ARAF recurrent mutation causes central conducting lymphatic anomaly treatable with a MEK inhibitor.

The treatment of lymphatic anomaly, a rare devastating disease spectrum of mostly unknown etiologies, depends on the patient manifestations1. Identifying the causal genes will allow for developing affordable therapies in keeping with precision medicine implementation2. Here we identified a recurrent gain-of-function ARAF mutation (c.640T>C:p.S214P) in a 12-year-old boy with advanced anomalous lymphatic disease unresponsive to conventional sirolimus therapy and in another, unrelated, adult patient. The mutation led to loss of a conserved phosphorylation site. Cells transduced with ARAF-S214P showed elevated ERK1/2 activity, enhanced lymphangiogenic capacity, and disassembly of actin skeleton and VE-cadherin junctions, which were rescued using the MEK inhibitor trametinib. The functional relevance of the mutation was also validated by recreating a lymphatic phenotype in a zebrafish model, with rescue of the anomalous phenotype using a MEK inhibitor. Subsequent therapy of the lead proband with a MEK inhibitor led to dramatic clinical improvement, with remodeling of the patient's lymphatic system with resolution of the lymphatic edema, marked improvement in his pulmonary function tests, cessation of supplemental oxygen requirements and near normalization of daily activities. Our results provide a representative demonstration of how knowledge of genetic classification and mechanistic understanding guides biologically based medical treatments, which in our instance was life-saving.

Determining preventability of pediatric readmissions using fault tree analysis.

BACKGROUND: Previous studies attempting to distinguish preventable from nonpreventable readmissions reported challenges in completing reviews efficiently and consistently. OBJECTIVES: (1) Examine the efficiency and reliability of a Web-based fault tree tool designed to guide physicians through chart reviews to a determination about preventability. (2) Investigate root causes of general pediatrics readmissions and identify the percent that are preventable. DESIGN/SETTING/PATIENTS: General pediatricians from The Children's Hospital of Philadelphia used a Web-based fault tree tool to classify root causes of all general pediatrics 15-day readmissions in 2014. INTERVENTION/MEASUREMENTS: The tool guided reviewers through a logical progression of questions, which resulted in 1 of 18 root causes of readmission, 8 of which were considered potentially preventable. Twenty percent of cases were cross-checked to measure inter-rater reliability. RESULTS: Of the 7252 discharges, 248 were readmitted, for an all-cause general pediatrics 15-day readmission rate of 3.4%. Of those readmissions, 15 (6.0%) were deemed potentially preventable, corresponding to 0.2% of total discharges. The most common cause of potentially preventable readmissions was premature discharge. For the 50 cross-checked cases, both reviews resulted in the same root cause for 44 (86%) of files (κ = 0.79; 95% confidence interval: 0.60-0.98). Completing 1 review using the tool took approximately 20 minutes. CONCLUSION: The Web-based fault tree tool helped physicians to identify root causes of hospital readmissions and classify them as either preventable or not preventable in an efficient and consistent way. It also confirmed that only a small percentage of general pediatrics 15-day readmissions are potentially preventable. Journal of Hospital Medicine 2016;11:329-335. © 2016 Society of Hospital Medicine.