Generation and optimization of off-the-shelf immunotherapeutics targeting TCR-Vß2+ T cell malignancy.

Current treatments for T cell malignancies encounter issues of disease relapse and off-target toxicity. Using T cell receptor (TCR)Vß2 as a model, here we demonstrate the rapid generation of an off-the-shelf allogeneic chimeric antigen receptor (CAR)-T platform targeting the clone-specific TCR Vß chain for malignant T cell killing while limiting normal cell destruction. Healthy donor T cells undergo CRISPR-induced TRAC, B2M and CIITA knockout to eliminate T cell-dependent graft-versus-host and host-versus-graft reactivity. Second generation 4-1BB/CD3zeta CAR containing high affinity humanized anti-Vß scFv is expressed efficiently on donor T cells via both lentivirus and adeno-associated virus transduction with limited detectable pre-existing immunoreactivity. Our optimized CAR-T cells demonstrate specific and persistent killing of Vß2+ Jurkat cells and Vß2+ patient derived malignant T cells, in vitro and in vivo, without affecting normal T cells. In parallel, we generate humanized anti-Vß2 antibody with enhanced antibody-dependent cellular cytotoxicity (ADCC) by Fc-engineering for NK cell ADCC therapy.

Acne accounts for an almost 2.5-fold higher proportion of dermatology visits among adult females compared to adult males in the United States: A study of the national ambulatory medical care survey from 2002-2016.

BACKGROUND: Acne vulgaris affects a significant number of females into adulthood. Juvenile acne and adult acne have different presentations and potentially distinctive pathogeneses. However, patterns in treatments specifically related to the adult female population have previously not been studied. METHODS: Retrospective database analysis of healthcare utilization and medications prescribed for acne using the National Ambulatory Medical Care Survey (NAMCS) data from 2002-2016 was performed. RESULTS: After age 20, acne accounted for an almost 2.5-fold higher proportion of dermatology visits among females compared to males (10.1% vs. 4.1%, P < 0.001). Tetracycline-class antibiotics were the most prescribed therapy within all age groups of females between 2002-2016. However, there was also a substantial rise in prescriptions of spironolactone beginning in 2012. CONCLUSION: A significantly greater proportion of dermatology visits by adult females are for acne in comparison to adult males. Tetracycline-class antibiotics remain the most prescribed therapy in adult age groups despite a potentially different pathogenesis of adult acne. Therefore, there is a need for further studies comparing the effectiveness of therapies specifically for adult female acne.

Nanoparticles as a Therapeutic Delivery System for Skin Cancer Prevention and Treatment.

The use of nanoparticles (NPs) as a therapeutic delivery system has expanded markedly over the past decade, particularly regarding applications targeting the skin. The delivery of NP-based therapeutics to the skin requires special consideration owing to its role as both a physical and immunologic barrier, and specific technologies must not only take into consideration the target but also the pathway of delivery. The unique challenge this poses has been met with the development of a wide panel of NP-based technologies meant to precisely address these considerations. In this review article, we describe the application of NP-based technologies for drug delivery targeting the skin, summarize the types of NPs, and discuss the current landscape of NPs for skin cancer prevention and skin cancer treatment as well as future directions within these applications.

All clinical stressors are not created equal: Differential task stress in a simulated clinical environment.

Background: A variety of stressors are encountered while working in the emergency department and are often recreated in simulation-based medical education. We seek to examine the physiologic and stress state response of participants in a simulated clinical environment to commonly encountered stressors. Methods: Emergency medicine (EM) residents participated in a randomized, controlled trial of six simulated patient encounters with one of three stressors, medical difficulty, interpersonal challenge, and technology/equipment failure, randomized into each scenario. Participants wore smart shirts to measure heart rate variability (HRV) at rest and just after the introduced stressor and completed the Short Stress State Questionnaire (SSSQ) before and after each scenario. Results: Twenty-seven EM residents participated in the study. Interpersonal challenge resulted in increased distress as measured by SSSQ compared to the other two stressors (one way ANOVA, F[2,144] = 9.95, p < 0.001). There was no difference in worry or task engagement across stressors. HRV decreased significantly from rest for all stressors (p = 0.0003, p = 0.0112, p = 0.0027 for medical difficulty, interpersonal challenge, and equipment failure, respectively), but there was no statistically significant difference between mean change in HRV across stressors (one way ANOVA, F[2,120] = 0.17, p = 0.8452). Conclusions: Interpersonal challenge stressor was significantly associated with an increase in distress in EM residents during the simulated encounters as compared to the other stressors. While heart rate variability decreased from rest for each stressor as expected following stressor introduction, differing stressors did not produce a differential change.

Burnout and Post-traumatic Stress Disorder Symptoms Among Emergency Medicine Resident Physicians During the COVID-19 Pandemic.

INTRODUCTION: Emergency medicine is characterized by high volume decision-making while under multiple stressors. With the arrival of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus in early 2020, physicians across the world were met with a surge of critically ill patients. Emergency physicians (EP) are prone to developing burnout and post-traumatic stress disorder (PTSD), due to experiencing emotional trauma as well as the cumulative stress of practice. Thus, calls have been made for attempts to prevent physician PTSD during this current pandemic. METHODS: From July 2019-January 2020, emergency medicine (EM) resident physicians at a large, academic healthcare system were surveyed for symptoms of burnout using the Maslach Burnout Inventory (MBI). In late April and early May 2020, during the outbreak surge of coronavirus disease 2019 (COVID-19) in the Northeast USA, these same residents and the whole EM residency at the institution were again surveyed for symptoms of burnout as well as post-traumatic stress using the PTSD Checklist for Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (PCL-5). A final survey was administered to the EM residents after the COVID-19 surge had largely subsided in June 2020. RESULTS: Twenty-two residents participated in the pre-pandemic study and completed the MBI. Twelve (55%) completed the two follow-up MBI surveys. In the larger EM residency cohort, 31/60 residents completed the MBI and PCL-5 survey during the pandemic peak and 30/60 (50%) completed the follow-up surveys. There were no significant differences in the three MBI burnout category measures of emotional exhaustion (P = 0.49), depersonalization (P = 0.13), and personal accomplishment (P = 0.70) pre-, during, and post-COVID. Of 31 participants, 11 (35%) scored greater than 31 on the PCL-5. Two residents had scores between 21-30, interpreted as "at risk." At greater than one month follow-up, 2/30 continued to meet criteria for a preliminary PTSD diagnosis, and five were "at risk." CONCLUSION: A significant proportion of residents (35%) experienced post-traumatic symptoms acutely during the COVID-19 pandemic crisis, potentially indicating a high prevalence of acute stress disorder in this population and increased risk of developing PTSD. However, there was no significant difference in burnout levels in this cohort before, during, or after the initial COVID-19 surge. Early screening for physicians at risk and referral for assessment and treatment may be important to mitigate pandemic-related PTSD.

A Novel Application of the Modified Angoff Method to Rate Case Difficulty in Simulation-Based Research.

INTRODUCTION: Simulation use in research is often limited by controlling for scenario difficulty when using repeated measures. Our study assesses the feasibility of the Modified Angoff Method to reach expert consensus regarding difficulty of medical simulations. We compared scores with participant physiologic stress. METHODS: Emergency medicine physicians with expertise in simulation education were asked to review 8 scenarios and estimate the percentage of resident physicians who would perform all critical actions using the modified Angoff method. A standard deviation (SD) of less than 10% of estimated percentage correct signified consensus. Twenty-five residents then performed the 6 scenarios that met consensus and heart rate variability (HRV) was measured. RESULTS: During round 1, experts rated 4/8 scenarios within a 10% SD for postgraduate year 3 (PGY3) and 3/8 for PGY4 residents. In round 2, 6/8 simulation scenarios were within an SD of 10% points for both years. Intraclass correlation coefficient was 0.84 for PGY3 ratings and 0.89 for PGY4 ratings. A mixed effects analysis of variance showed no significant difference in HRV change from rest to simulation between teams or scenarios. Modified Angoff Score was not a predictor of HRV (multiple R2 = 0.0176). CONCLUSIONS: Modified Angoff ratings demonstrated consensus in quantifying the estimated percentage of participants who would complete all critical actions for most scenarios. Although participant HRV did decrease during the scenarios, we were unable to significantly correlate this with ratings. This modified Angoff method is a feasible approach to evaluate simulation difficulty for educational and research purposes and may decrease the time and resources necessary for scenario piloting.

Inferring Intracellular Signal Transduction Circuitry from Molecular Perturbation Experiments.

The development of network inference methodologies that accurately predict connectivity in dysregulated pathways may enable the rational selection of patient therapies. Accurately inferring an intracellular network from data remains a very challenging problem in molecular systems biology. Living cells integrate extremely robust circuits that exhibit significant heterogeneity, but still respond to external stimuli in predictable ways. This phenomenon allows us to introduce a network inference methodology that integrates measurements of protein activation from perturbation experiments. The methodology relies on logic-based networks to provide a predictive approximation of the transfer of signals in a network. The approach presented was validated in silico with a set of test networks and applied to investigate the epidermal growth factor receptor signaling of a breast epithelial cell line, MFC10A. In our analysis, we predict the potential signaling circuitry most likely responsible for the experimental readouts of several proteins in the mitogen-activated protein kinase and phosphatidylinositol-3 kinase pathways. The approach can also be used to identify additional necessary perturbation experiments to distinguish between a set of possible candidate networks.