Downregulation of exhausted cytotoxic T cells in gene expression networks of multisystem inflammatory syndrome in children.

Multisystem inflammatory syndrome in children (MIS-C) presents with fever, inflammation and pathology of multiple organs in individuals under 21 years of age in the weeks following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Although an autoimmune pathogenesis has been proposed, the genes, pathways and cell types causal to this new disease remain unknown. Here we perform RNA sequencing of blood from patients with MIS-C and controls to find disease-associated genes clustered in a co-expression module annotated to CD56dimCD57+ natural killer (NK) cells and exhausted CD8+ T cells. A similar transcriptome signature is replicated in an independent cohort of Kawasaki disease (KD), the related condition after which MIS-C was initially named. Probing a probabilistic causal network previously constructed from over 1,000 blood transcriptomes both validates the structure of this module and reveals nine key regulators, including TBX21, a central coordinator of exhausted CD8+ T cell differentiation. Together, this unbiased, transcriptome-wide survey implicates downregulation of NK cells and cytotoxic T cell exhaustion in the pathogenesis of MIS-C.

Cytotoxic lymphocytes are dysregulated in multisystem inflammatory syndrome in children.

Multisystem inflammatory syndrome in children (MIS-C) presents with fever, inflammation and multiple organ involvement in individuals under 21 years following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. To identify genes, pathways and cell types driving MIS-C, we sequenced the blood transcriptomes of MIS-C cases, pediatric cases of coronavirus disease 2019, and healthy controls. We define a MIS-C transcriptional signature partially shared with the transcriptional response to SARS-CoV-2 infection and with the signature of Kawasaki disease, a clinically similar condition. By projecting the MIS-C signature onto a co-expression network, we identified disease gene modules and found genes downregulated in MIS-C clustered in a module enriched for the transcriptional signatures of exhausted CD8 + T-cells and CD56 dim CD57 + NK cells. Bayesian network analyses revealed nine key regulators of this module, including TBX21 , a central coordinator of exhausted CD8 + T-cell differentiation. Together, these findings suggest dysregulated cytotoxic lymphocyte response to SARS-Cov-2 infection in MIS-C.

Author Correction: Sampling the host response to SARS-CoV-2 in hospitals under siege.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Olanzapine for the Prevention of Postdischarge Nausea and Vomiting after Ambulatory Surgery: A Randomized Controlled Trial.

BACKGROUND: Postdischarge nausea and vomiting after ambulatory surgery is a common problem that is not adequately addressed in current practice. This prospective, randomized, double-blind, parallel-group, placebo-controlled study was designed to test the hypothesis that oral olanzapine is superior to placebo at preventing postdischarge nausea and vomiting. METHODS: In a single-center, double-blind, randomized, placebo-controlled trial, the authors compared a single preoperative dose of olanzapine 10 mg to placebo, in adult female patients 50 years old or less, undergoing ambulatory gynecologic or plastic surgery with general anesthesia. All patients received standard antiemetic prophylaxis with dexamethasone and ondansetron. The primary composite outcome was nausea and/or vomiting in the 24 h after discharge. Secondary outcomes included severe nausea, vomiting, and side effects. RESULTS: A total of 140 patients were randomized and evaluable. The primary outcome occurred in 26 of 69 patients (38%) in the placebo group and in 10 of 71 patients (14%) in the olanzapine group (relative risk, 0.37; 95% CI, 0.20 to 0.72; P = 0.003). Severe nausea occurred in 14 patients (20%) in the placebo group and 4 patients (6%) in the olanzapine group (relative risk, 0.28; 95% CI, 0.10 to 0.80). Vomiting occurred in eight patients (12%) in the placebo group and two patients (3%) in the olanzapine group (relative risk, 0.24; 95% CI, 0.05 to 1.10). The median score for sedation (scale 0 to 10, with 10 being highest) in the 24 h after discharge was 4 (interquartile range, 2 to 7) in the placebo group and 6 (interquartile range, 3 to 8) in the olanzapine group (P = 0.023). CONCLUSIONS: When combined with ondansetron and dexamethasone, the addition of olanzapine relative to placebo decreased the risk of nausea and/or vomiting in the 24 hafter discharge from ambulatory surgery by about 60% with a slight increase in reported sedation.