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Cellular Mechanisms Governing Tau Propagation
Full text linkTau aggregation underlies neurodegenerative diseases called tauopathies such as Alzheimer's. Tau aggregates are amyloid assemblies that originate in one area and spread to other brain regions by being released and internalized by neighboring cells. In the recipient cell, tau aggregates can function like prions by recruiting the naïve monomer to faithfully template on its unique conformation, a process termed seeding. The biology of tau aggregation has been mostly focused in neurons, however, with limited understanding of the role of glia. I sought to study the role of astrocytes in tau aggregation and show that astrocytes can internalize recombinant tau fibrils, seed these fibrils, and transfer those to other astrocytes in a co-culture model.
An important question in the field that remains unresolved is what cellular mechanisms facilitate the initial stages of tau prion templating and propagation. Through an unbiased investigation of the aggregation process in its initial stages, I discovered the disaggregase VCP's roles in regulating tau seeding. Using cellular models of tau aggregation, I show that VCP functions early in the aggregation cascade, processing tau seeds for amplification and degradation. Pharmacologic modulations of VCP show that it can differentially up- and down- regulate tau seeding. Through a genetic screen, I have identified distinct cofactors of VCP that are specific to tau seeding and dictate the fate of tau aggregation through their known roles in ubiquitylation and ER-associated degradation pathways. These findings offer novel and precise targets for therapeutic interventions in tauopathies
Capturing Clinical Red Flags for Secondary Headaches: A Guideline-Based Ontology Approach
No full textPoster session at the 2025 Texas Regional CTSCA Consortium Conference in San Antonio, Texas.The 2025 Texas Regional CTSCA Consortium Conference was held at the University of Texas at San Antonio in San Antonio, Texas, on June 12-13, 2025.INTRODUCTION: Headache is one of the most common neurological complaints, affecting approximately 90% of people in the U.S. during their lifetime. While most headaches are benign, secondary headaches, those caused by underlying medical conditions such as vascular, neoplastic, infectious, or intracranial pressure-related disorders can be serious and require urgent evaluation1. Prompt identification is critical. We propose the development of a guideline-based decision support tool to help clinicians quickly recognize and triage potential secondary headaches based on signs and symptoms that warrant immediate attention.
OBJECTIVE: To develop a custom, guideline-informed interoperable ontology for secondary headache computable phenotype identification.
METHODS: We manually reviewed 10 clinical guidelines from U.S. and North American sources focused on the diagnosis, management, and referral of secondary headaches. From decision trees, algorithms, and narrative text, we extracted 141 unique features associated with secondary headaches, particularly red flag symptoms. We analyzed the overlap among guidelines to identify consistently flagged features, with "focal neurological deficit" emerging as a common indicator. Using this insight, we built a custom ontology, mapping features to SNOMED CT concepts. We further queried each concept to extract associated synonyms, abbreviations, related symptoms, and anatomical associations, organizing them under semantic relationships such as: "has_laterality", "Is_a", "associated_with", or "affects_anatomical_site".
DISCUSSION: Our ontology provides a standardized, evidence-based framework derived from clinical guidelines, allowing for classifying secondary headache phenotypes based on red flag symptoms in the Electronic Health record (EHR). By embedding this ontology into clinical documentation and decision support workflows, clinicians can be guided toward appropriate next steps such as ordering neuroimaging (Magnetic Resonance versus Computerized Tomography) or refer to a specialist, based on the presence of high-risk features.
CONCLUSION: This project builds on prior efforts using ontology-based models to encode domain knowledge for CDS2 and represents preliminary work in building an advanced clinical decision support system. Future work will involve integrating the ontology into the EHR and developing Natural Language Processing tools for referral triage, information transfer for referrals, documentation management recommendations, and cohort definition for secondary research.
REFERENCES: (1) Robbins MS. Diagnosis and Management of Headache: A Review. Jama. May 11 2021;325(18):1874-1885. doi:10.1001/jama.2021.1640 (2) Rousseau JF, Oliveira E, Tierney WM, Khurshid A. Methods for development and application of data standards in an ontology-driven information model for measuring, managing, and computing social determinants of health for individuals, households, and communities evaluated through an example of asthma. Journal of Biomedical Informatics. 2022/12/01/ 2022;136:104241. doi:https://doi.org/10.1016/j.jbi.2022.10424
Consumption of Ultra-Processed Foods and Their Associations with Overall Cancer and Gastrointestinal-Specific Cancer Incidence in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL)
Full text linkThe 63rd Annual Medical Student Research Forum at UT Southwestern Medical Center (Tuesday, January 28, 2025; 3-6 p.m.; D1.700 Lecture Hall)Ultra-processed foods (UPFs), which are industrially manufactured with additives like preservatives and emulsifiers, have become a staple in global diets, accounting for 50-60% of daily energy intake in some high-income countries. In the U.S., UPF consumption is disproportionately higher among individuals with lower income, education, and food security, and differs by race/ethnicity. While non-Hispanic white and Black adults have the highest UPF consumption, Hispanic/Latino adults still consume a significant proportion (47.7%) of their daily calories from UPFs. The health implications of UPF consumption are profound, with evidence linking higher consumption to an increased risk of diabetes, hypertension, dyslipidemia, obesity, and cancer. A 10% increase in UPF consumption correlates with an increased risk of overall cancer-related incidence (HR 1.02; CI 1.01-1.04) and cancer mortality (HR 1.06; CI 1.03-1.09), particularly in gastrointestinal (GI) cancers.
Cancer is the leading cause of death among Hispanic/Latino adults in the U.S., and rates of gastric and colorectal cancers are increasing in this population. However, few studies have explored the link between diet and cancer risk in Hispanic/Latino communities. This study aims to investigate the association between UPF intake and both overall and GI-specific cancer risks using data from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), from baseline (2008-2011) through 2021.
In this prospective cohort study, we will analyze 715/16,000 participants with both UPF intake, measured using the NOVA classification system and cancer incidence data. Cox proportional hazards models will be used to assess the relationship between UPF intake and cancer risk, adjusting for potential confounders like socioeconomic factors and past medical history.
Analysis is ongoing but preliminary results should be available by the conference. The study's findings will provide critical insights into dietary risk factors for cancer within Hispanic/Latino populations, potentially guiding public health strategies to reduce cancer disparities and improve health equity.Southwestern Medical Foundatio
Placental Effects on Early Postnatal Cerebral Autoregulation in Neonates with Hypoplastic Left Heart Syndrome
Full text linkThe 63rd Annual Medical Student Research Forum at UT Southwestern Medical Center (Tuesday, January 28, 2025; 3-6 p.m.; D1.700 Lecture Hall)PURPOSE: Neonates with severe forms of congenital heart disease (CHD), such as hypoplastic left heart syndrome (HLHS), are at increased risk of neurologic complications. Disorders of the placenta have been linked to brain abnormalities in this population, but mechanisms by which the placenta increases this risk are unknown. We hypothesized that placental pathologies impact the development of cerebral autoregulation (CAR) and that placental vascular malperfusion lesions may be most likely to exert deleterious effects on cerebral hemodynamics. The purpose of this study was to compare the percentage of time spent with impaired CAR during the early postnatal period in neonates with HLHS and healthy placenta versus those with histopathologic lesions of the placenta.
METHODOLOGY: We analyzed time synchronized vital sign data in neonates with HLHS born at ≥35 weeks' gestation. CAR was determined in the early postnatal and pre-operative time period using the temporal relationship between mean arterial blood pressure (MAP) and regional cerebral oxygen saturation (rSO₂). To assess intact versus impaired CAR, we used a rolling calculation of the Cerebral Oximetry Index (COx), a dynamic correlation in which values ≥0.3 were considered impaired CAR in accordance with prior studies. We used a student's t-test to determine differences between mean time spent with impaired CAR in HLHS neonates with normal versus abnormal placentas. In subgroup analyses, we compared those with normal placentas to neonates with vascular malperfusion lesions of the placenta.
RESULTS: In our cohort of 26 neonates with HLHS, we analyzed an average of 86 hours of continuous monitoring. There was a total of 18 (69%) patients with evidence of placental pathology and 8 (31%) with normal placentas. COx showed a wide range in time spent with impaired CAR between subjects (range 0-35%). Mean time spent with impaired CAR in those with normal placentas was significantly less than those with placental histopathology (3.0 ± 1.8% vs. 8.4 ± 9.0%; p=0.02). In exploratory subgroup analyses, those with vascular malperfusion lesions of the placenta had similar time spent with impaired CAR (8.8 ± 6.5%; n=5) to those with normal placentas (p=0.12).
CONCLUSION: In neonates with severe forms of CHD, like HLHS, placental histopathologies may increase the risk of brain injury through disrupted development of CAR.Southwestern Medical Foundatio
APOL1-associated kidney disease
Full text linkDetailed formal protocol with illustrations and extensive bibliography.A recording of the protocol presentation is available on UT Southwestern's Mediasite. Note: Access to the video is restricted to authorized UT Southwestern users only.UT Southwestern--Internal Medicin
Efficacy and Safety of Obeticholic Acid for Treating Hepatic Steatosis in Patients with Familial Partial Lipodystrophy
No full textThe attached file includes supplementary tables. This submission meets the Extended Data Sets and Supplemental Materials requirements that are included in author guidelines for the Journal of Clinical Endocrinology & Metabolism (Print ISSN 0021-972X, Online ISSN 1945-7197).CONTEXT: Patients with familial partial lipodystrophy (FPLD) have increased risk of hepatic steatosis and its complications for which there is no approved therapy.
OBJECTIVE: To investigate the efficacy and safety of obeticholic acid, a farnesoid X receptor agonist, for reducing hepatic steatosis in patients with FPLD.
DESIGN: Randomized, double-blind, placebo-controlled, cross-over trial.
SETTING: Academic referral center.
PATIENTS: 10 females with Dunnigan variety of FPLD (FPLD2), harboring pathogenic heterozygous variants in lamin A/C gene, (age 19-60 years) and hepatic steatosis (liver fat > 5.6% by proton-density fat fraction mapping by magnetic resonance imaging).
INTERVENTION: Obeticholic acid 25 mg daily versus matched placebo for 4 months each with a 4 month wash out period in-between. MAIN OUTCOME MEASURES: Primary end point variable was liver fat. Secondary endpoint variables were serum triglycerides and aminotransferases levels.
RESULTS: All patients completed the trial. Obeticholic acid therapy caused significant (39.6%) reduction in liver fat as compared to placebo (median liver fat (minimum – maximum); 6.4% (2.4% - 18.0%) vs. 10.6% (3.4% - 29.3%), respectively; P value for treatment x month interaction = 0.03). There were no significant differences in serum triglycerides or aminotransferases levels during obeticholic acid and placebo therapy. Overall, obeticholic acid was well tolerated except for itching in four patients compared to two on placebo. Obeticholic acid, as compared to placebo, caused 24% increase in serum low density lipoprotein-cholesterol (mean 129 mg/dL vs. 104 mg/dL, respectively; P = 0.0016).
CONCLUSIONS: Obeticholic acid is safe and effective in lowering hepatic triglyceride levels in patients with FPLD2
Less is more: studying stem cells to improve diagnosis and therapy in myeloid malignancies
Full text linkDetailed formal protocol with illustrations and extensive bibliography.A recording of the protocol presentation is available on UT Southwestern’s Mediasite. Note: Access to the video is restricted to authorized UT Southwestern users only.UT Southwestern--Internal Medicin
Do Everything
Full text linkThe author submitted this entry in the Fictional Short Story category (Amateur division) for the 2025 On My Own Time™ (OMOT) Art Show.This work received a First Place Award in the "Fictional Short Story" category in the 2025 OMOT show.Working as an intensivist in the ICU, we are often faced with the death of patients under difficult circumstances when families have an understandable time accepting the death of a loved one. In an effort to hold off death, the request is to "do everything" to attempt to keep their loved one alive. Often times, they do not fully understand what doing everything entails and this also causes severe moral injury for the healthcare team. This works serves to illustrate what one such example may resemble as this happens multiple times a day in ICUs all over the world
A Randomized Controlled Trial of a Cellphone-Based Intervention to Promote Lethal Means Safety in Suicidal Adolescents
Full text linkThe prevalence of youth suicide is a significant public health concern. Lethal means restriction is the practice of removing potentially dangerous items from a suicidal individual's environment to promote safety. It is widely accepted that lethal means restriction is a best practice for the prevention of suicides, though the bulk of the evidence supporting this practice comes from ecological studies of population-level changes in suicide mortality rates. Phone-based interventions provide easily accessible, inexpensive means of influencing health behaviors. The primary aim of the present study was to evaluate the feasibility, acceptability, and user satisfaction of a novel text message-based intervention (Safe Home) designed to promote adherence to lethal means restriction practices among caregivers of adolescents discharged from an intensive outpatient suicide prevention program. Exploratory aims included evaluating the efficacy of the intervention at reducing suicide attempts and events among adolescents and investigating the adolescent's perception of their access to lethal means. Participants in this investigation included 40 adolescent-caregiver dyads recruited from the Suicide Prevention and Resilience at Children's (SPARC) intensive outpatient program. Families were randomized to receive either treatment as usual or the novel intervention for one month beginning at the adolescent's discharge from the SPARC program. Data were collected at the consent visit and at one-month post-discharge. Results indicated hypotheses regarding the feasibility of the intervention were partially supported and the intervention was acceptable and satisfactory to participating caregivers. Regarding exploratory aims, no significant differences were found between the two experimental groups. The development and evaluation of the novel Safe Home intervention addressed a gap in the literature regarding experimental investigations of lethal means restriction interventions
One world, one heart: stories from global cardiology and beyond
Full text linkDetailed formal protocol with illustrations and extensive bibliography.A link for the recording of this protocol presentation was not provided.UT Southwestern--Internal Medicin