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, 0.56–0.97; P = 0.028). Key measures of disease status, including functional class, Borg dyspnea score, and N-terminal pro–brain natriuretic peptide, all favored oral treprostinil treatment at Week 24 and beyond. A noninvasive risk stratification analysis demonstrated that oral treprostinil–assigned participants had a substantially higher mortality risk at baseline but achieved a lower risk profile from Study Weeks 12–60. 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)

Investigation of the Geometry of Metal Tube Walls after Necking in Uniaxial Tension

Abstract: In order to characterize the deformation and true stress–strain relation of metal tubes, the geometry of tube walls after necking in uniaxial tension need to be determined. The paper investigated the necking process of metal tube. A large number of tensile tests and finite element analysis of 1Cr18Ni9Ti tubes with different sizes were conducted. It was found that the geometry of outer tube wall in the necking region can be described using a logistic regression model. The final geometry of the tube is determined by original tube diameter and wall thickness. The offset of tube walls are affected by two competing factors: volume constancy and necking. The offset distances of outer and inner walls are mainly affected by original wall thickness. The length of the necking zone is more influenced by original tube diameter. Tube elongation at fracture increases slightly as tube diameter gets larger, while the wall thickness has almost no impact on the elongation

Advanced plasticity modeling for ultra-low-cycle-fatigue simulation of steel pipe

Pipelines and piping components may be exposed to extreme loading conditions, for instance earthquakes and hurricanes. In such conditions, they undergo severe plastic strains, which may locally reach the fracture limits due to either monotonic loading or ultra-low cycle fatigue (ULCF). Aiming to investigate the failure process and strain evolution of pipes enduring ULCF, a lab-scale ULCF test on an X65 steel pipeline component is simulated with finite element models, and experimental data are used to validate various material modeling assumptions. The paper focuses on plastic material modeling and compares different models for plastic anisotropy in combination with various hardening models, including isotropic, linear kinematic and combined hardening models. Both isotropic and anisotropic assumptions for plastic yielding are considered. As pipes pose difficulty for the measurement of plastic properties in mechanical testing, we calibrate an anisotropic yield locus using advanced multi-scale simulation based on texture measurements. Moreover, the importance of the anisotropy gradient across thickness is studied in detail for this thick-walled pipeline steel. It is found that the usage of a combined hardening model is essential to accurately predict the number of the cycles until failure, as well as the strain evolution during the fatigue test. The advanced hardening modeling featuring kinematic hardening has a substantially higher impact on result accuracy compared to the yield locus assumption for the studied ULCF test. Cyclic tension-compression testing is conducted to calibrate the kinematic hardening models. Additionally, plastic anisotropy and its gradient across the thickness play a notable, yet secondary role. Based on this research, it is advised to focus on improvements in strain hardening characteristics in future developments of pipeline steel with enhanced earthquake resistance.status: publishe