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Get PDFI enjoy word play and was exploring how to write about everyday objects. Mirrors are everywhere but only tell us partial truths
Testy Test
No full textTesting whether MathML continues to get weird when a dollar sign is included. Authors typically spend 1,750 discount.BACKGROUND: Since 1997, the Fellowship Council (FC) has evolved into a robust organization that is responsible for the advanced training of nearly half of the U.S. residency graduates entering general surgery practice. While FC fellowships are competitive (55% match rate) and offer outstanding educational experiences, funding is arguably vulnerable as external support has diminished. OBJECTIVE: The aim of this study was to investigate the current funding models of FC fellowships. METHODS: Under an IRB-approved protocol, an electronic survey was administered to 167 FC programs with subsequent phone interview follow-ups to collect data on total cost and sources of funding. De-identified data were also obtained via 2020-2021 Foundation for Surgical Fellowships (FSF) grant applications. Means and ranges are reported. RESULTS: Data were obtained from 59 programs (35% response rate) via the FC survey and 116 programs via FSF applications. The results from the FC and FSF data sets indicated that the average cost to train one fellow per year was 110,816, respectively. Similar averages were reported for the four components of cost. Programs received an average funding of 110,816, respectively. Most programs utilized departmental and grants funds. Additionally, 36% (FC data) to 39% (FSF data) of programs indicated that they billed for their fellow, generating 15,000-33,281 on average (range 66,259), respectively. 14% of programs via FC survey reported generating net positive revenue whereas 100% of programs from FSF application declared budget neutral. CONCLUSIONS: Our results indicated similar findings in support of the overall accuracy of these data. Most programs seemed to rely heavily on subsidies from both internal and external sources, although some programs were able to generate a positive revenue stream. The most notable difference was the revenue amount generated from billing. Programs that generated a positive revenue often billed for fellows. Given the value of these fellowships and the inherent vulnerabilities associated with graduate medical education funding, new alternative grant funding models are encouraged. In addition, standardization of annual cost and funding reports would provide greater insights into funding models
Dissection of the Roles of Synaptotagmins in Calcium Dependent Neurotransmitter Release
Get PDFNeuronal communication is mediated by neurotransmitter release, which is triggered in response to a calcium influx into the presynaptic cell, caused by the arrival of an action potential. Synaptotagmins (Syts) mediate this calcium-dependent regulation of neurotransmitter release by mechanisms that still remain elusive. Syts have two calcium-binding C2 domains (C2A and C2B) which are crucial for their function. Clarifying how Syt C2 domains interact with the neuronal membrane fusion machinery and the membranes is essential for gaining insights into the mechanisms of calcium-triggered neurotransmitter release.
To understand the role of Syts in neurotransmitter release, we explored the origins of functional differences between the C2 domains of two Syt isoforms, Syt1 and Syt7, which mediate synchronous and asynchronous release respectively. Calcium binding to the C2A domain is critical for Syt7 functions whereas Syt1 function depends more on calcium binding ability of its C2B domain. By solving the structures of Syt7 C2A and C2AB fragments and by analyzing their intrinsic calcium binding properties by ITC, we showed that these properties do not give rise to the functional differentiation between Syt1 and Syt7. By characterizing the calcium-dependent phospholipid binding of C2 domains by FRET, we demonstrated that C2A and C2B dominate membrane binding in Syt7 and Syt1, respectively. This suggests that membrane affinity of C2 domains might dictate their functional importance for Syt function.
In addition to membrane binding, Syt1 C2B domain is also involved in interactions with the SNARE complex, which is the central component of neuronal membrane fusion machinery. Clarifying the molecular details of these interactions is crucial for understanding how Syt1 cooperates with SNARE complex to trigger calcium-dependent membrane fusion. Previous structural studies have shown three distinct SNARE complex-binding interfaces on Syt1 C2B domain, two of which overlap with membrane binding regions. By using NMR, we showed that only two of these interfaces exist in solution. By using FRET to characterize interactions on membranes, we showed that Syt1-SNARE complex binding primarily occurs via one of the remaining interfaces (primary interface), and this interaction is almost abolished in the presence of calcium. Together, these results suggest a model where, a release of Syt1-SNARE complex interactions by calcium triggers membrane fusion
Deprescribing Unnecessary Pantoprazole Prescribed by Hospitalists on Parkland Hospital Non-ICU Inpatient Floors
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: Proton pump inhibitors are one of the most prescribed classes of drugs in the United States. Their efficacy and relatively low adverse event profile has resulted in their significant overuse both inpatient and at discharge. Long-term proton pump inhibitor use has been associated with many health consequences and any unnecessary prescribing leads to unnecessary expenses.
OBJECTIVES: The primary aim of this project was to achieve a 25% relative reduction in inappropriate inpatient pantoprazole prescribing by the hospital medicine physicians and advanced practice providers who account for the majority of the unnecessary proton pump inhibitor prescribing in non-critical patients at Parkland during the period of January 2018-May 2020.
METHODS: The baseline scope of the problem was determined using chart review and provider surveys. The chart review study population was any non-critical, medicine patient admitted to Parkland Memorial Hospital and prescribed inpatient pantoprazole by a hospitalist in June of 2017 (n=319 patients). This chart review helped quantify the pantoprazole use problem and identify the reasons for inappropriate prescription of inpatient pantoprazole. The hospitalists were surveyed to understand their prescribing practices and their perspective on the causes of unnecessary inpatient pantoprazole use. Using this information, a fishbone diagram outlining the causes of inappropriate inpatient pantoprazole use was created. Interventions addressing these causes were rated using a prioritization matrix and the best interventions were implemented. The interventions included removal of proton pump inhibitors from order sets, group and individual provider education, individual provider audit and feedback report cards, and changes to the proton pump inhibitor prescription auto-fill refill numbers in the electronic medical record. The 15 hospitalists accounting for 56% of the unnecessary prescribing at baseline were the study cohort. Prescribing data for these 15 hospitalists was then assessed post-intervention to determine the impact of the interventions. Chi squared analysis was performed. A p-value of <0.05 was considered significant.
RESULTS: In June of 2017, in all non-critical patients cared for by hospitalists, 58.3% of pantoprazole prescriptions were unnecessary. Of the patients that were started on inpatient pantoprazole, 52.4% of the 66.5% of patients discharged on pantoprazole had no indication and, six months later, 46.8% of those patients continued to use pantoprazole. At baseline, the study cohort of 15 providers prescribed 45% of the total inpatient pantoprazole prescriptions and 71.7% of those prescriptions were inappropriate (n= 145 patients). After the interventions, the rate of their pantoprazole prescribing decreased from a mean of 145 prescriptions to 89 prescriptions per month. The proportion of inappropriate pantoprazole prescriptions decreased from 71.7% to 47.9% (n= 178 patients). Of those inappropriate prescriptions post-intervention, a majority were continuations of outpatient proton pump inhibitors; not new pantoprazole prescriptions as before. The percentage of the study cohort's patients inappropriately discharged on pantoprazole decreased from 62.9% to 50.8%. The percentage of their patients still on a proton pump inhibitor six months after discharge decreased from 32.4% to 26.4%.
CONCLUSIONS: The interventions achieved a 33% relative reduction in inappropriate inpatient pantoprazole prescriptions in non-critical, medicine patients by the 15 worst prescribing hospitalists at Parkland. Further analysis will help elucidate if the audit and feedback received by these 15 hospitalists resulted in any additional benefit beyond the group education all the hospitalists received. Future directions would include continued re-education, audit and feedback and accountability for the proper utilization of proton pump inhibitors. As the opportunity for reducing unnecessary inpatient prescribing of proton pump inhibitors diminishes, resources may be redirected to decreasing inappropriate discharge prescriptions and improving outpatient prescribing practices
60th Annual Medical Student Research Forum
Get PDFThe 60th Annual Medical Student Research Forum at UT Southwestern Medical Center (Tuesday, February 1, 2022, 3-6 p.m., Microsoft Teams)This 178-page booklet is the proceedings of the 60th Annual Medical Student Research Forum and includes a list of oral presentations, a table of contents to the abstracts, and the abstracts divided into three categories: Basic Research and Disease Models; Clinical Research; and Quality Improvement, Global Health, Community Health, Medical Education, and Research Design.Southwestern Medical Foundatio
Decellularized Normal and Cancer Susceptible Mice Colons to Study the Contribution of the Extracellular Matrix to Cell Behavior and Colon Cancer Progression
Get PDFCurrent 3D culture models to study colorectal cancer lack architectural support and signaling proteins provided by the tissue extracellular matrix (ECM) which may influence cell behavior and cancer progression. Therefore, the ability to study cancer cells in the context of a matrix that is physiologically more relevant and to understand how the ECM affects cancer progression has been understudied. To address this, I developed an ex-vivo 3D system, provided by intact wild type (WT) and colon cancer susceptible decellularized mouse colons (DMC), to support the growth of human cancer cells. DMC are free of viable cells but still contain extracellular matrix proteins including subsets of collagens. Stiffness, an important mechanical property, is also maintained in DMCs. Importantly, I observed that the DMC is permissive for cell proliferation and differentiation of a human colon cancer cell line (HT-29). Notably, the ability of cells in the WT DMC to differentiate was also greater when compared to Matrigel TM, an extracellular matrix extract from a mouse tumor cell line. Additionally, I observed using invasion assays that DMC obtained from polyps from a colon cancer susceptible mouse model facilitated increased cell migration/invasion of colorectal cancer cells and immortalized non-tumor colonic epithelial cells compared to DMC from WT mice. Finally, using mass spectrometry, I identified extracellular matrix proteins that are more abundant in DMC from a colorectal cancer mouse model compared to age and sex-matched WT mice. I propose that these abundantly expressed proteins in the tumor microenvironment are potentially involved in colorectal cancer progression
Density Analysis of Spontaneous Lower Extremity Fractures Using Computed Tomography: A Case-Control Study
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: Spontaneous fractures are predominantly caused by osteoporosis and have significant morbidity and mortality associated with them. The current gold standard of clinical imaging for these osteopenic patients, Dual Energy X-Ray Absorptiometry (DXA), has a number of inherent deficiencies, including limited scanner availability, inaccuracies of projective areal density measurements, and lag in visualized radiographic change when following disease and treatment progress of osteopenic bone. Computed Tomography (CT) imaging has the potential to address these limitations, but the existing literature which discusses its potential use in this situation is limited in scope.
OBJECTIVE: It is hypothesized that the patients with spontaneous fractures will exhibit reduced bone mineral density (BMD) as quantified by Hounsfield (HU) measurements in the trabecular bone on CT imaging when compared to appropriately matched controls.
METHODS: A retrospective consecutive series of 522 adult patients with admission for fracture were initially obtained from the hospital electronic medical record (EMR). A number of chart review exclusion criteria were then applied, including traumatic history, evidence of malignancy, known renal disease or other secondary pathology that could be ascribed as the etiology of the bone insufficiency, or surgical hardware placement. These patients with CT imaging of the fracture site were then subdivided by anatomic location to select for femoral fractures and were then age and sex matched to appropriate control patients who had 5underwent KUB (kidney, ureters, and bladder) non-contrast CT scans with clinical indication for nephrolithiasis.
Following obtaining the case and control CT studies, elliptical fixed region 3 cm² measurements in the trabecular bone were obtained without cortical sampling at three locations (the site of the fracture, proximally at the femoral head, and distally at the lesser trochanter) on both the fractured and contralateral side in both fracture cases and controls. Inter- and intra-patient comparisons were performed, including Chi-square and t-test analyses.
RESULTS: A total of 24 spontaneous fractures and 25 controls were analyzed in this study. No significant differences in all captured demographic parameters, including mean age, gender, height, weight, and body mass index (BMI), were observed. There were statistically significant differences in the recorded BMD between the fracture and contralateral non-fracture sides at (p = 0.0001) and distal (p < 0.0001) to the fracture, with elevation of the trabecular bone density at the fracture site's ROI. Proximal and distal bone density differences existed between case fracture and control non-fracture sites (p < 0.0001, p = 0.0001), and between the case non-fracture and control non-fracture sites (p < 0.0001, p < 0.0001). The reliability for measurements was good to excellent proximal to the fracture site (ICC = 0.63-0.87), moderate to excellent at the fracture site (ICC = 0.43-0.78), and fair to good distal to the fracture site (ICC = 0.24-0.68). Additionally, at the proximal site, the odds ratio of every 50 unit decrease in HU is 1.744 (95% CI: 1.291 to 2.356).
CONCLUSION: Patients with spontaneous femoral fractures exhibit reduced BMD when compared to 6asymptomatic controls that can be distinguished on CT imaging per reduced HU density in the trabecular bone. Bone insufficiency is best demonstrated proximal or distal to, rather than at, the fracture site as the site of fracture demonstrates trabecular bone compression and hemorrhage that artificially elevates the BMD and obscures any present osteopenia. Opportunistic use of pre-existing CT imaging could therefore be invaluable in identifying a patient's true osteopenic status, saving patients an additional DXA scan while providing accurate, three-dimensional information regarding the true material density of a patient's skeleton
IMPACT: women changing the face of medicine
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
Association of African Ancestry with Electrocardiographic Voltage and Concentric Left Ventricular Hypertrophy: The Dallas Heart Study
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: Compared with white individuals, black individuals have increased electrocardiographic voltage and an increased prevalence of concentric left ventricular (LV) hypertrophy. Whether environmental or genetic factors lead to these racial differences is unknown.
OBJECTIVE: To determine whether proportion of genetically determined African ancestry among self-reported black individuals is associated with increased electrocardiographic voltage and concentric LV hypertrophy (LVH).
METHODS: The Dallas Heart Study is a probability-based cohort study of English- or Spanish-speaking Dallas County, Texas, residents, with deliberate oversampling of black individuals. Participants underwent extensive phenotyping, which included electrocardiography (ECG), cardiac magnetic resonance imaging (CMR), and dual-energy radiography absorptiometry (DEXA) at a single center. Participants aged 18 to 65 years who enrolled in the Dallas Heart Study between July 2000 and December 2002, self-identified as black (n = 1251) or white (n = 826), and had ECG, CMR, and DEXA data were included in this analysis. Data were analyzed from June 2017 to September 2018.
RESULTS: Of the 2077 participants included in the study, 1138 (54.8%) were women, and the mean (SD) age was 45.2 (9.9) years. Black race and African ancestry were individually associated with increased ECG voltage, LV concentricity^0.67, LVWT, and prevalent LVH in multivariable analyses adjusting for age, sex, systolic blood pressure, antihypertensive medication use, and body composition. When African ancestry and black race were entered together into multivariable models, African ancestry but not black race remained associated with ECG voltage, LVWT, LV concentricity0.67, and prevalent LVH. Among black participants, African ancestry remained associated with these 4 phenotypes (12-lead voltage: β, 0.05; P = .04; LVWT: β, 0.05; P = .02; LV concentricity^0.67: β, 0.05; P = .045; prevalent LVH: odds ratio, 1.2; 95% CI, 1.03-1.4; P = .02).
CONCLUSION: Genetically determined African ancestry was associated with electrocardiographic voltage, measures of concentric LV remodeling, and prevalent LVH. These data support a genetic basis related to African ancestry for the increased prevalence of these cardiovascular traits in black individuals
The Role of CK1 in Necroptosis and Confirmation of Amyloid-Like Fibers in Necroptosis Using 2D SDD-AGE
Get PDFNecroptosis is a regulated necrotic cell death pathway, mediated by a supermolecular complex called the necrosome, which contains receptor-interacting protein kinase 1 and 3 (RIPK1, RIPK3) and mixed-lineage kinase domain-like protein (MLKL). Phosphorylation of human RIPK3 at serine 227 (S227) has been shown to be required for downstream MLKL binding and necroptosis progression. Tandem immunoprecipitation of RIPK3 reveals that casein kinase 1 (CK1) family proteins associate with the necrosome upon necroptosis induction, and this interaction depends on the kinase activity of RIPK3. In addition, CK1 proteins colocalize with RIPK3 puncta during necroptosis. Importantly, CK1 proteins directly phosphorylate RIPK3 at S227 in vitro and in vivo. Loss of CK1 proteins abolishes S227 phosphorylation and blocks necroptosis. Furthermore, a RIPK3 mutant with mutations in the CK1 recognition motif fails to be phosphorylated at S227, does not bind or phosphorylate MLKL, and is unable to activate necroptosis. These results strongly suggest that CK1 proteins are necrosome components which are responsible for RIPK3-S227 phosphorylation.
During necroptosis, RIPK1 and RIPK3 are known to form an amyloid fiber. During our lab's investigation into the necroptosis signaling pathway, an amyloid fiber containing MLKL was observed. Based on size, the MLKL fiber appeared to represent a previously undescribed complex. However, the possibility this was the result of either degradation or dissociation of some of the proteins during electrophoresis could not be ruled out. To address this, I developed a protocol based on semi-denaturing detergent agarose gel electrophoresis (SDD-AGE) which allows detection of the SDS-resistant amyloid-like fibers in the cell extracts without purification. Performing second dimension of SDD-AGE determined that the size heterogeneity previously noted was due to a distinct amyloid species. This method allows fast, qualitative confirmation that the amyloid or amyloid-like fibers are not partially dissociating during the SDD-AGE process, and is not limited to use in the necroptosis field