Pulmonary-to-Systemic Arterial Shunt to Treat Children With Severe Pulmonary Hypertension

BACKGROUND: The placement of a pulmonary-to-systemic arterial shunt in children with severe pulmonary hypertension (PH) has been demonstrated, in relatively small studies, to be an effective palliation for their disease. OBJECTIVES: The aim of this study was to expand upon these earlier findings using an international registry for children with PH who have undergone a shunt procedure. METHODS: Retrospective data were obtained from 110 children with PH who underwent a shunt procedure collected from 13 institutions in Europe and the United States. RESULTS: Seventeen children died in-hospital postprocedure (15%). Of the 93 children successfully discharged home, 18 subsequently died or underwent lung transplantation (20%); the mean follow-up was 3.1 years (range: 25 days to 17 years). The overall 1- and 5-year freedom from death or transplant rates were 77% and 58%, respectively, and 92% and 68% for those discharged home, respectively. Children discharged home had significantly improved World Health Organization functional class (P < 0.001), 6-minute walk distances (P = 0.047) and lower brain natriuretic peptide levels (P < 0.001). Postprocedure, 59% of children were weaned completely from their prostacyclin infusion (P < 0.001). Preprocedural risk factors for dying in-hospital postprocedure included intensive care unit admission (hazard ratio [HR]: 3.2; P = 0.02), mechanical ventilation (HR: 8.3; P < 0.001) and extracorporeal membrane oxygenation (HR: 10.7; P < 0.001). CONCLUSIONS: A pulmonary-to-systemic arterial shunt can provide a child with severe PH significant clinical improvement that is both durable and potentially free from continuous prostacyclin infusion. Five-year survival is comparable to children undergoing lung transplantation for PH. Children with severely decompensated disease requiring aggressive intensive care are not good candidates for the shunt procedure

Cardiac catheterization in children with pulmonary hypertensive vascular disease:Consensus statement from the Pulmonary Vascular Research Institute, Pediatric and Congenital Heart Disease Task Forces

Cardiac catheterization is important in the diagnosis and risk stratification of pulmonary hypertensive vascular disease (PHVD) in children. Acute vasoreactivity testing provides key information about management, prognosis, therapeutic strategies, and efficacy. Data obtained at cardiac catheterization continue to play an important role in determining the surgical options for children with congenital heart disease and clinical evidence of increased pulmonary vascular resistance. The Pediatric and Congenital Heart Disease Task Forces of the Pulmonary Vascular Research Institute met to develop a consensus statement regarding indications for, conduct of, acute vasoreactivity testing with, and pitfalls and risks of cardiac catheterization in children with PHVD. This document contains the essentials of those discussions to provide a rationale for the hemodynamic assessment by cardiac catheterization of children with PHVD.</p

Cardiac catheterization in children with pulmonary hypertensive vascular disease:Consensus statement from the Pulmonary Vascular Research Institute, Pediatric and Congenital Heart Disease Task Forces

Cardiac catheterization is important in the diagnosis and risk stratification of pulmonary hypertensive vascular disease (PHVD) in children. Acute vasoreactivity testing provides key information about management, prognosis, therapeutic strategies, and efficacy. Data obtained at cardiac catheterization continue to play an important role in determining the surgical options for children with congenital heart disease and clinical evidence of increased pulmonary vascular resistance. The Pediatric and Congenital Heart Disease Task Forces of the Pulmonary Vascular Research Institute met to develop a consensus statement regarding indications for, conduct of, acute vasoreactivity testing with, and pitfalls and risks of cardiac catheterization in children with PHVD. This document contains the essentials of those discussions to provide a rationale for the hemodynamic assessment by cardiac catheterization of children with PHVD.</p

Adoption incentives and environmental policy timing under asymmetric information and strategic firm behaviour

We consider the incentives of a single firm to invest in a cleaner technology under emission quotas and emission taxation. We assume asymmetric information about the firm's cost of employing the new technology. Policy is set either before the firm invests (commitment) or after (time consistency). Contrary to conventional wisdom, we find that with commitment (time consistency), quotas give higher (lower) investment incentives than taxes. With quotas (taxes), commitment generally leads to higher (lower) welfare than time consistency. Under commitment with quadratic abatement costs and environmental damages, a modified Weitzman rule applies and quotas usually lead to higher welfare than taxes

A systematic analysis of splicing variants identifies new diagnoses in the 100,000 Genomes Project

Background Genomic variants which disrupt splicing are a major cause of rare genetic diseases. However, variants which lie outside of the canonical splice sites are difficult to interpret clinically. Improving the clinical interpretation of non-canonical splicing variants offers a major opportunity to uplift diagnostic yields from whole genome sequencing data. Methods Here, we examine the landscape of splicing variants in whole-genome sequencing data from 38,688 individuals in the 100,000 Genomes Project and assess the contribution of non-canonical splicing variants to rare genetic diseases. We use a variant-level constraint metric (the mutability-adjusted proportion of singletons) to identify constrained functional variant classes near exon–intron junctions and at putative splicing branchpoints. To identify new diagnoses for individuals with unsolved rare diseases in the 100,000 Genomes Project, we identified individuals with de novo single-nucleotide variants near exon–intron boundaries and at putative splicing branchpoints in known disease genes. We identified candidate diagnostic variants through manual phenotype matching and confirmed new molecular diagnoses through clinical variant interpretation and functional RNA studies. Results We show that near-splice positions and splicing branchpoints are highly constrained by purifying selection and harbour potentially damaging non-coding variants which are amenable to systematic analysis in sequencing data. From 258 de novo splicing variants in known rare disease genes, we identify 35 new likely diagnoses in probands with an unsolved rare disease. To date, we have confirmed a new diagnosis for six individuals, including four in whom RNA studies were performed. Conclusions Overall, we demonstrate the clinical value of examining non-canonical splicing variants in individuals with unsolved rare diseases