Rapid temperature increases under isoflurane sedation

(...)Letter, Intensive Care Medicine (2023

Manufacturing of W/steel composites using electro-discharge sintering process

Tungsten-steel metal matrix composites are consolidated using electro-discharge sintering. At first steel and tungsten powders are sintered separately and then 25 vol% W, 50 vol% W and 75 vol% W mixed powders are sintered. A thorough process parametric study is carried out involving analysis of the influence of particle size distribution, sintering pressure, and discharge energy on the maximum discharge current and obtained residual porosity. Thermal expansion coefficient and the specific heat capacity of the optimized sintered composites are almost same as their theoretical values, however the thermal conductivities and the mechanical properties are lower than the expected values

Microstructure, oxidation behaviour and thermal shock resistance of selfpassivating W-Cr-Y-Zr alloys

Self-passivating tungsten based alloys for the first wall armor of future fusion reactors are expected to provide an important safety advantage compare to pure tungsten in case of a loss-of-coolant accident with simultaneous air ingress, due to the formation of a stable protective scale at high temperatures in presence of oxygen preventing the formation of volatile and radioactive WO3. In this work, Zr is added to self-passivating W-10Cr-0.5Y alloy, manufactured by mechanical alloying and HIP, in view of improving its mechanical strength and thus, its thermal shock resistance. The as-HIPed W-10Cr-0.5Y-0.5Zr exhibits a nanocrystalline microstructure with the presence of an extremely fine nanoparticle dispersion. After heat treatment at 1555 °C for 1.5 h, the grain size growths from less than 100 nm to 620 nm and nanoparticles are present both at the grain boundaries and inside the grains. Oxidation tests at 1000 °C revealed that the alloy with Zr exhibits also a strong oxidation reduction compared to pure W. The long-term oxidation rate is similar to that of the alloy without Zr. Under thermal shock loading simulating 1000 ELM-like pulses at the divertor, the heat treated Zr-containing alloy did not present any damage

Riociguat treatment in patients with chronic thromboembolic pulmonary hypertension: Final safety data from the EXPERT registry

Objective: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) following Phase 3 randomized trials. The EXPosurE Registry RiociguaT in patients with pulmonary hypertension (EXPERT) study was designed to monitor the long-term safety of riociguat in clinical practice. Methods: EXPERT was an international, multicenter, prospective, uncontrolled, non-interventional cohort study of patients treated with riociguat. Patients were followed for at least 1 year and up to 4 years from enrollment or until 30 days after stopping riociguat treatment. Primary safety outcomes were adverse events (AEs) and serious adverse events (SAEs) coded using Medical Dictionary for Regulatory Activities preferred terms and System Organ Classes version 21.0, collected during routine clinic visits and collated via case report forms. Results: In total, 956 patients with CTEPH were included in the analysis. The most common AEs in these patients were peripheral edema/edema (11.7%), dizziness (7.5%), right ventricular (RV)/cardiac failure (7.7%), and pneumonia (5.0%). The most common SAEs were RV/cardiac failure (7.4%), pneumonia (4.1%), dyspnea (3.6%), and syncope (2.5%). Exposure-adjusted rates of hemoptysis/pulmonary hemorrhage and hypotension were low and comparable to those in the long-term extension study of riociguat (Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase-Stimulator Trial [CHEST-2]). Conclusion: Data from EXPERT show that in patients with CTEPH, the safety of riociguat in routine practice was consistent with the known safety profile of the drug, and no new safety concerns were identified

Riociguat treatment in patients with pulmonary arterial hypertension: Final safety data from the EXPERT registry

Objective: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension following Phase 3 randomized trials. The EXPosurE Registry RiociguaT in patients with pulmonary hypertension (EXPERT) study was designed to monitor the long-term safety of riociguat in clinical practice. Methods: EXPERT was an international, multicenter, prospective, uncontrolled, non-interventional cohort study of patients treated with riociguat. Patients were followed for at least 1 year and up to 4 years from enrollment or until 30 days after stopping riociguat treatment. Primary safety outcomes were adverse events (AEs) and serious adverse events (SAEs) coded using Medical Dictionary for Regulatory Activities preferred terms and System Organ Classes version 21.0, collected during routine clinic visits (usually every 3-6 months) and collated via case report forms. Results: In total, 326 patients with PAH were included in the analysis. The most common AEs in these patients were dizziness (11.7%), right ventricular (RV)/cardiac failure (10.7%), edema/peripheral edema (10.7%), diarrhea (8.6%), dyspnea (8.0%), and cough (7.7%). The most common SAEs were RV/cardiac failure (10.1%), pneumonia (6.1%), dyspnea (4.0%), and syncope (3.4%). The exposure-adjusted rate of hemoptysis/pulmonary hemorrhage was 2.5 events per 100 patient-years. Conclusion: Final data from EXPERT show that in patients with PAH, the safety of riociguat in clinical practice was consistent with clinical trials, with no new safety concerns identified and a lower exposure-adjusted rate of hemoptysis/pulmonary hemorrhage than in the long-term extension of the Phase 3 trial in PAH

Medical treatment of pulmonary hypertension in adults with congenital heart disease : updated and extended results from the International COMPERA-CHD Registry

Funding Information: The authors are indebted to the COMPERA investigators and their staff. We explicitly thank Dr. Claudia S. Copeland for the professional editing of the final draft of the manuscript. Funding: COMPERA is funded by unrestricted grants from Acceleron, Actelion Pharmaceuticals (Janssen), Bayer, OMT and GSK. These companies were not involved in data analysis or the writing of this manuscript. Funding Information: ICMJE uniform disclosure form (available at https:// dx.doi.org/10.21037/cdt-21-351). The series “Current Management Aspects in Adult Congenital Heart Disease (ACHD): Part IV” was commissioned by the editorial office without any funding or sponsorship. Dr. DH reports non-financial support from Actelion, Boehringer-Ingelheim, and Shire, outside the submitted work; Dr. DP reports personal fees from Actelion, Biogen, Aspen, Bayer, Boehringer Ingelheim, Daiichi Sankyo, and Sanofi, outside the submitted work; Dr. MD reports personal fees from Actelion, Bayer, GSK and MSD, outside the submitted work; Dr. HAG reports personal fees from Actelion, Bayer, Gilead, GSK, MSD, Pfizer and United Therapeutics, outside the submitted work; Dr. MG reports personal fees from Actelion, Bayer and GSK, outside the submitted work; Dr. MMH reports personal fees from Acceleron, Actelion, Bayer, MSD and Pfizer, outside the submitted work; Dr. CDV reports personal fees from Actelion, Bayer, GSK, MSD, Pfizer, and United Therapeutics, outside the submitted work; Dr. RE reports personal fees from Actelion, Boehringer Ingelheim, OMT, Bayer, and Berlin Chemie; grants from Actelion and Boehringer Ingelheim, outside the submitted work; Dr. MH reports grants and personal fees from Actelion, personal fees from Bayer, Berlin Chemie, Boehringer Ingelheim, GSK, Janssen, Novartis and MSD, outside the submitted work; Dr. MH reports personal fees from Acceleron, Actelion, AstraZeneca, Bayer, BERLIN CHEMIE, GSK, MSD, Novartis and OMT, outside the submitted work; Dr. HW reports personal fees from Action, Bayer, Biotest, Boehringer, GSK, Pfizer, and Roche, outside the submitted work; Dr. DS reports personal fees from Actelion, Bayer, and GSK, outside the submitted work; Dr. LS reports personal fees from Actelion, Bayer, and MSD, outside the submitted work; Dr. SU reports grants from Swiss National Science Foundation, Zurich Lung, Swiss Lung, and Orpha Swiss, grants and personal fees from Actelion SA/Johnson & Johnson, Switzerland, and MSD Switzerland, outside the submitted work; Dr. TJL reports personal fees from Actelion, Janssen-Cilag, BMS, MSD, and OMT GmbH, outside the submitted work; Dr. LB reports personal fees from Actelion, outside the submitted work; Dr. MC reports personal fees from Boehringer Ingelheim Pharma GmbH, Roche Pharma, and Boehringer Ingelheim, outside the submitted work; Dr. HW reports personal fees from Boehringer Ingelheim, and Roche, outside the submitted work. Dr. EG reports personal fees from Actelion, Janssen, Bayer, MSD, Bial, OrPha Swiss GmbH, OMT and Medscape, outside the submitted work; Dr. SR reports personal fees from Actelion, Bayer, GSK, Pfizer, Novartis, Gilead, MSD, and United Therapeutics, outside the submitted work. The authors have no other conflicts of interest to declare. Publisher Copyright: © Cardiovascular Diagnosis and Therapy. All rights reserved.Background: Pulmonary arterial hypertension (PAH) is common in congenital heart disease (CHD). Because clinical-trial data on PAH associated with CHD (PAH-CHD) remain limited, registry data on the long-term course are essential. This analysis aimed to update information from the COMPERA-CHD registry on management strategies based on real-world data. Methods: The prospective international pulmonary hypertension registry COMPERA has since 2007 enrolled more than 10,000 patients. COMPERA-CHD is a sub-registry for patients with PAH-CHD Results: A total of 769 patients with PAH-CHD from 62 specialized centers in 12 countries were included into COMPERA-CHD from January 2007 through September 2020. At the last follow-up in 09/2020, patients [mean age 45.3±16.8 years; 512 (66%) female] had either post-tricuspid shunts (n=359; 46.7%), pre-tricuspid shunts (n=249; 32.4%), complex CHD (n=132; 17.2%), congenital left heart or aortic valve or aortic disease (n=9; 1.3%), or miscellaneous CHD (n=20; 2.6%). The mean 6-minute walking distance was 369±121 m, and 28.2%, 56.0%, and 3.8% were in WHO functional class I/II, III or IV, respectively (12.0% unknown). Compared with the previously published COMPERA-CHD data, after 21 months of followup, the number of included PAH-CHD patients increased by 91 (13.4%). Within this group the number of Eisenmenger patients rose by 39 (16.3%), the number of “Non-Eisenmenger PAH” patients by 45 (26.9%). Currently, among the 674 patients from the PAH-CHD group with at least one follow-up, 450 (66.8%) received endothelin receptor antagonists (ERA), 416 (61.7%) PDE-5 inhibitors, 85 (12.6%) prostacyclin analogues, and 36 (5.3%) the sGC stimulator riociguat. While at first inclusion in the COMPERA-CHD registry, treatment was predominantly monotherapy (69.3%), this has shifted to favoring combination therapy in the current group (53%). For the first time, the nature, frequency, and treatment of significant comorbidities requiring supportive care and medication are described. Conclusions: Analyzing “real life data” from the international COMPERA-CHD registry, we present a comprehensive overview about current management modalities and treatment concepts in PAH-CHD. There was an trend towards more aggressive treatment strategies and combination therapies. In the future, particular attention must be directed to the “Non-Eisenmenger PAH” group and to patients with complex CHD, including Fontan patients.publishersversionPeer reviewe

Idiopathic pulmonary arterial hypertension phenotypes determined by cluster analysis from the COMPERA registry

Funding Information: Marius M. Hoeper has received fees for lectures and/or consultations from Acceleron, Actelion, Bayer, MSD, and Pfizer. Nicola Benjamin has received fees for lectures and/or consultations from Actelion. Ekkehard Grünig has received fees for lectures and/or consultations from Actelion, Bayer, GSK, MSD, United Therapeutics, and Pfizer. Karen M. Olsson has received fees for lectures and/or consultations from Actelion, Bayer, United Therapeutics, GSK, and Pfizer. C. Dario Vizza has received fees from Actelion, Bayer, GSK, MSD, Pfizer, and United Therapeutics Europe. Anton Vonk-Noordegraaf has received fees for lectures and/or consultation from Actelion, Bayer, GSK, and MSD. Oliver Distler has/had a consultancy relationship with and/or has received research funding from 4-D Science, Actelion, Active Biotec, Bayer, Biogen Idec, Boehringer Ingelheim Pharma, BMS, ChemoAb, EpiPharm, Ergonex, espeRare foundation, GSK, Genentech/Roche, Inventiva, Lilly, medac, MedImmune, Mitsubishi Tanabe, Pharmacyclics, Pfizer, Sanofi, Serodapharm, and Sinoxa in the area of potential treatments of scleroderma and its complications including pulmonary arterial hypertension. In addition, Prof Distler has a patent for mir-29 for the treatment of systemic sclerosis licensed. Christian Opitz has received fees from Actelion, Bayer, GSK, Pfizer, and Novartis. J. Simon R. Gibbs has received fees for lectures and/or consultations from Actelion, Bayer, Bellerophon, GSK, MSD, and Pfizer. Marion Delcroix has received fees from Actelion, Bayer, GSK, and MSD. H. Ardeschir Ghofrani has received fees from Actelion, Bayer, Gilead, GSK, MSD, Pfizer, and United Therapeutics. Doerte Huscher has received fees for lectures and consultations from Actelion. David Pittrow has received fees for consultations from Actelion, Biogen, Aspen, Bayer, Boehringer Ingelheim, Daiichi Sankyo, and Sanofi. Stephan Rosenkranz has received fees for lectures and/or consultations from Actelion, Bayer, GSK, Pfizer, Novartis, Gilead, MSD, and United Therapeutics. Martin Claussen reports honoraria for lectures from Boehringer Ingelheim Pharma GmbH and Roche Pharma and for serving on advisory boards from Boehringer Ingelheim, outside the submitted work. Heinrike Wilkens reports personal fees from Boehringer and Roche during the conduct of the study and personal fees from Bayer, Biotest, Actelion, GSK, and Pfizer outside the submitted work. Juergen Behr received grants from Boehringer Ingelheim and personal fees for consultation or lectures from Actelion, Bayer, Boehringer Ingelheim, and Roche. Hubert Wirtz reports personal fees from Boehringer Ingelheim and Roche outside the submitted work. Hening Gall reports personal fees from Actelion, AstraZeneca, Bayer, BMS, GSK, Janssen-Cilag, Lilly, MSD, Novartis, OMT, Pfizer, and United Therapeutics outside the submitted work. Elena Pfeuffer-Jovic reports personal fees from Actelion, Boehringer Ingelheim, Novartis, and OMT outside the submitted work. Laura Scelsi reports personal fees from Actelion, Bayer, and MSD outside the submitted work. Siliva Ulrich reports grants from Swiss National Science Foundation, Zurich Lung, Swiss Lung, and Orpha Swiss, and grants and personal fees from Actelion SA/Johnson & Johnson Switzerland and MSD Switzerland outside the submitted work. The remaining authors have no conflicts of interest to disclose. Funding Information: This work was supported by the German Centre of Lung Research (DZL). COMPERA is funded by unrestricted grants from Acceleron , Actelion Pharmaceuticals , Bayer , OMT , and GSK . These companies were not involved in data analysis or the writing of this manuscript. Publisher Copyright: © 2020 The Authors Copyright: Copyright 2020 Elsevier B.V., All rights reserved.The term idiopathic pulmonary arterial hypertension (IPAH) is used to categorize patients with pre-capillary pulmonary hypertension of unknown origin. There is considerable variability in the clinical presentation of these patients. Using data from the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension, we performed a cluster analysis of 841 patients with IPAH based on age, sex, diffusion capacity of the lung for carbon monoxide (DLCO; <45% vs ≥45% predicted), smoking status, and presence of comorbidities (obesity, hypertension, coronary heart disease, and diabetes mellitus). A hierarchical agglomerative clustering algorithm was performed using Ward's minimum variance method. The clusters were analyzed in terms of baseline characteristics; survival; and response to pulmonary arterial hypertension (PAH) therapy, expressed as changes from baseline to follow-up in functional class, 6-minute walking distance, cardiac biomarkers, and risk. Three clusters were identified: Cluster 1 (n = 106; 12.6%): median age 45 years, 76% females, no comorbidities, mostly never smokers, DLCO ≥45%; Cluster 2 (n = 301; 35.8%): median age 75 years, 98% females, frequent comorbidities, no smoking history, DLCO mostly ≥45%; and Cluster 3 (n = 434; 51.6%): median age 72 years, 72% males, frequent comorbidities, history of smoking, and low DLCO. Patients in Cluster 1 had a better response to PAH treatment than patients in the 2 other clusters. Survival over 5 years was 84.6% in Cluster 1, 59.2% in Cluster 2, and 42.2% in Cluster 3 (unadjusted p < 0.001 for comparison between all groups). The population of patients diagnosed with IPAH is heterogenous. This cluster analysis identified distinct phenotypes, which differed in clinical presentation, response to therapy, and survival.publishersversionPeer reviewe

Pulmonary Hypertension in Adults with Congenital Heart Disease: Real-World Data from the International COMPERA-CHD Registry

Introduction: Pulmonary hypertension (PH) is a common complication in patients with congenital heart disease (CHD), aggravating the natural, post-operative, or post-interventional course of the underlying anomaly. The various CHDs differ substantially in characteristics, functionality, and clinical outcomes among each other and compared with other diseases with pulmonary hypertension. Objective: To describe current management strategies and outcomes for adults with PH in relation to different types of CHD based on real-world data. Methods and results: COMPERA (Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension) is a prospective, international PH registry comprising, at the time of data analysis, >8200 patients with various forms of PH. Here, we analyzed a subgroup of 680 patients with PH due to CHD, who were included between 2007 and 2018 in 49 specialized centers for PH and/or CHD located in 11 European countries. At enrollment, the patients’ median age was 44 years (67% female), and patients had either pre-tricuspid shunts, post-tricuspid shunts, complex CHD, congenital left heart or aortic disease, or miscellaneous other types of CHD. Upon inclusion, targeted therapies for pulmonary arterial hypertension (PAH) included endothelin receptor antagonists, PDE-5 inhibitors, prostacyclin analogues, and soluble guanylate cyclase stimulators. Eighty patients with Eisenmenger syndrome were treatment-naïve. While at inclusion the primary PAH treatment for the cohort was monotherapy (70% of patients), with 30% of the patients on combination therapy, after a median observation time of 45.3 months, the number of patients on combination therapy had increased significantly, to 50%. The use of oral anticoagulants or antiplatelets was dependent on the underlying diagnosis or comorbidities. In the entire COMPERA-CHD cohort, after follow-up and receiving targeted PAH therapy (n = 511), 91 patients died over the course of a 5-year follow up. The 5-year Kaplan–Meier survival estimate for CHD associated PH was significantly better than that for idiopathic PAH (76% vs. 54%; p < 0.001). Within the CHD associated PH group, survival estimates differed particularly depending on the underlying diagnosis and treatment status. Conclusions: In COMPERA-CHD, the overall survival of patients with CHD associated PH was dependent on the underlying diagnosis and treatment status, but was significantly better as than that for idiopathic PAH. Nevertheless, overall survival of patients with PAH due to CHD was still markedly reduced compared with survival of patients with other types of CHD, despite an increasing number of patients on PAH-targeted combination therapy

Riociguat treatment in patients with pulmonary arterial hypertension: Final safety data from the EXPERT registry

ObjectiveThe soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension following Phase 3 randomized trials. The EXPosurE Registry RiociguaT in patients with pulmonary hypertension (EXPERT) study was designed to monitor the long-term safety of riociguat in clinical practice.MethodsEXPERT was an international, multicenter, prospective, uncontrolled, non-interventional cohort study of patients treated with riociguat. Patients were followed for at least 1 year and up to 4 years from enrollment or until 30 days after stopping riociguat treatment. Primary safety outcomes were adverse events (AEs) and serious adverse events (SAEs) coded using Medical Dictionary for Regulatory Activities preferred terms and System Organ Classes version 21.0, collected during routine clinic visits (usually every 3–6 months) and collated via case report forms.ResultsIn total, 326 patients with PAH were included in the analysis. The most common AEs in these patients were dizziness (11.7%), right ventricular (RV)/cardiac failure (10.7%), edema/peripheral edema (10.7%), diarrhea (8.6%), dyspnea (8.0%), and cough (7.7%). The most common SAEs were RV/cardiac failure (10.1%), pneumonia (6.1%), dyspnea (4.0%), and syncope (3.4%). The exposure-adjusted rate of hemoptysis/pulmonary hemorrhage was 2.5 events per 100 patient-years.ConclusionFinal data from EXPERT show that in patients with PAH, the safety of riociguat in clinical practice was consistent with clinical trials, with no new safety concerns identified and a lower exposure-adjusted rate of hemoptysis/pulmonary hemorrhage than in the long-term extension of the Phase 3 trial in PAH.</p