78 research outputs found
Studies on the influence on flexural wall deformations on the development of the flow boundary layer
Flexural wave-like deformations can be used to excite boundary layer waves which in turn lead to the onset of turbulence in the boundary layer. The investigations were performed with flow velocities between 5 m/s and 40 m/s. With four different flexural wave transmissions a frequency range from 0.2 kc/s to 1.5 kc/s and a phase velocity range from 3.5 m/s to 12 m/s was covered. The excitation of boundary layer waves becomes most effective if the phase velocity of the flexural wave coincides with the phase velocity region of unstable boundary layer waves
Combination therapy with oral treprostinil for pulmonary arterial hypertension. A double-blind placebo-controlled clinical trial
Rationale: Oral treprostinil improves exercise capacity in patients with pulmonary arterial hypertension (PAH), but the effect on clinical outcomes was unknown.
Objectives: To evaluate the effect of oral treprostinil compared with placebo on time to first adjudicated clinical worsening event in participants with PAH who recently began approved oral monotherapy.
Methods: In this event-driven, double-blind study, we randomly allocated 690 participants (1:1 ratio) with PAH to receive placebo or oral treprostinil extended-release tablets three times daily. Eligible participants were using approved oral monotherapy for over 30 days before randomization and had a 6-minute-walk distance 150 m or greater. The primary endpoint was the time to first adjudicated clinical worsening event: death; hospitalization due to worsening PAH; initiation of inhaled or parenteral prostacyclin therapy; disease progression; or unsatisfactory long-term clinical response.
Measurements and Main Results: Clinical worsening occurred in 26% of the oral treprostinil group compared with 36% of placebo participants (hazard ratio, 0.74; 95% confidence interval, 0.56â0.97; Pâ=â0.028). Key measures of disease status, including functional class, Borg dyspnea score, and N-terminal proâbrain natriuretic peptide, all favored oral treprostinil treatment at Week 24 and beyond. A noninvasive risk stratification analysis demonstrated that oral treprostinilâassigned participants had a substantially higher mortality risk at baseline but achieved a lower risk profile from Study Weeks 12â60. The most common adverse events in the oral treprostinil group were headache, diarrhea, flushing, nausea, and vomiting.
Conclusions: In participants with PAH, addition of oral treprostinil to approved oral monotherapy reduced the risk of clinical worsening.
Clinical trial registered with www.clinicaltrials.gov (NCT01560624)
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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 â 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 (2.45Ă, p = 2.5eâ5). 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 genesâFBLN2 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
Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis
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 11744 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 1·55â2·08], p=5·13Ă10â
Âčâ”) and a second locus in
HLA-DPA1 and HLA-DPB1 (collectively referred to as HLA-DPA1/DPB1 here; rs2856830, 1·56 [1·42â1·71],
p=7·65Ă10â
ÂČâ°) 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 [1·25â1·48],
p=1·69Ă10â
ÂčÂČ; 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 [6·02â8·05]), 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 SOX17. Further studies are needed
to confirm the association between HLA typing or rs2856830 genotyping and survival, and to determine whether HLA
typing or rs2856830 genotyping improves risk stratification in clinical practice or trials.
Funding UK NIHR, BHF, UK MRC, Dinosaur Trust, NIH/NHLBI, ERS, EMBO, Wellcome Trust, EU, AHA,
ACClinPharm, Netherlands CVRI, Dutch Heart Foundation, Dutch Federation of UMC, Netherlands OHRD and
RNAS, German DFG, German BMBF, APH Paris, INSERM, Université Paris-Sud, and French ANR
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