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Multi-system Inflammatory Syndrome in Children (MIS-C) is a major complication of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection in pediatric patients. Weeks after an often mild or asymptomatic initial infection with SARS-CoV-2 children may present with a severe shock-like picture and marked inflammation. Children with MIS-C present with varying degrees of cardiovascular and hyperinflammatory symptoms. Here we perform a comprehensive analysis of the plasma proteome of more than 1400 proteins in children with SARS-CoV-2. We hypothesize that the proteome would reflect heterogeneity in hyperinflammation and vascular injury, and further identify pathogenic mediators of disease. We show that protein signatures demonstrate overlap between MIS-C, and the inflammatory syndromes macrophage activation syndrome (MAS) and thrombotic microangiopathy (TMA). We demonstrate that PLA2G2A is an important marker of MIS-C that associates with TMA. We find that IFNγ responses are dysregulated in MIS-C patients, and that IFNγ levels delineate clinical heterogeneity. Multi-inflammatory syndrome in children (MIS-C) can be associated with SARS-CoV-2 infection but can also be similar to other inflammatory syndromes. Here the authors characterise the plasma proteome phenotype in MIS-C and compare to other SARS-CoV-2 related syndromes and find disproportionately high IFN-γ responses in MIS-C patients.

Septic shock is a low-frequency but high-stakes condition in children requiring prompt resuscitation, which makes it an important target for simulation-based education. In this study, we aimed to design and implement an augmented reality app (PediSepsisAR) for septic shock simulation, test the feasibility of measuring the timing and volume of fluid administration during septic shock simulation with and without PediSepsisAR, and describe PediSepsisAR as an educational tool. We hypothesized that we could feasibly measure our desired data during the simulation in 90% of the participants in each group. With regard to using PediSepsisAR as an educational tool, we hypothesized that the PediSepsisAR group would report that it enhanced their awareness of simulated patient blood flow and would more rapidly verbalize recognition of abnormal patient status and desired management steps. We performed a randomized controlled feasibility trial with a convenience sample of pediatric care providers at a large tertiary care pediatric center. Participants completed a prestudy questionnaire and were randomized to either the PediSepsisAR or control (traditional simulation) arms. We measured the participants' time to administer 20, 40, and 60 cc/kg of intravenous fluids during a septic shock simulation using each modality. In addition, facilitators timed how long participants took to verbalize they had recognized tachycardia, hypotension, or septic shock and desired to initiate the sepsis pathway and administer antibiotics. Participants in the PediSepsisAR arm completed a poststudy questionnaire. We analyzed data using descriptive statistics and a Wilcoxon rank-sum test to compare the median time with event variables between groups. We enrolled 50 participants (n=25 in each arm). The timing and volume of fluid administration were captured in all the participants in each group. There was no statistically significant difference regarding time to administration of intravenous fluids between the two groups. Similarly, there was no statistically significant difference between the groups regarding time to verbalized recognition of patient status or desired management steps. Most participants in the PediSepsisAR group reported that PediSepsisAR enhanced their awareness of the patient's perfusion. We developed an augmented reality app for use in pediatric septic shock simulations and demonstrated the feasibility of measuring the volume and timing of fluid administration during simulation using this modality. In addition, our findings suggest that PediSepsisAR may enhance participants' awareness of abnormal perfusion.

To investigate whether differences in raft recruitment account for differences in signaling and T cell receptor (TCR) macromolecular complex organization in Th1 and Th2 cells, we questioned whether the signaling proteins found associated with lipid rafts prior to and during activation differ in these two subsets of T cells. We show here that TCR complex members are recruited efficiently to rafts and aggregate with rafts at the site of MHC/peptide contact in Th1 but not Th2 cells. Functionally, these observations are supported by the analysis of calcium mobilization in response to TCR signaling in the presence of a raft disrupting agent, which demonstrates that calcium mobilization is dependent on raft integrity in Th1 but not Th2 cells. Interestingly, while the pattern of signaling in response to a high affinity peptide is similar in Th1 and Th2 cells, there is a marked defect in the response of Th2 cells to low affinity peptides, particularly in downstream events such as calcium mobilization and cell division. To investigate the role of CD4 as a regulatory molecule which may control these processes, we examined both recruitment of the TCR to lipid rafts and immunological synapse formation in T cells from CD4 deficient mice. We show that the differential raft recruitment of the TCR in Th1 vs. Th2 cells is in fact regulated by CD4, suggesting that CD4-dependent signaling may aid in recruitment and/or aggregation of rafts upon TCR signaling. We then show that the requirement for CD4 in governing immunological synapse formation is dependent on the strength of peptide used to stimulate the TCR: CD4 deficient T cells stimulated with agonist peptides show a partial defect in immunological synapse formation, whereas CD4 deficient cells stimulated with a lower affinity antigenic peptide show more profound defects. These differences correlate with downstream defects in AP-1 and NFκB activation, particularly in response to low affinity peptide stimulation. Finally, we demonstrate that these defects can be rescued by retroviral transduction of wild type, but not tailless or palmitoylation mutant CD4, indicating that both CD4 signaling function and recruitment to rafts are required for efficient immunological synapse formation.