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Pulmonary function testing: history, "normal" values, and implications for bias
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 argument for a liberal public health: reflections on a discipline in flux after COVID-19 (The Daniel W. Foster, M.D., Visiting Lectureship in Medical Ethics)
No full textThe Daniel W. Foster, M.D. Visiting Lectureship In Medical Ethics (in conjunction with Ethics Grand Rounds). Tuesday, October 11, 2022; noon to 1 p.m. (Central Time); Room D1.502 or via Zoom. "An Argument for a Liberal Public Health: Reflections on a Discipline in Flux after COVID-19". Sandro Galea, M.D., M.P.H., Dr.P.H., Dean and the Robert A. Knox Professor, Boston University School of Public Health, and Professor of Family Medicine, Boston University School of Medicine.Health has been in the spotlight in an unprecedented fashion during the COVID-19 pandemic. While there is no question that much that was done during the pandemic saved lives, it is also the case that the pandemic should be cause for reflection about what we did not do as well as we should have. How should we rethink what we do and how we do it in health in the aftermath of COVID-19? What are the key takeaways from the pandemic that can make for better efforts towards the health of populations?UT Southwestern--Program in Ethic
Retrospective Review of Postpartum Hemorrhage Incidence, Risk Factors, and Maternal Morbidity
Get PDFBACKGROUND: Postpartum hemorrhage (PPH) remains one of the most common causes of maternal mortality worldwide. In the US, PPH accounts for 2-3% of yearly maternal deaths and is also associated with serious morbidity including the need for blood transfusion, ICU admission, and hysterectomy. In the recent years, PPH risk assessment tools have been widely implemented in an attempt to identify woman at risk for hemorrhage and preemptively mobilize resources. The most commonly used trinary assessment tool from the California Maternal Quality Care Collaborative (CMQCC) assigns women to a low, medium or high-risk category; however, its utility has only been validated in relation to need for blood transfusion, which can be subjective.
LOCAL PROBLEM: The American College of Obstetricians and Gynecologists (ACOG) recently released maternal safety bundles to reduce obstetric complications and rates of maternal morbidity and mortality. At UT Southwestern's Clements University Hospital (CUH), obstetricians and gynecologists recognized that a three-category approach to PPH risk stratification may hinder efficient PPH diagnosis and management. The Maternal-Fetal Medicine team developed a quality improvement project to identify hemorrhage risk factors and implement a PPH risk score in the labor and delivery unit.
METHODS: Retrospective cohort review of all deliveries at CUH between January 1, 2018 and December 31, 2018 was conducted. Data on all antepartum and intrapartum hemorrhage risk factors using the trinary risk score developed by the CMQCC was analyzed and used to assign a risk category low, medium or high. A validated formula, utilizing maternal height, weight, ante- and post-partum hematocrits, was used to calculate each patient's blood loss. Calculated blood loss, need for intervention (uterotonic administration) and maternal morbidities (need for blood transfusion, intensive care unit (ICU) admission, and/or hysterectomy) were correlated to PPH risk categorization as well as to a developed numeric risk score. PPH was defined as blood loss exceeding 1,000 mL. Data was analyzed using standard methods of rates and proportions, Chi-square, and Wilcoxon rank-sum tests with p<0.05 considered significant. Quality improvement tools, including PDSA cycles, process maps, a SIPOC diagram, and FMEA were developed.
INTERVENTIONS: A modified PPH risk assessment score that assigned a point value of 1 or 2 to hemorrhage risk factors based on their perceived potential to lead to PPH was developed.
RESULTS: Of the 1855 deliveries, the median calculated blood loss was 879 mL. The overall PPH rate was 25.9%. The rates according to PPH risk groups were 19.5%, 36.6%, and 27.9%, respectively. The rate of PPH was significantly lower in the low risk group (p<0.001) but did not differ between the medium and high-risk groups (p= 0.11). The median blood loss was lowest in the low risk group (p<0.001). The transfusion rate correlated with risk stratification, with rates of 0.9%, 2.7% and 7% in the low, medium and high-risk groups, respectively. Overall, 178 women (9.5%) were treated with uterotonics, 38 (2.0%) required transfusion, 7 (0.4%) needed ICU admission and 12 (0.6%) underwent hysterectomy. Relative to low and medium-risk stratifications, women in the high-risk group were 2.3 times more likely to require uterotonic administration. Women in the low-risk group were 83% less likely to experience transfusion, ICU admission or hysterectomy compared to medium and high-risk women. Conversely, women in the high-risk group had a 4.1 fold increase in these same morbidities.
CONCLUSION: Relative to the low and medium-risk stratifications, women classified as high risk for hemorrhage are indeed more likely to require uterotonic administration and also suffer disproportionately higher maternal morbidity. The trinary risk stratification tool commonly used to predict PPH distinguishes women at lower risk for hemorrhage compared to the general population. However, determining which women are most likely to hemorrhage at delivery evades prediction using current risk assessment tools. Though hypothesized that a numeric scoring system would better predict PPH and morbidity than the currently used trinary risk assessment, this was not substantiated by our data. More work needs to be conducted to understand which of the identified risk factors is most highly associated with hemorrhage, particularly in the low and medium risk groups, since women in these groups make up the majority of the obstetric population
Lifestyle Factors Related to Cognitive Aging
Get PDFCognitive changes are a hallmark feature of Alzheimer's disease (AD) and lifestyle behaviors have been associated with a reduced risk of disease onset and slower rate of cognitive decline. Research examining the relationship of lifestyle factors (LFs) to brain health has typically focused on individual factors in isolation (more physical activity (PA) and reduced risk of AD); however, few studies have examined the combined effects of multiple LFs on cognition. The current study aimed to 1) determine which LFs best predict cognition cross-sectionally; 2) derive and compare different approaches to developing a Health Score (HS) to help predict cognition; and 3) discern if a healthy lifestyle was associated with slower rate of cognitive decline.
This study included 467 older adults (Mage=83; No Cognitive Impairment=361, Mild Cognitive Impairment (MCI=94), Alzheimer's dementia (AD=12)) enrolled in a longitudinal (Myears=3.72) aging study with yearly evaluations, including neuropsychological testing, clinical evaluation, and detailed assessment of lifestyle behaviors: diet, PA, sleep, social activities, stress, depression, alcohol, smoking, body mass index (BMI), and APOE genotyping. Cognitive z-scores were derived for global cognition, verbal memory, processing speed, and working memory. HS based on a Scientific (i.e., data driven), Lifestyle/Health (i.e., only healthy lifestyle behaviors), Risk/Disease (i.e., only unhealthy behaviors), or Comprehensive (i.e., all healthy/unhealthy behaviors) approaches were calculated and categorized (Unfavorable, Minimally Favorable, Moderately Favorable, Favorable) based on quartiles. Rate of cognitive change was also calculated.
Multiple linear regression analyses in the full sample revealed demographic and lifestyle (i.e., social activities, diet) factors consistently predicted cognition cross-sectionally. In the MCI/AD group, diet, PA and BMI were significant predictors with minimal demographic predictors. HS comparisons via Meng's test revealed a Lifestyle/Health approach as the best predictor of cognition compared to the other approaches. In addition, individuals with HSs in the Favorable category had significantly slower rates of cognitive decline than individuals in other categories.
Overall, LFs better predicted cognition than risk factors commonly used in clinical and research settings. Results from this study corroborate prior findings and encourage continued support and resources for lifestyle research and intervention programs to help prevent and slow cognitive decline and AD
Innate and Adaptive Immune Mechanisms of Pathogen-Specific T Helper 17 Cell Differentiation
No full textPages 216-271 are misnumbered as pages 218-273.Dendritic cells (DCs) are critical for the differentiation of pathogen-specific CD4 T cells. However, to what extent innate cues from DCs dictate transcriptional changes in T cells remains elusive. Here, we used DCs stimulated with distinct pathogens to prime CD4 T cells in vitro, and found that these T cells express unique transcriptional profiles dictated by the nature of the priming pathogen. More specifically, the transcriptome of in vitro pathogen-primed T helper 17 (Th17) cells resembled that of in vivo primed Th17 cells but was remarkably distinct from cytokine-polarized Th17 cells. We identified caspase-1 as one of the unique genes upregulated only in pathogen-primed Th17 cells and discovered a critical role for T-cell-intrinsic caspase-1, independent of its function in inflammasome, in optimal priming of Th17 responses. T cells lacking caspase-1 failed to induce colitis or confer protection to C. rodentium infection due to suboptimal Th17 cell differentiation in vivo. This study underlines the importance of DC-mediated priming in identifying novel regulators of T cell differentiation.
DC sensing of fungal pathogens, certain commensal bacteria and extracellular enteric pathogens leads to the generation of Th17 response. However, the nature of specific innate signals that uniquely promote Th17 cells has not been fully understood. We find that sensing of C. rodentium and other enteric pathogens induces unfolded protein response (UPR) in DCs that is critical for Th17 differentiation. Mechanistically, activation of PERK-eIF2α-ATF4 arm of UPR in DCs selectively enhances the production of IL-6 and IL-23. Genetic ablation of PERK in DCs or pharmacological inhibition of eIF2α phosphorylation blunts the production of IL-23 and IL-6, leading to impairment of Th17/22 differentiation and defective protection against enteropathogenic infection. Additionally, forced induction of UPR led to Th17 cell differentiation by non-Th17-inducing pathogens. We propose that the integration of PRR signaling with other sensors of disturbed cellular homeostasis, such as pathogen-induced stress, allows the innate immune system to induce tailored adaptive immune responses
Diverticular disease in 2022: digestible updates for the clinician
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
Safety and Accuracy of Employing Active Breathing Coordinator (ABC) Based Deep Inspiration Breath Hold (DIBH) Technique in Delivery of Radiation Therapy for Locally Advanced Left Sided Breast Cancer
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: Patients with locally advanced breast cancer typically require complex field matching technique for radiation treatment delivery. While field matching has been demonstrated to be safe and effective in free breathing patients, its safety and accuracy in the setting of deep inspiration breath hold (DIBH) with active breathing coordinator technology (ABC) use has not been reported.
OBJECTIVE: The purpose of this study is to determine the safety of ABC technology in DIBH of breast cancer patients requiring multi-field matching techniques.
METHODS: 202 patients treated with DIBH/ABC technique at UT Southwestern between 2013-2018 were reviewed for this study. The amount of overlap or gap between the supraclavicular field and the chest wall field were measured and recorded for each treatment fraction prospectively to determine accuracy of setup. Optically stimulated luminescent dosimeter (OSLD) readings were taken at 1 cm above, below, and at the junction on at least 3 different fractions from 10 patients to determine accuracy of treatment dose. Acute and delayed skin toxicities, as defined by the common terminology criteria for adverse events v4.0, were collected and analyzed as a measure of treatment safety.
RESULTS: 4973 fractions with gap/overlap measurements were analyzed. The average gap/overlap measured at junction was 0.28 mm+/-0.13 mm. 72% of fractions had a perfect match with 0 mm measurement, while 5.6% had an overlap and 22.7% had a measurable gap. Moreover, gap/overlap measurements neither improved nor worsened as patients received more treatment fractions. The median OSLD dose at 1 cm above the junction was 106%+/-7% of planned dose (range 94% to 116%); 1 cm below the junction, 114%+/-11% of planned dose (range 95% to 131%); at the junction, 106%+/-16.3% of planned dose (range 86% to 131%). These range of values appear to be within acceptable limits, since OSLD itself has a 10% calibration error, along with a likely minimal setup error. No significant acute or delayed skin toxicity at the matchline occurred in any patient.
CONCLUSION: This work suggests that ABC assisted DIBH is a safe method of delivering radiation therapy in the setting of complex matching field technique for breast and regional nodal treatments
Examining the Feasibility and Acceptability of a Phone Application for Safety Planning in Youth with Suicidality
Get PDFPages 55-63 are misnumbered as pages 54-62.Suicide is the second-leading cause of death in adolescents. Despite the documented efficacy of the safety plan, research has suggested that youth do not always refer to their plans when experiencing suicidal ideation. Accessibility is often cited as a primary concern. Addressing this concern in youth may mean turning to technological means, such as phone applications, to improve access and utilization. To date, there are relatively few suicide specific apps available, and even fewer that have been empirically tested. In response to this gap in the literature, BRITE was developed as a means of utilizing technology for safety planning. This study examined the feasibility and acceptability of BRITE as a stand-alone intervention in a group of 40 youth who had been recently hospitalized for suicidality. This was measured utilizing the Post-Study System Usability Questionnaire (Lucas & Spitler, 1999; Davis, 1989), an exit interview containing both qualitative and quantitative questions, and data gathered on app usage from the BRITE clinician portal. Additional exploratory analyses around efficacy of the app were conducted utilizing the Concise Health Risk Scale- Self-Report (Trivedi et al. 2011). Results from this study indicated good feasibility and acceptability of the BRITE app. The majority of participants approached for the study gave consent and were retained in the study at four-week follow-up. Most participants (85.7%) utilized the app at least once, and many (66.7%) of these participants went on to engage with app-recommended activities. Analysis showed that there was a significant improvement in pre- and post-app usage ratings of distress. Surveyed participants, on average, rated the app as helpful, accessible and useful and reported that the platform was effective for safety planning. Qualitative analyses supported the quantitative findings, and participants reported overall satisfaction with the app as a whole and its specific components. Despite feasibility and acceptability of the app, exploratory analyses did not reveal any difference in the suicide propensity or suicide risk scores between groups. These findings suggest that BRITE compares favorably to other suicide prevention apps on the market, and adds to the literature suggesting the use of technology in suicide prevention for adolescents
Metabolic Regulation at Sub-Organelle Length Scales: Inter-Organelle Contacts and Lipid Droplets
Get PDFPage xii is misnumbered as page xi.For cells to properly respond to environmental changes, cellular interiors must be exquisitely organized both spatially and temporally. In particular, metabolism must be spatially coordinated so metabolites are appropriately shunted into either storage or growth. Despite our understanding of how membrane-bound organelles organize metabolic processes, little is known about how metabolic regulation occurs at sub-organelle length scales. At these length scales, physical interactions between the endoplasmic reticulum (ER) and other organelles at ER-membrane-contact-sites (ER-MCSs) are now recognized as sub-organelle hubs for the regulation of metabolic processes. Our work uses the nucleus-vacuole-junction (NVJ) in S. cerevisiae (yeast) as a model ER-MCS to further an understanding about potential general functions of ER-MCSs. We have noted that the NVJ, a physical connection between the nuclear-ER and the vacuole, is a hub for lipid metabolic enzymes and regulators.
When yeast are exposed to low glucose conditions, the NVJ recruits several metabolic proteins, including the enzyme Hmg1. Hmg1 catalyzes the conversion of HMG-CoA to mevalonate and is the rate-limiting enzyme in sterol biogenesis. We noted that Hmg1 is less catalytically active when Nvj1, the protein that recruits Hmg1 to the NVJ, is genetically ablated, or when Nvj1 lacks a minimal motif required to recruit Hmg1. Hmg1 NVJ partitioning is accompanied by its assembly into high molecular weight species, which may underlie its increase in enzymatic efficiency. Indeed, artificial tetramerization of Hmg1 overcomes the deficiencies of an Nvj1 knock-out. During Hmg1 partitioning, mevalonate is preferentially shunted into synthesis of sterol-esters (SEs), which are storage lipids found in large cytoplasmic organelles, lipid droplets (LDs). Coordinately, glucose starvation promotes the degradation of triglycerides (TAGs), the other major lipid species contained in LDs. We found that the SE/TAG imbalance in LDs during glucose starvation leads to a phase separation of SEs from a liquid to liquidcrystalline state. Upon SE phase separation, the proteome of LDs is considerably changed. Collectively, our studies of the NVJ have identified a novel function for an ER-MCS and connected it to a lipid metabolic circuit that controls the proteome of LDs