In a phase 2 trial, selexipag, an oral selective IP prostacyclin-receptor agonist, was shown to be beneficial in the treatment of pulmonary arterial hypertension.
In this event-driven, phase 3, ...randomized, double-blind, placebo-controlled trial, we randomly assigned 1156 patients with pulmonary arterial hypertension to receive placebo or selexipag in individualized doses (maximum dose, 1600 μg twice daily). Patients were eligible for enrollment if they were not receiving treatment for pulmonary arterial hypertension or if they were receiving a stable dose of an endothelin-receptor antagonist, a phosphodiesterase type 5 inhibitor, or both. The primary end point was a composite of death from any cause or a complication related to pulmonary arterial hypertension up to the end of the treatment period (defined for each patient as 7 days after the date of the last intake of selexipag or placebo).
A primary end-point event occurred in 397 patients--41.6% of those in the placebo group and 27.0% of those in the selexipag group (hazard ratio in the selexipag group as compared with the placebo group, 0.60; 99% confidence interval, 0.46 to 0.78; P<0.001). Disease progression and hospitalization accounted for 81.9% of the events. The effect of selexipag with respect to the primary end point was similar in the subgroup of patients who were not receiving treatment for the disease at baseline and in the subgroup of patients who were already receiving treatment at baseline (including those who were receiving a combination of two therapies). By the end of the study, 105 patients in the placebo group and 100 patients in the selexipag group had died from any cause. Overall, 7.1% of patients in the placebo group and 14.3% of patients in the selexipag group discontinued their assigned regimen prematurely because of adverse events. The most common adverse events in the selexipag group were consistent with the known side effects of prostacyclin, including headache, diarrhea, nausea, and jaw pain.
Among patients with pulmonary arterial hypertension, the risk of the primary composite end point of death or a complication related to pulmonary arterial hypertension was significantly lower with selexipag than with placebo. There was no significant difference in mortality between the two study groups. (Funded by Actelion Pharmaceuticals; GRIPHON ClinicalTrials.gov number, NCT01106014.).
The 4th World Symposium on Pulmonary Hypertension was the first international meeting to focus not only on pulmonary arterial hypertension (PAH) but also on the so-called non-PAH forms of pulmonary ...hypertension (PH). The term “non-PAH PH” summarizes those forms of PH that are found in groups 2 to 5 of the current classification of PH, that is, those forms associated with left heart disease, chronic lung disease, recurrent venous thromboembolism, and other diseases. Many of these forms of PH are much more common than PAH, but all of them have been less well studied, especially in terms of medical therapy. The working group on non-PAH PH focused mainly on 4 conditions: chronic obstructive lung disease, interstitial lung disease, chronic thromboembolic PH, and left heart disease. The medical literature regarding the role of PH in these diseases was reviewed, and recommendations regarding diagnosis and treatment of PH in these conditions are provided. Given the lack of robust clinical trials addressing PH in any of these conditions, it is important to conduct further studies to establish the role of medical therapy in non-PAH PH.
There is increasing evidence to suggest that complications of coronavirus disease 2019 (COVID-19) infection are not only limited to the pulmonary system but can also involve the central nervous ...system. Here, we report 6 critically ill patients with COVID-19 infection and neuroimaging findings of leukoencephalopathy. While these findings are nonspecific, we postulate that they may be a delayed response to the profound hypoxemia the patients experienced due to the infection. No abnormal enhancement, hemorrhage, or perfusion abnormalities were noted on MR imaging. In addition, Severe Acute Respiratory Syndrome coronavirus 2 was not detected in the CSF collected from the 2 patients who underwent lumbar puncture. Recognition of COVID-19-related leukoencephalopathy is important for appropriate clinical management, disposition, and prognosis.
The rapid technological developments of the past decade and the changes in echocardiographic practice brought about by these developments have resulted in the need for updated recommendations to the ...previously published guidelines for cardiac chamber quantification, which was the goal of the joint writing group assembled by the American Society of Echocardiography and the European Association of Cardiovascular Imaging. This document provides updated normal values for all four cardiac chambers, including three-dimensional echocardiography and myocardial deformation, when possible, on the basis of considerably larger numbers of normal subjects, compiled from multiple databases. In addition, this document attempts to eliminate several minor discrepancies that existed between previously published guidelines.
After many years of intense research, most aspects of the motion of entangled polymers have been understood. Long linear and branched polymers have a characteristic entanglement plateau and their ...stress relaxes by chain reptation or branch retraction, respectively. In both mechanisms, the presence of chain ends is essential. But how do entangled polymers without ends relax their stress? Using properly purified high-molar-mass ring polymers, we demonstrate that these materials exhibit self-similar dynamics, yielding a power-law stress relaxation. However, trace amounts of linear chains at a concentration almost two decades below their overlap cause an enhanced mechanical response. An entanglement plateau is recovered at higher concentrations of linear chains. These results constitute an important step towards solving an outstanding problem of polymer science and are useful for manipulating properties of materials ranging from DNA to polycarbonate. They also provide possible directions for tuning the rheology of entangled polymers.
Chronic thromboembolic pulmonary hypertension (CTEPH) is a late sequel of venous thromboembolism that cannot be completely reproduced in animal models. The prevalence of CTEPH in humans is estimated ...at roughly 17-20 per million; however, partly because up to 50% of patients with CTEPH never experience symptomatic pulmonary embolism, precise numbers on the incidence and prevalence are not known. Because CTEPH is diagnosed at a median age of 63 years in patients who often have other concomitant cardiovascular disease or lung disease, assessment of pathophysiology in patients can be challenging, We do know that CTEPH is a dual vascular disorder. Stenoses, webs, and occlusions predominate in large and medium-sized pulmonary arteries at the sites of previous pulmonary emboli. A "secondary vasculopathy" resembling the pulmonary arteriopathy encountered in other forms of pulmonary hypertension predominates in low-resistance vessels. Anastomoses between bronchial artery branches and precapillary pulmonary arterioles appear during evolution of the disease. Other acquired vascular connections between bronchial arteries and pulmonary veins may trigger venous remodeling. Current concepts regarding the pathophysiology of CTEPH include contributions of hyperactive coagulation (e.g., high coagulation factor VIII, combined coagulation defects, dysfibrinogenemias), insufficient anticoagulation, non-O blood groups, and misguided thrombus resolution (e.g., infection, inflammation, dysfunctional innate immunity, abnormal circulating phospholipids). Current research focuses on the question as to whether a genetic predisposition leads to misguided vascular healing after pulmonary thromboembolism in susceptible individuals.
Models for double parton distributions that are realistic and consistent with theoretical constraints are crucial for a reliable description of double parton scattering. We show how an ansatz that ...has the correct behaviour in the limit of small transverse distance between the partons can be improved step by step, such as to fulfil the sum rules for double parton distributions with an accuracy around 10%.
Risk assessment requires a description of the probabilistic properties of hydrological variables. In a number of cases, this description is made on a single variable, whereas most hydrological events ...are intrinsically multivariate. In this context, copulas have recently received attention in order to derive a multivariate frequency analysis. After a reminder of the general results in the field of multivariate extreme value theory, the paper gives a description of a very simple copula, the Gaussian copula. Four case studies demonstrate its usefulness in the contexts of field significance determination, regional risk analysis, discharge-duration-frequency (QdF) models with design hydrograph derivation and regional frequency analysis. The limitations and potential errors related to this statistical tool are also highlighted.
While the occurrence of rituals in anxiogenic contexts has been long noted and supported by ethnographic, quantitative and experimental studies, the purported effects of ritual behaviour on anxiety ...reduction have rarely been examined. In the present study, we investigate the anxiolytic effects of religious practices among the Marathi Hindu community in Mauritius and test whether these effects are facilitated by the degree of ritualization present in these practices. Seventy-five participants first experienced anxiety induction through the public speaking paradigm and were subsequently asked to either perform their habitual ritual in a local temple (ritual condition) or sit and relax (control condition). The results revealed that participants in the ritual condition reported lower perceived anxiety after the ritual treatment and displayed lower physiological anxiety, which was assessed as heart-rate variability. The degree of ritualization in the ritual condition showed suggestive albeit variable effects, and thus further investigation is needed. We conclude the paper with a discussion of various mechanisms that may facilitate the observed anxiolytic effects of ritual behaviour and should be investigated in the future. This article is part of the theme issue 'Ritual renaissance: new insights into the most human of behaviours'.
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