RESUMO
OBJECTIVE: We hypothesized that collaborative intervention to improve weighted pediatric readiness score (WPRS) will be associated with decreased pediatric intensive care (PICU) mortality, PICU and hospital length of stay. METHODS: This study analyzes the transfer of acutely ill and injured patients from general emergency departments (GEDs) to our institution. The intervention involved customized assessment reports focusing on team performance and systems improvement for pediatric readiness, sharing best practices and clinical resources, designation of a nurse PECC at each GED and ongoing interactions at 2 and 4 months. Data was collected from charts before and after the intervention, focusing on patients transferred to our pediatric emergency department (ED) or directly admitted to our PICU from the GEDs. Clinical outcomes such as PICU length of stay (LOS), hospital LOS, and PICU mortality were assessed. Descriptive statistics were used for demographics, and various statistical tests were employed to analyze the data. Bivariate analyses and multivariable models were utilized to examine patient outcomes and the association between the intervention and outcomes. RESULTS: There were 278 patients in the pre-intervention period and 314 patients in the post-intervention period. Multivariable analyses revealed a significant association between the change in WPRS and decreased PICU LOS (ß=-0.05 [95% CI: -0.09, -0.01), p=0.023), and hospital LOS (ß=-0.12 [95% CI: -0.21, -0.04], p=0.004), but showed no association between the intervention and other patient outcomes. CONCLUSIONS: In this cohort, improving pediatric readiness scores in GEDs was associated with significant improvements in PICU and hospital length of stay. Future initiatives should focus on disseminating pediatric readiness efforts to improve outcomes of critically ill children nationally. WHATS NEW: Improving pediatric readiness scores in general emergency departments is associated with improved downstream clinical outcomes demonstrated by reduced PICU and hospital length of stay.
RESUMO
Neurofibromatosis type 1 (NF1) is a common cancer predisposition syndrome caused by mutations in the NF1 tumor suppressor gene. NF1 encodes neurofibromin, a GTPase-activating protein for RAS proto-oncogene GTPase (RAS). Plexiform neurofibromas are a hallmark of NF1 and result from loss of heterozygosity of NF1 in Schwann cells, leading to constitutively activated p21RAS. Given the inability to target p21RAS directly, here we performed an shRNA library screen of all human kinases and Rho-GTPases in a patient-derived NF1-/- Schwann cell line to identify novel therapeutic targets to disrupt PN formation and progression. Rho family members, including Rac family small GTPase 1 (RAC1), were identified as candidates. Corroborating these findings, we observed that shRNA-mediated knockdown of RAC1 reduces cell proliferation and phosphorylation of extracellular signal-regulated kinase (ERK) in NF1-/- Schwann cells. Genetically engineered Nf1flox/flox;PostnCre+ mice, which develop multiple PNs, also exhibited increased RAC1-GTP and phospho-ERK levels compared with Nf1flox/flox;PostnCre- littermates. Notably, mice in which both Nf1 and Rac1 loci were disrupted (Nf1flox/floxRac1flox/flox;PostnCre+) were completely free of tumors and had normal phospho-ERK activity compared with Nf1flox/flox ;PostnCre+ mice. We conclude that the RAC1-GTPase is a key downstream node of RAS and that genetic disruption of the Rac1 allele completely prevents PN tumor formation in vivo in mice.
