Towards a New Generation of Permissioned Blockchain Systems

With the release of Satoshi Nakamoto's Bitcoin system in 2008 a new decentralized computation paradigm, known as blockchain, was born. Bitcoin promised a trading network for virtual coins, publicly available for anyone to participate in but owned by nobody. Any participant could propose a transaction and a lottery mechanism decided in which order these transactions would be recorded in a ledger with an elegant mechanism to prevent double spending. The remarkable achievement of Nakamoto's protocol was that participants did not have to trust each other to behave correctly for it to work. As long as more than half of the network participants adhered to the correct code, the recorded transactions on the ledger would both be valid and immutable. Ethereum, as the next major blockchain to appear, improved on the initial idea by introducing smart contracts, which are decentralized Turing-complete stored procedures, thus making blockchain technology interesting for the enterprise setting. However, its intrinsically public data and prohibitive energy costs needed to be overcome. This gave rise to a new type of systems called permissioned blockchains. With these, access to the ledger is restricted and trust assumptions about malicious behaviour have been weakened, allowing more efficient consensus mechanisms to find a global order of transactions. One of the most popular representatives of this kind of blockchain is Hyperledger Fabric. While it is much faster and more energy efficient than permissionless blockchains, it has to compete with conventional distributed databases in the enterprise sector. This thesis aims to mitigate Fabric's three major shortcomings. First, compared to conventional database systems, it is still far too slow. This thesis shows how the performance can be increased by a factor of seven by redesigning the transaction processing pipeline and introducing more efficient data structures. Second, we present a novel solution to Fabric's intrinsic problem of a low throughput for workloads with transactions that access the same data. This is achieved by analyzing the dependencies of transactions and selectively re-executing transactions when a conflict is detected. Third, this thesis tackles the preservation of private data. Even though access to the blockchain as a whole can be restricted, in a setting where multiple enterprises collaborate this is not sufficient to protect sensitive proprietary data. Thus, this thesis introduces a new privacy-preserving blockchain protocol based on network sharding and targeted data dissemination. It also introduces an additional layer of abstraction for the creation of transactions and interaction with data on the blockchain. This allows developers to write applications without the need for low-level knowledge of the internal data structure of the blockchain system. In summary, this thesis addresses the shortcomings of the current generation of permission blockchain systems

TimeFabric: Trusted Time for Permissioned Blockchains

As the popularity of blockchains continues to rise, blockchain platforms must be enhanced to support new application needs. In this paper, we propose one such enhancement that is essential for financial applications and online marketplaces - support for time-based logic such as verifying deadlines or expiry dates and examining a time window of recent account activity. We present a lightweight solution to reach consensus on the current time without relying on external time oracles. Our solution assigns timestamps to blocks at transaction validation time and maintains a cache reflecting the effects of recent transactions. We implement a proof-of-concept prototype, called TimeFabric, in Hyperledger Fabric, a popular permissioned blockchain platform, and experimentally demonstrate high throughput and minimal overhead (approximately 3%) of maintaining trusted time. We also demonstrate a 2x performance improvement due to the cache, compared to reconstructing account histories from the ledger

Genetic testing and blood biomarkers in paediatric pulmonary hypertension. Expert consensus statement on the diagnosis and treatment of paediatric pulmonary hypertension. The European Paediatric Pulmonary Vascular Disease Network, endorsed by ISHLT and DGPK

Childhood-onset pulmonary arterial hypertension (PAH) is considered complex and multifactorial, with relatively poor estimates of the natural history of the disease. Strategies allowing earlier detection, establishment of disease aetiology together with more accurate and sensitive biomarkers could enable better estimates of prognosis and individualise therapeutic strategies. Evidence is accumulating that genetic defects play an important role in the pathogenesis of idiopathic and hereditary forms of PAH. Altogether nine genes have been reported so far to be associated with childhood onset PAH suggesting that comprehensive multigene diagnostics can be useful in the assessment. Identification of disease-causing mutations allows estimates of prognosis and forms the most effective way for risk stratification in the family. In addition to genetic determinants the analysis of blood biomarkers are increasingly used in clinical practice to evaluate disease severity and treatment responses. As in genetic diagnostics, a multiplex approach can be helpful, as a single biomarker for PAH is unlikely to meet all requirements. This consensus statement reviews the current evidence for the use of genetic diagnostics and use of blood biomarkers in the assessment of paediatric patients with PAH

Genetic testing and blood biomarkers in paediatric pulmonary hypertension. Expert consensus statement on the diagnosis and treatment of paediatric pulmonary hypertension. The European Paediatric Pulmonary Vascular Disease Network, endorsed by ISHLT and DGPK

Childhood-onset pulmonary arterial hypertension (PAH) is considered complex and multifactorial, with relatively poor estimates of the natural history of the disease. Strategies allowing earlier detection, establishment of disease aetiology together with more accurate and sensitive biomarkers could enable better estimates of prognosis and individualise therapeutic strategies. Evidence is accumulating that genetic defects play an important role in the pathogenesis of idiopathic and hereditary forms of PAH. Altogether nine genes have been reported so far to be associated with childhood onset PAH suggesting that comprehensive multigene diagnostics can be useful in the assessment. Identification of disease-causing mutations allows estimates of prognosis and forms the most effective way for risk stratification in the family. In addition to genetic determinants the analysis of blood biomarkers are increasingly used in clinical practice to evaluate disease severity and treatment responses. As in genetic diagnostics, a multiplex approach can be helpful, as a single biomarker for PAH is unlikely to meet all requirements. This consensus statement reviews the current evidence for the use of genetic diagnostics and use of blood biomarkers in the assessment of paediatric patients with PAH

Hemodynamic and genetic analysis in children with idiopathic, heritable, and congenital heart disease associated pulmonary arterial hypertension

Background: Aim of this prospective study was to compare clinical and genetic findings in children with idiopathic or heritable pulmonary arterial hypertension (I/HPAH) with children affected with congenital heart defects associated PAH (CHD-APAH). Methods: Prospectively included were 40 consecutive children with invasively diagnosed I/HPAH or CHD-APAH and 117 relatives. Assessment of family members, pedigree analysis and systematic screening for mutations in TGFß genes were performed. Results: Five mutations in the bone morphogenetic protein type II receptor (BMPR2) gene, 2 Activin A receptor type II-like kinase-1 (ACVRL1) mutations and one Endoglin (ENG) mutation were found in the 29 I/HPAH children. Two mutations in BMPR2 and one mutation in ACVRL1 and ENG, respectively, are described for the first time. In the 11 children with CHD-APAH one BMPR2 gene mutation and one Endoglin gene mutation were found. Clinical assessment of relatives revealed familial aggregation of the disease in 6 children with PAH (HPAH) and one CHD-APAH patient. Patients with mutations had a significantly lower PVR. Conclusion: Mutations in different TGFß genes occurred in 8/29 (27.6%) I/HPAH patients and in 2/11 (18.2%) CHD-APAH patients and may influence the clinical status of the disease. Therefore, genetic analysis in children with PAH, especially in those with I/HPAH, may be of clinical relevance and shows the complexity of the genetic background

Executive summary. Expert consensus statement on the diagnosis and treatment of paediatric pulmonary hypertension. The European Paediatric Pulmonary Vascular Disease Network, endorsed by ISHLT and DGPK

The European Paediatric Pulmonary Vascular Disease (PVD) Network is a registered, non-profit organisation that strives to define and develop effective, innovative diagnostic methods and treatment options in all forms of paediatric pulmonary hypertensive vascular disease, including specific forms such as pulmonary arterial hypertension (PAH)-congenital heart disease, pulmonary hypertension (PH) associated with bronchopulmonary dysplasia, persistent PH of the newborn, and related cardiac dysfunction. Methods The writing group members conducted searches of the PubMed/MEDLINE bibliographic database (1990-2015) and held five face-to-face meetings with votings. Clinical trials, guidelines, and reviews limited to paediatric data were searched using the terms 'pulmonary hypertension' and 5-10 other keywords, as outlined in the other nine articles of this special issue. Class of recommendation (COR) and level of evidence (LOE) were assigned based on European Society of Cardiology/American Heart Association definitions and on paediatric data only, or on adult studies that included >10% children. Results A total of 9 original consensus articles with graded recommendations (COR/LOE) were developed, and are summarised here. The topics included diagnosis/monitoring, genetics/biomarker, cardiac catheterisation, echocardiography, cardiac magnetic resonance/chest CT, associated forms of PH, intensive care unit/ventricular assist device/lung transplantation, and treatment of paediatric PAH. Conclusions The multipaper expert consensus statement of the European Paediatric PVD Network provides a specific, comprehensive, detailed but practical framework for the optimal clinical care of children with PH

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

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

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