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Systematic Design, Synthesis, and Evaluation of Ionizable Lipids for Lipid Nanoparticles Delivering mRNA
No full textThe general metadata -- e.g., title, author, abstract, subject headings, etc. -- is publicly available, but access to the submitted files is restricted to UT Southwestern campus access and/or authorized UT Southwestern users.Nucleic acids offer immense potential to act as targeted therapeutics and overcome limitations of traditional small molecule drugs. Diseases that are conventionally deemed untreatable and "untargetable" by small molecules are being addressed by alternative approaches, including nucleic acid therapeutics. However, to enable the feasibility of nucleic acid therapeutics, the challenge of delivery must be answered. To deliver RNA, both extracellular and intracellular barriers must be overcome. Due to the immune system's ability to safeguard against foreign materials and RNA's propensity for degradation, the delivery of RNA requires a carrier to protect it. Lipid nanoparticles (LNPs) have been developed to provide a modality enabling delivery of genetic cargos and represent the most promising vehicle to date for its reproducibility, safety, and efficacy.
The works within this dissertation provide an insight into how chemical structures of ionizable amino lipids can control the functional mRNA delivery. Ionizable amino lipids were synthesized to study the fundamental structure-activity relationship (SAR) between the lipids and the in vitro and in vivo delivery of mRNA. Identification of potent ionizable amino lipids led to analysis of its respective physiochemical properties as it relates to in vivo LNP potency, revealing a range of physiochemical properties that expanded beyond the previously established ranges. Additionally, a systematic design, synthesis, and evaluation of ionizable amino lipids containing unsaturated motifs was conducted, inspired by the importance of unsaturated lipids in nature. These studies revealed that increased number of unsaturation does not necessarily result in improved mRNA-LNP potency. The inclusion of unsaturated motifs derived from natural products were most successful. Mechanistic studies highlighted how unsaturation can improve fusogenicity and affect cellular trafficking of LNPs. Combining unsaturated lipids with saturated lipids resulted in the best performing LNP formulations, suggesting there needs to be a fine balance of both components for successful mRNA delivery. These studies reiterate the importance of the design of chemical structure of the ionizable lipid used in LNPs, but also highlights the complexity of delivering mRNA
Glucagon-like peptide-1 receptor agonists for chronic kidney disease
Get PDFDetailed 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
Frailty-guided clinical management: emerging evidence and its potential for personalized care for older adults
Get PDFDetailed 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
Resilience - Nurses' Second Nature
Get PDFThe author submitted this entry in the Creative Non-Fiction category (Amateur division) for the 2024 On My Own Time (OMOT) Art Show.This work received a First Place Award in the "Creative Non-Fiction" category in the 2024 On My Own Time show.This piece was inspired from experiencing and hearing stories of COVID survival from friends and colleagues. This was a tough time for entire world but more so for health care personals. I wanted to pay tribute and show my gratitude for the nursing fraternity. Nurses were, are, and will be unsung heroes
Molecular Underpinnings of Human Brain Evolution and Cognition at Cellular Resolution
No full textThe second part of Chapter 1 is modified from a commissioned book chapter (accepted for publication) titled "Differences in brain gene expression between humans and primates", which has been accepted for publication as a chapter in the book titled "The evolutionary roots of human brain diseases". This chapter is an edited version of the author's own original writing with additional edits by the author's thesis supervisor and from feedback from the editors of the book. The citation to the book is included below.Chapters 2-5 were published as individual journal articles, and the citations are listed below. Links to the journals are also included as related URIs.Molecular and functional characterization of the human brain is challenging due to its experimental inaccessibility. Most of our understanding about human brain function relies on the assumption that biological processes uncovered in model organisms are conserved in humans. Comparisons of the humanii brain with non-human primate brains offer to both uncover the novelties in human brain evolution and better evaluate the insights obtained from model organisms about human brain function. To achieve this, highthroughput sequencing methods on post-mortem brain tissues provide a rewarding readout to understand human brain evolution at the molecular level. In addition to their use in comparative studies, these technologies were also utilized with a hope to understand molecular underpinnings of measurable human brain activity metrics. During my dissertation, I read relevant literature extensively (Chapter 1) and sought to understand human-specific epigenomic and transcriptomic changes at cellular resolution in the cortical brain (Chapter 2). Additionally, after in-depth analysis of many human brain single-nuclei RNA-seq datasets, I found a pervasive ambient RNA contamination problem, and devised in silico solutions to tackle this problem. My efforts improved the analytical approach in the field as well as in my research (Chapter 3). I have also been involved in efforts to identify transcriptomic correlates of brain activity in human subjects (Chapters 4-5). After detailing these efforts, I discuss the implications of these findings, weigh their impact on our understanding of human brain function and offer ideas for further research (Chapter 6)
How Learning Strategies and Academic Parameters Predict Medical Student Success
Get PDFThe 62nd Annual Medical Student Research Forum at UT Southwestern Medical Center (Tuesday, January 30, 2024, 3-6 p.m., D1.700 Lecture Hall)BACKGROUND: Student scores on the Learning and Study Strategies Inventory (LASSI), an assessment of academic skills, have been shown in previous studies to be significantly different between U.S. medical students based on their scores in various examinations during the preclerkship curriculum. This study aimed to evaluate LASSI and other early academic performance markers for predicting the likelihood of shelf exam underperformance in third-year medical students.
METHODS: A retrospective analysis of student-specific demographic information and medical school exam performance from 220 medical students from the University of Texas Southwestern was performed. Students were then categorized based on underperformance (score in <25th percentile) on each NBME shelf exam and statistical analysis was performed to identify predictors of shelf underperformance.
RESULTS: For predicting Surgery shelf underperformance, pre-clerkship final exam average (PCA), STEP 1, and LASSI Time Management (TMT) were statistically significant in univariate analysis. Internal Medicine: PCA, STEP 1, LASSI Attitude (ATT), Test Strategies (TST), and TMT. Pediatrics: PCA and STEP 1 quartile. Obstetrics-Gynecology: PCA, STEP 1, and LASSI Anxiety (ANX), with ANX an independent predictor on multivariate analysis. Neurology: PCA, STEP 1, LASSI ANX, Information Processing (INP), TST, and average LASSI, with PCA, LASSI Concentration (CON), TMT, and ANX independent predictors on multivariate analysis. Family Medicine: PCA, STEP 1, LASSI ANX, TST, and Using Academic Resources (UAR), with PCA an independent predictor on multivariate analysis. Psychiatry: only STEP 1 was significant.
CONCLUSION: In contrast to previous studies, no single LASSI scale was significantly associated with underperformance on all 7 NBME shelf exams. Univariate analysis identified several LASSI scales that correlated with NBME underperformance, but the drastic inter-clerkship heterogeneity makes use of these scales in early academic intervention impractical. Conversely, PCA was found to be strongly associated with shelf exam underperformance.Southwestern Medical Foundatio
The science of pandemic response: lessons learned from COVID-19
Get PDFDetailed 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
An Atypical Minimal Kinase Inactivates the Molecular Chaperone Hsp90
No full textBacteria utilize a wide variety of proteins, termed effectors, to achieve virulence. We have identified an atypical kinase, HopBF1, found primarily in the plant pathogen Pseudomonas syringae. HopBF1 specifically inactivates Hsp90 causing the degradation of numerous Hsp90 clients, ultimately culminating in cell death and tissue necrosis. We further propose a remarkable betrayal mechanism in which HopBF1 masquerades as a host Hsp90 client to achieve specificity, followed by inactivation of the molecular chaperone
My Faithful Friend
No full textThe author submitted this entry in the Open Verse Poetry category (Amateur division) for the 2024 On My Own Time (OMOT) Art Show.This was inspired from a situation that one of my family friend was going through. Prayers were offered while looking to God for an answer. This was my reflection of the situation and trust in God
Improving Teamwork Competencies and Patient Handovers of Students in the Emergency Medicine Clinical Learning Environment
No full textPages 1-81 are misnumbered as pages 2-82.BACKGROUND: Communication failures contribute to significant teamwork failures causing adverse events for patients and providers, especially during patient handovers when providers transition care of patients to each other. Teamwork education has been shown to improve knowledge, skills, and communication in prelicensure learners. Despite knowledge of the problem and potential solutions, as well as requirements and recommendations by national medical accreditation and oversight agencies, there exists a gap in standardized teamwork education and assessment. The Emergency Department is a setting rife with inherent barriers to teamwork with a high frequency of patient handovers.
LOCAL PROBLEM: At UT Southwestern, students used to have limited opportunities to improve teamwork in structured ways during their time on the clinical wards. In response, the institution developed and is implementing an educational quality enhancement plan - TeamFIRST - with the goal of developing a competency-based teamwork education (CBTE) strategy for students that is progressive, interprofessional, and continuous through the pre-clerkship, clerkship, and post-clerkship phases of medical school. Module 4 out of the 5 modules TeamFIRST developed focuses on improving teamwork competencies specifically in the clinical learning environment, i.e. during clinical rotations in most students' second years and beyond. This includes the Emergency Medicine clinical rotation, which most students undergo at Parkland Memorial Hospital, the busiest emergency department in the nation, as well as at other local Emergency Departments like Clements University Hospital and Presbyterian Dallas. Until now, the Emergency Medicine clinical rotation at UT Southwestern did not have any formal handover or teamwork education, despite being the clinical setting in which teamwork and handovers arguably provide the most value.
METHODS: Continuous Quality Improvement (QI) and Implementation Science tools and methodologies were used in the study of the current state of handovers in the ED and in the design of interventions to implement effective handovers. Define-Measure-Analyze-Design-Verify methodology was used to iterate our interventions. Interviews with stakeholders were conducted to determine critical needs, learn about the main drivers for intervention, and map the current state of the ED clerkship rotation so that a suitable educational module could be developed. These stakeholders mainly included faculty, course directors, residents, and students in the Emergency Medicine rotation as well as members of TeamFIRST. Shared requirements from stakeholders included focusing on improving handovers, limiting time commitment due to already busy schedules, and mixing virtual with in-person education. Information was also gathered on the state of different handover types in the ED to design assessment tools that captured the critical components. TeamFIRST identified nine of the twelve Teamwork Competencies - Structured Communication, Closed Loop Communication, Asking Clarifying Questions, Sharing Unique Information, Mutual Trust, Team Mental Models, Mutual Performance Monitoring, Obstacles to Teamwork, and Psychological Safety - for the Module 4 interventions to address. Working in concert with TeamFIRST and the Emergency Medicine stakeholders, we developed a teamwork education curriculum that integrated into the existing Emergency Medicine clerkship rotation and focused specifically on improving patient handovers. Each teamwork competency was explored to differing degrees among the spectrum of inform, demonstrate, practice, and feedback. We selected various process, outcome, and balancing measures such as impact (effectiveness), fidelity of activities, acceptability and appropriateness, and feasibility. Impact of the curriculum was measured by assessing students' knowledge, confidence in skills, and attitudes on the teamwork competencies. Both quantitative and qualitative data was collected. Statistical methods such as Z test of proportion and Mann-Whitney U test were used to analyze pre- and post- data to determine any significant changes.
INTERVENTIONS: The teamwork curriculum initially designed for the Emergency Medicine clerkship rotation (the "test" phase, designated "Curriculum 1.0") had three main aspects: a pre-orientation, asynchronous, virtual educational module on teamwork and handovers, integrated handover practice and assessment throughout the rotation, integrated teamwork participation/observation, reflection, and debriefing during the rotation. The pre-orientation module was designed with a pre-assessment to determine students' capacities before being exposed to the material and a post-assessment to measure changes in knowledge and receive feedback after going through the didactic curriculum that covered the teamwork competencies and dedicated a full section to patient handovers. The handover practice was scattered throughout teaching shifts, simulation center cases and a dedicated handover station, and while working on regular emergency department shifts with accompanying assessment tools made to allow residents and faculty to evaluate student handovers and provide learners feedback. Lastly, students participated in and observed teamwork instances throughout their rotation and were encouraged to note these experiences down in a Teamwork Competency Journal so they could reflect and debrief on them in a group session late in the rotation. Finally, an end-of-rotation assessment was administered to capture changes in knowledge, skills, and attitudes, as well as feedback on acceptability, appropriateness, and feasibility. Whereas feasibility data were derived from the qualitative feedback, fidelity to the learning activities were assessed quantitatively. These interventions were first tested with a non-representative student sample outside of the EM rotation at the end of the summer 2020 and during field tests in Spring 2021 to improve the process and optimize the interventions. The official, representative test within the clerkship, "Curriculum 1.0", began in June 2021 and ran through March 2023 (22 months total). "Curriculum 2.0", the more streamlined version, is our pilot phase, and has been running from April 2023 through the present.
RESULTS: We had 124 students participate in the Curriculum 1.0 test over 13 rotation blocks and collected qualitative and quantitative data on acceptability, appropriateness, fidelity, feasibility, and impact. So far, the curriculum has shown to be effective in improving knowledge (significant in 5/8 categories, p4/5). However, some learning activities were deemed less feasible, and the fidelity (completion as intended) of different activities was low (48% completion or less). Feedback was generally positive, with common themes being that the handover education and practice were useful and relevant, the teamwork debrief was excellent, and the course was unique. Negative feedback commonly addressed a lack of clarity in communication about the curriculum requirements and the need for more active student roles.
CONCLUSION: Overall, the impact and acceptability/appropriateness of Curriculum 1.0 were high, feasibility of the curriculum was moderate, and fidelity was low. Some of the key takeaways include that our stakeholders found the education to be effective and valuable, a combination of asynchronous and synchronous learning seemed the most feasible and acceptable, and that the time pressures on our EM residents and faculty are high. Going forward, we will continue to pilot the streamlined "Curriculum 2.0", which has already shown to be more feasible and sustainable, to improve the experience for learners and instructors, improve data collection, and focus on getting students more practice on patient handovers