WHAT'S KNOWN ON THIS SUBJECT: Accurately identifying ill hospitalized children with vital signs concerning for clinical deterioration is fundamental to inpatient pediatrics. Normal vital sign ranges for healthy children are useful for outpatient practice but have limited application to detecting deterioration in the hospital setting.WHAT THIS STUDY ADDS: Percentile curves for heart and respiratory rate in hospitalized children were developed and validated. The distributions differed from existing reference ranges and early warning scores. They may be useful to identify vital signs deviating from ranges expected among hospitalized children.abstract OBJECTIVE: To develop and validate heart and respiratory rate percentile curves for hospitalized children and compare their vital sign distributions to textbook reference ranges and pediatric early warning score (EWS) parameters. METHODS:For this cross-sectional study, we used 6 months of nursedocumented heart and respiratory rates from the electronic records of 14 014 children on general medical and surgical wards at 2 tertiary-care children' s hospitals. We developed percentile curves using generalized additive models for location, scale, and shape with 67% of the patients and validated the curves with the remaining 33%. We then determined the proportion of observations that deviated from textbook reference ranges and EWS parameters. RESULTS:We used 116 383 heart rate and 116 383 respiratory rate values to develop and validate the percentile curves. Up to 54% of heart rate observations and up to 40% of respiratory rate observations in our sample were outside textbook reference ranges. Up to 38% of heart rate observations and up to 30% of respiratory rate observations in our sample would have resulted in increased EWSs. CONCLUSIONS:A high proportion of vital signs among hospitalized children would be considered out of range according to existing reference ranges and pediatric EWSs. The percentiles we derived may serve as useful references for clinicians and could be used to inform the development of evidence-based vital sign parameters for physiologic monitor alarms, inpatient electronic health record vital sign alerts, medical emergency team calling criteria, and EWSs.

A learning health system (LHS) integrates research done in routine care settings, structured data capture during every encounter, and quality improvement processes to rapidly implement advances in new knowledge, all with active and meaningful patient participation. While disease-specific pediatric LHSs have shown tremendous impact on improved clinical outcomes, a national digital architecture to rapidly implement LHSs across multiple pediatric conditions does not exist. PEDSnet is a clinical data research network that provides the infrastructure to support a national pediatric LHS. A consortium consisting of PEDSnet, which includes eight academic medical centers, two existing disease-specific pediatric networks, and two national data partners form the initial partners in the National Pediatric Learning Health System (NPLHS). PEDSnet is implementing a flexible dual data architecture that incorporates two widely used data models and national terminology standards to support multi-institutional data integration, cohort discovery, and advanced analytics that enable rapid learning.

Summary Background Rare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes. Methods We did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial hypertension. These GWAS used data from four international case-control studies across 11 744 individuals with European ancestry (including 2085 patients). One GWAS used genotypes from 5895 whole-genome sequences and the other GWAS used genotyping array data from an additional 5849 individuals. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and tested associations with duration of survival. All-cause mortality was the primary endpoint in survival analyses. Findings A locus near SOX17 (rs10103692, odds ratio 1·80 [95% CI 1·55–2·08], p=5·13 × 10 –15 ) and a second locus in HLA-DPA1 and HLA-DPB1 (collectively referred to as HLA-DPA1/DPB1 here; rs2856830, 1·56 [1·42–1·71], p=7·65 × 10 –20 ) within the class II MHC region were associated with pulmonary arterial hypertension. The SOX17 locus had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25–1·48], p=1·69 × 10 –12 ; and rs10103692). Functional and epigenomic data indicate that the risk variants near SOX17 alter gene regulation via an enhancer active in endothelial cells. Pulmonary arterial hypertension risk variants determined haplotype-specific enhancer activity, and CRISPR-mediated inhibition of the enhancer reduced SOX17 expression. The HLA-DPA1/DPB1 rs2856830 genotype was strongly associated with survival. Median survival from diagnosis in patients with pulmonary arterial hypertension with the C/C homozygous genotype was double (13·50 years [95% CI 12·07 to >13·50]) that of those with the T/T genotype (6·97 years [6·02–8·05]), despite similar baseline disease severity. Interpretation This is the first study to report that common genetic variation at loci in an enhancer near SOX17 and in HLA-DPA1/DPB1 is associated with pulmonary arterial hypertension. Impairment of SOX17 function might be more common in pulmonary arterial hypertension than suggested by rare mutations in ...