High-content screening assay-based discovery of paullones as novel podocyte-protective agents.

Podocyte dysfunction and loss is an early event and a hallmark of proteinuric kidney diseases. A podocyte's normal function is maintained via its unique cellular architecture that relies on an intracellular network of filaments, including filamentous actin (F-actin) and microtubules, that provides mechanical support. Damage to this filamentous network leads to changes in cellular morphology and results in podocyte injury, dysfunction, and death. Conversely, stabilization of this network protects podocytes and ameliorates proteinuria. This suggests that stabilization of podocyte architecture via its filamentous network could be a key therapeutic strategy for proteinuric kidney diseases. However, development of podocyte-directed therapeutics, especially those that target the cell's filamentous network, is still lacking, partly because of unavailability of appropriate cellular assays for use in a drug discovery environment. Here, we describe a new high-content screening-based methodology and its implementation on podocytes to identify paullone derivatives as a novel group of podocyte-protective compounds. We find that three compounds, i.e., kenpaullone, 1-azakenpaullone, and alsterpaullone, dose dependently protect podocytes from puromycin aminonucleoside (PAN)-mediated injury in vitro by reducing PAN-induced changes in both the filamentous actin and microtubules, with alsterpaullone providing maximal protection. Mechanistic studies further show that alsterpaullone suppressed PAN-induced activation of signaling downstream of GSK3ß and p38 mitogen-activated protein kinase. In vivo it reduced ADR-induced glomerular injury in a zebrafish model. Together, these results identify paullone derivatives as novel podocyte-protective agents for future therapeutic development.

A Realistic, Low-Cost Simulated Automated Chest Compression Device.

Audience: This simulated automated chest compression device was designed for use in simulation cardiac arrest cases involving emergency medicine residents, but it would be applicable to other learners such as nurses, pharmacists, and medical students. Background: Automated chest compression devices (ACCD) are commonly utilized in cardiac arrest in the emergency department and by emergency medical services (EMS) as patients arrive in the ED.1 Prolonged simulated cardiac arrest can be challenging to maintain proper chest compression depth and technique.2 Resident learning may be enhanced during cardiac arrest in the simulation environment by implementing the use of a simulated ACCD. Educational Objectives: By the end of this educational session using a resuscitation trainer or high-fidelity manikin, learners should be able to:Recognize appropriate application of simulated ACCD to an ongoing resuscitation caseDemonstrate proper positioning of simulated ACCD in manikin modelIntegrate simulated ACCD to provide compressions appropriately throughout cardiac arrest scenario. Educational Methods: We developed a cost-effective simulated ACCD for use in resuscitation simulation cases. An initial pilot session identified components of fidelity that were used to model the simulated ACCD after those utilized in clinical situations. Three simulated devices were created and then tested for efficacy during high-fidelity simulation with 25 emergency medicine residents. Research Methods: Visual analog scales were used to explore how the simulated ACCD affected perceived realism and stress level during the cardiac arrest simulation. Qualitative data were collected through open-ended learner feedback comments. The institutional review board at our institution reviewed this project and determined that it was exempt. Results: With inclusion of the simulated ACCD device, learners rated the simulation "more realistic" with an average rating of 74/100 and "less stressful" with an average rating of 69/100 on the visual analog scales. Learner comments noted that the use of the ACCD in simulation resulted in better resource availability and accurate environmental noise. Discussion: The simulated ACCD presented here was found to be effective, realistic, and practical for use by learners in a resuscitation curriculum. Our results suggest that implementating a cost-effective simulated ACCD ($98 for supplies) in high-fidelity simulation cardiac arrest cases enhances the perceived realism of the environment and offers physician learners a low-stress opportunity to practice the clinical application of ACCD in cardiac arrest resuscitation. Additionally, the use of the simulated ACCD, specifically in a prolonged resuscitation, eliminated the need for physically demanding manual chest compressions. Anecdotally, in simulated environments we have observed poor-quality manual chest compressions due to an understanding that the manikin is "not real," leading to decreased psychological fidelity from the shared acceptance of the poor-quality compressions. Thus, the presence of a simulated clinical device providing chest compressions could have increased the feel of realism through improved psychological fidelity. Additionally, we note that the physical and psychological fidelity of this simulated device was sufficient for physicians to perceive clinical implementation, but may be suboptimal for assistive staff, who are focused on the specific functionality and may benefit from training on the physical device in clinical use. Finally, our simulated ACCD resembles the clinical device our department uses; we advise modifications as appropriate to allow a simulated ACCD created for other learners to also resemble their clinically used ACCD. Topics: Automated chest compression device, ACLS, improvised equipment, high fidelity simulation.

Emotional Intelligence and Resilience "PROGRAM" Improves Wellbeing and Stress Management Skills in Preclinical Medical Students.

Purpose: The purpose of this study was to determine if implementation of a new educational curriculum focusing on Emotional Intelligence (EI) and Resilience improved second year medical student scores in these areas. Methods: Our EI-Resilience curriculum was offered as an elective for second year medical students to voluntarily enroll in. The elective consisted of six 2-hour sessions taught by a single faculty member over eight months. Sessions focused on development of EI skills and teaching a Resilience "PROGRAM" (Positive thinking, Reframing, Optimism, Gratitude, Reflection, Altruism, Meaning). Participants' EI levels were assessed before and after the elective using the Bar-On Emotional Quotient Inventory 2.0 (EQ-i 2.0). Results: Over a period of 2 years, 70 students participated in the elective. The overall mean EI score significantly improved after the educational elective (100.05 ± 12.94 versus 108.14 ±12.36, p < 0.001). Compared to the baseline scores, there was significant improvement in all EI components, including all five composite scales, all fifteen content subscales, and the well-being score (all p < 0.05). In a post-intervention survey assessing student perception of the elective, most students found the elective to be helpful (95%, 64/67), most students felt the elective should continue to be available for future students (95%, 64/67), and most would recommend the elective to other students (93%, 62/67). Conclusion: An EI-Resilience curriculum offered as an elective to second year medical students was well received by students. Our outcomes showed significant improvement in students' EI scores and all sub-scores, including all components of the stress management composite and well-being score. Teaching EI skills and Resilience strategies in the preclinical setting might be an opportune time for this type of educational intervention.