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Hypoxia Gene Networks in Gliomas
Get PDFBackground and Hypothesis:Gliomas are the most common primary brain tumor and range from low grade to high grade, with glioblastomas (GBM) being the most aggressive. Translation of therapies for these tumors from preclinical models to clinical practice has been limited. Preclinical studies are typically performed in ambient air (21% oxygen), while physiological oxygen tension (physioxia) is 3-5%. Extracranial tumor tissue processed in physioxia demonstrates distinct gene expression profiles and chemoresistance as compared to the same samples processed in ambient air. However, the role of varying oxygen tension in gliomas has not been well studied. GBMs often have areasof necrosis with presumed low oxygen tension, while these findings are typically absent in lower grade gliomas. In this study, we examine expression of hypoxia related genes in patient samples obtained from grade II, III and IV gliomas. We hypothesize that increasing tumor grade will be associated with differential expression of hypoxia-related genes.
Methods:Gene expression in patient brain tumor samples (glioblastoma, high grade astrocytoma, low grade astrocytoma) and normal brain samples (from epilepsy surgery) was assayed using real time PCR. Hypoxia-related gene expression was examined in cBioPortal for Cancer Genomics by comparing survival in the top-expressing and bottom-expressing quartile for these transcripts.
Results:Patient samples were screened for differences in gene expression with greater than two-fold upregulation in GBM as compared to normal brain tissue. Expression level of one of these genes, ADM, was significantly associated with survival in patients with GBM (p<0.05). Additional differences between grades of glioma will also be presented.
Potential Impact:This work demonstrates differential expression of hypoxia-related gene transcripts in gliomas. The next step is to assess differences between patient samples processed in differing oxygen tensions to assess efficacy of chemotherapeutics and gene expression in samples that have never been exposed to ambient air
Development of a Novel Atherosclerotic Heart Disease Biomarker Program
Get PDFBackground: Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of heart attack, stroke, and sudden death worldwide. Clinical risk scores help estimate the likelihood of adverse cardiac events to guide preventative strategies. Current risk scores for atherosclerotic events like heart attack and stroke use known cardiovascular risk factors including smoking, diabetes, lipid levels, and blood pressure. However, these scores underestimate risk in certain patient populations and do not predict the atherosclerotic disease in individual patients that leads to subsequent events. Our aim is to design a novel biomarker-enabled model to predict the presence and burden of coronary artery atherosclerosis in patients with diabetes, to ultimately help personalize preventive therapies that target disease burden, not just risk factors, for more effective prevention of ASCVD events.
Methods: Patients with diabetes have been prospectively enrolled in a health plans-based screening program with co-enrollment in the Indiana Biobank, which includes coronary CT angiography, an AI-based quantitation of atherosclerosis, and biobanking of DNA, plasma, and serum. We identified candidate biomarkers based on current literature and determined which could be impactful based on cost, efficacy, and feasibility of implementation guided by interviews with potential collaborating entities.
Results: We have identified polygenic risk scores, non-coding RNAs and candidate blood biomarkers with predictive potential for atherosclerotic heart disease. Subsequent work will entail i) direct assays of banked biospecimens for the selected minimally invasive biomarkers and ii) computational analysis to assess incremental predictive value for disease burden over clinically available risk scores.
Conclusions and Potential Impact: We are progressing towards the development of a novel mode to predict patient-specific burden of coronary atherosclerotic disease burden in patients with diabetes. We expect that a multidimensional approach including contemporary biomarkers will improve predictive value of atherosclerotic heart disease burden, affording more tailored treatment to prevent ASCVD events
Parkinson’s Disease Progression: Exploring the Relationship between Motor Performance and Cognitive Function
Get PDFBackground/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\u27s 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\u27 overall functional status
Health-Related Quality of Life Correlates with Bladder and Bowel Dysfunction: the Need for a New Patient-Centered Questionnaire
Get PDFBackground and Hypothesis: Children with voiding dysfunction (VD), such as incontinence or urinary frequency, may report lower quality of life (QOL) compared to their peers. QOL questionnaires which could be used in this population have several limitations. PinQ is a bladder-specific, health-related QOL questionnaire, but it was developed without stakeholder input and fails to separate symptoms from QOL. Kidscreen-10 is a generic QOL questionnaire. We aimed to understand how QOL captured using existing instruments correlates with VD severity in a cross-sectional study. We hypothesized that large differences in symptoms would correspond with large differences in bladder-specific QOL but small differences in generic QOL.
Methods: We recruited children 8-18 years old with VD at a pediatric urology clinic (June-July 2023). VD included daytime incontinence, enuresis, frequency, urgency, and dysuria. We excluded children with severe developmental delay, anatomical urological abnormalities, or history ofurologic surgery. We captured demographics, symptoms (Vancouver Dysfunction Voiding Symptom Score, DVSS), and QOL (PinQ and Kidscreen-10). Questionnaire scores were compared to weighted means from previous studies. We calculated Spearman correlations and QOL differences corresponding with the reported 20-point range of DVSS scores.
Results: Twenty children (11 girls) at a median age of 10 years old participated (Table 1). Mean DVSS score was 14, similar to previous studies (weighted mean: 15). PinQ scores had a moderate positive correlation with DVSS scores (r = 0.37) with a 20-point DVSS difference corresponding to a 24% difference in PinQ scores (Figure 1). Kidscreen-10 scores had a moderate negative correlation with DVSS scores (r = -0.33) with a 20-point DVSS difference corresponding to a 12% difference in Kidscreen-10 scores (Figure 2).
Conclusions: Previously published QOL questionnaires have significant limitations, limiting their clinical use in the care of patients with VD. A new, patient-centered, highly specific, and sensitive healthrelated QOL questionnaire is needed
Identifying Socio-Demographic and Behavioral Predictors of Prolonged Hospital Stay in an Urban Hospital in Northwest Indiana
Get PDFBackground: Hospital length of stay (LOS) is a crucial metric that impacts patient outcomes, healthcare resource utilization, and financial burden. In 2019 the CDC reported the average LOS in community hospitals was 5.4 days. Prolonged LOS is associated with an increased risk of hospital-acquired infections, decreased hospital bed availability limiting patient access to care, and cognitive impairment, particularly among the elderly. This indicates the importance of addressing LOS as a healthcare priority. This study examined the relationship between LOS and social determinants of health (SDOH), patient demographics, health behaviors, and health outcomes as part of a long-term Community Based Participatory Research partnership between IUSM-NW and St. Mary Medical Center (SMMC).
Methods: This retrospective study analyzed EPIC™-generated data for adult inpatient visits at an urban hospital in Northwest Indiana from January 2021 to March 2023. Data analysis was performed using SPSS 28.0, consisting of descriptive statistics, bivariate analysis (One-way ANOVA, Independent T-tests, Kruskal Wallis H; p<0.05), and Simple Linear Regression. This study was granted an exemption by the Indiana University Human Research Protection Program (IRB #14040).
Results: The sample comprised of 10,916 predominantly white (77.7%) patients with a median age of 65 (IQR=22) and a median LOS of 4 days (IQR= 5). Bivariate analysis revealed LOS was significantly associated with age (p<0.001), race (p<0.033), sex (p<0.012), insurance type (p<0.001), physical inactivity (p<0.001), and smoking tobacco (p<0.001). After controlling for all factors in the multivariate analysis, age (p<0.020), physical inactivity (p<0.013), and insurance type (p<0.013) retained their significance.
Conclusions: These findings highlight the significance of demographic, behavioral, and social factors in relation to hospital LOS. Understanding these factors holds immense potential to guide the development of targeted interventions and healthcare strategies to optimize patient care and reduce LOS
Neighborhood Disadvantage and Healthcare Utilization in Pediatric Sickle Cell Patients
Get PDFBackground: Sickle cell disease (SCD) is a complex heritable blood disorder associated with higher acute healthcare utilization further complicated by psychosocial and socioeconomic factors. Other studies have indicated a relationship between neighborhood disadvantage and increased healthcare utilization. We hypothesize that those with greater neighborhood disadvantage will have greater acute healthcare utilization.
Methods: Data was collected retrospectively from the electronic medical record between 9/30/2021 and 7/11/2023 for patients followed at Riley Hospital for Children’s Pediatric SCD Clinic who completed a psychosocial needs assessment (PAT). Number of emergency department (ED) visits, hospitalizations, and missed clinic visits were collected from the time the PAT was completed up to 1 year after (or the end of the data collection period). Data regarding area deprivation index (ADI) and childhood opportunity index (COI) were collected utilizing patient home address. Descriptive statistics were performed on all data above, as well as t-tests and chi square tests for univariate analyses.
Results: 142 patients completed a PAT during the study period. 88% had a primary care provider documented, and 73% had public insurance. The median state and national ADI (6, 76.5) and COI (2, 2) demonstrated greater neighborhood disadvantage and less childhood opportunity. There was no statistically significant difference between ADI or COI and number of ED encounters or hospitalizations. However, patients who missed 1 or more SCD visits had a higher median state ADI than those who did not miss a visit (7.5 vs 5, p=0.002). Median state COI was also lower in this group than those who did not miss a visit (1 vs 2, p=0.001).
Conclusion: Those with higher ADI and lower COI could benefit from more directed support to improve access to preventative care visits. Further analysis accounting for comorbidities (seizures, asthma, depression) could disambiguate a relationship between ADI or COI and acute care utilization
Racial Disparities in Childhood Vaccination Rates
Get PDFBackground: 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
Development of Assistive Devices for Eye Drop Administration in Patients with Cerebral Palsy
Get PDFBackground:Cerebral Palsy is a non-progressive neurological disorder that affects movement, posture, and muscle coordination, caused by damage to the developing brain. It is one of the most common motor disabilities in childhood, with significant implications for an individual\u27s physical and functional abilities. The severe impact on fine motor control in Cerebral Palsy patients is often most evident when performing actions where precision and accuracy are needed such as applying eye drops. This work addresses the design, development, and deployment of assistive devices for fine motor control of objects.
Methods:Using 3D modeling and printing, three prototypes were created and assessed for their efficacy in assisting patients with eye drop administration based on the needs and abilities of the individual, considering factors such as ease of use, affordability, and adaptability to different environments. After evaluation, changes were made to each prototype in order to better adapt the design according to the feedback received.
Results:Three final products were presented for patient review. Two of these addressed deficiencies of eye drop accuracy and the other fine motor control and bottle manipulation. Patients noted in their final evaluation of the assistive devices improvement in ability to manipulate eye drop bottles as well as better ability to aim the eye dropper for application in comparison to previous methods of application.
Conclusion and Impact:By understanding the challenges faced by the individual and evaluating the need for assistive devices, the fine motor challenges associated with eye drop administration due to cerebral palsy were addressed and three valuable products were created that improved patient autonomy and quality of life. Additionally, these devices could be useful for patients with a variety of motor limitations, enabling self-sufficiency while improving ease and accuracy of administration and minimizing waste
The Relationship Between Intensive Care Unit (ICU) Delirium Severity and 2-Year Mortality
Get PDFBackground:Delirium is an acute brain dysfunction characterized by altered cognition, attention, and level of consciousness. The presence of delirium is associated with increased risk of mortality, neurocognitive decline, and physical impairment; however, the role of ICU delirium severity in long-term health outcomes is less understood.
Objective:Characterize the relationship between delirium severity and mortality risk in ICU survivors 2-years after discharge.
Methods:A secondary analysis was performed on patient data collected in two randomized controlled trials (Pharmacological Management of Delirium and Deprescribing in the Pharmacologic Management of Delirium, 2009-2015). Participants received delirium assessments twice daily during hospitalization via the Confusion Assessment Method for the ICU (CAM-ICU-7). Patients enrolled at Eskenazi Hospital with complete mortality data were included in this study. Mean delirium severity was categorized as rapidly resolving (0-2), mild to moderate (2.1-5), or severe (>5). Cox proportional hazard model was used to quantify mortality risk associated with delirium severity. Analyses were adjusted for patient demographics, comorbidities, and severity-of-disease.
Results:The cohort (n=434) was 54.6% female and 48.6% African American with an average age of 59.8 (SD 16.4). The admission diagnosis was acute respiratory failure/sepsis in 47.9% of patients across medical (n=272), progressive (n=52), and surgical (n=110) ICU types. Approximately one third of the original cohort (n=143) died within 2 years of index discharge. In the multivariate analysis, patients with severe delirium (>5) had nearly twice the adjusted hazard ratio for 2-year mortality compared to patients with mild-moderate delirium (aHR 2.1 [95% CI, 1.3-3.4] and aHR 1.1 [95% CI, 0.7-1.6], p=0.008).
Conclusion:Severe delirium during ICU stay was significantly associated with increased 2-year mortality risk in comparison to mild-moderate (subsyndromal) delirium.
Impact:The relationship between delirium severity and 2-year mortality underscores the need for further research on the mechanisms underlying ICU delirium and specific interventions to improve long-term outcomes
12 Month vs 6 Month Follow-up Colonoscopy After Piecemeal Endoscopic Resection of Large Nonpedunculated Colorectal Lesions
Get PDFBackground and aims:Current colonoscopy guidelines recommend nonpedunculated lesions ≥20mm in size and removed piecemeal should have follow-up colonoscopy in 6 months to ensure complete resection. Some data suggest that a 12-month follow-up may be safe and effective for selected lesions. Standard follow-up is 6, 18, 54 and 114 months after piecemeal resection. If the first follow-up visit is 12 months, the sequence is 12, 48, and 108 months. We investigated whether planned 12-month follow-up colonoscopy is as safe and effective for selected lesions when compared to 6-month follow-up.
Methods:We utilized a prospectively collected database of 1599 consecutive, large, and nonpedunculated colorectal lesions referred to an expert colonoscopist at a tertiary center. Lesions were removed by endoscopic mucosal resection and assigned a follow-up interval based on their size, histology, and the need to resect additional synchronous lesions identified during the index colonoscopy at our center. Pedunculated polyps (n=158), no follow-up at our center (n=553), follow-up outside of 2 to 36 month reference range (n=10), no polyp or benign growth (n=81), patients referred to surgery for cancer (n=64), and inability to endoscopically resect the lesion (n=24), were excluded from this analysis. Polyp size, location, removal method, endoscopic mucosal resection (EMR) utilization, and lesion pathology were compared to reduce confounding factors.
Results:Lesions assigned to a 12-month surveillance interval (n=151) had a smaller mean size (19.48mm +- 7.59 vs. 34.32mm +- 17.84), were more likely to have serrated histology (n=69 (45.70%) vs. n=62 (11.85%), and more likely to be resected en bloc (n=31 (20.53%) vs. n=31 (5.93%) compared to lesions assigned to a 6-month surveillance interval. Of the 151 lesions assigned to a 12-month surveillance interval, 11 (7.3%) had recurrence and none had cancer at follow-up. Among 523 lesions assigned to a 6-month surveillance interval, 53 (10.1%) had recurrence and 1 had cancer at follow-up. Among 65 lesions ≥ 20 mm resected piecemeal and assigned to a 12-month surveillance interval, 8 (12.31%) had recurrence and none had cancer at follow-up.
Conclusion and Potential Impact:These results support a 12-month surveillance interval after piecemeal resection of selected large, nonpedunculated, colorectal lesions. Initial 12-month surveillance results in fewer colonoscopies, lower cost, and less inconvenience to patients