A multidisciplinary approach to severe bronchopulmonary dysplasia is associated with resolution of pulmonary hypertension

ObjectiveTo describe our multidisciplinary bronchopulmonary dysplasia (BPD) consult team's systematic approach to BPD associated pulmonary hypertension (PH), to report our center outcomes, and to evaluate clinical associations with outcomes.Study designRetrospective cohort of 60 patients with BPD-PH who were referred to the Seattle Children's Hospital BPD team from 2018 to 2020. Patients with critical congenital heart disease were excluded. Demographics, comorbidities, treatments, closure of hemodynamically relevant intracardiac shunts, and clinical outcomes including time to BPD-PH resolution were reviewed.ResultsMedian gestational age of the 60 patients was 25 weeks (IQR: 24–26). 20% were small for gestational age (SGA), 65% were male, and 25% received a tracheostomy. With aggressive cardiopulmonary management including respiratory support optimization, patent ductus arteriosus (PDA) and atrial septal defect (ASD) closure (40% PDA, 5% ASD, 3% both), and limited use of pulmonary vasodilators (8%), all infants demonstrated resolution of PH during the follow-up period, including three (5%) who later died from non-BPD-PH morbidities. Neither SGA status nor the timing of PH diagnosis (<36 vs. ≥36 weeks PMA) impacted the time to BPD-PH resolution in our cohort [median 72 days (IQR 30.5–166.5)].ConclusionOur multidisciplinary, systematic approach to BPD-PH management was associated with complete resolution of PH with lower mortality despite less sildenafil use than reported in comparable cohorts. Unique features of our approach included aggressive PDA and ASD device closure and rare initiation of sildenafil only after lack of BPD-PH improvement with respiratory support optimization and diagnostic confirmation by cardiac catheterization

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

Search for 22^{22}Na in novae supported by a novel method for measuring femtosecond nuclear lifetimes

Classical novae are thermonuclear explosions in stellar binary systems, and important sources of $^{26}$Al and $^{22}$Na. While gamma rays from the decay of the former radioisotope have been observed throughout the Galaxy, $^{22}$Na remains untraceable. The half-life of $^{22}$Na (2.6 yr) would allow the observation of its 1.275 MeV gamma-ray line from a cosmic source. However, the prediction of such an observation requires good knowledge of the nuclear reactions involved in the production and destruction of this nucleus. The $^{22}$Na($p,\gamma$)$^{23}$Mg reaction remains the only source of large uncertainty about the amount of $^{22}$Na ejected. Its rate is dominated by a single resonance on the short-lived state at 7785.0(7) keV in $^{23}$Mg. In the present work, a combined analysis of particle-particle correlations and velocity-difference profiles is proposed to measure femtosecond nuclear lifetimes. The application of this novel method to the study of the $^{23}$Mg states, combining magnetic and highly-segmented tracking gamma-ray spectrometers, places strong limits on the amount of $^{22}$Na produced in novae, explains its non-observation to date in gamma rays (flux < 2.5x$10^{-4}$ ph/(cm$^2$s)), and constrains its detectability with future space-borne observatories.Comment: 18 pages, 3 figures, 1 tabl

Rare variant analysis of 4241 pulmonary arterial hypertension cases from an international consortium implicates FBLN2, PDGFD, and rare de novo variants in PAH

Abstract: Background: Pulmonary arterial hypertension (PAH) is a lethal vasculopathy characterized by pathogenic remodeling of pulmonary arterioles leading to increased pulmonary pressures, right ventricular hypertrophy, and heart failure. PAH can be associated with other diseases (APAH: connective tissue diseases, congenital heart disease, and others) but often the etiology is idiopathic (IPAH). Mutations in bone morphogenetic protein receptor 2 (BMPR2) are the cause of most heritable cases but the vast majority of other cases are genetically undefined. Methods: To identify new risk genes, we utilized an international consortium of 4241 PAH cases with exome or genome sequencing data from the National Biological Sample and Data Repository for PAH, Columbia University Irving Medical Center, and the UK NIHR BioResource – Rare Diseases Study. The strength of this combined cohort is a doubling of the number of IPAH cases compared to either national cohort alone. We identified protein-coding variants and performed rare variant association analyses in unrelated participants of European ancestry, including 1647 IPAH cases and 18,819 controls. We also analyzed de novo variants in 124 pediatric trios enriched for IPAH and APAH-CHD. Results: Seven genes with rare deleterious variants were associated with IPAH with false discovery rate smaller than 0.1: three known genes (BMPR2, GDF2, and TBX4), two recently identified candidate genes (SOX17, KDR), and two new candidate genes (fibulin 2, FBLN2; platelet-derived growth factor D, PDGFD). The new genes were identified based solely on rare deleterious missense variants, a variant type that could not be adequately assessed in either cohort alone. The candidate genes exhibit expression patterns in lung and heart similar to that of known PAH risk genes, and most variants occur in conserved protein domains. For pediatric PAH, predicted deleterious de novo variants exhibited a significant burden compared to the background mutation rate (2.45×, p = 2.5e−5). At least eight novel pediatric candidate genes carrying de novo variants have plausible roles in lung/heart development. Conclusions: Rare variant analysis of a large international consortium identified two new candidate genes—FBLN2 and PDGFD. The new genes have known functions in vasculogenesis and remodeling. Trio analysis predicted that ~ 15% of pediatric IPAH may be explained by de novo variants

Pulmonary Vein Stenosis Associated with Germline PIK3CA Mutation

Pulmonary vein stenosis is a rare and frequently lethal childhood disease. There are few known genetic associations, and the pathophysiology is not well known. Current treatments include surgery, interventional cardiac catheterization, and more recently, medications targeting cell proliferation, which are not uniformly effective. We present a patient with PVS and a PIK3CA mutation, who demonstrated a good response to the targeted inhibitor, alpelisib

Cardiopulmonary exercise function among patients undergoing transcatheter pulmonary valve implantation in the US Melody valve investigational trial.

OBJECTIVES: We assessed the hypothesis that there is an improvement in clinical and physiologic parameters of cardiopulmonary exercise testing (CPET) after implantation of a transcatheter pulmonary valve (TPV). BACKGROUND: Transcatheter pulmonary valve provides a new tool for treating conduit stenosis and regurgitation in patients with right ventricle (RV) to pulmonary artery conduit dysfunction. METHODS: Patients who underwent a TPV placement between January 2007 and January 2010 (N = 150) were investigated with a standardized CPET protocol before and at 6 months after TPV placement. Cardiopulmonary exercise testing was performed on a mechanically braked cycle ergometer with respiratory gas exchange analysis. RESULTS: Six months post TPV, small but statistically significant improvements were observed in the maximum workload (65.0% ± 18.8% to 68.3% ± 20.3% predicted, P &lt; .001) and the ratio of minute ventilation to CO(2) production at the anaerobic threshold (30.8 ± 4.7 to 29.1 ± 4.1, P &lt; .001). There was no significant change in peak oxygen consumption (VO(2)). Patients with pre-TPV hemodynamics consistent with RV dysfunction and patients with a lower pre-TPV peak VO(2) tended to have the greatest improvement in peak VO(2). The correlation between TPV-related improvements in peak VO(2) and baseline clinical variables were weak, however, and these variables could not be used to reliably identify patients likely to have improved peak VO(2) after TPV. CONCLUSION: In patients with RV to pulmonary artery conduit dysfunction, TPV is associated with modest improvement in exercise capacity and gas exchange efficiency during exercise

A possible nitrogen crisis for Archaean life due to reduced nitrogen fixation by lightning

4 pages, 2 figures.-- PMID: 11452304 [PubMed].Nitrogen is an essential element for life and is often the limiting nutrient for terrestrial ecosystems. As most nitrogen is locked in the kinetically stable form, N2, in the Earth's atmosphere, processes that can fix N2 into biologically available forms —such as nitrate and ammonia— control the supply of nitrogen for organisms. On the early Earth, nitrogen is thought to have been fixed abiotically, as nitric oxide formed during lightning discharge. The advent of biological nitrogen fixation suggests that at some point the demand for fixed nitrogen exceeded the supply from abiotic sources, but the timing and causes of the onset of biological nitrogen fixation remain unclear. Here we report an experimental simulation of nitrogen fixation by lightning over a range of Hadean (4.5–3.8 Gyr ago) and Archaean (3.8–2.5 Gyr ago) atmospheric compositions, from predominantly carbon dioxide to predominantly dinitrogen (but always without oxygen). We infer that, as atmospheric CO2 decreased over the Archaean period, the production of nitric oxide from lightning discharge decreased by two orders of magnitude until about 2.2 Gyr. After this time, the rise in oxygen (or methane) concentrations probably initiated other abiotic sources of nitrogen. Although the temporary reduction in nitric oxide production may have lasted for only 100 Myr or less, this was potentially long enough to cause an ecological crisis that triggered the development of biological nitrogen fixation.This work was supported by grants from the National Autonomous University of Mexico, the National Council of Science and Technology of Mexico and the NASA Astrobiology programme.Peer reviewe

The Genetic Architecture of Grain Yield and Related Traits in Zea maize L. Revealed by Comparing Intermated and Conventional Populations

Using advanced intermated populations has been proposed as a way to increase the accuracy of mapping experiments. An F3 population of 300 lines and an advanced intermated F3 population of 322 lines, both derived from the same parental maize inbred lines, were jointly evaluated for dry grain yield (DGY), grain moisture (GM), and silking date (SD). Genetic variance for dry grain yield was significantly lower in the intermated population compared to the F3 population. The confidence interval around a QTL was on average 2.31 times smaller in the intermated population compared to the F3 population. One controversy surrounding QTL mapping is whether QTL identified in fact represent single loci. This study identifies two distinct loci for dry grain yield in the intermated population in coupling phase, while the F3 identifies only a single locus. Surprisingly, fewer QTL were detected in the intermated population than the F3 (21 vs. 30) and <50% of the detected QTL were shared among the two populations. Cross-validation showed that selection bias was more important in the intermated population than in the F3 and that each detected QTL explained a lower percentage of the variance. This finding supports the hypothesis that QTL detected in conventional populations correspond mainly to clusters of linked QTL. The actual number of QTL involved in the genetic architecture of complex traits may be substantially larger, with effect sizes substantially smaller than in conventional populations