission for neurovascular conditions.
Conclusion: Understanding how SDOH and behavioral factors influence neurovascular admissions and inequities in urban settings will enhance collaborative efforts to develop, implement, and evaluate evidence-based interventions. The subsequent CBPR phases will utilize these findings to explore how socioeconomic status affects these patients’ ability to seek emergent and/or surgical care. This will enable implementation of strategies that better account for SDOH in patient care.
Inhibition of HSF1 as a Mechanism for Overcoming Hsp90 Treatment Resistance
Authors: Chastain Zachary , Williams Imade , Ulhaskumar Vrushabh , Wang John , DeHart Haddie , Ray Haimanti , Carpenter Richard L.
Published: January 2024

Hsp90 inhibitors have been attempted as a targeted therapy with poor results. Despite numerous clinical trials, there are currently no FDA approved Hsp90 inhibitors available. It is known that Hsp90 sequesters HSF1 in the cytoplasm to suppress HSF1 activity, an oncogenic transcription factor. We hypothesize that HSF1 activation in response to Hsp90 inhibition is a significant reason that previous Hsp90 inhibitors have failed. Once released, HSF1 enters the nucleus and drives expression of many processes that promote the initiation and progression of tumors. This hypothesis was tested by evaluating the response of cancer cells to Hsp90 inhibition with or without combined inhibition of HSF1, thereby removing HSF1 activity as a consequence of Hsp90 inhibition. We observed synergy between Hsp90 inhibition (17-DMAG) and HSF1 inhibition (KRIBB11) from calculation of combination index in ovarian cancer cells (OVCAR8) and breast cancer cells (BT474). This synergy observed in cell viability assays were further reinforced in spheroid formation and clonogenic growth assays where the combination of these inhibitors had a greater effect than either treatment alone. These results further support the hypothesis that Hsp90 inhibition efficacy is mitigated by increased HSF1 activity and that HSF1 inhibitors synergize with Hsp90 inhibitors to improve their efficacy.
Health Disparities in Acidosis Risks
Authors: Gatz Allison , Xiong Chenxi , Li Xiaochun , Eadon Michael , Su Jing
Published: January 2024

Background: Health disparities in acidosis risk are entangled with a range of factors including clinical conditions, genomic traits, and demographic features. Current clinical guidelines and policies on the safety of metformin have not yet taken holistic considerations of health disparities and other risk factors. The All of Us (AoU) research dataset provides comprehensive information including longitudinal real-world data for diseases and treatments, genetic data, and surveys for social determinants of health, with a focus on minority groups and the underserved population. This study leverages the AoU data to understand the health disparities in acidosis risk and provides real-world evidence to support clinical decisions.
Methods: A case-control design was used to identify risk factors associated with emergent acidosis events, with a 1:4 matching using propensity scores specified by enrollment date, number of diagnoses, and length of medical history. Risk factors were sex, age, race, ethnicity, metformin use, Charlson comorbidities, and insurance status. Adjusted odds ratios (aOR) were estimated using conditional logistic regression.
Results: The study includes the case group (n=2,666) and the control group (n=10,664). Health disparities were observed among participants. Compared with those who did not have health insurance, those with employer provided insurance (aOR: 0.49, 95%CI: 0.40 – 0.61), Medicare (aOR: 0.62, 95%CI: 0.52 – 0.74), or Medicaid (aOR: 0.80, 95%CI: 0.66 – 0.97) were less likely to develop acidosis. African Americans (aOR: 1.35, 95%CI: 1.15 – 1.58) showed higher acidosis risk. Other major risk factors include liver disease, renal disease, diabetes, and metformin use.
Conclusion: Health insurance coverage is a major determinant of acidosis risk. Patients with kidney and liver diseases or diabetes should be monitored carefully for signs of acidosis, especially if they have been prescribed metformin. In future work, for diabetes patients with both kidney and liver diseases, pharmacogenomics analysis will be performed for precision management of metformin-related acidosis risks.
Racial Disparities in Childhood Vaccination Rates
Authors: Hayhurst Neal , O’Neill Meagan
Published: January 2024

Background: Despite the high efficacy and safety of routine vaccinations, most of the United States is currently falling well short of the Healthy People 2020 goals for childhood vaccination rates. A large racial disparity exists within the IU Health (IUH) system, with about a 26% difference between Black/African American (BAA) and white patient vaccination rates as of 2022. Within IUH, the most commonly missed appointment is the 4-month well child check, a critical appointment for staying up to date on vaccinations. In response to this disparity, a pilot program was launched to assist BAA patients in scheduling, attending visits, and getting vaccinated. This study also investigates the roles of insurance, race, ethnicity, and gender in racial disparities of routine vaccination rates among IU Health pediatric patients at the Riley Pediatric Care Center (PCC).
Project Methods: A cohort of patients at the PCC clinic who were not meeting vaccination recommendations were compared to the PCC patient population as a whole to identify drivers of under-vaccination. These patients were also compared to patients within the pilot vaccination program to assess program efficacy in scheduling and attending 4-month well child checks.
Results: The largest differences between the cohort not meeting the vaccination measure and the PCC patient population were race and insurance status. Patients not meeting vaccination recommendations were more likely to be BAA and to use Medicaid. The pilot program patient population had much higher rates of attendance at 4-month well child checks and vaccination rates for rotavirus among BAA patients than the IUH BAA patient population as a whole.
Conclusions: The data from this study will help identify drivers of racial disparities in vaccination rates and guide data-driven and community-informed interventions to ameliorate the disparity. The pilot program has shown great success and warrants strong consideration for increased investment and expansion.
Comparison of Wound Outcomes for Absorbable versus Non-absorbable Suture after Carpal Tunnel Release
Authors: Harmon Cameron , Gross Jeffrey N. , Adkinson Joshua M. , Christie Brian
Published: January 2024

Background and Hypothesis:Carpal tunnel release (CTR) is a common hand surgery procedure. Despite the large volume of CTRs performed worldwide (400,000-600,000 cases/year), there is no consensus as to the optimal suture material for incision closure. In this study, we sought to compare outcomes of absorbable and non-absorbable suture for skin closure after CTR. Our hypothesis was that that there is no statistically or clinically significant difference in wound-related outcomes between the cohorts.
Project Methods:All patients who underwent primary open carpal tunnel release (CTR) at a large, public county hospital in Indianapolis, IN were identified by CPT code (64721). All patients were treated by one of two fellowship-trained hand surgeons. The most recent 50 patients treated between September 2022 and May 2023 by each surgeon were identified. Surgeon “A” uses 4-0 vicryl rapide for closures (absorbable). Surgeon “B” uses 4-0 nylon for closures (non-absorbable). Adverse events (AE) were defined as infection, dehiscence, or suture granuloma observed at any follow-up appointment. This study was approved by the Institutional Review Board.
Results:100 patients were identified - 4 patients were lost to follow-up and were excluded from the study. Of the remaining 96 patients, 46 received absorbable suture and 50 non-absorbable suture. Of the 46 patients who received absorbable suture, 8 experienced AE (17.4%). None of the 50 patients who received non-absorbable suture experienced an AE. There was a statistically significant difference in AE between the absorbable and non-absorbable suture cohorts (p=0.002). Patients with absorbable suture averaged 1.61 follow-up appointments, whereas those with non-absorbable suture averaged 2.32 (p=.0008).
Conclusion and Potential Impact:In this study, absorbable suture resulted in more wound-related complications after CTR. However, patients with non-absorbable suture had more post-operative follow-up appointments. These findings should be considered when selecting suture material for skin closure after CTR.
Analysis of the Binding Partners of Clusterin in their Role in Increased Intraocular Pressure in Glaucoma
Authors: Hepp Clay , Magesh Anoop , Soundararajan Avinash , Pattabiraman Padmanabhan
Published: January 2024

Background and Objective:Elevated intraocular pressure (IOP) is a risk factor for primary open-angle glaucoma (POAG). Clusterin (CLU) is a secretory chaperone protein found in trabecular meshwork tissue that is implicated with POAG risk. In this study, we aimed at understanding the role of CLU and its binding partners in IOP homeostasis and POAG pathology.
Methods:Normal trabecular meshwork (NTM) cell lines were used. Half of the NTM cell lines were transfected with adenovirus empty (AdMT) while the other half of the NTM cell lines were transfected with adenovirus clusterin with histidine tag (AdCLUHIS). AdCLUHIS allows for the overexpression of CLU HIS in the NTM cells. After 72 hours of transfection, the media and cell lysate were collected. As CLU is a secretory chaperone protein, the media was analyzed. Immunoprecipitation (IP) was conducted to isolate CLU HIS and all the proteins bound to it. Western blot analysis was conducted to confirmed IP worked successfully. Once it was confirmed that CLU HIS with all its binding partners was isolated successfully using IP, the media samples were sent to proteomics to determine all the specific proteins that are bound directly to CLU.
Results:Western blot analysis confirmed that the overexpression of CLU HIS was successfully accomplished through adenovirus transfection. In addition, Western blot analysis confirmed that IP worked successfully. At the current moment, results of proteomics are still being developed, so the specific binding partners of CLU are still unknown at the time.
Conclusions and Potential Impact:Our preliminary study suggests that CLU can be overexpressed via adenovirus and analyzed via IP. Understanding this allows for the purification of the protein and its attached binding partners. Identifying these binding partners can be novel targets for improving aqueous humor outflow through trabecular meshwork to decrease IOP and decrease one’s risk for POAG.
Clinical Uses of Nanopore Sequencing in Recurrent Acute and Chronic Otitis Media
Authors: Holtzlander Ben , Burgin Sarah , Perkins Grace , Lei Guang-Sheng , Davis Thomas
Published: January 2024

Background. Otitis Media (OM) is a widespread problem that has an incidence of 10.85% worldwide, 51% occurring under the age of 5. Emergence of drug resistant bacteria contribute to high incidence of recurrent acute otitis media (AOM) and chronic otitis media with effusion (COME). Despite this, the standard of care for treatment is empiric antibiotics. Molecular microbiology diagnostics may enable clinicians to provided pathogen directed antibiosis. Nanopore sequencing is a highly accurate method of identifying a broad range of pathogens when compared with multiplex PCR. We hypothesize that nanopore sequencing is an effective method for detection of pathogens in the middle ear and nasopharynx of patients with recurrent or chronic OM.
Methods. Bacterial Culture, multiplex PCR (BioFire PNA panel), and nanopore sequencing (MinIon, Oxford Nanopore Technologies) were tested on 60 middle ear and nasopharynx samples. Chi-Square test was used to examined differences in bacterial identification among the methods.
Results. Bacterial identification using nanopore proves to be more sensitive in identification of 16 of the 18 unique pathogens when compared with multiplex testing. Of the 5 most common OM bacterial pathogens (S. pneumoniae, M. catarrhalis, H. influenza, S. aureus, P. aeruginosa), nanopore identified 3 pathogens (S. pneumoniae, M. catarrhalis, P. aeruginosa) at higher levels, 1 at the same rate (H. influenza), and 1 did not receive any readings (S. aureus).
Conclusion. This is the first study to utilize nanopore sequencing to assess pathogens in the middle ear fluid of children with OM. While nanopore genomic sequencing is still in the early stages of use, it has potential to comprehensively identify bacteria with more sensitivity when compared to the current clinical standards. The next step of data analyzation will include bacterial identification in nanopore that multiplex PCR and traditional bacterial cultures cannot test for.
Long-Term Outcomes in Stage II/III Thymic Epithelial Tumor Patients Treated with Post- Operative Radiotherapy
Authors: Lavu Nikhitha , Anand Aneesha , Loehrer Patrick J. , Kesler Kenneth A.
Published: January 2024

Thymic epithelial tumors (TETs) are rare malignancies that originate in the anterior mediastinum. Unlike other tumors of the chest, TETs recur most often in the pleura. The primary treatment of early stage TETs is surgical resection, with the role of adjuvant chemotherapy/radiotherapy controversial. Mixed results have been reported as to whether postoperative radiotherapy (PORT) decreases tumor recurrence or time to recurrence, but PORT can cause short-term and long-term toxicity. Therefore, assessing the benefit of PORT is important. For the present retrospective study, we created a database of stage II/III TET patients seen at Simon Cancer Center from 2000-2023 to examine long-term outcomes. Of the 214 stage II/III TET patients that underwent surgery in the database, 67 patients treated with PORT were isolated. Subsequently, 67 patients who did not receive PORT were matched to the PORT population based on similarities in histology, surgical margins, and chemotherapy received. Local vs. distant tumor recurrence, long-term complications, and overall survival were then compared. The PORT population had the following histologic distribution: 3 Type A, 3 Type AB, 47 Type B1/B2/B3, and 14 carcinoma; for the non-PORT population: 8 Type A, 13 Type AB, 36 Type B1/B2/B3, and 10 carcinoma. There were 16 stage IIA, 6 stage IIB, and 45 stage III patients in the PORT population, and 17 stage IIA, 9 stage IIB, and 41 stage III patients in the non-PORT population. The PORT population had 57 recurrences, whereas the non-PORT population had 20 recurrences (p=1.02 x 10-9). The PORT population had 5 deaths and 50 instances of long-term complications, while the non-PORT population had 3 deaths and 25 instances of long-term complications. Overall, these data do not support the routine usage of PORT in resected Stage II/III TET. Further analysis in larger data sets are warranted.
Tobacco smoking and early onset cataracts
Authors: Uddin Albab , Gross David
Published: January 2024

Background and Hypothesis:Cataracts are among the leading causes of blindness in the world. Smoking tobacco has been linked to cataract formation in old age. However, its linkage in causing an earlier onset is much more questionable. Assessing this linkage can help identify risk factors and help understand the causes and pathogenesis in development of cataracts over time. This can help direct modifiable risk factors in patients to prevent early deterioration in health, finance, physical capabilities, and overall comfort. It is hypothesized that history and intensity of smoking tobacco correlates with earlier onset cataracts.
Experimental Design or Project Methods:Patient data of patients aged 40-65 were gathered from the last two years of cataract surgeries from Deen-Gross Eye Centers EMR (n=718). Age at date of surgery was used as observed value for determining earlier onset, and pre-operation charts were used to collect patient data on smoking status (light, someday, every day, heavy, former, never), age, gender, hypertension, diabetes, number of eyes operated on, family history (cataracts/glaucoma), and glaucoma. Statistical analysis was performed among the gathered data.
Results:Statistical analysis revealed no significant difference in the ages of cataract surgeries between smokers and non-smokers. Controlling for non-hypertensive and non-diabetic patients revealed a similar result. There was no significant difference in smoking status between ages 40-55 and ages 56-65 who underwent surgery. There was no significant difference in age of surgery among each of the individual types of smokers.
Conclusion:No significant associations were found. This calls for further research to better understand the linkage between tobacco smoking and cataracts, as well as the pathogenesis of earlier onset cataracts. No modifications in directing patient care can be made yet.
Fracture-Induced Effects on the Onset & Progression of Alzheimer’s Disease
Authors: Wang Hannah S. , Scott Elizabeth , Nazzal Murad K. , Varner William A. , Parker Reginald , Margetts Tyler J. , Harris Alexander , Morris Ashlyn J. , Karnik Sonali J. , Blosser Rachel J. , Creecy Amy , Mostardo Sarah , Dragisic Marko , Fehrenbacher Jill C. , Fischer Kathryn D. , Movila Alexandru , Oblak Adrian L. , Kacena Melissa A.
Published: January 2024

Alzheimer’s disease and related dementias (AD/ADRD) are multifactorial, highly heterogeneous, and complex age-dependent disorders that severely affect memory and cognitive function, impacting nearly 35.6 million people worldwide. In the elderly, dementia increases the risk of falls and fractures by 2-3 times, due in part to neurovascular instability, low bone mineral density due to pre-existing osteoporosis, and poor musculature supporting joints due to cachexia and/or sarcopenia.
While the occurrence of fractures due to AD/ADRD is well documented, an association between fractures and AD/ADRD onset or progression is underappreciated and warrants additional investigation. We aim to investigate the mechanistic actions underlying fracture healing as a precipitating event for AD/ADRD pathogenesis.
Four-month-old, male, 5xFAD (AD model) and wild-type control (C57BL/6) mice were divided into 2 groups: surgically induced femoral fractures and uninjured mice. Prior to surgery mice underwent baseline AD behavior testing including: spontaneous alternation in the y-maze, light-dark exploration in the open field, and active place avoidance assays. Mice are undergoing weekly x-ray imaging to monitor fracture healing progression and longitudinal AD behavior testing. 22 weeks post-surgery mice will be euthanized, and femurs and brains collected. Femurs will undergo uCT imaging and histological assessment of bone healing and immunohistochemical assessment of inflammatory markers. Brains will be processed for histology and neuroinflammatory marker analysis, including Aβ plaque deposition, tau tangles, neuronal survival, neurogenesis, and activation/proliferation of microglia and astrocytes.
At the conclusion of the study, we expect to see an increase in neuroinflammatory markers and delayed fracture healing in the experimental 5xFAD group. We anticipate that compared to uninjured controls, femoral fracture results in cognitive decline, Aβaccumulation/neurodegeneration, increases in neuroinflammation, and vascular impairment. We anticipate finding a correlation between fracture and worsened AD outcomes. By uncovering the mechanisms underlying this relationship, we hope to guide future studies to develop more robust therapeutics.