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BDNF-TrkB Signaling in Efficacy of CA3-CA1 Synapses and Ketamine-Mediated Antidepressant Effects
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.Brain-derived neurotrophic factor (BDNF) and its high affinity receptor, tropomyosin receptor kinase B (TrkB), regulate synaptic plasticity in the hippocampus. To directly examine the precise synaptic site of BDNF release and the action of TrkB receptors in synaptic plasticity, we used a viral mediated approach to delete BDNF or TrkB selectively in CA1 and CA3 regions of the Schaffer collateral pathway. We first examined the pre and postsynaptic BDNF or TrkB in classic high frequency stimulation (HFS)-induced BDNF-dependent long-term potentiation (LTP). Deletion of BDNF in CA3 or CA1 revealed presynaptic BDNF is involved in LTP induction while postsynaptic BDNF contributes to LTP maintenance. Similarly, loss of pre- or postsynaptic TrkB receptors led to distinct LTP deficits, with presynaptic TrkB required to maintain LTP while postsynaptic TrkB was essential for LTP formation. We also report loss of TrkB in CA3 significantly diminishes release probability uncovering a role for presynaptic TrkB receptors in basal neurotransmission. Taken together, this direct comparison of presynaptic and postsynaptic BDNF-TrkB revealed novel insight into BDNF release and TrkB activation sites in hippocampal LTP.
In the subsequent study, we examined BDNF-TrkB signaling in hippocampal CA1 subregion in ketamine-mediated antidepressant effects and synaptic potentiation, a distinctive plasticity process from LTP. Deletion of BDNF or TrkB in CA1 revealed that BDNF-TrkB signaling in CA1 is essential for ketamine-mediated antidepressant effects in both sexes of mice. Loss of BDNF or TrkB in CA1 abolished synaptic potentiation induced by ketamine, indicating the postsynaptic BDNF-TrkB signaling is required for the ketamine-mediated synaptic plasticity. Additionally, postsynaptic TrkB signaling, induced by ketamine, was initiated by a dynamin1-deprendent synaptic machinery in ketamine-mediated synaptic potentiation. These observations suggested the requirement of BDNF-TrkB signaling specific in CA1 in ketamine-induced antidepressant effects and synaptic plasticity, and the involvement of a dynamin1-dependent manner in postsynaptic TrkB signaling triggered by ketamine
Devising an Algorithm for Resection Amount in Conjunctiva Sparing Ptosis Surgery
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: The conjunctiva sparing posterior ptosis technique (PCSP) has been shown previously to be very effective. The objective of this study was to devise a standardized algorithm for the procedure. Essentially, an ophthalmic surgeon would be able to formulate the amount of Müller's muscular tissue for resection and be able to correlate it to a predicted value of improvement in marginal reflex distance (MRD1) postoperatively at different time points. This would not only allow for more consistency with preoperative planning, but also allow for normalization of the procedure for more widespread use, improved patient outcomes, and less postoperative complications.
METHODS: This is a retrospective chart review that looked at patients who suffered from moderate to severe ptosis and underwent a conjunctiva sparing posterior ptosis surgery alone or concurrently with another procedure. Patients who had either unilateral or bilateral ptosis were both included in the chart review. Both preoperative and postoperative photos were measured for the MRD1 based off of the average corneal reflex diameters for men and women at 11.77 mm and 11.64 mm respectively. The program ImageJ was used for measuring MRD1. All other information such as demographics and tissue resection amount was taken from the postoperative notes of patient charts. No patients were actively recruited.
RESULTS: Patients who underwent the procedure from 2011-2017 with Dr. Ronald Mancini at UT Southwestern Medical Center were totaled at 32 patients. A significant increase in MRD1 was seen for both men and women with an average increase of at least 1.00 mm postoperatively from at least 3 months onwards. This increase was seen as statistically significant when compared to the amount of Müller's muscle resected at an average of 7.57 mm, however with increased variability. Multiple linear regressions were carried out with only one model showing a modest statistical relationship with a large amount of variability. This model presented the difference in postoperative MRD1 and amount of tissue resected, MRD1 (Y) = 0.192 + (0.260 * Tissue (mm)(X)). The results showed a r2 value of 0.0733.
CONCLUSION: Ptosis improvement was noted to be as early as 1 week postoperatively going as far out as 3 years for a patient. The algorithm of the difference in MRD1 vs amount of tissue resected (both eyes) showed modest correlation however did not serve as a means to standardize the conjunctiva sparing posterior ptosis surgery procedure. It would be prudent for further studies to be conducted with a larger patient population set for better control of sampling error. Also, some patients had a concurrent procedure such as a blepharoplasty that may have been a confounding variable on increased improvement of postoperative MRD1 rather than those patients who underwent ptosis repair alone
Prevalence and Characteristics of Violence Against Persons at Parkland Hospital
Get PDFThe 60th Annual Medical Student Research Forum at UT Southwestern Medical Center (Tuesday, February 1, 2022, 3-6 p.m., Microsoft Teams)BACKGROUND: Violence against persons (VAP) including interpersonal violence and human trafficking is a significant public health problem in the United States that affected 1.6% of the population in 2020. Systematic screening for VAP is inconsistent across hospital systems and often targets limited populations (i.e. pregnant women, homeless youth), resulting in inadequate broad detection of VAP. This study examined the prevalence of VAP and evaluated characteristics of VAP-positive patient encounters at a large safety-net hospital after implementation of an expanded screening program.
METHODS: We conducted an analysis of the first six months of an expanded VAP screening program in the Emergency Department (ED) at Parkland Health and Hospital system from January to July 2021. The program involved: 1) a mixed four-question survey and observational procedure 2) strengthening referral pathways to Parkland's Victim Intervention Program/Rape Crisis Center (VIP), and 3) clinical education on VAP. A prospective chart analysis was conducted using Electronic Health Records (EHR) data for all patients who received the new screening.
RESULTS: A total of 67,535 patient encounters were screened, out of which 1,349 (2.00%) were positive for VAP. On average, VAP positive patients were six years younger than VAP negative patients (38 vs 44 years respectively). VAP positive patients were more likely to be female (69.61%) than male (30.39%), and more likely to identify as Non-Hispanic Black (43.58%). VAP positive patients spent 28 less minutes in the ED in comparison to VAP-negative patients. The most prevalent VAP was physical abuse (71.76%), followed by psychological VAP (39.21%), observational signs VAP (37.06%), sexual VAP (31.36%), and control of food or money VAP (18.68%). The most referred VAP was physical with 48.33% of positive VAP encounters referred to VIP.
CONCLUSIONS: Our results showed evidence of successful implementation of a broad screening program for VAP at a safety-net hospital. The rate of VAP identified in screening our population was greater than the national average. Furthermore, demographic data showed a higher prevalence of VAP in patients who are young, female, or Non-Hispanic Black, highlighting the need for further research on compounded effects of gender and race on VAP.Southwestern Medical Foundatio
Improving Protocol Adherence in Central Line Placements
No full textBACKGROUND: The placement of central lines is a very common exercise in medicine. Central lines are required for everything from acute trauma scenarios to long term cancer treatments. However, this ubiquitous procedure has several morbid complications that are not uncommon. Possible complications include infection, catheter misplacement, arterial puncture, hematoma, pneumothorax, and death[1]. Not only are the complications severe they are also quite prevalent with a complication rate of 15 to 25 percent[2].
LOCAL PROBLEM: Due to a concern for the rates of central line infections across campuses at the University of Texas Southwestern Medical Center (UTSW) there was a project underway to create a standardized central line placement protocol for all departments in the system. This protocol was taught to all incoming residents on a simulation session day. However, because a significant period of time can pass between central line training and the clinical practice of placing central lines, the rate of resident retention and adherence to the standardized procedure for central line placement is unknown. This report describes the results of a QI experiment meant to reduce the rate of catheter associated blood stream infections and ensure better resident protocol adherence at UTSW medical center using checklists and visual aids to ensure implementation of the standardized protocols.
METHODS: The study was split into three phases. The first phase examined the baseline knowledge of UTSW residents regarding the placement of central lines and found the nursing position regarding possible interventions. The residents were interviewed regarding the standardized UTSW protocol and asked to detail the steps of placing a central line. The results were used to analyses areas of weakness in protocol adherence. Based on the results of the interviews, a checklist and visual aid were created highlighting key steps to ensure the adherence to the protocol. In phase two, to evaluate the feasibility of incorporating a checklist and CVA into the original CVC insertion methodology, a simulated pilot was conducted, and a survey was completed by the participants to determine how staff perceived the use of these new tools. In phase three after analyzing the ability to integrate the checklist and visual aid in a simulated setting, the utility of using a checklist to improve CVC insertions was tested by conducting a pilot study on real patients. During the pilot, CVCs placed in the ICU were observed by a medical student with the bedside nurse's participation and real time completion of the checklist
RESULTS:
Phase 1:
It was found that there were significant variations in the average adherence between departments and training years. On average, post graduate year (PGY)3s did better than PGY2s. Furthermore, it was found that 50% of missed steps were caused by only 8 out 36 questions and 75% of mistakes were caused by just 15 out of 36 questions.
Phase 2: Simulated pilot
Survey results showed that all participants felt that their team successfully followed the standardized placement method. The participants also said that the implemented huddle helped to create teamwork and organization, and that it could easily be incorporated into the normal workflow.
Phase 3: In-practice pilot
All trial participants were asked for feedback regarding the perceived benefit of the process. Results were very positive with most participants saying that they thought that the new workflow was helpful and easy to implement. Analysis of the completed checklists show that participants were able to complete the forms without issue ensuring that complete adherence to the standardized protocol was possible.
CONCLUSIONS: By interviewing residents to understand areas of difficulties and going through a multistep approach to ensure safety and efficacy of interventions, this project provides insight into the possible gaps in resident procedure adherences and retention of the UTSW protocol. It then also provides an intervention that strengthen the memory of the preforming physician and a layer of oversight to ensure that even if a mistake is made it is quickly corrected. The general concepts of simulation trials prior to clinical application and utilization of a checklist and cognitive visual aid can be applied not only to central lines at UTSW, but to many different procedures across multiple hospital systems
Automated Quantification of Image-Derived Phenotypes and Integration with the Electronic Health Record at Scale in an Academic Biobank
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: Radiographic images obtained during clinical care can yield a tremendous number of quantitative traits that facilitate translational research. Both liver fat and abdominal adipose mass are examples of quantitative traits that are highly relevant to human health and disease and can be quantitated from medical images such as CT scans. The Penn Medicine Biobank has generated genomic and biomarker data from >50,000 participants with consent to access EHR data. Among these patients, there are greater than 160,000 CT scans, representing over 19,000 patients from which these quantitative traits could be derived. However, manual review of imaging data is time-consuming, costly, and can produce variable results.
OBJECTIVE: The goal of this research was to develop a fully automated pipeline to quantify hepatic fat and abdominal adipose mass from CT scans that could be run at scale on patients within the Penn Medicine Biobank.
METHODS: We developed a fully automated image filtering and analysis pipeline to analyze CT imaging data. Deep learning networks were trained to identify the presence of IV contrast, delineate the borders of the liver and spleen, and detect visceral and subcutaneous fat. To identify CT studies, we queried our biobank of 52,441 patients for all non-contrast chest, abdomen, and all abdomen/pelvis scans and identified 161,748 CT scans from 19,624 patients. All scans were processed in our deep-learning pipeline in less than 96 hours using parallel processing with cloud-computing resources. From the imaging data, we extracted 12 different image-derived phenotypes that were used in association studies with the electronic health record (N>13000). We also performed genetic association studies (N>5000) on our CT-derived measure of liver fat (LF). Liver fat was defined as the difference in attenuation between the spleen and the liver. Receiver operator characteristic analysis of the liver fat metric was conducted by utilizing 135 patients who had both a CT scan as well as a liver biopsy. Finally, we performed principal component analysis to explore the interrelatedness of the image derived metrics in the context of the phenome.
RESULTS: Each component of the algorithm was individually validated for accuracy. The first deep learning network (CNN1) functioned to identify IV contrast, and on a testing set of 400 (half with IV contrast), CNN1 classified 399 scans correctly. CNN2 was tasked with identifying the superior and inferior borders of the abdominal cavity and on a testing set of 100 scans was on average within one slice of the superior (1.01±1.11) and inferior (0.70±0.64) borders. Performance of CNN3, which was tasked with labeling liver, spleen, visceral and subcutaneous fat was assessed by computing region-of-interest area overlap ratios (Dice coefficients). Dice coefficients for a validation set of randomly selected CT scans showed high values for liver (0.95±0.02, n=20), spleen (0.92±0.07, n=20), abdominal compartment (0.98±0.01, n=10), subcutaneous fat (1.00±0.00, n=10), and visceral fat (0.99±0.01, n=10). After extracting the liver fat (LF) metric for all patients, LF had a mean of -6.4 ± 9.1 Hounsfield units. Association studies with billing codes in the electronic health record yielded many known associations for LF including with chronic liver disease, diabetes mellitus, obesity, and hypertension. A genetic association study showed significant associations with variants located in PNPLA3 and TM6SF2. ROC analysis using pathology data yielded an AUC value of 0.81 with a balanced cutoff value of -6 HU for LF.
CONCLUSION: This paper presents a fully automated AI-based algorithm for the quantification of traits from medical imaging. This high-throughput algorithm was applied to over 160,000 scans to quantify 12 different traits and the results were integrated with phenome, genome, and pathology data in the Penn Medicine Biobank. This process is scalable, fast, and fault-tolerant and can power translational studies when integrated with clinical and genetic data
The Relationship between Pre-Operative Pain Characteristics and Periacetabular Osteotomy Outcomes in Patients with Acetabular Dysplasia
Get PDFThe 60th Annual Medical Student Research Forum at UT Southwestern Medical Center (Tuesday, February 1, 2022, 3-6 p.m., Microsoft Teams)INTRODUCTION: Bernese Periacetabular Osteotomy (PAO) is widely performed for patients with acetabular dysplasia, however the relationship between preoperative pain characteristics and patient-reported outcome measures (PROM) is not well-studied.
AIMS: (1) Does maximum severity of pain in a location other than the groin that is greater or equal to that of the groin affect PROM? (2) Does the presence of nongroin pain affect PROM? (3) Does the severity of pain affect PROM? (4) Does the number of pain locations affect PROM?
METHODS: We reviewed 52 hips (48 patients) treated with PAO for acetabular dysplasia from February 2017 to July 2020, using modified Harris Hip Score (mHHS), Hip Outcome Score (HOS), and international Hip Outcome Tool (iHOT-12) score, radiographic analysis, and pain location/severity questionnaires. Descriptive statistics, Analysis of Covariance (ANCOVA), and Spearman partial correlation coefficients were implemented.
RESULTS: Twenty-six hips experienced the most severe pre-operative pain in the groin, and 26 hips experienced equal or greater pain in a non-groin location. Outcome scores between these groups were not significantly different (mHHS P = .59, HOS P = .48, iHOT-12 P = .99). Additionally, the presence of pre-operative pain in any non-groin location had no significant relationship with PROM (all Pvalues ≥ .14). Furthermore, the maximum severity of pre-operative pain and number of pain locations showed no significant relationship with PROM (maximum severity: mHHS P = .82, HOS P = .99, iHOT-12 P = .36; number of pain locations: mHHS P = .56, HOS P = 0.10, iHOT-12 P = 0.62).
DISCUSSION: Location of most severe pre-operative pain and the presence of nongroin pain in a patient with acetabular dysplasia does not adversely affect PROM. Additionally, increased pain severity and pain locations does not appear to have any significant impact on outcomes. Therefore, a wide array of patients with acetabular dysplasia might expect similar, favorable outcomes from PAO regardless of pre-operative pain characteristics.
CLINICAL RELEVANCE: This study attempts to fill a current gap in knowledge that could help orthopaedic surgeons better understand the relationship between pain location and hip outcomes for patients following PAO.Southwestern Medical Foundatio
Dementia
Get PDFThis comes from personal experience with family members who have advanced dementia, and it is a frightening experience for them
From reading the genome for risk to rewriting it for cardiovascular health
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
Ethical use of surrogate measures in accelerated approval: aducanumab and beyond
Get PDF[Note: The slide presentation is not available from this event.] Tuesday, January 11, 2022; noon to 1 p.m. (Central Time); via Zoom. "Ethical use of Surrogate Measures in Accelerated Approval: Aducanumab and Beyond". Aaron S. Kesselheim, M.D., J.D., M.P.H., Professor of Medicine at Harvard Medical School and Director of the Program on Regulation, Therapeutics, and Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women's Hospital.[Note: The slide presentation is not available from this event.] The accelerated approval pathway was designed in the wake of the HIV epidemic to provide a pathway for drugs to reach the market based on showing changes to not-fully-validated surrogate measures. Since then, it has largely been applied to cancer drugs, and became the center of substantial attention with the June 2021 approval of aducanumab for Alzheimer's disease. We will review the ethical tensions at issue in approving drugs based on unproven surrogate measures, and consider how the accelerated approval pathway has been implemented.UT Southwestern--Program in Ethic
Development and Implementation of Audit and Feedback for Patient Blood Management
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: Red blood cell (RBC) transfusions, a common perioperative procedure, are overused nationwide¹ despite their association with numerous adverse postoperative outcomes² and often unnecessary administration. Patient blood management (PBM) programs respond to these trends by promoting responsible and restrictive transfusion to reduce unnecessary transfusions and overuse.
LOCAL PROBLEM: RBC transfusion is an overused procedure in cardiac surgery at a major academic medical center. Sources of overuse include the use of transfusions for avoidable indications and variability in transfusion practice between physicians within service lines.
METHODS: Physician surveys and interviews were conducted to understand the current state of transfusion practice and identify metrics of meaning for a blood utilization audit and feedback system, a potential future component to a PBM program. Retrospective review of cardiac and noncardiac thoracic surgical cases were conducted to establish baseline RBC transfusion rates. Following the development and implementation of an audit and feedback system for cardiovascular and thoracic anesthesiology and surgery, analysis was conducted to detect any effect on the population at hand.
INTERVENTIONS: The development of an audit and feedback system regularly reporting departmental and physician-specific trends in RBC transfusion practice aimed to inspire constructive self- evaluation and group discussion on areas of improvement.
RESULTS: Anemia and RBC transfusion are highly prevalent in cardiac surgery and are associated with the increased incidence of adverse postoperative outcomes. Variability exists among service line physicians in terms of adherence to evidence-based restrictive transfusion guidelines. Physician feedback supports an audit and feedback system and strongly advocates for risk-adjusted peer comparisons and granular feedback regarding transfusion trends. Though the implementation of the audit and feedback system did not have a significant effect on various process and outcomes measures, it may be associated with an increase in single-unit transfusion orders.
CONCLUSIONS: Data-driven audit and feedback, developed with physician collaboration and support, may be able to reduce avoidable RBC transfusions and improve perioperative transfusion practice by promoting thoughtful reflection and constructive conversation about current departmental trends and peer comparisons. However, such an effect may only be possible when the site at hand has enough capacity and infrastructure to support a widespread initiative