Kruskal's Tree Theorem for Acyclic Term Graphs

In this paper we study termination of term graph rewriting, where we restrict our attention to acyclic term graphs. Motivated by earlier work by Plump we aim at a definition of the notion of simplification order for acyclic term graphs. For this we adapt the homeomorphic embedding relation to term graphs. In contrast to earlier extensions, our notion is inspired by morphisms. Based on this, we establish a variant of Kruskal's Tree Theorem formulated for acyclic term graphs. In proof, we rely on the new notion of embedding and follow Nash-Williams' minimal bad sequence argument. Finally, we propose a variant of the lexicographic path order for acyclic term graphs.Comment: In Proceedings TERMGRAPH 2016, arXiv:1609.0301

Cost Reduction With Guarantees: Formal Reasoning Applied To Blockchain Technologies

Blockchain technologies are moving fast and their distributed nature as well as their high-stake (financial) applications make it crucial to “get things right”. Moreover, blockchain technologies often come with a high cost for maintaining blockchain infrastructure and for running applications. In this thesis formal reasoning is used for guaranteeing correctness while reducing the cost of (i) maintaining the infrastructure by optimising blockchain protocols, and (ii) running applications by optimising blockchain programs—so called smart contracts. Both have a clear cost measure: for protocols the amount of exchanged messages, and for smart contracts the monetary cost of execution. In the first result for blockchain protocols starting from a proof of correctness for an abstract blockchain consensus protocol using infinitely many messages and infinite state, a refinement proof transfers correctness to a concrete implementation of the protocol reducing the cost to finite resources. In the second result I move from a blockchain to a block graph. This block graph embeds the run of a deterministic byzantine fault tolerant protocol, thereby getting parallelism “for free” and reducing the exchanged messages to the point of omission. For blockchain programs, I optimise programs executed on the Ethereum blockchain. As a first result, I use superoptimisation and encode the search for cheaper, but observationally equivalent, program as a search problem for an automated theorem prover. Since solving this search problem is in itself expensive, my second result is an efficient encoding of the search problem. Finally for reusing found optimisations, my third results gives a framework to generate peephole optimisation rules for a smart contract compiler

Populating the Peephole Optimizer of a Smart Contract Compiler

Developing compiler optimizations, especially for new, rapidly evolving smart contract languages, can be onerous and error-prone, but is especially important for smart contracts, where deployment and execution directly translate to monetary cost and which cannot change once deployed. One common optimization technique is the use of peephole optimizations, replacement rules that are applied using pattern-matching. These rules are normally constructed using human expertise, which is both time-consuming and far from systematic in exploring opportunities for optimization. In this work we propose a pipeline to automatically populate the peephole optimizer of a smart contract compiler. We apply superoptimization to an existing code base to obtain sequences of instructions, which can be replaced by cheaper, observationally equivalent instructions. We then generate peephole optimization rules by extracting the underlying patterns of these optimizations. We provide a case study of our approach and a prototype implementation for bytecode of the Ethereum Virtual Machine, the tool ppltr, which combines the superoptimizer ebso and the rule generator sorg. Then we evaluate our approach by generating and applying nearly 1k peephole optimization rules extracted from 2k optimizations obtained from deployed bytecode

Genome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare inflammatory disease of unknown cause. 30% of patients have anti-neutrophil cytoplasmic antibodies (ANCA) specific for myeloperoxidase (MPO). Here, we describe a genome-wide association study in 676 EGPA cases and 6809 controls, that identifies 4 EGPA-associated loci through conventional case-control analysis, and 4 additional associations through a conditional false discovery rate approach. Many variants are also associated with asthma and six are associated with eosinophil count in the general population. Through Mendelian randomisation, we show that a primary tendency to eosinophilia contributes to EGPA susceptibility. Stratification by ANCA reveals that EGPA comprises two genetically and clinically distinct syndromes. MPO+\u2009ANCA EGPA is an eosinophilic autoimmune disease sharing certain clinical features and an HLA-DQ association with MPO+\u2009ANCA-associated vasculitis, while ANCA-negative EGPA may instead have a mucosal/barrier dysfunction origin. Four candidate genes are targets of therapies in development, supporting their exploration in EGPA

Genome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare inflammatory disease of unknown cause. 30% of patients have anti-neutrophil cytoplasmic antibodies (ANCA) specific for myeloperoxidase (MPO). Here, we describe a genome-wide association study in 676 EGPA cases and 6809 controls, that identifies 4 EGPA-associated loci through conventional case-control analysis, and 4 additional associations through a conditional false discovery rate approach. Many variants are also associated with asthma and six are associated with eosinophil count in the general population. Through Mendelian randomisation, we show that a primary tendency to eosinophilia contributes to EGPA susceptibility. Stratification by ANCA reveals that EGPA comprises two genetically and clinically distinct syndromes. MPO+ ANCA EGPA is an eosinophilic autoimmune disease sharing certain clinical features and an HLA-DQ association with MPO+ ANCA-associated vasculitis, while ANCA-negative EGPA may instead have a mucosal/barrier dysfunction origin. Four candidate genes are targets of therapies in development, supporting their exploration in EGPA

Progressive skin fibrosis is associated with a decline in lung function and worse survival in patients with diffuse cutaneous systemic sclerosis in the European Scleroderma Trials and Research (EUSTAR) cohort.

Objectives To determine whether progressive skin fibrosis is associated with visceral organ progression and mortality during follow-up in patients with diffuse cutaneous systemic sclerosis (dcSSc). Methods We evaluated patients from the European Scleroderma Trials and Research database with dcSSc, baseline modified Rodnan skin score (mRSS) ≥7, valid mRSS at 12±3 months after baseline and ≥1 annual follow-up visit. Progressive skin fibrosis was defined as an increase in mRSS >5 and ≥25% from baseline to 12±3 months. Outcomes were pulmonary, cardiovascular and renal progression, and all-cause death. Associations between skin progression and outcomes were evaluated by Kaplan-Meier survival analysis and multivariable Cox regression. Results Of 1021 included patients, 78 (7.6%) had progressive skin fibrosis (skin progressors). Median follow-up was 3.4 years. Survival analyses indicated that skin progressors had a significantly higher probability of FVC decline ≥10% (53.6% vs 34.4%; p<0.001) and all-cause death (15.4% vs 7.3%; p=0.003) than non-progressors. These significant associations were also found in subgroup analyses of patients with either low baseline mRSS (≤22/51) or short disease duration (≤15 months). In multivariable analyses, skin progression within 1 year was independently associated with FVC decline ≥10% (HR 1.79, 95% CI 1.20 to 2.65) and all-cause death (HR 2.58, 95% CI 1.31 to 5.09). Conclusions Progressive skin fibrosis within 1 year is associated with decline in lung function and worse survival in dcSSc during follow-up. These results confirm mRSS as a surrogate marker in dcSSc, which will be helpful for cohort enrichment in future trials and risk stratification in clinical practice

Influence of Antisynthetase Antibodies Specificities on Antisynthetase Syndrome Clinical Spectrum TimeCourse

Introduction: Increased cardiovascular (CV) morbidity and mortality is observed in inflammatory joint diseases (IJDs) such as rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis. However, the management of CV disease in these conditions is far from being well established.Areas covered: This review summarizes the main epidemiologic, pathophysiological, and clinical risk factors of CV disease associated with IJDs. Less common aspects on early diagnosis and risk stratification of the CV disease in these conditions are also discussed. In Europe, the most commonly used risk algorithm in patients with IJDs is the modified SCORE index based on the revised recommendations proposed by the EULAR task force in 2017.Expert opinion: Early identification of IJD patients at high risk of CV disease is essential. It should include the use of complementary noninvasive imaging techniques. A multidisciplinary approach aimed to improve heart-healthy habits, including strict control of classic CV risk factors is crucial. Adequate management of the underlying IJD is also of main importance since the reduction of disease activity decreases the risk of CV events. Non-steroidal anti-inflammatory drugs may have a lesser harmful effect in IJD than in the general population, due to their anti-inflammatory effects along with other potential beneficial effects.This research was partially funded by FOREUM—Foundation for Research in Rheumatolog