Timing of Tracheostomy in Critically Ill Infants and Children With Respiratory Failure: A Pediatric Health Information System Study.

OBJECTIVES: Tracheostomy placement in infants and children with respiratory failure has steadily increased over time, yet there is no consensus for optimal timing. We sought to: 1) describe tracheostomy timing and associated demographic and clinical characteristics in a large ICU cohort and 2) compare clinical outcomes between subgroups based on tracheostomy timing. DESIGN: Retrospective observational study using the Pediatric Health Information System (PHIS). SETTING: Neonatal ICUs and PICUs in the United States. PATIENTS: PHIS was queried for patients less than 18 years who underwent tracheostomy from 2010 to 2020. Patients were included if admitted to an ICU with need for mechanical ventilation (MV) prior to tracheostomy in the same hospitalization. Patients were categorized as early tracheostomy (ET) (placement at MV day ≤ 14), late tracheostomy (LT) (MV days 15-60), and extended tracheostomy (ExT) (MV day > 60). Primary endpoints included demographic and clinical characteristics. Secondary endpoints included patient outcomes: in-hospital mortality, length of stay (LOS), hospital-acquired pneumonia (HAP), and hospital costs. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Sixteen thousand one hundred twenty-one patients underwent tracheostomy at 52 children's hospitals. Ten thousand two hundred ninety-five had complete data and were included in the analysis. Thirty-nine percent (4,006/10,295) underwent ET, 40% (4,159/10,295) underwent LT, and 21% (2,130/10,295) underwent ExT. Majority of patients in all subgroups had complex chronic conditions. Median age was significantly different between subgroups with ET being the oldest ( p < 0.001). A multivariable regression analysis showed that ET was associated with lower in-hospital mortality ( p < 0.001), shorter hospital LOS ( p < 0.001), shorter ICU LOS ( p < 0.001), shorter post-tracheostomy LOS ( p < 0.001), decreased HAP ( p < 0.001), and lower hospital costs ( p < 0.001) compared with those who underwent LT or ExT. CONCLUSIONS: In a large cohort of pediatric patients with respiratory failure, tracheostomy placement within 14 days of MV was associated with improved in-hospital outcomes. ET was independently associated with decreased mortality, LOS, HAP, and hospital costs.

Identification of Ecdysone Hormone Receptor Agonists as a Therapeutic Approach for Treating Filarial Infections.

BACKGROUND: A homologue of the ecdysone receptor has previously been identified in human filarial parasites. As the ecdysone receptor is not found in vertebrates, it and the regulatory pathways it controls represent attractive potential chemotherapeutic targets. METHODOLOGY/ PRINCIPAL FINDINGS: Administration of 20-hydroxyecdysone to gerbils infected with B. malayi infective larvae disrupted their development to adult stage parasites. A stable mammalian cell line was created incorporating the B. malayi ecdysone receptor ligand-binding domain, its heterodimer partner and a secreted luciferase reporter in HEK293 cells. This was employed to screen a series of ecdysone agonist, identifying seven agonists active at sub-micromolar concentrations. A B. malayi ecdysone receptor ligand-binding domain was developed and used to study the ligand-receptor interactions of these agonists. An excellent correlation between the virtual screening results and the screening assay was observed. Based on both of these approaches, steroidal ecdysone agonists and the diacylhydrazine family of compounds were identified as a fruitful source of potential receptor agonists. In further confirmation of the modeling and screening results, Ponasterone A and Muristerone A, two compounds predicted to be strong ecdysone agonists stimulated expulsion of microfilaria and immature stages from adult parasites. CONCLUSIONS: The studies validate the potential of the B. malayi ecdysone receptor as a drug target and provide a means to rapidly evaluate compounds for development of a new class of drugs against the human filarial parasites.