Diagnosis of multisystem inflammatory syndrome in children by a whole-blood transcriptional signature

BACKGROUND: To identify a diagnostic blood transcriptomic signature that distinguishes multisystem inflammatory syndrome in children (MIS-C) from Kawasaki disease (KD), bacterial infections, and viral infections. METHODS: Children presenting with MIS-C to participating hospitals in the United Kingdom and the European Union between April 2020 and April 2021 were prospectively recruited. Whole-blood RNA Sequencing was performed, contrasting the transcriptomes of children with MIS-C (n = 38) to those from children with KD (n = 136), definite bacterial (DB; n = 188) and viral infections (DV; n = 138). Genes significantly differentially expressed (SDE) between MIS-C and comparator groups were identified. Feature selection was used to identify genes that optimally distinguish MIS-C from other diseases, which were subsequently translated into RT-qPCR assays and evaluated in an independent validation set comprising MIS-C (n = 37), KD (n = 19), DB (n = 56), DV (n = 43), and COVID-19 (n = 39). RESULTS: In the discovery set, 5696 genes were SDE between MIS-C and combined comparator disease groups. Five genes were identified as potential MIS-C diagnostic biomarkers (HSPBAP1, VPS37C, TGFB1, MX2, and TRBV11-2), achieving an AUC of 96.8% (95% CI: 94.6%-98.9%) in the discovery set, and were translated into RT-qPCR assays. The RT-qPCR 5-gene signature achieved an AUC of 93.2% (95% CI: 88.3%-97.7%) in the independent validation set when distinguishing MIS-C from KD, DB, and DV. CONCLUSIONS: MIS-C can be distinguished from KD, DB, and DV groups using a 5-gene blood RNA expression signature. The small number of genes in the signature and good performance in both discovery and validation sets should enable the development of a diagnostic test for MIS-C

Operationalizing Appropriate Sepsis Definitions in Children Worldwide: Considerations for the Pediatric Sepsis Definition Taskforce

Sepsis is a leading cause of global mortality in children, yet definitions for pediatric sepsis are outdated and lack global applicability and validity. In adults, the Sepsis-3 Definition Taskforce queried databases from high-income countries to develop and validate the criteria. The merit of this definition has been widely acknowledged; however, important considerations about less-resourced and more diverse settings pose challenges to its use globally. To improve applicability and relevance globally, the Pediatric Sepsis Definition Taskforce sought to develop a conceptual framework and rationale of the critical aspects and context-specific factors that must be considered for the optimal operationalization of future pediatric sepsis definitions. It is important to address challenges in developing a set of pediatric sepsis criteria which capture manifestations of illnesses with vastly different etiologies and underlying mechanisms. Ideal criteria need to be unambiguous, and capable of adapting to the different contexts in which children with suspected infections are present around the globe. Additionally, criteria need to facilitate early recognition and timely escalation of treatment to prevent progression and limit life-threatening organ dysfunction. To address these challenges, locally adaptable solutions are required, which permit individualized care based on available resources and the pretest probability of sepsis. This should facilitate affordable diagnostics which support risk stratification and prediction of likely treatment responses, and solutions for locally relevant outcome measures. For this purpose, global collaborative databases need to be established, using minimum variable datasets from routinely collected data. In summary, a "Think globally, act locally" approach is required

Early division of a modified Cutler-Beard flap with a free tarsal graft

AIMS: We describe a variation of the Cutler-Beard flap in the reconstruction of upper eyelid defects. METHODS: The technique of upper eyelid reconstruction with a free tarsal graft and a cutaneous lower eyelid advancement flap divided at 2 weeks is described. Four cases where this technique was used for reconstruction of eyelid defects due to periocular malignancy are also reported. RESULTS: There were three male and one female patients ranging in age from 61 to 78 years. The underlying diagnoses were squamous cell carcinoma, trichilemmal carcinoma, and two basal cell carcinomas. Follow-up of 6-28 months revealed a good outcome in all four cases with one patient developing a mild cicatricial lower eyelid ectropion that was managed conservatively. CONCLUSIONS: A modified Cutler-Beard flap with free tarsal graft and early division may provide an effective alternative for upper eyelid reconstruction in cases with sufficient lower eyelid skin laxity

Implications for dorsoventral axis determination from the zebrafish mutation janus

THE mechanisms underlying the formation of dorsoventral polarity in the zebrafish Danio rerio are unknown. Here we describe the zebrafish recessive maternal-effect mutation janusm55. The mutant phenotype is a division of the blastoderm along the first cleavage plane into two detached half-sized blastoderms. Partial-axis bifurcation occurs in a subset of mutants. Analysis of goosecoid expression in the mutant embryos indicates that only one organizer region is present in each embryo. Furthermore, the position of this organizer region is random with respect to the first cleavage plane bisecting the two blastoderms. Finally, cell tracing in wild-type embryos demonstrates that there is no strict correlation of the dorsoventral axis with early cleavage planes in zebrafish. These findings support the notion that the establishment of the dorsoventral axis and the first cleavage planes are determined by separate mechanisms in the zebrafish embryo