The composition of Event-B models

The transition from classical B [2] to the Event-B language and method [3] has seen the removal of some forms of model structuring and composition, with the intention of reinventing them in future. This work contributes to thatreinvention. Inspired by a proposed method for state-based decomposition and refinement [5] of an Event-B model, we propose a familiar parallel event composition (over disjoint state variable lists), and the less familiar event fusion (over intersecting state variable lists). A brief motivation is provided for these and other forms of composition of models, in terms of feature-based modelling. We show that model consistency is preserved under such compositions. More significantly we show that model composition preserves refinement

Knee MR-arthrography in assessment of meniscal and chondral lesions

SummaryIntroductionNo study, so far in France, has investigated the diagnosis value of knee MR-arthrography since the recent approval of intra-articular gadolinium use, by this country's healthcare authorities. This study objective is to verify the MR-arthrography superiority on conventional knee MRI, in meniscus and cartilage knee lesions diagnosing accuracy both in regard to sensitivity and specificity.HypothesisMR-arthrography, represents in some pathologic situations, a more accurate source of information than conventional MRI.Materials and methodsOver a 27 months period, 25 patients, scheduled to undergo a knee arthroscopy volunteered, after having been fully informed of the possible interest and risk of the MR-arthrography examination, to participate in this study. Twenty-one of them were finally included since in four cases the surgical indication was not confirmed. The group consisted of 15 males and six females with an average age of 35.7 years. All of them consecutively underwent conventional MRI, MR-arthrography finally followed by arthroscopy. The MRI and MR-arthrograms results were compared to the arthroscopy findings using the nonparametric Kappa test.ResultsTo diagnose meniscal tears, statistical agreement measure for MRI with arthroscopy was good (K=0.69) but not as good as the MR-arthrography/arthroscopy agreement which, by itself was excellent (K=0.84). As a diagnosis tool, the sensitivity and specificity of MR-arthrography (respectively 100 and 89.6%) were much higher than the corresponding values observed in conventional MRI (92.3 and 82.8%, respectively) which nonetheless remain satisfactory.The meniscal tears characterization seemed to be better interpreted using MR-arthrography. As far as the chondral lesions in this series, they were predominantly located on the patellar surface and in the medial femorotibial compartment. For diagnosing the latter, the MRI/arthroscopy agreement was good (K=0.70) but not as good as the MR-arthrography/arthroscopy agreement (K=0.805) which can be rated excellent. The detection sensitivity thus increased by 10% with gadolinium intra-articular injection. However, assessment accuracy of the lesions depth was mediocre, with frequent errors for the intermediary stages.DiscussionIntra-articular gadolinium injection improved MRI performances for numerous reasons: filling the joint, reinforcing the synovial fluid signal, and enhancing anatomic structures contrast on the T1-weighted sequences images. In this study, MR-arthrography appeared to be superior to conventional MRI in meniscal and cartilaginous lesions diagnosis, confirming the results previously obtained in other countries. In light of these results and other data from the literature, MR-arthrography can be indicated as an alternative to CT-arthrography in various clinical situations: detection of recurrent tears on operated menisci, search for cartilaginous lesions or foreign bodies in the joint space, and preoperative assessment before chondral repair procedures. However, conventional MRI remains the reference examination for studying cartilage, because the low resolution of MR-arthrography limits its performances in quantitative assessment of lesions depth.Level of evidence: Level III. Non randomized comparative prospective study

Real-Time DSP-Free 100Gbit/s/λ PAM-4 Fiber Access Link using EML and Direct Detection

A 100 Gbit/s/ λ PAM-4 fiber link with an optical budget of 30 dB and 20 km fiber reach is achieved in real time experiments. This is compliant with class A (20 dB) point to point (PtP) applications as mobile fronthaul for example, and with class N1 (29 dB) point to multipoint (PtMP) for residential market. We used an integrated externally modulated laser, an analog pre-equalizer, an optical booster amplifier and/or non-filtered preamplifier and direct detection without any digital signal processing (whether real-time or offline)

Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility

Brugada syndrome (BrS) is a cardiac arrhythmia disorder associated with sudden death in young adults. With the exception of SCN5A, encoding the cardiac sodium channel NaV1.5, susceptibility genes remain largely unknown. Here we performed a genome-wide association meta-analysis comprising 2,820 unrelated cases with BrS and 10,001 controls, and identified 21 association signals at 12 loci (10 new). Single nucleotide polymorphism (SNP)-heritability estimates indicate a strong polygenic influence. Polygenic risk score analyses based on the 21 susceptibility variants demonstrate varying cumulative contribution of common risk alleles among different patient subgroups, as well as genetic associations with cardiac electrical traits and disorders in the general population. The predominance of cardiac transcription factor loci indicates that transcriptional regulation is a key feature of BrS pathogenesis. Furthermore, functional studies conducted on MAPRE2, encoding the microtubule plus-end binding protein EB2, point to microtubule-related trafficking effects on NaV1.5 expression as a new underlying molecular mechanism. Taken together, these findings broaden our understanding of the genetic architecture of BrS and provide new insights into its molecular underpinnings

Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility

Brugada syndrome (BrS) is a cardiac arrhythmia disorder associated with sudden death in young adults. With the exception of SCN5A, encoding the cardiac sodium channel NaV1.5, susceptibility genes remain largely unknown. Here we performed a genome-wide association meta-analysis comprising 2,820 unrelated cases with BrS and 10,001 controls, and identified 21 association signals at 12 loci (10 new). Single nucleotide polymorphism (SNP)-heritability estimates indicate a strong polygenic influence. Polygenic risk score analyses based on the 21 susceptibility variants demonstrate varying cumulative contribution of common risk alleles among different patient subgroups, as well as genetic associations with cardiac electrical traits and disorders in the general population. The predominance of cardiac transcription factor loci indicates that transcriptional regulation is a key feature of BrS pathogenesis. Furthermore, functional studies conducted on MAPRE2, encoding the microtubule plus-end binding protein EB2, point to microtubule-related trafficking effects on NaV1.5 expression as a new underlying molecular mechanism. Taken together, these findings broaden our understanding of the genetic architecture of BrS and provide new insights into its molecular underpinnings

Cardiac sodium channelopathies

Cardiac sodium channel are protein complexes that are expressed in the sarcolemma of cardiomyocytes to carry a large inward depolarizing current (INa) during phase 0 of the cardiac action potential. The importance of INa for normal cardiac electrical activity is reflected by the high incidence of arrhythmias in cardiac sodium channelopathies, i.e., arrhythmogenic diseases in patients with mutations in SCN5A, the gene responsible for the pore-forming ion-conducting α-subunit, or in genes that encode the ancillary β-subunits or regulatory proteins of the cardiac sodium channel. While clinical and genetic studies have laid the foundation for our understanding of cardiac sodium channelopathies by establishing links between arrhythmogenic diseases and mutations in genes that encode various subunits of the cardiac sodium channel, biophysical studies (particularly in heterologous expression systems and transgenic mouse models) have provided insights into the mechanisms by which INa dysfunction causes disease in such channelopathies. It is now recognized that mutations that increase INa delay cardiac repolarization, prolong action potential duration, and cause long QT syndrome, while mutations that reduce INa decrease cardiac excitability, reduce electrical conduction velocity, and induce Brugada syndrome, progressive cardiac conduction disease, sick sinus syndrome, or combinations thereof. Recently, mutation-induced INa dysfunction was also linked to dilated cardiomyopathy, atrial fibrillation, and sudden infant death syndrome. This review describes the structure and function of the cardiac sodium channel and its various subunits, summarizes major cardiac sodium channelopathies and the current knowledge concerning their genetic background and underlying molecular mechanisms, and discusses recent advances in the discovery of mutation-specific therapies in the management of these channelopathies

Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility.

Brugada syndrome (BrS) is a cardiac arrhythmia disorder associated with sudden death in young adults. With the exception of SCN5A, encoding the cardiac sodium channel Na1.5, susceptibility genes remain largely unknown. Here we performed a genome-wide association meta-analysis comprising 2,820 unrelated cases with BrS and 10,001 controls, and identified 21 association signals at 12 loci (10 new). Single nucleotide polymorphism (SNP)-heritability estimates indicate a strong polygenic influence. Polygenic risk score analyses based on the 21 susceptibility variants demonstrate varying cumulative contribution of common risk alleles among different patient subgroups, as well as genetic associations with cardiac electrical traits and disorders in the general population. The predominance of cardiac transcription factor loci indicates that transcriptional regulation is a key feature of BrS pathogenesis. Furthermore, functional studies conducted on MAPRE2, encoding the microtubule plus-end binding protein EB2, point to microtubule-related trafficking effects on Na1.5 expression as a new underlying molecular mechanism. Taken together, these findings broaden our understanding of the genetic architecture of BrS and provide new insights into its molecular underpinnings