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Transcatheter aortic valve replacement: coming soon to a patient near you
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
Physician burnout: contributors, consequences and solutions
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
HIV-associated Kaposi sarcoma
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
Comparing PROMIS-29 to SF-12 in Evaluating Quality of Life in Patients with Diabetes-Related Foot Disease
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.BACKGROUND: With the increasing prevalence of diabetes mellitus (DM), DM-related foot disease (DFD) is an underappreciated problem with far-reaching consequences. Understanding the impact of DFD on clinical outcomes and patient-reported quality of life (QOL) is an important step for improving patient care. Historically, the 12-item Short Form (SF-12) has been commonly used to evaluate QOL in this population. However, with recent innovations in survey methods such as in the Patient-Reported Outcomes Measurement Information System (PROMIS) and computer adaptive testing (CAT), these emerging surveys should be evaluated and compared to the legacy surveys for effectiveness in measuring patient QOL.
OBJECTIVE: The aim of this research was to describe patient-reported quality of life in those with and without DFD using the SF-12 and the PROMIS-29.
METHODS: All patients included in the study were treated in a foot and ankle clinic in a tertiary care hospital and completed both the SF-12 and the PROMIS surveys. Patients who did not complete both surveys during the same clinic visit were not included. Patient-reported QOL was compared statistically between those with and without DFD.
RESULTS: One-hundred fifty patients were included in the study. Seventy-two (48%) had DFD. Between groups, those with DFD were younger, more often male, and had poorer DM-related parameters. Patient responses on the SF-12 and PROMIS surveys correlated significantly on most parameters including SF-12 mental component summary (MCS-12) and PROMIS Depression and Anxiety subscales as well as SF-12 physical component summary (PCS-12) and PROMIS physical function. However, when evaluating ceiling and floor effects, the PROMIS survey was found to have a longer ceiling effect in patients with DFD than the SF-12.
CONCLUSION: The PROMIS survey correlates well with the legacy standard, SF-12, for patient-reported QOL in those with and without DFD. In addition, the PROMIS survey may be less sensitive to ceiling effects correlated with the effects of DFD on physical and mental health, potentially being a more effective tool than SF-12 for long-term monitoring of patient QOL. In addition, the technologic advance of CAT in surveys, the patient burden of repeated survey evaluation may be diminished
Bias and equity teaching rounds: an educational exercise to minimize bias in patient care
No full textDetailed 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
Development of a Lipidomics Platform to Discover Enzymatic Activities of Mycobacterial Proteins of Unknown Function
Get PDFMycobacterium tuberculosis (Mtb), a facultative intracellular pathogen, is responsible for 10 million new cases of tuberculosis and 1.5 million deaths annually. Mtb infection can be acute but also lifelong. Indeed, despite the devastating global impact on health, how Mtb is able to adapt to the human body and survive for years is unknown. To better understand the physiology of Mtb infection, exploring the functions of individual proteins produced by Mtb is critical. Less than half of the proteins encoded in the M. tuberculosis genome have been fully characterized either directly through experimentation or indirectly through annotation. Many of these unknown genes likely encode proteins important for pathogenesis and adaptation to host responses. I created a novel method to facilitate the identification of novel substrates and products using direct infusion tandem mass spectrometry (DI-MS/MS) analysis of nonpolar metabolite fluctuations after transient and rapid protein overexpression. I studied 24 proteins using this lipidomic method. Of these, several demonstrate unique patterns of metabolites secondary to rapid induction of protein expression, and work towards identifying their specific enzymatic activities is ongoing. I selected one protein, Cor (Rv1829), for further characterization as it was recently shown to be fundamental to carbon monoxide (CO) resistance and pathogenesis of Mtb during host infection. To study Cor in vitro, I purified recombinant Cor from E. coli and used activity based metabolic profiling (ABMP) to measure changes in mycobacterial metabolites exposed to Cor. In the ABMP assay, exposure of mycobacterial metabolites to Cor led to consumption of acetyl phosphate and accumulation of phosphatidic acid (PA). I developed direct enzymatic assays for Cor activity, and confirmed the consumption of acetyl phosphate. To assess substrate binding, I used isothermal titration calorimetry (ITC) and demonstrated binding of Cor to acetyl phosphate. Additionally, Cor interacted directly with cardiolipin (CL), phosphatidylglycerol (PG), phosphatidylserine (PS), phosphatidylinositol (PI), and sulfatide on membrane lipid strips. I overexpressed Cor in M. smegmatis and Mtb and lipids were extracted and analyzed through DI-MS/MS to assess changes in lipid composition. I combined in vivo lipidomics and in vitro ABMP to biochemically characterize Cor and found that Cor is interacting with bacterial lipids. In vivo lipidomic analysis revealed an accumulation of PA and PG by 3 hours. Our findings suggest that Mtb Cor is interacting with lipids involved in the phospholipid biosynthesis pathway and modifying bacterial lipid composition by accumulating PG. These experiments provide mechanistic insight into the enzymatic function of Cor. Furthermore, the metabolomics and lipidomics approaches developed in this study can be broadly applied to study proteins of unknown function from other organisms
Characterization of Ubiquitin Ligase Targeting by Anticancer Sulfonamides
Get PDFAryl sulfonamides are small molecules that are selectively toxic to a subset of human cancer cell lines. Clinical trials of the aryl sulfonamide indisulam have resulted in modest clinical activity against a subset of solid tumors. Recent work revealed that indisulam recruits the RNA binding protein RBM39 to DCAF15, a component of the CRL4-DCAF15 E3 ubiquitin ligase. This recruitment results in RBM39 ubiquitination and degradation, leading to splicing defects and cancer cell death (Han et al., 2017; Uehara et al., 2017). The mechanism of action of sulfonamides is similar to that of immunomodulatory drugs (IMiDs), which recruit substrates to the closely related CRL4-CRBN E3 ubiquitin ligase for ubiquitination. Known for their roles in inhibiting embryonic development and cancer cell growth, IMiDs exert their pleiotropic effects by targeting a variety of substrate proteins to the CRL4-CRBN E3. Despite major advances in our understanding of aryl sulfonamides, it is unclear whether sulfonamides also target multiple substrates or modulate the endogenous function of the CRL4-DCAF15 E3 ligase. This dissertation describes our efforts to define the requirements for RBM39 ubiquitination, identify other substrates that are recruited to the CRL4-DCAF15 E3 ligase, and further our understanding of the cellular consequences of indisulam treatment. In Chapters 2 and 3, we define the components required for RBM39 ubiquitination using a combination of in vitro and in vivo techniques. In Chapters 4 and 5, we identify putative endogenous substrates and a previously undescribed neo-substrate recruited to the CRL4-DCAF15 for ubiquitination. In Chapter 6, we characterize the cellular consequences of indisulam treatment and neo-substrate degradation. In aggregate, this work aims to contribute to our understanding of the sulfonamide mechanism of action and the field of targeted protein degradation
Gallium-68 DOTATATE PET/CT in Neuroendocrine Tumors
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.BACKGROUND: Ga-68 DOTATATE PET/CT has been increasingly used for diagnosis and therapy response assessment of patients with neuroendocrine tumors (NETs). Point spread function (PSF) modeling is a partial volume correction method that can be used within PET imaging reconstruction. However, little is known about the effects of PSF reconstruction on quantitative measurements of Ga-68 DOTATATE PET/CT.
OBJECTIVE: The objective is to investigate the impact of PSF reconstruction and lesion size on Ga-68 DOTATATE PET/CT quantitative parameters.
METHODS: A total of 38 patients with 42 Ga-68 DOTATATE PET/CT scans and 125 lesions were included. Scans were reconstructed with and without PSF modulation. For each lesion, maximum and peak standardized uptake value (SUVmax, SUVpeak), metabolic tumor volume (MTV), total lesion somatostatin avidity (TLS), and tumor somatostatin receptor expression heterogeneity (TH) using area under the curve method were measured. Intraclass correlation coefficients (ICC) and Bland-Altman analyses were used to compare PSF and non-PSF values. Subgroup analysis was performed to determine the impact of lesion size.
RESULTS: Of the 125 lesions, 51 were in the liver, 31 in lymph nodes, 17 in bone, 8 in pancreas, 4 in lung, and 14 in other sites. ICC between PSF and non-PSF values were excellent for SUVmax, SUVpeak, MTV, and TLS (0.97-0.99), and was good for TH (0.81). Comparison of PSF with non-PSF values showed a bias (mean percent change ± standard deviation) of +27.5 ± 14.7% for SUVmax, +15.5 ± 9.5% for SUVpeak, -18.6 ± 37.6% for MTV, +0.8 ± 28.1% for TLS, and -7.1 ± 11.0% for TH. For lesions less than 2 cm in size (n=75), comparison of PSF with non-PSF values showed corresponding biases larger than for lesions greater than 2 cm.
CONCLUSION: PSF reconstruction effected higher values for SUVmax and SUVpeak, lower values for TH, and had a variable effect on MTV and TLS depending on lesion size. Clinical readers of Ga-68 DOTATATE PET/CT should be aware of such effects, as comparison between baseline and post-treatment follow-up scans can result in spurious artifact without any true change if different reconstruction methods are used between two time points
Radiographic Challenges and Considerations with Cancer Immunotherapy
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.Pages 1-36 are misnumbered as pages 2-37.BACKGROUND: With immune checkpoint inhibitor therapy, we observe new and challenging radiographic patterns such as hyperprogression and pseudoprogression. This begs the question - are there radiographic parameters that can predict response to immune checkpoint inhibitors? Historically, tumor burden has been considered an impediment to efficacy of immunotherapeutic agents, such as vaccines and allogeneic stem cell transplant. However, the association between tumor burden and efficacy of immune checkpoint inhibitors is unknown. We sought to determine the association between radiographic tumor burden parameters and efficacy of immune checkpoint inhibitors in advanced lung cancer.
MATERIALS AND METHODS: We performed a retrospective analysis of patients with advanced lung cancer treated with immune checkpoint inhibitor monotherapy. Demographic, disease, and treatment data were collected. Serial tumor dimensions were recorded according to Response Evaluation Criteria in Solid Tumors 1.1. Associations between radiographic tumor burden (baseline sum of longest diameters [BSLD], longest single diameter) and clinical outcomes (radiographic response, progression-free survival, and overall survival) were determined using log-rank tests, cox proportional-hazard regression, and logistic regression.
RESULTS: Among 105 patients, median baseline sum of longest diameters was 6.4 cm; median longest single diameter was 3.6 cm. BSLD was not associated with radiographic response, progression-free survival, or overall survival. In univariate and multivariate analyses, no significant associations were observed for the other radiographic parameters and outcomes when considered as categorical or continuous variables.
CONCLUSIONS: Although tumor burden has been considered a mediator of efficacy of earlier immunotherapies, in advanced lung cancer it does not appear to impact outcomes from immune checkpoint inhibitors