A Realistic, Low-Cost Simulated Automated Chest Compression Device

Audience: This simulated automated chest compression device was designed for use in simulation cardiacarrest cases involving emergency medicine residents, but it would be applicable to other learners such asnurses, pharmacists, and medical students.Background: Automated chest compression devices (ACCD) are commonly utilized in cardiac arrest in theemergency department and by emergency medical services (EMS) as patients arrive in the ED.1 Prolongedsimulated cardiac arrest can be challenging to maintain proper chest compression depth and technique.2Resident learning may be enhanced during cardiac arrest in the simulation environment by implementing theuse of a simulated ACCD.Educational Objectives: By the end of this educational session using a resuscitation trainer or high-fidelitymanikin, learners should be able to:1. Recognize appropriate application of simulated ACCD to an ongoing resuscitation case2. Demonstrate proper positioning of simulated ACCD in manikin model3. Integrate simulated ACCD to provide compressions appropriately throughout cardiac arrest scenarioEducational Methods: We developed a cost-effective simulated ACCD for use in resuscitation simulationcases. An initial pilot session identified components of fidelity that were used to model the simulated ACCDafter those utilized in clinical situations. Three simulated devices were created and then tested for efficacyduring high-fidelity simulation with 25 emergency medicine residents.Research Methods: Visual analog scales were used to explore how the simulated ACCD affected perceivedrealism 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 projectand determined that it was exempt.Results: With inclusion of the simulated ACCD device, learners rated the simulation "more realistic" with anaverage 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 andaccurate environmental noise.Discussion: The simulated ACCD presented here was found to be effective, realistic, and practical for use bylearners in a resuscitation curriculum. Our results suggest that implementating a cost-effective simulatedACCD ($98 for supplies) in high-fidelity simulation cardiac arrest cases enhances the perceived realism of theenvironment and offers physician learners a low-stress opportunity to practice the clinical application ofACCD in cardiac arrest resuscitation. Additionally, the use of the simulated ACCD, specifically in a prolongedresuscitation, eliminated the need for physically demanding manual chest compressions. Anecdotally, insimulated environments we have observed poor-quality manual chest compressions due to an understandingthat the manikin is “not real,” leading to decreased psychological fidelity from the shared acceptance of thepoor-quality compressions. Thus, the presence of a simulated clinical device providing chest compressionscould have increased the feel of realism through improved psychological fidelity. Additionally, we note thatthe physical and psychological fidelity of this simulated device was sufficient for physicians to perceive clinicalimplementation, but may be suboptimal for assistive staff, who are focused on the specific functionality andmay benefit from training on the physical device in clinical use. Finally, our simulated ACCD resembles theclinical device our department uses; we advise modifications as appropriate to allow a simulated ACCDcreated for other learners to also resemble their clinically used ACCD

The TLR4 Agonist Monophosphoryl Lipid a Drives Broad Resistance to Infection via Dynamic Reprogramming of Macrophage Metabolism

Monophosphoryl lipid A (MPLA) is a clinically used TLR4 agonist that has been found to drive nonspecific resistance to infection for up to 2 wk. However, the molecular mechanisms conferring protection are not well understood. In this study, we found that MPLA prompts resistance to infection, in part, by inducing a sustained and dynamic metabolic program in macrophages that supports improved pathogen clearance. Mice treated with MPLA had enhanced resistance to infection with Staphylococcus aureus and Candida albicans that was associated with augmented microbial clearance and organ protection. Tissue macrophages, which exhibited augmented phagocytosis and respiratory burst after MPLA treatment, were required for the beneficial effects of MPLA. Further analysis of the macrophage phenotype revealed that early TLR4-driven aerobic glycolysis was later coupled with mitochondrial biogenesis, enhanced malate shuttling, and increased mitochondrial ATP production. This metabolic program was initiated by overlapping and redundant contributions of MyD88- and TRIF-dependent signaling pathways as well as downstream mTOR activation. Blockade of mTOR signaling inhibited the development of the metabolic and functional macrophage phenotype and ablated MPLA-induced resistance to infection in vivo. Our findings reveal that MPLA drives macrophage metabolic reprogramming that evolves over a period of days to support a macrophage phenotype highly effective at mediating microbe clearance and that this results in nonspecific resistance to infection. The Journal of Immunology, 2018, 200: 3777–3789

A Hematogenous Route for Medulloblastoma Leptomeningeal Metastases

While the preponderance of morbidity and mortality in medulloblastoma patients are due to metastatic disease, most research focuses on the primary tumor due to a dearth of metastatic tissue samples and model systems. Medulloblastoma metastases are found almost exclusively on the leptomeningeal surface of the brain and spinal cord; dissemination is therefore thought to occur through shedding of primary tumor cells into the cerebrospinal fluid followed by distal re-implantation on the leptomeninges. We present evidence for medulloblastoma circulating tumor cells (CTCs) in therapy-naive patients and demonstrate in vivo, through flank xenografting and parabiosis, that medulloblastoma CTCs can spread through the blood to the leptomeningeal space to form leptomeningeal metastases. Medulloblastoma leptomeningeal metastases express high levels of the chemokine CCL2, and expression of CCL2 in medulloblastoma in vivo is sufficient to drive leptomeningeal dissemination. Hematogenous dissemination of medulloblastoma offers a new opportunity to diagnose and treat lethal disseminated medulloblastoma

Divergent clonal selection dominates medulloblastoma at recurrence

The development of targeted anti-cancer therapies through the study of cancer genomes is intended to increase survival rates and decrease treatment-related toxicity. We treated a transposon-driven, functional genomic mouse model of medulloblastoma with 'humanized' in vivo therapy (microneurosurgical tumour resection followed by multi-fractionated, image-guided radiotherapy). Genetic events in recurrent murine medulloblastoma exhibit a very poor overlap with those in matched murine diagnostic samples (<5%). Whole-genome sequencing of 33 pairs of human diagnostic and post-therapy medulloblastomas demonstrated substantial genetic divergence of the dominant clone after therapy (<12% diagnostic events were retained at recurrence). In both mice and humans, the dominant clone at recurrence arose through clonal selection of a pre-existing minor clone present at diagnosis. Targeted therapy is unlikely to be effective in the absence of the target, therefore our results offer a simple, proximal, and remediable explanation for the failure of prior clinical trials of targeted therapy

Divergent clonal selection dominates medulloblastoma at recurrence

The development of targeted anti-cancer therapies through the study of cancer genomes is intended to increase survival rates and decrease treatment-related toxicity. We treated a transposon-driven, functional genomic mouse model of medulloblastoma with 'humanized' in vivo therapy (microneurosurgical tumour resection followed by multi-fractionated, image-guided radiotherapy). Genetic events in recurrent murine medulloblastoma exhibit a very poor overlap with those in matched murine diagnostic samples (<5%). Whole-genome sequencing of 33 pairs of human diagnostic and post-therapy medulloblastomas demonstrated substantial genetic divergence of the dominant clone after therapy (<12% diagnostic events were retained at recurrence). In both mice and humans, the dominant clone at recurrence arose through clonal selection of a pre-existing minor clone present at diagnosis. Targeted therapy is unlikely to be effective in the absence of the target, therefore our results offer a simple, proximal, and remediable explanation for the failure of prior clinical trials of targeted therapy