bluuebunny/crossref_metadata_2025 huggingface dataset:
Contabilidad crítica. Una revisión bibliométrica de las investigaciones
Authors: Chamorro González Candy , Jaramillo Giraldo Verónica , Pescador Muñoz Elizabeth , Rodelo Sehuanes Mario
Published: January 2023

The academic production focused on critical accounting issues has been integrating multiple situations that highlight the importance of qualitative studies and research in accounting. Therefore, this article developed a bibliometric review on critical accounting, which allowed it to classify the scientific production found in the Scopus database. According to the search criteria, 71 texts were analyzed, which were classified by type of document: empirical, case study, review and reflection, then filtered by thematic area: research, history, profession and education. The results illustrate that a large part of the publications are approached from an empirical typology, showing critical orientations based on multiple discussions of the profession. This evidences the different tensions that the accounting field currently faces regarding the economy, the social, the digitization, professional practice, theoretical and scientific aspects.
Contaduría pública, entre el Derecho positivo y la autorregulación
Authors: Franco-Ruiz Rafael , Betancur Jaramillo Liliam , León Paime Edison Fredy
Published: January 2023

This text intends to present a critical view of the process of adoption of international standards for the Accounting profession in Colombia, identifying the main problems incorporated and the consequences derived from the process, considering questionable aspects such as the role of self-regulation in a Social State of Law, but also some elements on the effects on the quality of information and the quality of professional practice.
 
The work method used is based on critical analysis of the process, anchored in hermeneutic practices, especially legal, which allowed the identification of perverse effects on the national legal structure and the creation of uncertainty scenarios for the professional practice, which requires urgent rectifications that should be the reason for governmental decisions aimed at the construction of legal security, autonomy of the legal jurisdictions avoiding problems of non-observance of the constitutional organization such as the one that determines that in times of peace only the Congress of the Republic can modify the tax structures, a rule that is threatened today because the bases of determination of taxes and withholdings can be modified by the adoption of rules or frameworks of self-regulation issued by foreign private entities. 
The conclusions obtained refer to the identification of conditions for the construction of anomie in regulation and professional practice, the deinstitutionalization of the social rule of law and the need for social and professional actions to rebuild the threatened institutionality as a factor for the construction of trust and regulatory stability in business and professional practice.
Análisis comparativo de las diferentes normatividades sobre insolvencia económica: Colombia vs. cinco países considerados grandes potencias económicas
Authors: Mazo Orozco Ana , Espinosa Tavera Mariana , Velásquez Pérez Mariela
Published: January 2023

This article aims to make a comparative analysis of the laws and different regulations on insolvency between Colombia and five countries considered major economic powers. The methodology is contemplated from a qualitative approach and is based on a documentary review, both of bankruptcy laws and specialized literature on the phenomenon of business failure. For this purpose, a comparative matrix is developed with the bankruptcy laws of Colombia to compare them with those of the five most influential countries worldwide: Japan, Germany, France, the United Kingdom and the United States. The results identified substantial differences in the bankruptcy legislation of the five countries, among them the inclinations of protection for third parties, because in some cases they seek to protect the economy in general, in others they denote preferences for maintaining employment or commercial relations, but in general they coincide in the organization of the administration of the companies. It is thus concluded that the regulations consider a diversity of elements that, according to the analysis of the variables, are all aimed at stabilizing the country's economy in order to avoid a domino effect in the fall of the companies caused by the cessation of payments in the acquired obligations.
An Update on the Financial Impact of Value-based Care Innovations in North Carolina
Authors: DuBard C. Annette , Mullineaux Alex
Published: January 2023

“We demonstrated better outcomes at lower cost in every population segment (Medicare, Medicare Advantage, commercial, and Medicaid), for both adults and children, in rural and urban settings, and across a wide variety of practices including solo practitioners, large multispecialty groups, federally qualified health centers, family medicine, internal medicine, and pediatric practices.”
Ensuring Rights of Victims Under the Criminal Procedure Code of Ukraine: Current Issues and Prospects
Authors: Rakipova Inna , Torbas Oleksandr , Voloshyna Vladlena , Shylin Denys , Pidgorodynska Anastasiia
Published: January 2023

Legal regulation and practical issues of ensuring of rights of victims under the Criminal Procedure Code of Ukraine are considered in the article. The criminal procedure legislation of Ukraine lacks legal regulation of the mandatory participation of a lawyer representing the victim in criminal proceedings. This situation puts the participants of proceedings in an unequal position. Victims during the trial and in court are unable to properly defend their legitimate interests due to lack of legal awareness. The authors also state that the participation of the victim’s representative in the conclusion of the conciliation agreement should be mandatory. The cases in which victims can receive free legal aid have been analyzed. It is proposed to define the cases of mandatory participation of the representative of victims in the current legislation of Ukraine.
Determining Barriers to Care in Pediatric Patients with SLE or JIA
Authors: Garcia Gloria E. , Kwan Olivia , Rodriguez Martha
Published: January 2023

Background and Hypothesis: Every year in the US 5,000-10,000 children develop child-onset systemic lupus erythematous (SLE), while 294,000 children are diagnosed with Juvenile idiopathic arthritis (JIA). Among the affected, it remains unknown if barriers to care affect pediatric patients with rheumatic diseases. It is the goal of this study to identify what barriers to care pediatric rheumatology patients mention during focus group sessions.
Methods: This is a qualitative focus group study. 13 focus groups, 60 minutes each with 3+ participants. Patients aged from 5-22 and their caregivers were recruited from different demographics and purposively selected for a more representative sample. Focus groups were conducted via the videoconference program Zoom and led by one facilitator in either English or Spanish. All meetings were recorded, transcribed, analyzed, and were independently coded using the constant comparison method and the NVIVO program.
Results: Thus far, we have recruited 14 parents and 17 patients. Demographics are shown in Table 1. Guardians/parents have concerns with cost of medications and future challenges once their child reaches age 26. Among the patients, almost all expressed problems with school attendance, and adjustments to their daily life. Most concerning however, was the impact that SLE and JIA have on their social life. There were topics that participants felt they were satisfied with such as communication with medical staff and health literacy.
Conclusion and Potential Impact: The preliminary information collected in this study showed different concerns among caretakers and patients. However, both groups suggested that a social group for children with SLE and JIA be created. The next phase of this study is to develop a survey based on these responses to try to identify patients’ and caregivers’ perspectives on barriers to care with the final goal of improving patient quality of life.
Evaluating the Effects of Targeted Drug Therapies for 8q24.3 Amplified Breast Cancer
Authors: Phipps Savannah , Khatpe Aditi , Nakshatri Harikrishna
Published: January 2023

Background/Objective:
Cancer studies have helped us understand recurrent chromosome abnormalities leading to tumor progression. One such recurrent genomic aberration found in breast cancer is chromosome 8q24.3 (Chr. 8q24.3) amplification. We identified Tonsoku Like, DNA Repair Protein (TONSL) located within this amplicon as an immortalizing oncogene, with TONSL-overexpressing cells exhibiting distinctively upregulated homologous recombination (HR). Further experiments have shown that cancer cells with TONSL amplification are sensitive to the FACT inhibitor CBL0137, which is in early phase of clinical development. Based on known functions of TONSL in promoting dsDNA repair, we hypothesized that drug combinations targeting multiple pathways of DNA repair would synergize to kill chromosome 8q24.3 amplified breast cancer cell lines.
Methods:
Chr.8q24.3-amplified breast adenocarcinoma cell line TMD436 was utilized in this study. Cells were treated with various drugs targeting DNA repair pathways such as ATR inhibitor (VE-822), PARP inhibitor (Talazoparib), and PI3K inhibitor (BYL719). Cell proliferation rates were measured using bromodeoxyuridine incorporation ELISA.
Results:
Thus far, the use of PI3Ki and PARPi combination has had an additive effect - the combined effect of the two drugs is equal to the sum of the effect of each agent given alone. The effect of ATRi and PARPi combination was antagonistic.
Conclusion/Potential Impact:
This study establishes the potential feasibility of using DNA repair signaling inhibitors in the treatment of TONSL-overexpressing breast cancer. Future studies extending the range of drug concentrations and newer combinations may ultimately lead to translation of these drugs to in vivo models and clinical trials. By targeting multiple DNA repair pathways, similar approaches may sensitize patients to lower doses of chemotherapeutics, thus decreasing unwanted side effects. Moreover, negative data concerning the ATRi/PARPi combination helps to further refine which drugs may be used to treat Chr. 8q24.3 amplified tumors and to understand signaling pathways active in TONSL-overexpressing breast cancer.
Descriptive Analysis of Lipid Panels and Other Biomarkers in Early and Late Pregnancy in the Hoosier Moms Cohort
Authors: Grecu Mitchell , Kotarski Aric , Saha Chandan , Scifres Christina , Haas David
Published: January 2023

Background/Objective: Early identification of and intervention for pregnant persons with a high risk of developing gestational diabetes mellitus (GDM) may lead to better health outcomes for both mother and infant. We aimed to assess both biomarkers and clinical predictors in early and late pregnancy to aid in the future development of an early pregnancy predictive model for GDM.
Methods: This project is part of the Hoosier Moms Cohort, a prospective, longitudinal cohort study of pregnant women followed from early pregnancy through the postpartum period. Blood samples were taken in early and late pregnancy to discover clinical laboratory biomarkers which could be used for GDM risk prediction. Other pertinent medical history and findings were collected through patient surveys and chart abstraction. Data analysis included general descriptive statistics, Pearson’s correlation, and nonparametric tests.
Results: 409 participants’ data were analyzed. Many biomarkers weakly correlated with maternal age and BMI in early and late pregnancy. Early pregnancy HbA1c was moderately correlated with BMI (0.32, p<0.001), and fructosamine was moderately negatively correlated with BMI (-0.43, p<0.001). Total cholesterol (TC), fructosamine, HDL, LDL, and triglycerides (TG) were weakly correlated with maternal age in early pregnancy. Blood glucose (BG) and TG were weakly correlated with BMI, and HDL was weakly negatively correlated with BMI in early pregnancy. Similar correlations were found with the biomarkers later in pregnancy with maternal age and BMI. White women had significantly lower HbA1c and higher TC and HDL levels when compared to Black/African American and “other race/ethnicity” women. Black/African American women had significantly lower fructosamine levels. LDL and TG were significantly lower and higher in “other race/ethnicity” women, respectively.
Conclusion: BMI and race/ethnicity have significant relationships with biomarkers in early pregnancy that must be adjusted for in the development of a GDM predictive model.
Temporal Trends in Primary Total Hip and Knee Arthroplasty Preoperative PROMs from 2013-2021
Authors: Hamersly Jackson , Deckard Evan , Meneghini R. Michael , Sonn Kevin
Published: January 2023

Background: Patient reported outcome measures (PROMs) are utilized in total joint arthroplasty (TJA) to objectively evaluate patient function and track progress over time. Limited data exists on temporal trends of preoperative PROMs and any specific effect of COVID-19 on preoperative functional status. The objective of this study was to identify changes in preoperative PROMs over time, and determine the influence of COVID-19 on patient function prior to TJA.
Methods: All patients undergoing unilateral primary total hip (THA) or total knee arthroplasty (TKA) by a single surgeon from 2013-2021 were retrospectively reviewed. Joint-specific preoperative PROMs and relevant covariates were compiled and evaluated. Time series, univariate, and multivariate analyses were performed to identify predictors of preoperative PROMs.
Results: After exclusions, 1,105 THAs and 1,909 TKAs were available for analysis. Preoperative activity level steadily increased from 2015 to 2021 for THA patients. For TKA patients, PROMs similarly increased from 2015 to 2019, however, a decrease in activity level occurred in 2020. No time series differences were observed for HOOS JR or Knee Society “knee normal” scores. KOOS JR scores increased from 2016 to 2019, then decreased in 2020 and 2021. Knee pain with level walking and stair climbing steadily increased from 2013-2019 with an increase in 2020 for both scores. The COVID-19 era (cases performed from 2020 onward) was a significant predictor of higher UCLA scores for THAs (p=0.020); and worse pain with level walking, and KOOS JR scores for TKAs in multivariate analysis (p≤0.038).
Conclusion: This study demonstrated detrimental effects of COVID-19 on preoperative patient functional status, particularly for TKA patients. Providers should consider the effects of surgical delays and how trends in preoperative PROMs are changing over time. These include rising activity levels of preoperative TJA patients overall and worsening knee pain and function in TKA patients during the COVID era.
Predicting Response to Polytrauma through Resolution of Immunologic Mediators
Authors: Ali Iyad , McKinley Todd O.
Published: January 2023

Background/Objective:
Traumatic injury can lead to hemorrhagic shock and hypoperfusion in patients precipitating multiple organ dysfunction. This study adopts a precision medicine approach to identifying biological markers in predicting patient response to polytraumatic injury. Clusters of cytokines can be used to model the immunologic response to traumatic injury. We hypothesized that analyzing the resolution of immunologic mediators in clusters would reveal differences among groups of patients identified to be sensitive/tolerant to hemorrhagic shock.
Methods:
Patients were required to have a stay in the ICU, one surgical operation, and a lower extremity traumatic injury. Blood samples were collected on patients at 0, 1, 12, 24, and 48 hours after injury. Multiplex analyses of 33 immunologic mediators were performed. A square- root transformation was applied to Luminex data before calculating z-scores (scores > 3 eliminated). Z-scores were summed to calculate composite cluster scores. T-tests were conducted to determine statistical significance.
Results:
High SHVL shows higher inflammatory cluster levels and lower orchestration than low SHVL. Low SHVL shows higher reparative cluster levels and lower orchestration than high SHVL. High SHVL shows higher proinflammatory 1 levels before 12 hr and at 48 hr than low SHVL. Low SHVL has higher proinflammatory 2 levels and less orchestration at 0, 12, and 24 hr. Low SHVL has higher type 2 cluster levels than high SHVL. SS shows higher lymphoid cluster levels at 0 hr and 1 hr than ST. SS has higher reparative cluster levels than ST, while ST has more orchestration. SS has higher proinflammatory 2 cytokine levels, while ST shows more orchestration. SS has higher type 2 cluster levels, while ST shows more orchestration.
Conclusions:
Cumulative hypoperfusion at time of injury is correlated with higher inflammatory cluster and proinflammatory 1 and 2 cluster cytokine levels as shown by both high SHVL and SS groups. Sensitivity to hemorrhagic shock and lesser hypoperfusion correlate to higher reparative cytokine cluster levels. Proinflammatory 2 cluster cytokine levels can be used to predict organ dysfunction.
Clinical Impact and Implications:
This work presents findings that can inform acute trauma care through immunologic mediators and patient characteristics.
Examining the Bone Marrow Niche in a Fracture Healing Model with the Use of Multiplex Imaging and Transcriptomics Technologies
Authors: Hartman Melissa L. , Karnik Sonali J. , Khurram Izza , Gulbronson Connor J. , Dunn Kenneth W. , Srour Edward F. , Kacena Melissa A.
Published: January 2023

Background: In the US, 6.3 million fractures occur annually. Additionally, 5-10% of fractures do not heal without additional interventions. The bone microenvironment is comprised of cells such as osteoblasts (OBs), megakaryocytes (MKs), and endothelial cells (ECs). Traditional technologies, such as flow cytometry, immunofluorescence (IF), and qPCR have limitations that prevent studying the bone microenvironment as a whole.
Project Methods: Some of the advanced multiplexed technologies that can be useful tools in studying a complex microenvironment such as bone are the PhenoCycler™, previously known as CODEX (CO-Detection by indEXing) and Nanostring nCounter which use fluorescent probe hybridization to either visualize the tissue or quantify gene expression, respectively. Phenocycler addresses the limitations of IF by imaging up to 60 cell markers, thus, allowing for better identification of cells within the bone microenvironment. This complex information can then be used for image analysis with the HALO image analysis software, providing the spatial context as well as functional aspects of cell interactions during homeostatic, disease, and injury states. Nanostring nCounter maps out hundreds of genetic pathways without requiring amplification or the need to convert mRNA to cDNA. This process is highly reproducible and decreases variability.
Results: In the current study, we are standardizing and optimizing protocols for both of these technologies for bone which are more difficult to process than soft tissues. Regarding Nanostring, samples have been submitted to the SNRI Biomarker Core and are awaiting processing.
Potential Impact: We anticipate that both the multiplexed technologies will allow us to determine which interconnected pathways, such as angiogenesis, inflammation, and immune response are differentially regulated during normal fracture repair, repair using new therapies, and repair in aged or diseased animal models.
Using Wheat Germ Agglutinin Stain for Visualizing Biofilm in a Porcine Wound Model
Authors: Metzman Andrew , Banerjee Pradipta , Roy Sashwati
Published: January 2023

One of the most challenging aspects of wound care is overcoming recalcitrant infections, namely in the form of biofilms. Biofilms are a product of bacteria that can have negative effects on the healing of wounds due to their ability to reduce immune response and the efficacy of antibiotics, as well as the difficulty of identifying biofilm presence in a wound. Biofilms are characterized as aggregations of bacterial cells with various extracellular polymeric substances. There is a risk of biofilm formation in chronic wounds, implanted devices, and catheters, and they continue to be difficult to identify with readily available clinical markers. An estimated 60% of chronic wounds are infected with biofilms. Methodological studies are necessary to quickly address potential biofilm infections . A wheat germ agglutinin (WGA) staining method was used to visualize biofilm presence in vitro. WGA binds to polysaccharide elements in biofilms, and further fluorescent staining allows for visualization. A porcine wound model involved full-thickness dorsal burn wounds which were inoculated with bacteria; 6-8mm punch biopsies of these wounds were taken 7, 14, and 35 days post-inoculation and sectioned. To measure the success of the WGA stain, two strains of S aureus, a common biofilm forming bacteria, were used: sarA (hypo-biofilm forming) and RexB (hyper-biofilm forming). Quantitative measurements were taken to compare the levels of biofilm in visualizations of biopsies infected with each strain. The hypothesis was that biopsies infected with sarA would show less biofilm presence than those infected with RexB. The staining optimization is ongoing, with results expected in time for presentation. Concurrently, scanning electron microscopy (SEM) analysis from the same samples are complete and available. If successful, having a stain that can provide quantitively measure biofilm presence in clinical wound samples is an important step to producing a method for identifying biofilm infection in clinical settings.Acknowledgements. IMPRS summer fellowship to AM and DoD award # W81XWH-20-9-0024 to SR
Protease-Activated-Receptors 1 and 2 are Essential in the Initiation of Food Allergy Early in Life
Authors: Miller Jessica , Martin Anna , Cook-Mills Joan
Published: January 2023

Background and Hypothesis:Because food allergies can be life-threatening, it is imperative to investigate the underlying pathways of food allergy initiation to progress towards treatment and prevention. Food allergies occur at an increased rate in children with altered skin barriers. Previous RNAseq studies have identified increased ApoE gene expression in mouse pups with skin barrier mutations sensitized with house dust mite and peanut allergens. Furthermore, PAR2 has been shown to be involved in the synthesis pathway of ApoE when activated by household allergens. We hypothesize that PAR2 is necessary for the initiation of food allergy in mice with skin barrier mutations.Project Methods:Pups heterozygous for skin barrier mutations in FLG and Tmem79 were sensitized with Alternaria alternata (Alt) and peanut extract (PNE) on postnatal days 3, 6, 9, 13, and 15. Pups received injections of PAR1 or PAR2 antagonist, no antagonist, or saline before each sensitization. At day 17, the pups received a PNE oral gavage. Rectal temperatures were incrementally measured for 80 minutes after the gavage to monitor anaphylaxis. Tissues were collected 8 hours after the gavage. Skin punches and intestine are currently being processed and analyzed by qPCR for IL33, OSM, and Areg.Results:Statistical analysis was completed using area under the curve by summation of average temperature changes for each pup. Pups that received PAR1 or PAR2 antagonists and application of Alt and PNE did not exhibit significant temperature drops whereas pups that received no inhibitor and Alt and PNE did undergo anaphylaxis, indicating blocking PAR1 and PAR2 blocked anaphylaxis. There were no statistically significant differences between male and female pup responses.Conclusion:The results of this study indicate that PAR2 and PAR1 are essential for development of food allergy and are potential cellular targets for treatment and prevention of food allergy early in life.
Racial disparities in a community-based addiction reduction (CARE) program for women of reproductive age with substance use disorder
Authors: Yakovlyeva Anastasiya , Worden Allison , Roth Sarah , Griffin Wilma , DeChant Paige , Butler Dawn , Tang Qing , Park Seho , Litzelman Debra K.
Published: January 2023

Background and Objective: In 2018, 51% of the 63 pregnancy-associated deaths of women in Indiana were attributed to substance use disorder (SUD), with Black women being disproportionately affected. To address the need for more effective SUD treatment interventions, the community-based addiction reduction (CARE) program connects women of child-bearing ages with SUD with addiction recovery coaches (ARCs) to provide personalized supports throughout recovery. To identify program characteristics that influence the retention of women of color in the program, quantitative analysis of CARE survey data and qualitative analysis of CARE ARC narrative entries of participant encounters were performed.
Project Methods: 251 women were enrolled in the CARE program. Chi-square/T-tests compared survey responses by race for treatment status, treatment motivation scales, and retention in the program at intake, 2-, 6-, 9-, and 12-month follow ups. Qualitative analysis of ARC narrative entries was conducted following thematic analysis and crystallization immersion analytic methods based on the grounded theory.
Results: Statistical analyses revealed White compared with Black women in the CARE program were significantly more likely to be in treatment at intake (p<.001) and more motivated to engage in recovery treatment (p<.001). Despite these differences, Black women were retained longer in the CARE Program at 2- (p<.006), 6- (p<.011) and 9-(p<.004) months. The ARC narrative entries were initially coded and emergent themes mapped well to the four types of supports provided by peer recovery coaches as outlined by the Substance Abuse and Mental Health Services Administration: emotional, instrumental, informational, and affiliational. Qualitative analysis of ARC narrative entries by race are currently underway.
Conclusion and Potential Impact: The inclusion of ARCs as integral members of SUD recovery programs may preferentially provide Black women with SUD the opportunity to build more trusting relationships with these peer coaches, thereby increasing their participation and retention in SUD-related treatment.
Improving Family and Surrogate Research Engagement in Nursing Homes
Authors: Mungcal Liam , Unroe Kathleen T.
Published: January 2023

Background: Nursing homes (NHs) are important sites of care for people with cognitive and physical disabilities; nearly half of NH residents have dementia. Unfortunately, NHs continue to be plagued with quality of care issues including lack of person-centered care and under-treatment of symptoms. The UPLIFT-AD (Utilizing palliative Leaders In Facilities to Transform care for Alzheimer’s Disease) stepped wedge trial aims to address these issues by using palliative care (PC) specialists in NHs. Measuring the impact of this intervention is challenging because people with dementia often have difficulties communicating, and thus, much research relies on the observations of staff and surrogate decision-makers (usually family members). The latter has yielded a low response rate for the first timepoint of the UPLIFT-AD project.Project Methods: A brief literature scan for similar PC NH interventions and surrogate engagement in NH research was performed, with support from a medical librarian, and revised strategies for surrogate recruitment were utilized during the second timepoint survey for two first-wave NHs.Results: Two first-wave NHs (n=47 and 43) had surrogate baseline survey completion rates of 42.6% (n=20) and 34.9% (n=15). Following the implementation of the additional strategies—calling surrogates from NH phones, calling at varied times, and emailing research information—the overall survey completion rate was relatively unaffected—42.6% (n=20) and 37.2% (n=16). Of the surrogates from these facilities (n=90), 30.0% (n=27) refused to participate and 17.8% (n=16) were “unable to contact.” The reasons for refusal included “not interested” (37.0%), “too busy” (18.5%), “no reason” (11.1%), “hung up” (11.1%), and “other” (22.2%). The literature scan yielded few published articles containing strategies to improve engagement of surrogates in NH PC research.Conclusion: Strategies to enhance surrogate engagement in NH research are underdeveloped. Engaging surrogates in research requires multiple strategies and presents an ongoing challenge but represents a critical perspective for studies involving people with dementia.
Granule Cell Layer Morphology and Wnt Signaling in Temporal Lobe Epilepsy
Authors: Nickerson Margaret , Mardones Muriel , Gupta Kunal
Published: January 2023

Background and Hypothesis: Temporal lobe epilepsy (TLE) is the most common human seizure disorder and can develop after neurologic insults such as trauma or infection. No treatment exists to prevent the development of epilepsy during this critical period. Epileptogenesis is characterized by pathological neuronal network remodeling in the hippocampal dentate gyrus (DG). Previously, we found that Wnt pathway signaling is dysregulated in the kainate (KA) mouse model of TLE, such that Wnt antagonism exacerbated epileptogenic DG remodeling. We hypothesize that Wnt agonism will mitigate pathological DG remodeling of the granule cell layer (GCL) during epileptogenesis.Project Methods: TLE was induced by unilateral intrahippocampal KA injection in POMC-eGFP transgenic mice, while controls received saline. Mice received injections of vehicle or Wnt agonist Chir99021 daily. eGFP+ immature dentate granule cells were characterized by confocal microscopy. GCL width and immature dentate granule neuronal migration in the ictal/ipsilateral and peri-ictal/contralateral DG were quantified. Quantitative analyses were performed to compare means of the 4 groups.Results: We found that GCL width significantly increased in the ictal zone 2 weeks after seizure induction in both KA groups and was not mitigated by Chir treatment. Immature dentate granule cell migration also increased in the ictal zone in the KA groups and was not altered by Chir treatment. In the peri-ictal zone, GCL width and cell migration were unchanged across KA and saline control mice.Conclusion and Potential Impact: The Wnt agonist Chir99201 did not appear to alter GCL morphology in control or KA mice. It is likely that Wnt signaling may impact neuronal functioning rather than morphology in DG remodeling, and this will be explored through future electrophysiological studies. The Wnt pathway remains a potential therapeutic target in the prevention of the development of epilepsy.
One-Carbon Metabolism, a Nutrient Dependent Mediator of Angiogenesis and Alveolar Formation in the Developing Lung
Authors: Nisen Noah , Ranasinghe Dushani , Kim Andrew , Schwarz Margaret
Published: January 2023

Background/Objective: Lung maturation has discrete dynamic shifts in metabolic derivatives that give rise to stage specific metabolite signatures. Components of one-carbon metabolism (OCM) are significantly increased in the late saccular and alveolar stage while hyperoxia disrupts OCM metabolism during these lung developmental stages. We hypothesize that disrupted OCM metabolites in the immature lung disrupts vessel dependent alveolar formation thus contributing to alveolar dysplasia. Our studies explore the impact that restoration of OCM has on angiogenesis and alveolar formation.Methods: Isolated human neonatal circulating Endothelial Colony Forming Cells (ECFCs) were examined for proliferation (WST-1), migration (scratch assay), and angiogenesis (matrigel) in response to supplementation of OCM derivatives, essential amino acid methionine and nicotinamide. OCM enzyme levels were assessed via Western blotting, NNMT, NAMPT, DNMT. Lastly, alveolar formation in a hyperoxia murine model of prematurity (HMMP) with dietary supplement of methionine vs control was assessed, MLI, H&E, and vessel formation (endomucin).Results: Methionine and nicotinamide increased ECFC proliferation (p<0.05) and OCM enzymes. Nicotinamide increased ECFC angiogenesis (p<0.05). ECFC migration was not impacted by methionine or nicotinamide supplementation (p NS). Methionine dietary supplementation in a HMMP model improved distal alveolar formation.Conclusion and Clinical Implications: Lung maturation is dependent on shifting metabolic needs during development. Replenishment of disrupted key OCM metabolites in HMMP promotes vessel and alveolar formation. Future studies are necessary to explore the role of precision nutritive supplementation in alveolar development of premature infants.
Immunoreactive Trypsinogen Levels in Infants Born to Women with Cystic Fibrosis Taking Elexacaftor-Tezacaftor-Ivacaftor
Authors: Patel Payal , Yeley Jana , Wesson Melissa , Lesko Barb , Slaven James E. , Chmiel James F. , Sanders Don B.
Published: January 2023

Background/Objective:Cystic Fibrosis (CF) is a lethal autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene affecting people of every race and ethnicity in the US. Highly effective modulator therapies (HEMT), such as elexacaftor-tezacaftor-ivacaftor (ETI), correct misfolding and/or improve functioning of the abnormal CFTR protein to lessen disease severity. Most people with CF are diagnosed following abnormal newborn screening (NBS), which involves measuring levels of immunoreactive trypsinogen (IRT). There have been case reports of falsely low IRT levels among infants with CF exposed to ETI in utero, but an overall assessment of IRT levels among these infants has not been conducted. We hypothesize that infants born to mothers with CF taking ETI (ETI-exposed) may have lower IRT levels than newborns with CF, CFTR-related metabolic syndrome (CRMS), or CF carriers.Methods:NBS data from infants born between 2020-22 in Indiana with at least one CFTR mutation were collected and compared to infants born to mothers with CF taking ETI followed at Indiana University, regardless of CFTR mutation status. Infants were categorized as: CF, CRMS, Carrier, ETI-exposed, and Unknown (i.e., diagnosis not determined). An ANOVA test was performed on log-transformed data, with p-values adjusted for Dunnett’s to compare IRT levels of infant groups to ETI-exposed group.Results:There were 51 children with CF, 21 with CRMS, 489 CF carriers, and 19 ETI-exposed infants. Compared to other groups, ETI-exposed infants had a lower median IRT value and IQR (p<0.0001). To our knowledge, there are no CF diagnoses among ETI-exposed infants.Conclusion:IRT levels for ETI-exposed infants, who are obligate CF carriers, were lower than for other infants with CF-related diagnoses, raising the likelihood of false normal NBS results. ETI-exposed infants should have CFTR mutation analysis performed to correctly categorize them as CF, CRMS, or CF carriers.
The Effects of Propofol on Efflux Activity in Alzheimer’s Disease Human Stem Cell-Derived Blood-Brain Barrier Models
Authors: Pavelka Matthew , Hughes Jason , Canfield Scott G.
Published: January 2023

Propofol is a common induction anesthetic that recently has been shown to diminish the integrity of the blood brain barrier (BBB) while maintaining efflux protein expression and activity. Furthermore, Alzheimer’s disease (AD), a neurodegenerative condition, compromises the integrity of the BBB including suppressed efflux activity. Efflux transporters, notably MRP-1, BCRP, and P-gp, play a role in clearing cytotoxic metabolites. The role of propofol on the activity of efflux proteins in AD patients is unknown. The goal of this study was to utilize human induced pluripotent stem cell (iPSC)-derived brain microvascular endothelial cells (BMECs) differentiated from familial AD iPSCS (APP, PSEN1, and PSEN2) and healthy iPSCs to determine the effects of propofol on efflux activity and expression.To measure the effect of propofol on efflux activity, treated cells were exposed to 50μM propofol for three hours and then specific efflux fluorescent substrates and inhibitors were utilized to determine efflux activity ( P-gp: Rhodamine 123/CsA; MRP-1: DCFDA/MK571; BCRP: Hoechst/KO143). Cells were lysed and the fluorescent substrate was quantified by a plate reader and normalized to the uninhibited group. The difference between the inhibited and uninhibited groups were used to determine the efflux activity. Efflux protein expression was also qualitatively assessed using immunostaining.Our preliminary results demonstrated that propofol did not affect efflux activity similar to previous literature. Interestingly, PSEN 1 and PSEN2 had suppressed baseline efflux transporter activity and did not show any change following propofol exposure. APP-derived BMECs displayed suppressed P-GP activity and similarly to PSEN 1/2-derived BMECs were not altered by propofol. Our preliminary results implicate that AD-derived BMECs have suppressed baseline efflux activity; however propofol exposure did not further alter activity level. Additional studies are needed to determine the role of anesthesia-induced injury on efflux activity and expression.
Investigating a Closed Loop Neural Control System to Optimize Sacral Neuromodulation
Authors: Wood Jacob , Lim Jongcheon , Lee Hyowon , Ward Matthew P.
Published: January 2023

Background and Hypothesis:Approximately 16% of the American population suffers from overactive bladder, with 25-40% of patients reporting unsatisfactory results following first line treatments. Sacral neuromodulation is a well-established, minimally invasive treatment option for several forms of bladder and bowel dysfunction that are non-responsive to first line pharmacologic or behavioral therapies. While more broadly applicable stimulus parameters are being investigated, the precise set of nerve fibers whose activity regulates optimal bladder function(s) is not known, leading to high levels of treatment variability between patients and within patients over time. We hypothesize that treatment efficacy and durability could be rapidly improved by continuously tuning the electrical stimulus waveform and pattern of stimulation to recruit the nerve fiber populations that mediate micturition.
Experimental Approach:We aim to access the sacral (S2-4) nerves and implant a set of recording and stimulating bipolar cuff electrodes (FNC-400-V-R-C-2C-30, Micro-Leads, Somerville, MA, USA) to measure the evoked CAP of the sacral nerves at various combinations of pulse amplitude and duration. Simultaneously, we will measure changes in bladder pressure using a pressure transducer attached to a bladder catheter and amplifier. By measuring how the bladder responds to all applied nerve stimulation parameters we will be able use an Autonomous Neural Control algorithm to identify the compound nerve action potential response that produces the most robust changes in pressure.
Results:We developed a surgical protocol, currently pending PACUC approval, that allows us to decode and encode specific CAP signatures that represent the firing activity of distinct subsets of nerve fibers, each differing in diameter, degree of myelination, activation threshold, conduction speed, and presumably function.
Conclusion and Potential Impact:This study aims to act as proof of concept for a system that selects stimulation parameters based on fibers required to produce a desired response rather than patient tolerance to stimulation parameters, ultimately improving efficacy of sacral neuromodulation therapy.
The Contribution of Genetic Risk for Alzheimer’s & Cardiovascular Disease to Recovery from Traumatic Brain Injuries
Authors: Wood Ethan , Nudelman Kelly K.
Published: January 2023

Polygenic risk scores (PRS) represent the genetic likelihood of developing a phenotype and represent an exciting opportunity for the development of personalized medicine. This study used PRS to determine if individuals at high-risk for Alzheimer’s (AD) or cardiovascular disease (CVD) would recover differently after TBI compared to low-risk individuals.
GWAS with the Illumina Global Screening Array was performed on DNA available for a subset of the BI-Model Systems cohort (N=189). PRS were chosen from the PGS Catalog (https://www.pgscatalog.org) and calculated using the Michigan Imputation Server. 1-year follow-up data (1Y) for the Functional Independence Measure (FIM) was used to evaluate TBI recovery. FIM represents the subject’s self-care ability after TBI and includes a cognitive and motor component.
ANCOVA models were used to elucidate the relationship between PRS risk groups (score in top 20% vs. 80%) and 1Y FIM scores. Covariates included age, education, FIM scores at discharge, injury severity, and genetic ancestry. Post-hoc analysis was conducted using 1Y FIM scores of subjects stratified by AD risk and APOE e4 carrier status, a major risk factor for AD onset. Additional post-hoc analysis evaluated hypertension at 1Y by CVD PRS groups using a cox survival model.
Individuals with high AD PRS had lower 1Y FIM scores than those with low risk (p= 0.041). Post-hoc analysis showed a trend for APOE e4 carriers with high AD PRS performing worse on FIM motor testing (p=0.145). There was not significant association between the CVD high-risk group and FIM scores (p=0.389). The cox survival model of hypertension trended towards earlier age of onset in the high-risk subjects (p=0.155).
This pilot study shows the potential for PRS to identify individuals at risk for worse TBI recovery, allowing for future research on early interventions and their effects on TBI recovery.
Determining the Best First-line Modality for Identifying and Localizing Skull Base CSF Leaks
Authors: Whitted Cody , Okecheku Vanessa , Koontz Nicholas A.
Published: January 2023

Background: Patients with skull base cerebrospinal fluid (CSF) leaks present with headaches, fluid in the ear(s), and/or rhinorrhea, which are vague symptoms. Beta-2-transferrin protein assays are the gold standard for identifying CSF leaks, but adequate samples cannot always be collected, and the results give no specific localizing information. Medical imaging, including Computed Tomography (CT), Magnetic Resonance (MR), and Nuclear Medicine (NM) cisternography can be utilized to identify and localize CSF leaks, but are imperfect tests. This study aims to determine the best imaging modality for identifying and localizing skull base CSF leaks by comparing CT, MR, and NM Cisternogram results to beta-2-transferrin assay and intraoperative visualization as criterion standards.
Methods: In this ongoing study, patient cisternogram and pre-cisternogram imaging and results were acquired from the electronic medical record, radiology information system, and picture archiving and communication system. Inclusion criteria include age greater than 18, suspected skull base CSF leak, and CT, MR, and/or NM cisternogram performed. MR cisternogram procedure included intrathecal gadolinium and NM SPECT-CT cisternogram procedure included intrathecal Tc-99m Sulfur Colloid. These data will be analyzed for positive and negative predictive values, sensitivity, specificity, and ROC Curve comparing to beta-2-transferrin assay results and surgical findings.
Results: From 2018-2022, 30 patients with suspected skull base CSF leaks were evaluated. In this limited preliminary data set, MR was more sensitive than CT, CT was more sensitive than NM, there were three false negatives, and there were no false positives. Performing two types of cisternogram increased the chance of identifying leaks. More data is needed to draw stronger conclusions in this ongoing study.
Conclusion/Potential Impact: The initial data suggests that MR cisternogram with intrathecal gadolinium is superior to CT and SPECT-CT cisternogram for detecting skull base CSF leaks. Localizing skull base CSF leaks helps enable surgeons to perform less invasive corrective procedures.
Characterization of a Chimeric MmuPV1 Genome with HPV-16E6E7
Authors: Pyles Josephine , DeSmet Marsha , Jose Leny , Androphy Elliot
Published: January 2023

Background/Objectives: Papilloma Viruses (PVs) are double-stranded DNA viruses that infect cutaneous and mucosal epithelium. In humans, there are over 100 types of PVs. HPV-16 is a high-risk type that causes ~50% of cervical cancers and ~70% of oropharyngeal cancers by expressing viral oncogenes E6 and E7 in replicating keratinocytes. The mouse PV, MmuPV1, displays species tropism and causes neoplastic lesions. Its discovery in 2011 introduced the opportunity to study PVs from early stages of infection to cancer development. Such an in vivo model of HPV-16 could uncover novel mechanisms for treatment intervention and disease prevention. Our study aims to characterize a small-animal infection model using a chimeric MmuPV1 genome with HPV-16 E6 and E7 in place of mouse E6 and E7 (MmuPV1-16E6E7). The goal of our study is to investigate the genome’s ability to express the HPV-16 oncogenes in vitro and to cause tumors in vivo.
Methods: To increase selective pressure in vitro, we replaced the MmuPV1 L1 and L2 genes with a neomycin cassette (MmuPV1-16E6E7neo). We packaged these genomes into infectious quasiviruses using a HEK 293TTF viral packing cell line. After isolating quasiviruses, we infected two donor human foreskin keratinocytes (HFK) cell lines. Forty-eight hours post infection, we isolated mRNA for qPCR to quantify HPV-16 E6 expression. To investigate whether MmuPV1-16E6E7 can cause tumors in in vivo, we infected athymic nude (N/J) mice orally with quasiviruses to evaluate infection and viable genome persistence.
Results: HPV-16 E6 cDNA was detected in three HFK isolates.
Conclusions/Future Directions: The presence of HPV-16 E6 cDNA indicates that the gene can be successfully transcribed from MmuPV1-16E6E7neo in HFKs. Future studies will assess this ability in primary mouse keratinocytes. If tumors are observed, we can use this model to study the efficacy of antiviral compounds to inhibit HPV16 E6 in vivo.
Complications and Outcomes Associated with Two-Stage Treatment of Periprosthetic Total Knee Infection
Authors: Thomas Jacob , Ziemba-Davis Mary , Meneghini R. Michael
Published: January 2023

Background and Hypothesis: Periprosthetic joint infection (PJI) is treated with implant resection, debridement, and component reimplantation after infection eradication. Treatment consists of either a single surgery or two-stage surgery with intravenous antibiotic therapy between stages. We replicated a recent study which concluded two-stage treatment is associated with high morbidity, hypothesizing that complication rates would be similar, but that morbidity is not always conclusively a consequence of two-stage treatment for PJI
Project Methods: Prospectively documented data on all primary and revision knees undergoing two-stage treatment for PJI by a single surgeon were retrospectively reviewed. Surgical complications were quantified for the interstage and post-reimplantation periods. Chi-squared tests were used to compare current findings to published findings.
Results: Patient demographics and comorbidities were equivalent in the two studies (p ≥ .137). More complex infections characterized the current study as evidenced by significantly more polymicrobial infections (p < .001) and greater use of static spacers due to bone loss (p = .002). Nonetheless, only 1.5% of cases in the current study did not undergo component reimplantation compared to 7.8% in the comparison study (p = .129). There were no differences in the number of additional interstage and post-reimplantation septic surgeries (p ≥ .492). Using a proposed system which penalizes additional operations required to eradicate infection, treatment success rates at minimum one year follow-up were 64% and 71%, respectively (p = .473). Without these penalties, treatment success in the current study was 95.6% (equivalent proportion not available for comparison study). All-cause mortality was statistically equivalent in the two studies (15.6 versus 7.6%, p = .144) but no deaths from PJI were observed in the current study (unknown for comparison study).
Potential Impact: Study findings suggest that morbidity attributed to two-stage treatment reflect the inherent complexity of this patient group, and not the two-stage treatment itself.