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A Rare Complication of Left Atrial Appendage Occlusion: Right-to-Left Shunting Post-Transseptal Puncture in a High-Risk Patient
No full textBackground: Transcatheter closure of the left atrial appendage (LAA) is a instrumental intervention for stroke prevention in atrial fibrillation patients who have contraindications to oral anticoagulants. Though generally effective, the transseptal puncture carries complications, including pericardial effusion, cardiac tamponade, air embolus, and device embolization, especially in patients with structural or valvular heart comorbidities. This case highlights a rare complication—right-to-left cardiac shunting—during LAA occlusion (LAAO) procedure in a patient with severe tricuspid regurgitation. We emphasize the need for careful patient selection and monitoring in high-risk populations. Case: An 83-year-old male with a CHA2DS2-VASc score of 5 presented for an elective LAAO. His medical history included atrial fibrillation with a leadless pacemaker, coronary artery disease, left ventricular dysfunction, tricuspid regurgitation, and pulmonary hypertension secondary to obstructive sleep apnea. Pre-procedural transesophageal echocardiogram (TEE) assessed LAA sizing and showed severe eccentric tricuspid regurgitation. The procedure was initiated with ultrasound-guided catheterization entry through the right femoral vein into the superior vena cava, followed by transseptal puncture using the BRK1 needle to access the left atrium. A 14F delivery sheath was advanced into the LAA. Following successful sheath deployment, the patient developed respiratory distress and hypotension, which were unresponsive to 100% FiO2. The procedure was thus aborted, and an intra-procedural TEE revealed a right-to-left shunt, likely aggravated by the pre-existing tricuspid regurgitation, with the jet directed toward the septal defect. Upon extubation, the patient experienced hypoxia and bradycardia, leading to a code blue. He improved with increasing his VVIR-mode pacemaker to 80 bpm and one round of resuscitation. The patient was re-intubated and transferred to critical care for management of intermittent hypoxia, requiring 24 hours of mechanical ventilation before hemodynamic stabilization. Discussion of closing the septal defect was halted after a follow-up transthoracic echocardiogram confirmed the closure of the shunt. Patient was extubated successfully after intensive care but required physical therapy due to frailty. He was eventually discharged to a skilled nursing facility for rehabilitation. Discussion: Transseptal puncture—a common technique during device implantation in LAAO—has current literature documenting its array of associated complications. The FDA Manufacturer and User Facility Device Experience (MAUDE) database reports a 7.3% adverse event rate and a 0.4% mortality rate for Watchman device implants between 2015 and 2019, with most complications occurring intraoperatively4. Common adversities include pericardial effusions and cardiac tamponade, while possible air emboli could lead to acute coronary ischemia or stroke1. LAAOs often result in iatrogenic atrial septal defects, which occur in up to 87% of cases immediately following transseptal catheterization5. These defects typically resolve within six months, and less than 10% of patients experience persistent defects without hemodynamic consequences5. However, right-to-left shunting, particularly with concomitant use of large-diameter sheaths, is a rare but concerning complication that warrants further study. Conclusion: This case underscores a rare but significant complication of right-to-left shunting during LAAO, particularly in patients with severe tricuspid regurgitation. Further investigation to better understand complication predictors and optimize care strategies is vital for vulnerable atrial fibrillation populations undergoing LAAO
Case Report of Spontaneous Coronary Artery Dissection in 33-year-old G4P4 Female
No full textA 33-year-old G4P4 female with past medical history of Generalized Anxiety Disorder, Anemia, Hypertension, Gestational Diabetes Mellitus presented with concern of chest pain, lightheadedness, palpitations, and bilateral lower extremity paresthesias 4 days after uncomplicated vaginal delivery. Patient was found to have NSTEMI (troponins up to 25,000+) and hypokalemia (2.8). She was taken for cardiac catheterization which demonstrated no stenosis, abnormal left ventriculogram, and kinking of the mid LAD. Given benign and unimpressive findings, patient was discharged the next day with atorvastatin, clopidogrel, lisinopril, and potassium chloride. The patient returned to the emergency department 2 days later with chief concern of bilateral lower extremity pain, which was managed conservatively with analgesics and the patient was discharged. Eight days later, she presented to the emergency department with chest pain. Her troponins were elevated to 2381. Given concern for spontaneous coronary artery dissection, a CTA of the coronary arteries was done and demonstrated dissection of the mid-distal left circumflex artery with stenosis. Patient was transferred to Dallas for higher level of care and surgical evaluation
Undifferentiated Carcinoma with Osteoclast-like Giant Cells of the Pancreas in a Double Lung Transplant Recipient: The Role of Immunosuppression in Carcinogenesis
No full textBackground: Undifferentiated carcinoma with osteoclast-like giant cells (UCOGC) of the pancreas is an extremely rare tumor, accounting for less than 1% of all pancreatic malignancies. Medical literature on UCOGC of the pancreas remains limited to sporadic case reports. We report the first case of UCOGC of the pancreas in a double lung transplant recipient and review the role of immunosuppression in carcinogenesis. Case Presentation: Patient was a 72-year-old man with a history of double lung transplantation for idiopathic pulmonary fibrosis 4 years ago. He had been immunosuppressed with tacrolimus and mycophenolate. He presented with one week of epigastric pain, nausea, vomiting, early satiety, poor oral intake, and weight loss. Blood work showed Hgb 10, platelet 75K, bilirubin 1.3, AST 29, ALT 60, AP 66. CT and MRI showed a 3.4 cm mass arising from the head of the pancreas, a 2.4 cm necrotic portacaval lymph node, and multiple low-attenuation lesions in the liver. EGD showed complete duodenal stenosis due to extrinsic compression. Endoscopic ultrasound showed a 6 cm x 5 cm heterogeneous mass in the pancreatic head with invasion into the portal vein and metastatic lesions throughout the liver. FNB of the pancreatic mass showed UCOGC. FNA of the liver lesions showed metastases from the pancreatic cancer. Patient deteriorated rapidly with respiratory distress and gastric outlet obstruction. Oncology offered port placement followed by gemcitabine-based chemotherapy, but patient declined due to his grave prognosis. He requested palliative intervention for the gastric outlet obstruction. Patient underwent a Roux-en-Y gastrojejunostomy which relieved the GI obstruction. He was discharged to home hospice. Conclusion: Immunosuppression after solid organ transplantation is an established risk factor for carcinogenesis, with a 20-fold increased risk compared to the general population. Calcineurin inhibitors such as tacrolimus increase cytokine-transforming growth factor levels. Immunosuppression leads to decreased activity of anti-neoplastic natural killer cells. Opportunistic viral infections such as EBV can also increase the risk of carcinogenesis. Given that malignancy is a significant obstacle to long-term survival in this patient population , future research should focus on understanding how immunosuppression increases malignancy risk, developing novel diagnostic tools that allow for early detection, and providing targeted treatments
Novel kinase inhibitor compound alters EMT marker gene expression in triple-negative breast cancer
No full textBackground: Breast cancer is one of the most prevalent types of cancer in the United States. Triple-negative breast cancer (TNBC) is particularly challenging to treat, as it lacks receptors for estrogen (ER) and progesterone (PR), as well as human epidermal growth factor receptor 2 (HER2). Therefore, TNBC is associated with poorer prognoses. Kinase dysregulation is implicated in several cancers, including TNBC. Kinase inhibitor compounds do not target hormone receptors but instead target cell signaling and regulatory proteins, offering a potential therapeutic option for TNBC. Our lab previously screened a kinase inhibitor compound library to identify kinase targets against TNBC. One compound of interest, GW525701, is largely uncharacterized. For this study, we aimed to characterize the effect of GW525701 treatment on gene expression of key epithelial-to-mesenchymal transition (EMT) markers and actin filament staining at various time points and concentrations to assess migratory potential and morphology changes, respectively. Methods: This study used a patient-derived xenograft (PDX)-derived TNBC cell line: TU-BcX-4IC. TU-BcX-4IC cells were seeded in a 6-well plate. The following day, cells were treated with GW525701 at concentrations of 1, 10, or 100nM and collected 24, 48, 72, or 96 hours later. RNA was extracted, quantified, and reverse-transcribed to synthesize cDNA. qRT-PCR was then performed to determine changes in CDH1, CD24, and JAG1 expression in the treated groups compared to the vehicle-treated control. To monitor the effect of GW525701 treatment on actin filament morphology, TU-BcX-4IC cells were seeded in an 8-well chamber slide. Cells were treated at 1, 10, or 100nM the following day. At 24, 48, 72, and 96 hours later, cells were stained with DAPI and phalloidin and visualized via fluorescent microscopy. Results: TU-BcX-4IC cells exhibited significant upregulation of CDH1 and downregulation of CD24 after 10nM treatment for 24 hours. Significant downregulation of JAG1 was observed at 100nM at the same time point. Interestingly, after treatment at 1nM for 48 hours, CDH1 expression increased. Treatment for 72 hours at 1nM decreased expression of JAG1, while 10nM and 100nM treatments caused upregulation of CDH1. Lastly, expression of CDH1 was significantly increased after treatment with GW525701 for 96 hours at 10nM. Similarly, CD24 expression increased after a 100nM treatment, but 1nM treatment caused diminished expression after 96 hours. At 100nM concentrations, DAPI-stained multi-nucleated cells are present. At lower concentrations, phalloidin appears to be associated with the edge of the cells. Conclusions: Treating TU-BcX-4IC cells with GW525701 resulted in significant upregulation of CDH1 at multiple time points and concentrations. CDH1 is an epithelial marker, indicating the potential decreased EMT that may be associated with treatment with GW525701. GW525701 also diminished the expression of mesenchymal markers JAG1 and CD24. Therefore, GW525701 may decrease TNBC migration. However, interesting morphologic alterations associated with leading-edge formation were observed, which may indicate migration. It should be noted that multi-nucleation was observed at higher doses, which may indicate cellular dysregulation. This underscores the need for more research to confirm the role of GW525701 in TNBC therapies and the urgency of this research in the context of TNBC treatment
Effects of Place Based Disparities and Early Life Stress on Health Outcomes and Research Solutions: A Literary Analysis
No full textPurpose: Place based disparities (PBD) is defined as how the area where someone lives effects his or her health outcome(s). PBD encompass a multitude of factors including segregation, neighborhoods, employment, education, and stress. These environments also contribute to childhood development and are correlated with early life stressors (ELS). This literary analysis was conducted to identify research solutions to limit the effects of PBD and ELS. Methods: A literary analysis was conducted to determine specific health factors effected by both PBD and ELS. The specific type of research modality was identified with each study. A further analysis was then done to find how different research methods can better solve the current problems with health disparity research. Results: Research shows that segregated communities of color and neighborhoods of poverty trapped areas are associated with poor long term health outcomes. These types of environments are prone to effect children, specifically, through ELS. Exposures to stressors in the early life of residents who grow up in areas of concentrated & inter-generational poverty play a critical role in their development and have negative long term health outcomes. Conclusion: Historically, efforts to research topics related to health disparity have taken one of two approaches: (1) population- based/epidemiological studies which include variable environmental factors inherent to the human experience or (2) animal model-based biomedical/basic science studies which allow for tight control over variables. Both offer distinct perspectives and insight; however, application of this knowledge has not been well applied due to lack of communication between fields. This analysis looks at solutions to bridge the gaps between these research approaches through the integration of more multidisciplinary and interventional studies
Non-invasive in vivo Imaging of Beta-Cell Function in the Rodent Pancreas Using a Zinc Responsive Contrast Agent
No full textBackground: Regulated glucose-stimulated insulin secretion (GSIS) by pancreatic b-cells is crucial for maintaining blood glucose homeostasis, which is often compromised in diabetes; particularly in type 2 diabetes [1]. It is well-established that insulin is stored in beta-cell granules along with excess Zn²⁺ ions. During exocytosis, when blood glucose levels rise, these granules release both insulin and Zn²⁺ ions into the extracellular space surrounding the islets [2]. Given that glucose stimulated insulin secretion (GSIS) is a critical feature of normal beta-cell operation, comprehending the pathological processes that result in its dysfunction is an essential challenge. Therefore, in real-time imaging of pancreatic b-cells function, particularly at the level of individual islets, could be key to understanding the pathophysiology of diabetic progression. Previous studies have shown that b-cells secrete Zn²⁺ along with insulin in response to elevated blood glucose levels. Additionally, our earlier research demonstrated that Zn²⁺ secretion can be detected using magnetic resonance imaging (MRI) with a responsive contrast agent [3, 4]. However, prior MRI signals were complicated by the clearance of the injected Zn²⁺ sensor during the detection of beta-cell function dynamics. To address this, we optimized the MRI protocol in this study by continuously administering the Zn²⁺ sensor during GSZS imaging, thereby avoiding confounding effects from first-pass agent clearance and fluctuations in Zn²⁺ sensor concentration. Methods: All animal experiment were performed in accordance with guidelines by the institute IACUC committee. MRI was performed in 7 T MR solution with 72 mm volume coil using Gd-based Zn²⁺ sensors (GdL₂), which was prepared as described previously [4]. Total 13 Sprague Dawley male-rats of 10–14 weeks age (Charles River Laboratories) were used for in vivo MR imaging experiments after fasting overnight before imaging. One group of 6 rats were imaged with infusion of GdL₂ plus glucose and the other group of 7 rats were imaged with infusion of GdL₂ plus saline. A GdL₂ infusion at a concentration of 0.1 mmol/kg was administered through a lateral tail vein catheter for 1 hour, either salin or combined with glucose (2.75 mmol/kg), which was injected intraperitoneally 30 minutes after the start of scanning. A series of gradient echo 2D multi-slice images with fat saturation were collected to monitor the dynamic Zn²⁺ release from the pancreas in response to glucose stimulation (TE/TR 5/121ms, matrix 256x256, FA=45, and FOV=65x65mm). Results: The continuous infusion of Zn²⁺-responsive agent GdL₂ enables non-invasive detection of Zn²⁺ secretion from beta cells during glucose-stimulated insulin secretion, with increased signal intensity observed in the pancreatic tail following intraperitoneal glucose injection. It could make a visualize localized 'hot spots' of initial beta-cell responders during GSIS. It enables the visualization of localized "hot spots" of initial beta-cell responders during glucose-stimulated insulin secretion (GSIS). Conclusion: This new imaging protocol enables non-invasive, real-time monitoring of beta-cell function during GSIS, without interference from first-pass clearance or fluctuations in contrast agent concentration. It is valuable for evaluating drug efficacy and tracking b-cell decline in type 2 diabetes progression in rodent models
Evaluating fairness of machine learning prediction of prolonged wait times in Emergency Department with Interpretable eXtreme gradient boosting
Full text linkIt is essential to evaluate performance and assess quality before applying artificial intelligence (AI) and machine learning (ML) models to clinical practice. This study utilized ML to predict patient wait times in the Emergency Department (ED), determine model performance accuracies, and conduct fairness evaluations to further assess ethnic disparities in using ML for wait time prediction among different patient populations in the ED. This retrospective observational study included adult patients (age >/=18 years) in the ED (n=173,856 visits) who were assigned an Emergency Severity Index (ESI) level of 3 at triage. Prolonged wait time was defined as waiting time >/=30 minutes. We employed extreme gradient boosting (XGBoost) for predicting prolonged wait times. Model performance was assessed with accuracy, recall, precision, F1 score, and false negative rate (FNR). To perform the global and local interpretation of feature importance, we utilized Shapley additive explanations (SHAP) to interpret the output from the XGBoost model. Fairness in ML models were evaluated across sensitive attributes (sex, race and ethnicity, and insurance status) at both subgroup and individual levels. We found that nearly half (48.43%, 84,195) of ED patient visits demonstrated prolonged ED wait times. XGBoost model exhibited moderate accuracy performance (AUROC=0.81). When fairness was evaluated with FNRs, unfairness existed across different sensitive attributes (male vs. female, Hispanic vs. Non-Hispanic White, and patients with insurances vs. without insurance). The predicted FNRs were lower among females, Hispanics, and patients without insurance compared to their counterparts. Therefore, XGBoost model demonstrated acceptable performance in predicting prolonged wait times in ED visits. However, disparities arise in predicting patients with different sex, race and ethnicity, and insurance status. To enhance the utility of ML model predictions in clinical practice, conducting performance assessments and fairness evaluations are crucial.The project described was supported by the National Institute on Minority Health and Health Disparities through the Texas Center for Health Disparities (NIMHD) 5S21MD012472- 05 (US), and the National Institute of Health/ Artificial Intelligence/Machine Learning Consortium to Advance Health Equity and Researcher Diversity Grant # 1OT2OD032581- 01 (US). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NI
Type of pre-existing chronic conditions and their associations with Merkel cell carcinoma (MCC) treatment: Prediction and interpretation using machine learning methods
Full text linkOBJECTIVE: This study examined the prevalence of pre-existing chronic conditions and their association with the receipt of specific cancer-directed treatments among older adults with incident primary Merkel Cell Carcinoma (MCC) using novel predictive and interpretable machine learning methods. METHODS: We adopted a retrospective cohort study design with data from linked Surveillance, Epidemiology, and End Results (SEER) registry and Medicare Fee-For-Service claims databases of older adults (>/= 66 years) diagnosed with primary incident MCC between 2008 and 2017. The study cohort consisted of 1,668 older adults with incident MCC and continuous fee-for-service Medicare enrollment for 24 months. Chronic conditions were identified during 12 months before cancer diagnosis date. Type of any MCC treatment (surgery-SRx, radiotherapy-RTx, chemotherapy-CTx, immunotherapy-ITx, and hormonal therapy-HTx) were derived for 12 months following cancer diagnosis. Receipt of any of these treatments and their associations with pre-existing chronic conditions were analyzed using separate eXtreme Gradient Boosting (XGBoost) predictive models and SHapley Additive exPlanations (SHAP) methods. RESULTS: High cholesterol (75.5%), HIV (71.5%), hypertension (67.7%), arthritis (54.9%), coronary artery disease (47.1%), diabetes (43.5%), and hepatitis (37.1%) were some of the highly prevalent pre-existing chronic conditions. MCC treatment varied by type of chronic conditions and treatment modality. For example, a lower percentage of those with hypertension received ITx compared to those without hypertension (5.7% vs. 17.1%). A higher percentage of those with high cholesterol (13.9% vs 10.8%) received HTx compared to those without high cholesterol. XGBoost predictions revealed high predictive accuracy (area under the curve ranged from 0.72 (CTx) to 0.99 (ITx)). Hypertension (ITx), diabetes and thyroid disorders (HTx), congestive heart failure (RTx), and high cholesterol (CTx) were among the top ten predictors of MCC treatment. Congestive heart failure (RTx), hypertension (CTx), heart disease (ITx), thyroid disorders (HTx), and osteoporosis (HTx) positively predicted treatment, whereas high cholesterol (CTx), hypertension (ITx, HTx) and diabetes (ITx, HTx) negatively predicted treatment. CONCLUSIONS: Pre-existing conditions were highly prevalent among older MCC adults. Cardiovascular and metabolic diseases were the top 10 leading predictors of cancer treatment. However, the associations varied by type of treatment. In spite of the good performance of the model, especially for ITx and HTx, there is a need to replicate these findings using other data sources that provide access to larger population subgroups.This study was funded by EMD Serono Research & Development Institute, Inc. The funders had a role in the study design and the decision to publish
The Round-Up Spring 2025
Full text linkThe NNLM Region 3 newsletter contains information about upcoming training and funding opportunities, interesting projects from around the region, details about staff and partners, and more. In this issue: Note from the Executive Director; Special Edition Of Health Bytes: Alzheimer's & Dementia: Beyond The Diagnosis; NNLM Reading Club: Complementary and Integrative Medicine; Kansas Hosa Spring Leadership Conference; Harvey Health Matters Initiative: A County-Wide Health Advocacy Collaboration; NNLM Book Discussion: The Well-Gardened Mind; Learning Opportunities: 3D Basic
The efficacy of an allosteric modulator of the alpha 7 nicotinic acetylcholine receptor in a murine model of stroke
Full text linkINTRODUCTION: Ischemic strokes contribute significantly to cardiovascular-related deaths in the U.S., with current interventions limited to thrombolytic agents. However, these agents present challenges such as a limited therapeutic window, incomplete reperfusion rates, risk of transformation, reperfusion-induced inflammation, and a lack of promoting neuroprotection. We investigated an additional strategy in which prior studies indicated a neuroprotective role. Using a murine transient middle cerebral artery occlusion (tMCAO) model, we sought to evaluate the neurotherapeutic efficacy of a positive allosteric modulator of the alpha7 nicotinic acetylcholine receptor (alpha7-nAChR), PNU-120596 (PNU), specifically examining whether PNU would modulate stroke-induced neurological dysfunction and neuropathology, with modulation of neuroinflammation as a possible mechanism. METHODS: Young male C57BL/6J mice received a subcutaneous injection of 20mg/kg of vehicle (DMSO) or PNU-120596 immediately after reperfusion, and infarct area and Bederson score were analyzed 24 hours post-stroke. In the 72-hour post-stroke study, the animals were injected with 20mg/kg of PNU or vehicle subcutaneously immediately after reperfusion, followed by two additional doses of 10mg/kg of PNU or vehicle at 24 and 48 hours post-tMCAO. Seventy-two hours later, behavior function and infarct area were assessed. RESULTS: In contrast to previous rat studies that demonstrated improvements in clinical outcomes, a single administration of PNU following stroke induction led to a reduction in acute neuropathology but did not produce a significant improvement in motor outcomes. Prolonged treatment showed no significant changes in acute neuropathology or sensorimotor function. Additionally, an assessment of neuroinflammation revealed no changes in CD4 T-cell cellularity or phenotype. DISCUSSION: These findings, alongside prior studies, suggest that the therapeutic efficacy of PNU may be contingent upon the timing of administration, dosage, and pharmacokinetics.The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This publication was supported by the National Institute on Minority Health and Health Disparities of the National Institutes of Health under Award Number U54MD006882 and the National Institutes of Health/National Institute on Aging (T32 AG020494), and startup funds from the Microbiology, Immunology, and Genetics Department and the College of Biomedical and Translation Sciences at the University of Health Science Center