bluuebunny/crossref_metadata_2025 huggingface dataset:
A Comparison of the Accuracy of WATCHMAN and WATCHMAN FLX Device Sizing between CT, TEE, and Patient Specific 3D Models
Authors: Troitino Ivette , White T. Eric , Lozo John
Published: December 2021

Background and Hypothesis: In patients with Atrial fibrillation (AF), the Left Atrial Appendage (LAA) is the most common site of thrombus formation. The LAA occlusion procedure using the WATCHMAN device implant is an alternative for stroke prevention in AF patients. Transesophageal echocardiogram (TEE) and Computed tomography (CT) scans aid in measuring the LAA to predict implant device sizes. However, due to varying LAA anatomy and limited spatial resolution, the current imaging techniques often predict one of two sized devices. The objective of this retrospective study is to compare the accuracy of measurements made preoperatively of the LAA with those on 3D models to determine if they can be used in preoperative planning. We hypothesize 3D models will be more accurate in predicting device size and any anatomical impediments than traditional TEE planning.
Project Methods: There were 21 subjects selected who underwent the WATCHMAN FLX procedure at Parkview Heart Institute in 2021. 3D models of LAA were created from CT scans using a Form 2 3D printer. The device sizes predicted for the procedure were determined from Boston Scientific FLX guidelines based on the maximum LAA orifice diameter from TEE, CT, and 3D models.
Results: Two-proportion z-test between the 3D model predicted sizes to the actual size deployed demonstrated no statistical significance (p=0.298) demonstrating no difference between 3D model predicted sizes and actual size deployed. Two-proportion z-test between TEE vs actual size and CT vs actual size demonstrated statistical significance, suggesting a difference between the group's predictions. 3D models predicted the accurate device size for 20/21(95%) subjects. TEE measurements of maximum orifice diameter were, on average, lower compared to CT and 3D model measurements.
Conclusion and Potential Impact: 3D printed models provide the most accurate device size predictions and can be used to optimize presurgical planning while reducing intraoperative complications.
Effective Telehealth – Open Heart Readmissions
Authors: Rao Varun , GeRue Michael , Gray Douglas
Published: December 2021

Background 
The purpose of this study is to compare open heart surgery (OHS) Telehealth patients (TP) and non-Telehealth patients (NTP) using outcomes data such as hospital readmission, emergency department (ED) presentations, observation hours, and office visits. Visits for atrial fibrillation (Afib), pleural effusions (PE), and sternal wound complications (SWC) are of particular interest for this study.   
 
Methods 
A retrospective chart review of 110 patients above 18 years old who had OHS at Parkview Heart Institute from 2020 were assessed using hospital readmissions, ED presentations, observation hours, and office visits outcomes. Separate forms for blinding, demographic data, and surgery information were completed for every patient. A Telehealth form was completed out for every Telehealth intervention had per TP. An outcomes form was completed for each outcome had by each patient. TP outcomes were compared with NTP outcomes. Fisher’s exact test and X2 was used for statistical analysis (p=0.05). 
 
Results 
Results display a sample size of the total patient population (110/436). There was no significant difference found between NTP and TP in terms of office visits (79.5% vs 93%, p=0.598), readmissions (3 vs 6, p=0.889), and observation visits (0 vs 3, p=0.558). Significance was found between NTP and TP in terms of ED visits (0 vs 9, p=0.025). Most frequent reason for NTP readmission “other” (7.7%) and TP “other” (4.2%), reason for ED visit for NTP (all 0%) and TP “other” (7.0%), reason for observation visit for NTP (all 0%) and TP “other” (1.4%), reason for office visit for NTP “other” (76.9%) and TP “other” (91.5%).  
 
Conclusion 
TP presented to the ED significantly more than NTP. The largest outcome category was “surgery follow up” office visits listed in the “other” section. Data collection and analysis are in progress. At the time of writing this abstract, final results are not yet available.
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.
Identification of Immunogenic Epitopes That Permit the Detection of Antigen-Specific T Cell Reponses to Coxsackievirus B3
Authors: Wesson Troy , Dhalech Adeeba , Robinson Christopher M.
Published: December 2021

Background and Hypothesis:Coxsackievirus B3 (CVB3) is a non-enveloped RNA virus from the Picornaviridae family and is a primary cause of viral myocarditis in the United States. Approximately 5% of all symptomatic CVB3 infections are fatal. Therefore, there is a need to identify the mechanism(s) that regulate a protective immune response to CVB3. However, viral epitopes that stimulate T cell responses to CVB3 remain poorly characterized. To this end, we used a mouse model of CVB3 infection to identify the viral immunogenic CD8 T cell epitopes. We hypothesized that isolated antigen-experienced CD8 T cells from infected mice would be stimulated in the presence of predicted viral epitopes, confirming CVB3-specific T cells.
Experimental Design: To identify novel CD8 T cell epitopes, predicted 9-mer MHC binding peptides from the CVB3-Nancy polyprotein were identified using the Immune Epitope Database (IEDB) analysis resource consensus tool. The top ten predicted peptides were synthesized for our assays. Splenocytes from CVB3-infected male and female IFNAR -/- mice were stimulated with each peptide in the presence of brefeldin A for 6 hours at 37˚C. Following stimulation, cells were surfaced stained with antibodies specific for antigen-experienced CD8 T cells. Next, we performed intracellular staining for IFN-gamma. Cells were analyzed using flow cytometry. Candidate epitopes were identified as having results ≥2 standard deviations over the control.
Results: Thus far, our analysis has revealed responses to three novel CD8 T cell epitopes within the peptide library, including the viral epitopes within VP1 protein and the RNA-dependent RNA polymerase.
Conclusion and Potential ImpactOverall, these data provide an advancement in CVB3 immunology. Further, these data generate new tools like MHC-tetramers to track endogenous T cell responses to CVB3 infection.
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.
Dissecting RAS Oncogene-Induced Kinome Involved in Breast Cancer Metastasis
Authors: Yaqub Amna , Harikrishna Nakshatri2 Harikrishna
Published: December 2021

Background and Hypothesis:
The RAS and PI3K-AKT-mTOR signaling pathways are often dysregulated in cancer. RAS pathway alterations, however, are more common in breast cancer metastasis. The laboratory’s recently developed model system demonstrated the ability of RAS but not PIK3CA-induced signals in promoting metastasis of breast cancer. Unbiased kinome analyses of isogenic RAS-transformed primary tumor and metastatic cells and PIK3CA-transformed primary tumor cells enabled identification of RAS-activated kinome, which included FER, PAK4, LIMK1, PIK3CD and Casein Kinase 2 (CK2). We hypothesized that therapeutic targeting of these kinases may reduce breast cancer metastasis. As a proof-of-principle, the effect of the CK2 inhibitor Silmitasertib, which is in clinical trial for COVID-19 and refractory multiple myeloma, was tested.
Experimental Design:
The study included four isogenic cell lines: “normal” (KTB34-hTERT), PIK3CA-transformed (TKTB34-PIK3CA), RAS-transformed (TKTB34-RAS), and RAS-transformed cells metastasized to lungs (MKTB34-RAS). Active kinomes in these cells were identified using phospho-proteomics and functional kinome profiling using multiplexed kinase inhibitor beads. Expression levels of FER, PAK4, LIMK1, and PIK3CD kinases were compared through Western Blot using the phospho-antibodies as an indicator of kinase activation. Sensitivity to Silmitasertib was measured using the BrdU Cell Proliferation Assay.
Results:
FER, PAK4, LIMK1, and PIK3CD were all overexpressed in the TKTB34-RAS and MKTB34-RAS cells compared to KTB34-hTERT and TKTB34-PIK3CA cells. The tested concentration range for Silmitasertib (500 nM to 5 µM) was ineffective in killing the RAS-transformed cells and was overly toxic to “normal” cells.
Conclusion and Potential Impact:
FER, PAK4, LIMK1, PIK3CD, and CK2 are potential therapeutic targets for breast cancer metastasis. However, Silmitasertib may not be a good candidate as it is more toxic to “normal” cells compared to cancer cells. The isogenic “normal” and transformed cell line model system described here may help to discover new targets and drugs that kill cancer but not normal cells.
Assessment of T cell chemotaxis to S1P
Authors: Leon Brandon , Chelvanambi Sarvesh , Rabab ElMergawy Rabab , Noda Moraima , Maier Bernhard , Clauss Matthias A.
Published: December 2021

Introduction: Migration of leukocytes in response to chemical gradients, chemotaxis, is dependent on many factors, including cell type, surface markers, the chemoattractant, etc. Sphinogsine-1-phosphate (S1P) is a chemoattractant playing a large role in migrating activated T cells out of lymph nodes by binding to their S1P receptor, S1P1. The importance of the egress in T cells from lymph nodes is highlighted by pharmacological disruption of this migration can lead to immune dampening and thus control of multiple sclerosis, an autoimmune disease. In the case of human immunodeficiency virus (HIV), it has been shown that HIV downregulates S1P1 surface expression, effectively inhibiting chemotaxis. Our experiments attempt to study a particular HIV-encoded protein, Nef in S1P-elicited T cell migration, and to optimize the conditions for assessing T cell migration in response to S1P.
Methods: In our Transwell migration assays, migration of serum-starved SupT1 cells was induced using various concentrations of S1P bound to delipidated bovine serum albumin (BSA). Before migration, cells were labeled using Calcein AM. Cells were allowed to migrate for 2-4 hours at 37°C in serum-free media. After migration, fluorescence intensity was measured using a CLARIOstar microplate reader.
Results: S1P showed a direct dose-dependent response to SupT1 cell migration from 0 to 100 nM S1P. Optimization of the migration showed that both number of trans-migrated cells and those still present within the transwell filter were significant indicators of SupT1 migration.
Conclusion: S1P’s chemoattractant ability is prevalent in the migration of SupT1 cells in concentrations lower than 125nM. Because we have inducible systems for HIV-Nef expression established in this cell line, these data are useful for testing the role of Nef in HIV-mediated T cell retention.
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.
Relationship between dementia severity in older women and family caregivers’ preferences for shared decision making about breast cancer screening
Authors: Frank Molly , Fowler Nicole
Published: December 2021

Background/Objective: Mammography is one of the most effective ways to diagnose breast cancer early; however, its perceived benefits are complicated by terminal conditions such as dementia. By undergoing mammography, women with dementia risk treatment complications and false-positive results, which can exacerbate psychological distress. The lack of a standard of care confounds the individual roles of the patient, family caregiver, and physician in the decision-making process. This study evaluates the relationship between dementia severity and family caregiver preferences for shared decision making.
Methods: Data were gathered from the Decisions about Cancer screening in Alzheimer’s Disease trial, which uses the Dementia Severity Rating Scale (DSRS) and a revised version of the Control Preferences Scale (CPS) to assess family caregiver preferences for decision-making as a dyad (patient and caregiver) and triad (patient, caregiver, and physician). Two multinomial logistic regression models assessed the relationship between DSRS and CPS categories (active, passive, and collaborative), while controlling for the caregivers’ age, gender, education, relationship to patient, self-perceived income, and race. Both models used the “active” group as the baseline; however, Model 1 examined preferences as a dyad and Model 2 as a triad.
Results: Model 1 found a statistically significant association between dementia severity and a collaborative approach (p<0.001), and between dementia severity and a passive approach (p=0.014). For every one-unit increase in DSRS score, the odds of being in the collaborative group decreased by 0.083 and the odds of being in the passive group decreased by 0.085. There was no statistically significant association between dementia severity and decision-making preferences in Model 2.
Clinical Significance: The association between dementia severity and family caregiver decision-making preferences supports the need for a standard of care regarding breast cancer screening in women with dementia.
AEBP1 is Upregulated in Diabetic Nephropathy Biopsies
Authors: Freije Benjamin , Ferreira Ricardo Melo , Cheng Ying-Hua , Parikh Samir , Eadon Michael
Published: December 2021

Background: Worldwide, one in eleven adults have diabetes mellitus and 30% to 40% will develop diabetic kidney disease (DKD). A mechanistic understanding of DKD is crucial to develop treatment strategies. To unravel DKD’s pathogenesis, single cell (scRNA) sequencing has proven a powerful tool, but is limited by a lack of localization. Spatial transcriptomics allows the mapping of scRNA sequencing data back to histology.
Methods: Frozen human nephrectomy and biopsy samples were processed according to Visium spatial gene expression protocols, stained with H&E, and imaged. Samples were permeabilized for RNA capture, reverse transcribed and sequenced on an Illumina NovaSeq 6000. Mapping and counting were completed in Space Ranger and data was processed in Seurat. Samples were laser microdissected, protein was isolated, and protein was quantified by HPLC-MS.
Results: Clusters from scRNAseq were mapped upon reference and DKD spatial transcriptomic images (N=4 reference, 2 DKD). Differentially expressed genes were identified in diabetic kidneys, including the upregulation of Adipocyte Enhancer Binding Protein (AEBP1).  Pathway analysis revealed enrichment of extracellular matrix organization and immune process pathways. To increase the confidence of these findings, glomeruli and the tubulointerstitium were laser microdissected (N=7 diseased, 4 reference) for proteomic analysis. AEBP1 was upregulated in the tubular interstitium of diseased kidneys and selectively upregulated in the glomeruli of Diabetic Nephropathy samples (N=2). AEBP1 localized to the interstitium by spatial transcriptomics and was expressed in highly fibrotic regions. Glomerular expression was not observed due to glomerulosclerosis.
Conclusion: AEBP1 upregulation is a marker of interstitial fibrosis, with specific expression in the glomeruli of diabetic nephropathy specimens with glomerulosclerosis.
Impact: This is the first study utilizing spatial transcriptomics to define and localize markers of human kidney disease. Confirmatory studies are required in larger sample sizes. AEBP1 is a previously unidentified marker of DKD previously associated with fibrosis in other organ-specific diseases.
We’re in This Together: Community Coalition Approaches to Treating Depression
Authors: Jeong Naari , Savaiano Dennis
Published: December 2021

Background and Objective: Depression is the leading cause of disability worldwide, yet approximately one-third of adults diagnosed with major depressive disorder do not receive treatment. Health coalitions are one strategy towards addressing this issue through collaborative, multi-sector interventions implemented within community organizations. In this narrative review, we examine what evidence exists that coalitions may improve outcomes of depression.  
 
Methods: A search for peer-reviewed literature was conducted using PubMed, CINHAL, MEDLINE, and PsychINFO databases. The search was limited to studies published in the English language. No limitations were placed on location or date of publication. Initial search produced a total of 236 articles. Of these, 34 met inclusion criteria. Papers that did not address depression interventions in the context of community health coalitions were excluded.  
 
Results: Community Partners in Care, a double-blinded randomized control trial, is the primary model in literature that describes outcomes of coalitions in addressing depression. 6-month outcomes revealed that participants treated through a coalition model (n=504) as opposed to those in a non-coalition approach (n=512) had significantly improved self-reported mental health related quality of life and a reduced number of behavioral health hospitalizations. 3-year and 4-year outcomes revealed participants in the coalition model had increased odds of clinical depression remission. While many other studies documented coalition-based interventions, there was little to no report of treatment effectiveness.   
 
Project Impact: Current literature suggests that coalitions may be an effective method of addressing depression, particularly in under-resourced areas where community members are more likely to access care through social services. In addition, churches and schools were identified as key partners for coalitions, as trusted informal networks for mental health support. While results support coalition utility for mental health intervention, more research is needed to determine what, if any, unique attributes of coalitions are necessary to insure effective mental health interventions.
Rates of Ischemia Amongst Asymptomatic Patients with High Coronary Artery Calcium Scores
Authors: Jones Aaron , Thomas Dustin
Published: December 2021

CACS may be used to recommend lifestyle changes or other treatment recommendations to reduce the risk of heart disease. The incidence of asymptomatic ischemia in patients with elevated CACS is poorly defined.  Furthermore, the CACS cut-off above which it is clinically important and cost effective to look for and diagnose ischemia is also not well defined. The purpose of this study is to better define the incidence of asymptomatic ischemia in Parkview Heart Institute (PHI) patients with elevated CACS, including an examination of demographic data that may also influence the rate of ischemia. 118 Patients who were screened for CAD, received CACS ≥ 400, and subsequently had stress testing or invasive coronary angiogram within 6 months were admitted into the study. Through statistical analysis it was determined there was no statistical difference in rates of ischemia between patients with CACS of 400-999 and those >1000. However, due to a small sample size this study will be continued to strengthen its results and investigate if demographics play a role in rates of ischemia.
Treatment of FRI after intramedullary nailing of tibia fractures: assessment of nail retention and nail removal
Authors: Jones Jenna , Mullis Brian , Weaver Bree , Natoli Roman
Published: December 2021

Objectives: Fracture related infection (FRI) is a severe, potentially limb-threatening complication after fracture fixation. Dilemma exists with regard to removing or retaining implants while treating the infection. The purpose of this study was to compare primary bone union and infection clearance in patients who had an infection following intramedullary nailing of the tibia treated either by retaining the implant or by removing the implant. 
 
Methods: Patients from two level-I trauma centers were identified through billing registries and retrospectively reviewed between January 2013 and December 2020. We identified 44 patients who had a diagnosis of FRI within 90 days of their initial fixation and returned to the OR for operative treatment of the infection. The incidences of both primary union and infection clearance were calculated for both groups and multiple parameters that may be associated with success or failure were assessed.  
 
Results: Four patients did not have complete records and were excluded. Of the remaining patients, 20 (50%) achieved infection clearance. Twenty-three (59%) patients achieved primary union whereas 16 (41%) had a primary outcome of either delayed union, nonunion, or amputation (one additional patient excluded as healing status unknown). Further analysis showed no significant difference (X2 (39) = 1.13, p < .29) in infection clearance between patients treated with nail retention (64%) versus nail removal (68%). No significant difference was seen in primary bone union (X2 (39) = 3.24, p < .07) with 36% of patients treated with nail retention and 68% of patients treated with nail removal reaching primary union; however, this does trend toward an association. Fewer surgeries performed for infection and complication after initial fixation was positively associated with infection clearance (p < .04, M=4.6, SD=2.13, df=39) and primary union (p < .001, M=4, SD=2, df=38). 
 
Conclusion: Infection clearance seems similarly possible with both nail retention and nail removal strategies, with fewer number of surgeries performed for infection and complication improving the likelihood of infection clearance and bone union. This may suggest that more severe FRI’s are less likely to unite and clear infection. Nail removal may play a role in increasing primary bone union; however, a larger sample size is needed for more definitive assessment.
Periviable Breech Delivery Decision Analysis
Authors: Kirksey Makayla , Tucker Edmonds Brownsyne
Published: December 2021

Background/Objective: The optimal mode of delivery (MOD) for malpresentation in periviable deliveries (22-24 weeks), remains a source of debate. Neonatal and maternal complications can arise from both vaginal (VD) and cesarean delivery (CD), and the threat of maternal morbidity extends to subsequent pregnancies. It has been difficult to compare these risks while counseling patients about MOD options, so we sought to create a decision tree that maps probable outcomes associated with breech deliveries at 23- and 24-weeks’ gestation, as well as complications posed for subsequent pregnancies.  
 
Methods: An extensive literature review was conducted to identify risk estimates of periviable maternal and neonatal outcomes, along with elective repeat CD (ERCD) and trial of labor after cesarean (TOLAC) for subsequent pregnancies. Probabilities were inputted into TreeAge software, starting with primary maternal health states that may result from CD and VD – “death”, “hysterectomy”, or “no hysterectomy”, followed by the probability of neonatal health states– “death”, “severe morbidity”, or “no severe morbidity”. The likelihood of placenta previa or normal placenta was considered for subsequent pregnancies. We factored in the possibility of ERCD or TOLAC and the associated maternal and neonatal risks for each.   
 
Results: Final design of the tree is complete and risk estimates have been inputted. Primary analysis and sensitivity analyses are planned for August 2021. Ultimately, we will also be able to use measured utility values to calculate quality adjusted life years (QALYs) for each health state.   
 
Conclusion and Clinical Impact: Whether CD or VD is optimal for breech presentation in periviable delivery is influenced by a complex array of factors, including future reproductive plans and maternal values related to potential neonatal and maternal morbidity and mortality. Quantifying risks associated with each MOD will aid providers in their efforts to help families make informed decisions and reduce morbidity across the reproductive lifespan.
The Roll of Toll-like Receptors in the Stem Cell Inflammatory Response
Authors: Lawson Katelyn , Markel Troy
Published: December 2021

Background: Toll-like receptors serve as ligands for LPS and other inflammatory mediators. Previous studies have shown that TLR4 is deleterious, while TLR9 is beneficial in the setting of inflammation and ischemia. Umbilical stem cells (USCs) have shown promise in the acute treatment of inflammation but their response to inflammatory mediators has not been fully elucidated. We hypothesized that knockdown of TLR4 in USCs would result in lower levels of IL-6 and VEGF production, while knockdown of TLR9 would produce higher levels of these cytokines when cells were exposed to LPS or hypoxia. 
 
Methods: USCs were cultured in polystyrene flasks in Mesenpro media at 37C in 5% CO2 in air. Cells were plated into 12-well plates at a concentration of 100,000 cells/well. Cells were transfected for 24h with siRNA to knockdown TLR4 and TLR9, respectively. Knockdown was confirmed by PCR. Experimental groups were: 1) Control, 2) Scramble siRNA for negative control, 3) TLR4 siRNA and 4) TLR9 siRNA. After 24 hours the media was changed and cells were exposed to either LPS (200ng/ml) or 5% oxygen for 24 hours. The supernatant was then collected and analyzed with ELISA for VEGF and IL-6. Data were analyzed by Mann Whitney test and p<0.05 was significant.  
 
Results: TLR4 and TLR9 were effectively knocked down by the transfection process. However, no significant levels of VEGF or IL-6 were detected from any of the experimental groups. 
 
Conclusion and Implications: Although no significant levels of VEGF or IL-6 were detected in the ELISA after exposure to inflammatory agents, there is still indication that TLR4 and TLR9 play critical roles in inflammation. The experiment should be run again and tested for more inflammatory cytokines. Positive results from this study can translate to an in vivo model, in which engineered TLR4KD stem cells have the potential to minimize tissue inflammation and beyond standard cell therapy. 
 
Acknowledgement: This project was funded, in part, with support from the Indiana Clinical and Translational Sciences Institute funded, in part by UL1TR002529 from the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.