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Parental Leave Experience for Academic Neurology Faculty at 19 Academic Centers
Get PDFThe 61st Annual Medical Student Research Forum at UT Southwestern Medical Center (Tuesday, January 31, 2023, 3-6 p.m., D1.600)Despite the rising number of women in academic neurology, there continues to be variability in parental leave (PL) policy, and we need to better understand the impact of PL on career achievements and burnout for academic neurology faculty. We hypothesize PL does not impact academic achievements; however, women who take PL experience higher burnout.
The survey was administered to 19 US academic neurology centers from 2/2021-4/2022. Participants self-reported academic achievements (rank, leadership positions, publications, funded projects, awards, and speakerships), experience of PL, family work conflict, and burnout. Groupwise comparisons and regression analyses were performed to examine the effects of PL and gender on academic achievement outcomes and on burnout.
Among 239 survey participants, 155 reported taking PL (75% female) and 84 did not (NoPL; 29% female). PL faculty received fewer awards (p=0.018) and experienced greater family-work conflict (p<0.001) than NoPL faculty. No significant group differences were found with other achievement metrics. Among PL faculty that had children, PL women had significantly lower numbers of first/last author publications compared to PL men (p=0.020). When holding rank constant, PL women received awards at rate 1.2 times that of NoPL women, while PL men received awards at rate of 0.34 times that of NoPL men. When holding rank constant, PL women are 6.7 times more likely to experience moderate emotional exhaustion compared to PL men.
Parental leave disproportionately affects women and men with respect to academic achievement and emotional exhaustion. In principle, PL is meant to provide support to faculty during a major life event, but the current climate in academic neurology is such that PL policies fall short of this. More work is necessary to resolve existing inequities in academic neurology, provide greater support for working parents, and develop more equitable PL policies.Southwestern Medical Foundatio
Outcomes of Patients Diagnosed with Psychogenic Non-Epileptic Seizures
No full textBACKGROUND: Psychogenic Non-Epileptic Seizures (PNES) is a complex neuropsychiatric illness that is very difficult to diagnose due to complex comorbidities and symptoms. There are also several risk factors associated with development of PNES that can contribute to the patient's presentation. However, there is very little literature on patient outcomes, management guidelines, and prognostic factors. Therefore, patients may not receive treatment according to a standard of care or in a streamlined manner which may worsen patient outcomes.
OBJECTIVE: This study will examine 1) if patient outcomes improve with psychiatric or multidisciplinary management and 2) the influence of specific risk factors on patient outcomes.
METHODS: This was a retrospective cohort study with data from chart review of the Parkland EMR. A total of 122 patients were examined who were diagnosed with PNES during an EMU admission in 2016. Demographic variables, risk factors for PNES, and treatment intervention information were extracted from each patient chart to be compared with the primary outcome variable. Patient outcomes were measured by recurrent symptoms leading to ED visits and/or EMU admissions after the initial 2016 admission. Descriptive analysis was done using Excel while statistical analysis comparing independent variables to patient outcome variables was done using SPSS 25. If the independent variable was a categorical variable, chi-square tests were used, but for continuous variables, Kruskal-Wallis rank sum tests were used.
RESULTS: Preliminary findings showed no significant associations between receiving any singular intervention and patient outcomes. Unexpectedly multidisciplinary management such as therapy and psychiatric follow-up had no significant relationship with patient outcomes. Risk factors that may be associated with increased recurrent PNES symptoms include prior psychiatric disorders, prior ED visits or EMU admissions, and socioeconomic factors such as type of insurance and homelessness.
CONCLUSION: Although multidisciplinary management did not show significant reduction in readmissions or ED visits for PNES symptoms, prior literature shows that psychiatric/psychological involvement can improve PNES outcomes. Treatment of PNES should be tailored for patients based on psychiatric/neurologic comorbidities and risk factors. Future research will need to explore the benefits of combinations of interventions and a multidisciplinary clinic such as a PNES clinic for these patients
A Silent Conversation in Global Health
No full textThe author submitted this entry in the AI Literature category (Amateur division) for the 2023 On My Own Time (OMOT) Art Show.Originally inspired by meeting a friend's deaf parents, I revisited this work when AI bots began gaining in popularity. In the piece, I write about virtual avatar translation systems, and it made me curious what a chatbot would think of the piece. I ran it through ChatGPT, and it provided feedback as well as a revised version that I have attached here
The Role of the cGAS-STING Pathway in Cancer and Autoimmunity
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.The DNA sensor cyclic GMP-AMP synthase (cGAS) detects cytosolic DNA derived from infections, cancer, or aberrant self-DNA accumulation. DNA-bound cGAS synthesizes cGAMP, which activates the stimulator of interferon genes (STING) protein to induce type I interferons, inflammatory cytokines, and autophagy.
The cGAS-STING pathway played a critical role in cancer immune surveillance by detecting tumor-derived DNA. Furthermore, stimulating the pathway using STING agonists conferred antitumor effects in preclinical tumor models. The induction of type I interferons through the transcription factor IRF3 is considered a major outcome of STING activation that drives immune responses against tumors, but the roles of IFN-independent functions of STING in cancer are not well understood. Here, I generated STING mouse strains with mutations that confer selective loss of STING functions. Using these STING-mutant mice, I show that TBK1 recruitment to STING promotes antitumor effects that are both type I interferon-dependent and -independent. In addition, using mice with selective deletion of the cGAS genes in specific immune cells, I show that dendritic cells, but not macrophages, are responsible for the cancer immune surveillance. By staining intracellular cGAMP, I show that tumor-infiltrating immune cells with greater pinocytosis ability take up cGAMP efficiently.
When aberrantly activated, the cGAS-STING pathway can lead to autoimmune diseases. cGAS was responsible for the autoimmunity in mice deficient in intracellular DNase and was shown to be activated in some SLE patients. In order to develop a therapeutic strategy targeting cGAS-mediated autoimmune diseases, I tested if the AAV-CRISPR system targeting the cGAS gene can confer a therapeutic effect in TREX1-deficient mice. In addition, I tested if cGAS drives disease pathogenesis in a mouse SLE model, which closely mimics the human SLE disease. Furthermore, I designed an ImageStream assay to detect the activation of the cGAS-STING pathway in SLE patient PBMCs.
In addition to the role in diseases, I observed cell-specific functions of the cGAS-STING pathway in promoting the endosome-to-cytosol protein delivery and mediating T cell death. Altogether, these results improve our understanding of the role of the cGAS-STING pathway in cancer and autoimmune diseases
Translational Control by the Ribosome-Associated Complex in the Unfolded Protein Response
Get PDFRibosome-associated chaperones are ubiquitous and highly conserved. There are two classes of ribosome-associated chaperones in eukaryotes, the nascent polypeptide-associated complex (NAC) and the ribosome-associated complex (RAC). Mammalian RAC consists of Hsp70L1, an Hsp70 chaperone homologue, and Mpp11, a DnaJ cofactor. RAC interacts with the nascent chain near the polypeptide exit tunnel and the decoding center on the 60S and 40S ribosomal subunits, respectively. Its unique position on the ribosome implies the coordinating role of de novo protein folding with translation. Deletion of RAC causes growth defects and sensitizes to osmotic, cold, and aminoglycoside stresses in yeast. Furthermore, studies have shown that Mpp11 is over-expressed in head and neck squamous cell cancer and leukemia. However, the function of RAC in stress responses and its role in oncogenesis remain obscure.
The current hypothesis predicts that RAC supports co-translational folding of nascent cytosolic polypeptides. To directly test this hypothesis, I altered levels of RAC components and monitored the cytosolic heat shock response (HSR) and the unfolded protein response (UPR) in the ER, two stress pathways known to be activated by accumulation of misfolded proteins. Contrary to its presumptive role in cytosolic protein folding, the reduction of RAC expression did not activate the cytosolic HSR. Unexpectedly, reduction of RAC sensitizes cells to ER stress by selectively attenuating activation of the IRE1 branch of UPR. When RAC is reduced, Xbp1 mRNA splicing is inhibited upon ER stress. Consistent with this activity, ER stress induces changes in the subcellular distribution of RAC, which coincides with the localization of Xbp1 mRNA. Mechanistically, reduction of RAC affects the pathway at a very early step, as IRE1 self-association is inhibited. Additionally, this study shows that the reduction of RAC enhances cellular mRNA translation, including Xbp1 mRNA translation. Interestingly, reduction of Pelo, a protein involved in recognizing stalled ribosomes, counters the inhibition of Xbp1 mRNA splicing, and IRE1 foci formation due to RAC knockdown. Collectively, these results suggest that RAC plays a central role in the IRE1 branch of the UPR tuning IRE1 clustering and mRNA translation
Reclaiming our voice: activism as antidote
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
Love Revival
No full textThe author submitted this entry in the 10-Word Story category (Amateur division) for the 2023 On My Own Time (OMOT) Art Show.Love is resilient and even in the face of a heartbreak, it always can find a way to flourish again. Love does conquer all things and we just have to let it
The Climb
Get PDFThe author submitted this entry in the 10-Word Story category (Amateur division) for the 2023 On My Own Time (OMOT) Art Show.I hiked up the mountaintop and was determined to make it all the way to the top
The Path Traveled
Get PDFThe author submitted this entry in the Creative Non-Fiction category (Amateur division) for the 2023 On My Own Time (OMOT) Art Show.I am always hiking, walking, taking a path whether it be with Mother Nature or Metaphorically. We should slow down and notice things during our path in life
The Impact of Lipid Nanoparticle Chemistry on RNA Delivery and Therapeutic Outcomes
Get PDFThis dissertation aims to understand how two individual components of the traditional four-component lipid nanoparticle system, the PEG lipid component and the ionizable cationic lipid component, impact RNA delivery. To systematically investigate how PEG lipid chemistry impacted LNP formulation and RNA delivery, a series of linear-dendritic poly(ethylene glycol) (PEG) lipids were synthesized with modulated hydrophobic domains. The chemical structure of the hydrophobic domain did not impact the formulation of 5A2-SC8 LNPs, including nanoparticle size, RNA encapsulation, and stability. However, the chemical structure did affect RNA delivery efficacy both in vitro and in vivo. The chemical structure of the hydrophobic domain of the PEG lipids impacted the escape of 5A2-SC8 LNPs from endosomes at early cell incubation time points. Overall, the results indicated that PEG lipid anchoring and chemical structure modulated RNA delivery.
Although most LNPs accumulate in the liver after intravenous administration (suggesting that liver delivery is straightforward), it was observed that two similar LNP formulations (5A2-SC8 and 3A5-SC14 LNPs) resulted in distinct RNA delivery within the liver organ. Despite both LNPs possessing similar physical properties, the ability to silence RNA in vitro, strong accumulation within the liver, and sharing a pKa of 6.5, only 5A2-SC8 LNPs were able to functionally deliver RNA to hepatocytes. Protein corona analysis indicated that 5A2-SC8 LNPs bind Apolipoprotein E (ApoE), which can drive LDL-R receptor mediated endocytosis in hepatocytes. In contrast, the surface of 3A5-SC14 LNPs was enriched in Albumin but depleted in ApoE, which likely led to Kupffer cell delivery and detargeting of hepatocytes. In an aggressive MYC-driven liver cancer model, 5A2-SC8 LNPs carrying let-7g miRNA were able to significantly extend survival compared the non-treatment group. Since disease targets exist in an organ- and cell-type specific manner, the clinical development of RNA LNP therapeutics will require an improved understanding of LNP cellular tropism within organs. Overall, the results from this work illustrates the importance of understanding the cellular localization of RNA delivery and incorporating further checkpoints when choosing nanoparticles beyond biochemical and physical characterization, as small changes in the chemical composition of LNPs can have an impact on both the biofate of LNPs and therapeutic outcomes