bluuebunny/crossref_metadata_2025_split huggingface dataset:
SIRT1 Inhibition Impairs Ca2+ Buffering in Coronary Smooth Muscle Cells of Ossabaw Miniature Swine
Authors: Reed John , Thamba Aish , Strobel John , Byrd James , Alloosh Mouhamad , Coutts Alex , Sturek Michael 
Published: December 2021

Background: SIRT1 is a deacetylase that has diverse roles in intracellular Ca2+ signaling, metabolism, and cardiovascular disease. SIRT1 increases sarco-endoplasmic reticulum Ca2+ ATPase (SERCA) activity that is essential to buffer the increase in Ca2+ induced by release from the sarcoplasmic reticulum (SR). Our lab has shown that metabolic syndrome (MetS) impairs SERCA activity in coronary smooth muscle cells and causes coronary artery disease in Ossabaw miniature swine. We hypothesized that SIRT1 inhibition and MetS would impair Ca2+ buffering.
Methods: CRISPR/Cas9 methods delivered a leucine to proline point mutation in SIRT1 (SIRT1L100P) into the Ossabaw swine genome to compare to wild type (WT) and mimic the naturally occurring mutation in humans and decrease SIRT1 activity. Four treatment groups of juvenile swine were based on genotype and diet: WT Lean, SIRT1 Lean, WT MetS, and SIRT1 MetS. Lean swine were fed normal chow and MetS were fed a hypercaloric, atherogenic diet for 7 months. The left anterior descending coronary artery was harvested and enzymatically digested to obtain cells. Fluorescence microscopy measured the Ca2+ indicator fura-2 in single cells. The cells were exposed to 5 mM caffeine to maximally release stores of Ca2+ from the SR. Ca2+ buffering capacity of each cell was analyzed after the caffeine-induced peak increase to assess Ca2+ efflux and SERCA activity.
Results: MetS was confirmed by increased body weight, impaired glucose tolerance, hyperinsulinemia, and hypercholesterolemia. Coronary atherosclerosis was shown by angiography, intravascular ultrasound, and gross imaging. The rapid phase of Ca2+ buffering due to Ca2+ efflux was not affected by SIRT1 mutation or MetS. The slower phase of Ca2+ buffering due to SERCA activity was impaired only by SIRT1 mutation (p<0.0005), not by MetS.
Conclusion: SIRT1 mutation alone inhibited SERCA buffering of Ca2+ in coronary smooth muscle. (Support: NIH T35HL110854, DK120240, DK09751.)
Developing a Survey for Analyzing Attitudes of Adolescent and Young Adult Cancer Survivors Towards Diet, Exercise, and Social Media
Authors: Rodriguez Samantha , Sajdyk Tammy , Renbarger Jamie 
Published: December 2021

Background and Hypothesis: Due to improved multidrug treatments over the past 40 years, the 5-year survival rate for children diagnosed with cancer has increased from approximately 60% to 85%. However, these treatments also cause long-term health issues, so patients must be equipped with adequate information regarding potential future complications. Only 18% of survivors report follow-up visits to a physician to discuss reducing risks resulting from their cancer, thus, there is a huge gap in health education for this population. To address this gap, a questionnaire was developed to collect data on the critical concerns adolescent and young adult (AYA) survivors have regarding wellness. We hypothesize that this survey will allow for healthcare workers to have a greater understanding of the wellness needs of AYA cancer survivors and aid in the development of an educational program that can be delivered in a manner that is acceptable to the AYA survivor population.
Project Methods: A 5-point Likert scale survey was created to gather information on topics such as diet, exercise, body image, relationships, and social media. Additional questions that gather data on background information were also asked. This survey will be distributed to subjects who have recovered from cancer and are between the ages of 18 and 39. After data has been collected, statistical tests such as Spearman’s correlation and chi-square tests for independence will be used to find correlations.
Expected Results: Results from this survey will be useful in understanding the experiences of AYA cancer survivors, how they view their wellness needs, and how they prefer to receive healthcare information.
Potential Impact: The data from this study will inform oncology providers as to which health concerns the AYA survivor population find most important and how best to deliver that information so survivors can receive better management of their long-term health.
Loss of FVIII Expression by Possible Interlinked Immune and Cellular Stress Response in Hemophilia A Mice Treated with AAV Gene Therapy
Authors: Rogers Christopher , Bertolini Thais , Herzog Roland 
Published: December 2021

Background
Hemophilia A is an X-linked genetic disorder caused by a mutation in the gene for factor VIII (FVIII) protein that reduces the ability of blood to clot. Clinical drug trials have shown the potential of adeno-associated virus (AAV) gene therapy as a one-time treatment for hemophilia A that can produce sustained high levels of FVIII. However, a gradual decline in protein levels has been observed in patients after 2-4 years. The hypothesis being tested in the Herzog Lab is that an interlinked immune and cellular stress response could be causing the loss of expression.

Methods
Two groups of Hemophilia A mice were administered AAV therapy, with one group receiving recurrent doses of Rapamycin. Blood samples were taken at weeks 4, 8, 12 and 14. Mice were euthanized at weeks 4, 8, and 14, and their livers were harvested. qPCR was used to measure AAV copy numbers and FVIII mRNA at 4, 8, and 14 weeks. Cryosections of mice livers from weeks 4, 8, and 14 were stained with antibodies for FVIII protein and CD8.

Results
qPCR showed roughly half as much AAV copy numbers in the rapamycin group at all time points, and little difference in FVIII mRNA between the groups. There was also a large decrease in AAV copy numbers and FVIII mRNA in both groups between 8 and 14 weeks. Immunohistochemistry showed less CD8 and more FVIII signal in mice treated with rapamycin.

Discussion
Experiments are currently being performed to investigate the decline in AAV copy numbers and mRNA between weeks 8 and 14. The immunohistochemistry data shows a relationship between increased FVIII protein levels and decreased cellular immune response but does not explain the gradual decline in FVIII. Further investigation into FVIII expression following AAV gene therapy could lead to an effective one-time treatment for hemophilia A.
What a difference a year makes: A snapshot of the trends in vaccinations, hospitalizations, and mortality rates for SARS- CoV-2 across the state of Indiana
Authors: Roper Chinade , Han Amy , Brown Martin 
Published: December 2021

Background: Many efforts both scientifically and politically helped reduced the spread of SARS-CoV-2. In December of 2020, vaccinations were authorized for distribution. It is important to understand demographical correlations to COVID-19 acute illness rates and whether COVID-19 vaccinations significantly reduced these rates.

Project Methods: This study focused on data from seventeen counties in Indiana. This information was used to determine if there were correlations between demographics and COVID-19 illness rates. County demographics were obtained from the United States Census Bureau. COVID-19 hospitalization and mortality were collected from the Regenstrief Institute and the Indiana State Department of Health respectively. Linear regression analyses were performed to determine if there were significant correlations between demographics and rates COVID-19 illness. T-test analyses assuming unequal variances were performed in order to determine if there has been a significant reduction in COVID-19 illness.

Results: The results of this study revealed that the percentage of the population over the age of 65, with a bachelor’s degree, disabled under age 65, and the median income (r values: 0.729, 0.701, 0.661, and 0.533 respectively) are significantly correlated to the mortality rate. The percentage of the population over the age of 65 and with a bachelor’s degree (r values: 0.565 and 0.524 respectively) are significantly correlated to the hospitalization rate. When comparing the COVID-19 acute illness rates for each county from 07/27/20 until 02/01/21 to the rates after 02/01/21 until late- June of 2021, each county had significant decrease in the hospitalization and mortality rate after February 1, 2021.

Potential Impact: The result of this study suggests that vaccinating residents was a significant factor in the 50% or higher reduction in COVID-19 hospitalization and mortality rates. These findings emphasize the importance of COVID-19 vaccinations to protect Americans from COVID-19 severe illness.
Analysis of COVID-19 Case Demographics in Gary, Indiana
Authors: Al-Tarshan Yazan , Sabir Maryam , Snapp Cameron , Brown Martin , Walker Roland , Han Amy , Kostrominova Tatiana 
Published: December 2021

Background and Hypothesis
It has been reported in several recent studies that health disparities associated with COVID-19 infection r are prevalent in Black and impoverished populations. The contribution of multiple causes to these disparities is still not completely elucidated. Gary, Indiana has a large Black population (80%), high number of residents living below the poverty line (34%), and high unemployment rate (20%). We hypothesized that Black individuals in Gary have a higher rate of positive cases, hospitalizations, and deaths than non-Black individuals. Also, we hypothesized that (median household income measured by the zip code) is negatively correlated with COVID-19 positive cases, hospitalizations, and deaths.

Methods
In collaboration with the Gary Health Department, we analyzed data on all positive cases in the city from 06/16/2020 through 06/07/2021(totally 5149 cases). We compared this data to the data from 03/16/2020 through 06/16/2020 (totally 724 cases) that we analyzed previously. Data was de-identified and included age, race, ethnicity, and zip code. The data was analyzed using Pearson's chi-square test and regression analysis.

Results
When compared to the non-Black population in Gary age and population-adjusted rates of hospitalizations and deaths in the Black population are 3-fold (p<9.385E-11) and 2-fold (p<0.0171) higher, respectively. Surprisingly, the non-Black population had a higher infection rate than the Black population (p<2.69E-09). Median household income of a zip code is negatively correlated with COVID-19 hospitalizations in that zip code (R2=0.6345, p=0.03), but is does not affect the .rates of infections and deaths.

Conclusion
Our data show that in Gary, there is a clear health disparity of both income and race, specifically in the context of COVID-19. IUSMNW and Gary health officials can collaborate and utilize this data to reallocate resources to the highly populated, low income, and predominantly Black neighborhoods.
FOXP3 Isoforms and Human Regulatory T Cells
Authors: Santos Rebeca , Zhou Baohua 
Published: December 2021

Background:
Regulatory T-cells (Tregs) are critical to maintaining immune tolerance, thus prevent autoimmunity and allergic diseases. The master transcription factor FOXP3, expressed in humans as two isoforms through mRNA alternative splicing, controls the development and function of Tregs. However, the functions of the two isoforms remain unclear. We hypothesized that the oligonucleotides, developed by the lab, would efficiently shift FOXP3 to its shorter isoform, lacking exon 2 (FOXP3 ΔE2), which enables us to study how the FOXP3 ΔE2 isoform affects Treg function.

Methods:
Human peripheral blood mononuclear cells (PBMC) were obtained from healthy donors and cultured in the presence of 1 µM isoform-shifting oligonucleotides for three weeks. Expression of the FOXP3 isoforms, CD25, CTLA-4, CD40L, was examined through flow cytometry. Another goal was to study how the FOXP3 ΔE2 isoform shift affects the Treg response to inflammatory cytokines.

Results:
The oligonucleotides are highly effective in shifting the FOXP3 to the FOXP3 ΔE2 isoform. The majority of Tregs express only the FOXP3 ΔE2 isoform after two weeks of culturing in 1 µM oligo and had reduced expression of CD25, which plays a role in Treg differentiation, function, and homeostasis. Tregs display reduced expression of CTLA-4, a negative regulator of T-cell activation, but elevated CD40L, which costimulates and regulates the immune response. The FOXP3 ΔE2 isoform shift also sensitizes the Tregs to proinflammatory cytokine stimulation, allowing for increased IL-4, IL-17A, and IFN-γ production.

Conclusion:
Our studies demonstrate that FOXP3 ΔE2 Tregs are less stable because of the lower CD25 expression and less suppressive as determined by lower CTLA-4 but higher CD40L expression. In the inflammatory environment, the FOXP3 ΔE2 Tregs also produce more inflammatory cytokines, which further reduces their regulatory function. This study establishes an understanding of FOXP3ΔE2 Tregs’ role in autoimmunity and provides a potential novel target to treating autoimmune diseases.

Acknowledgements:
This study was funded, in part, with support from the Immunology and Infectious Diseases Training Program Grant funded, in part by T32 AI 060519 from the National Institutes of Health to RS and NIH AI159804 to BZ.
Perfusion Index as an Indicator for Mortality in Children with Plasmodium falciparum Severe Malaria
Authors: Boland Wes , Bond Caitlin , Namazzi Ruth , Bangirana Paul , Opoka Robert O. , Datta Dibyadyuti , John Chandy C. 
Published: December 2021

Background:Severe malaria (SM) remains a major global health problem causing ~275,000 pediatric deaths annually, worldwide. Continuous, non-invasive monitoring of peripheral perfusion can help detect abnormalities in systemic circulation, a common problem in critically ill patients, and can improve outcomes in children hospitalized with SM. Perfusion index (PI), an indicator of peripheral perfusion measured using a point-of-care pulse oximeter, is the ratio of pulsatile blood flow to static blood in peripheral tissue.
Objective: To investigate the role of PI as an indicator of adverse outcomes including mortality in children hospitalized with SM.
Methods: We measured PI in a prospective cohort study of 600 children <5 years of age with 5 different clinical manifestations of SM, and 120 healthy community children (CC) at two hospitals in Uganda. PI was measured at 6-hr intervals during hospitalization using a Masimo Rad 57 pulse oximeter.
Results: Children with SM had significantly lower admission PI values (1.2 [IQR: 0.58, 2.2] compared to CC (2.8 [1.7, 4.3], p<0.001). Children with SM manifesting as respiratory distress syndrome or severe malarial anemia had lower median PI compared to other manifestations including cerebral malaria, the deadliest form of SM in children. In children with SM, a log decrease in admission PI was associated with 2.7 higher odds of in-hospital mortality (p=0.01). A log reduction in PI was also associated with in-hospital clinical complications associated with SM, including circulatory shock, deep acidotic breathing and acidosis, hypoglycemia, and severe anemia (all P<0.03). In survivors of SM, there were no significant associations between PI and cognitive outcomes at 12-month follow-up.
Conclusion: The role of PI as an indicator of mortality in children with SM and the use of point-of-care tools for continuous monitoring of PI warrants further investigation in the management of SM to prevent or reduce the incidence of adverse outcomes.
Congregations as Health Connectors – Addressing Health and Social Needs of Neighbors Through Conversations, Not Surveys
Authors: Buss Kristen , Craig David , Hardwick Emily , Wiehe Sarah 
Published: December 2021

Background and Hypothesis: Social determinants of health (SDOH) directly affect health outcomes and indirectly limit access to resources needed to maintain individual health. In an effort to address the negative impacts of SDOH on the urban communities of Indianapolis, four congregations have employed Site Connectors to directly form relationships with neighbors, learn about their health journey, and connect them to resources addressing expressed needs. It is our hypothesis that through research of similar models and discussion with community partners, an optimized model for fostering relationships and assessing the health and social needs of neighbors can be developed for use by the Site Connectors.
Project Methods: A search was performed for examples of health and social needs assessments utilized by established care providers, and thirteen were identified. The items within these assessments were then organized into six groups based on SDOH topic (ie. Housing, Transportation, etc.). Additionally, six interviews with community partners performing similar work were conducted utilizing a fixed set of questions.
Results: It was determined that the best format for our assessment would not be a survey, as in the example assessments, but rather a visual aid resembling a concept map. This model lends itself more to the nature of relationship-building by guiding Connector-Neighbor conversations rather than dictating them, with three starter questions at the center and six offshoots covering each of the SDOH topics. A post-encounter checklist was also developed for Connectors to retroactively record priority items from their conversations.
Potential Impact: It is yet to be determined whether our model will be useful in practice, as the Connectors begin their work in August. However, it is our hope that we have developed a novel format for assessing needs that more holistically addresses the impacts of SDOH through respecting the vulnerability and energy required for relationship-building.
Development of a Natural Language Processing Machine to Enhance Identification of Opioid Use Disorder in Electronic Health Records
Authors: Chadd Avery , Silvola Rebecca , Vorontsova Yana , Broyles Andrea , Cummins Jonathan , Hood Daniel , Stratford Robert , Quinney Sara 
Published: December 2021

Background/Objective: Real-world data, including electronic health records (EHRs), has shown tremendous utility in research relating to opioid use disorder (OUD). Traditional analysis of EHR data relies on explicit diagnostic codes and results in incomplete capture of cases and therefore underrepresentation of OUD rates. Machine learning can rectify this by surveying free clinical notes in addition to structured codes. This study aimed to address disparities between true OUD rates and cases identified using traditional ICD codes by developing a natural language processing (NLP) machine for identifying affected patients from EHRs.
Methods: Patients (≥12 years old) who had received an opioid prescription from IU Health or Eskenazi Health between 1/1/2009 and 12/31/2015 were identified by the Regenstrief Institute. Exclusion criteria included any cancer, sickle cell anemia, or palliative care diagnoses. Cases of OUD were identified through ICD codes and NLP. The NLP machine was developed using a dictionary of key OUD terms and a training corpus of 300 patient notes. A testing corpus of 148 patient notes was constructed and validated by manual review. The NLP machine and ICD 9/10 codes were independently tested against this corpus.
Results: Although ICD codes identified OUD cases with high specificity (98.08%), this method demonstrated moderate sensitivity (53.13%), accuracy (68.92%), and F1 score (68.92%). Testing using the NLP method demonstrated increased sensitivity (93.75%), increased accuracy (89.19%), and increased F1 score (91.84%); specificity mildly decreased (80.77%).
Conclusion: Our revised NLP machine was more effective at capturing OUD cases in EHRs than traditional identification using ICD codes. This illustrates NLP’s enhanced capability of identifying OUD cases compared to structured data.
Potential Impacts: These findings establish a role for NLP in OUD research involving large datasets. Ultimately, this is intended to improve identification of risk factors for OUD, which is of significant clinical importance during a public health crisis.
The Relative Contribution of Medical Comorbidities in the OARA Score: A Machine Learning Analysis
Authors: Chang Joshua , Ziemba-Davis Mary , Deckard Evan R. , Meneghini R. Michael 
Published: December 2021

Background/Objective: The Outpatient Arthroplasty Risk Assessment (OARA) score has been used successfully to identify patients who can safely undergo outpatient primary total joint arthroplasty (TJA) based on medical risk stratification. The targeted score (0 to 79) was conservatively established to ensure patient safety. However, the number of points associated with each of the 52 comorbidities in the OARA score were assigned based on physician experience with early discharge. This study applied machine learning (ML) to empirically identify the relative contribution/importance of each medical comorbidity to safe same-day discharge (SDD).
Methods: 3,047 patients who underwent primary unilateral TJA by a single surgeon at a single institution were included in the analysis; 573 were SDDs. Before ML analysis, associations among binary (yes/no) comorbidities were examined using Cramér's V. A CART decision tree model using Gini method was used to develop a model for SDD (yes/no) based on the presence or absence of the comorbidities.
Results: To produce interpretable results with acceptable face validity the 52 comorbidities were grouped in 19 common medical categories (heart disease, liver disease, etc.). Although the resulting model was less than perfectly predictive (AROC = 0.652, 95% CI 0.629–0.675), it resulted in an interpretable classification tree identifying heart disease, kidney disease, immunosuppression, chronic sedative use, pulmonary disease, thrombophilia, anemia, and history of stroke, in order, as the most important predictors of SDD.
Conclusion: Model limitations expressed as AROC were not unexpected because the relative contribution (expressed as points) of comorbidities to the OARA score are based on physician decision-making, not empirical identification of the importance of each medical condition to safe SDD. Study results moved the goal of empirical classification forward but the low prevalence of many of the comorbidities limited variability and hence model performance and accuracy. Future work with a larger sample is being planned.