Framework for Real-time collaboration on extensive Data Types using Strong Eventual Consistency

La collaboration en temps réel est un cas spécial de collaboration où les utilisateurs travaillent sur le même élément simultanément et sont au courant des modifications des autres utilisateurs en temps réel. Les données distribuées doivent rester disponibles et consistant tout en étant répartis sur plusieurs systèmes physiques. "Strong Consistency" est une approche qui crée un ordre total des opérations en utilisant des mécanismes tel que le "locking". Cependant, cela introduit un "bottleneck". Ces dix dernières années, les algorithmes de concurrence ont été étudiés dans le but de garder la convergence de tous les replicas sans utiliser de "locking" ni de synchronisation. "Operational Trans- formation" et "Conflict-free Replicated Data Types (CRDT)" sont utilisés dans ce but. Cependant, la complexité de ces stratégies les rend compliquées à intégrer dans des logicielles conséquents, comme les éditeurs de modèles, spécialement pour des data structures complexes comme les graphes. Les implémentations actuelles intègrent seulement des data linéaires tel que le texte. Dans ce mémoire, nous présentons CollabServer, un framework pour construire des environnements de collaboration. Il a une implémentation de CRDTs pour des data structures complexes tel que les graphes et donne la possibilité de construire ses propres data structures.Real-time collaboration is a special case of collaboration where users work on the same artefact simultaneously and are aware of each other’s changes in real-time. Shared data should remain available and consistent while dealing with its physically distributed aspect. Strong Consistency is one approach that enforces a total order of operations using mechanisms, such as locking. This however introduces a bottleneck. In the last decade, algorithms for concurrency control have been studied to keep convergence of all replicas without locking or synchronization. Operational Transformation and Conflict free Replicated Data Types (CRDT) are widely used to achieve this purpose. However, the complexity of these strategies makes it hard to integrate in large software, such as modeling editors, especially for complex data types like graphs. Current implementations only integrate linear data, such as text. In this thesis, we present CollabServer, a framework to build collaborative environments. It features a CRDTs implementation for complex data types such as graphs and gives possibility to build other data structures

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition

ϒ production in p–Pb collisions at √sNN=8.16 TeV

ϒ production in p–Pb interactions is studied at the centre-of-mass energy per nucleon–nucleon collision √sNN = 8.16 TeV with the ALICE detector at the CERN LHC. The measurement is performed reconstructing bottomonium resonances via their dimuon decay channel, in the centre-of-mass rapidity intervals 2.03 < ycms < 3.53 and −4.46 < ycms < −2.96, down to zero transverse momentum. In this work, results on the ϒ(1S) production cross section as a function of rapidity and transverse momentum are presented. The corresponding nuclear modification factor shows a suppression of the ϒ(1S) yields with respect to pp collisions, both at forward and backward rapidity. This suppression is stronger in the low transverse momentum region and shows no significant dependence on the centrality of the interactions. Furthermore, the ϒ(2S) nuclear modification factor is evaluated, suggesting a suppression similar to that of the ϒ(1S). A first measurement of the ϒ(3S) has also been performed. Finally, results are compared with previous ALICE measurements in p–Pb collisions at √sNN = 5.02 TeV and with theoretical calculations.publishedVersio

En búsqueda de la definición de dilatación aórtica en individuos con sobrepeso y obesidad: rol de la indexación por altura. Análisis del Registro MATEAR

Introducción: El tamaño corporal es un determinante significativo de las dimensiones aórticas. El sobrepeso lleva a subestimar la dilatación aórtica. La altura (A) permanece estable durante la adultez, por lo que sería útil para indexar diámetros aórticos en pacientes obesos, aunque desconocemos los valores normales. Comparamos la indexación de diámetros aórticos por (IA) y superficie corporal (SC) en sujetos con y sin sobrepeso para determinar el límite superior normal (LSN, P97.5). Método: Se realizó un registro nacional, prospectivo, en 53 centros de Argentina. Se realizaron ecocardiogramas a 528 sujetos con índice de masa corporal (IMC) > 25 y 351 sujetos con IMC ≤ 25 seleccionados al azar. La población se subdividió en cuatro grupos según sexo e IMC y se compararon diámetros aórticos absolutos e indexados. Resultados: Se incluyeron 879 individuos (39.7 ± 11.4 años, 399 hombres). La indexación de los diámetros aórticos por SC mostró valores significativamente más bajos en sujetos con sobrepeso y obesidad en comparación con los de peso normal en cada sexo. Estas diferencias desaparecieron al indexar por altura en ambos géneros (todos p = NS). El LSN de los diámetros IA fue de 2.20 cm/m para senos, 1.99 cm/m para unión sino-tubular (UST) y 2.09 cm/m para aorta ascendente. Conclusiones: La indexación de los diámetros aórticos por SC en individuos con sobrepeso y obesidad subestima la dilatación aórtica. El IA permite establecer un LSN sin tener en cuenta el aumento espurio de la SC determinado por la grasa corporal. Podría ser utilizado en ambos sexos y de manera independiente del peso

Mecanismos de la disfunción valvular en valvulopatía aórtica bicúspide. Primer estudio Argentino de marcadores pronósticos en una cohorte de pacientes con seguimiento clínico y ecocardiográfico

Background: The most common complication of the bicuspid aortic valve (BAV) is aortic valve dysfunction, but it is difficult to predictwhich patients will develop aortic stenosis (AS) or significant aortic regurgitation (AoR) (moderate/severe).Objectives: The aim of this work was to analyze the progression and the variables associated with the development of AS and significantAoR in adults with BAV.Methods: Consecutive patients with BAV were studied between 2009 and 2017. The progression of their aortic valve dysfunctionwas analyzed and in the group without baseline dysfunction, significant predictors of AoR and AS were identified through univariateand multivariate analysis.Results: Two hundred and forty-three patients (mean age 43±14.9 years, 73.2% men) were included in the study. The majority(n=194, 79.8%) with type I and raphe BAV (n=179, 73.6%). In the baseline echocardiogram, 111 patients presented mild (45.6%);49, moderate (20.1%); and 10, severe (4.1%) AoR. Baseline AS was less frequent: 20 subjects had moderate (8.2%) and 12, severe(4.9%) AS.Two patients died and 20 valve surgeries (8.2%) were performed in 4.7±1.7 follow-up years. Patients with significant baselinevalve dysfunction presented a higher rate of progression requiring valve surgery (p<0.0001). There were 39 new cases (17.2%) ofsignificant AoR or AS at follow-up. Aortic valve prolapse (p<0.001) and male sex (p<0.04) were associated with the development ofsignificant AoR (p<0.001). Baseline calcification score was associated with significant AS (p<0.02).Conclusions: A high proportion of patients with BAV and significant baseline aortic valve dysfunction required short-term surgery.Clinical and morphological characteristics associated with the development of significant aortic valve dysfunction were identified.Introducción: La complicación más frecuente de la válvula aórtica bicúspide (VAB) es la disfunción valvular aórtica, pero resultacomplejo predecir qué pacientes desarrollarán estenosis aórtica (EAO) o insuficiencia aórtica (IAO) significativa (moderada/grave).Objetivos: Este trabajo busca analizar la progresión y las variables asociadas con el desarrollo de EAO e IAO significativa en adultoscon VAB.Material y métodos: Se incluyeron pacientes consecutivos con VAB (2009-2017), se analizó la progresión de la disfunción valvularaórtica y en el grupo sin disfunción basal se identificaron variables predictoras de IAO y EAO significativas mediante análisis uni- ymultivariados.Resultados: Se incluyeron 243 pacientes (43±14,9 años, 73,2% hombres). La mayoría (n=194, 79,8%) con VAB tipo I y rafe (n=179;73,6%). En el ecocardiograma basal, 111 pacientes presentaban IAO leve (45,6%); 49, moderada (20,1%); y 10, grave (4,1%). La EAObasal fue menos frecuente: 20 sujetos tuvieron EAO moderada (8,2%) y 12, EAO grave (4,9%).Hubo 2 muertes y 20 cirugías valvulares (8,2%) en 4,7±1,7 años de seguimiento. Los pacientes con disfunción valvular significativabasal presentaron mayor tasa de progresión y requerimiento de cirugía valvular (p<0,0001). Hubo 39 nuevos casos (17,2%) de IAO oEAO significativas en el seguimiento. El prolapso valvular aórtico(p<0,001) y el sexo masculino (p<0,04) se asociaron al desarrollode IAO significativa (p<0,001). El score de calcificación basal se asoció con EAO significativa (p<0,02).Conclusiones: Los pacientes con VAB y disfunción valvular aórtica significativa basal requirieron cirugía en una elevada proporcióna corto plazo. Se identificaron características clínicas y morfológicas asociadas con el desarrollo de disfunción valvular aórtica significativa

Dimensiones aórticas en deportistasde elite. Grado de dilatación y formas de evaluación

Some authors suggest that aortic dilatation is part of the athlete’s heart. The recent guidelines recommendindexing aortic diameters by body surface area (BSA). This variable can be greater in athletes due to increased muscle mass,and indexing for this parameter might underestimate the measurements.Objective: The aim of this study was to compare aortic dimensions between elite rugby athletes and controls, evaluating differentmethods of quantification.Methods: Maximum aortic diameter (MAD) and maximum diameter indexed by BSA (MAD-BSA) were quantified by echocardiography.The expected ideal weight was calculated for each individual and MAD was indexed by the expected body surfacearea (eBSA). Aortic dilatation was defined as MAD >40 mm or MAD-BSA to MAD-eBSA ratio >21 mm/m2.Results: Maximum aortic diameter was greater in athletes (34.9±2.6 mm vs.32.4±2.9 mm; p 40 mm was similar in controls and athletes (2.3% vs. 1.7%, respectively; p=NS). Noneof the patients presented indexed diameters above the normal ranges.Conclusions: Elite rugby players present larger maximum aortic diameters in absolute values in the context of greater BSA.Due to increased muscle mass, indexing by BSA could underestimate the measurements. The MAD-eBSA ratio could be auseful parameter. Aortic diameters above reference values should be considered abnormal.Algunos autores sugieren que la dilatación aórtica forma parte del corazón de atleta. Las guías recientes proponenindexar los diámetros aórticos por superficie corporal (SC). En deportistas esta variable puede aumentar solo a expensas dela masa muscular y la indexación podría subestimar las dimensiones.El objetivo del estudio fue comparar los diámetros aórticos en jugadores de rugby de elite vs controles, evaluando distintasformas de cuantificación.Material y métodos: Se cuantificó mediante ecocardiografía el diámetro aórtico máximo (AoMax) y el diámetro máximo indexadoa SC (AoSC). Se calculó en forma adicional el peso ideal esperado para cada individuo y se estableció el diámetro aórtico indexadopor SC esperada (AoSCe). Se definió como dilatación un AoMax mayor que 40 mm o un AoSC/AoSCe mayor que 21 mm/m².Resultados: El AoMax fue mayor en deportistas (34,9 ± 2,6 vs 32,4 ± 2,9 mm; p < 0,01). Los atletas tuvieron una SC significativamentemayor y, en este contexto, presentaron menor AoSC (15,6 ± 1,2 vs 16,2 ± 1,6 mm/m2; p = 0,02).Al realizar el cálculo del peso ideal y comparar el AoSCe, no se observaron diferencias (16,6 ± 1,3 vs 16,3 ± 1,3 mm/m2; p = 0,2).El porcentaje de pacientes con AoMax mayor que 40 mm fue similar en controles y deportistas (2,3% y 1,7%; p = NS). Ningúnpaciente presentó diámetros indexados en rango patológico.Conclusiones: Los deportistas presentan mayores diámetros aórticos en términos absolutos, en contexto de una mayor SC.Debido al desarrollo muscular, la indexación por SC podría subestimar las dimensiones. El cálculo del AoSCe podría ser unparámetro útil. Las dimensiones aórticas en rango patológico deben ser consideradas anormales

Incidence of paradoxical reactions in patients treated with tocilizumab for rheumatoid arthritis: Data from the French registry REGATE

International audienc

Abatacept THERAPY AND SAFETY MANAGEMENT

International audienceObjectives: To elaborate a how-to-use abatacept material intended to help physicians in the management of patients with inflammatory diseases treated with this drug in routine practice. Methods: 1) Selection of the relevant domains by a rheumatologists' panel; 2) Search for published evidence in each domain; 3) Elaboration of the clinical tool guide with a 3-level gradation of evidence (evidence-based medicine EBM, official recommendations and expert's opinion). The experts were 11 academic rheumatologists with a large experience in prescribing abatacept and in managing rheumatoid arthritis. They were all members of the CRI (Club Rhumatismes et Inflammation), a section of the French Rheumatology Society dedicated to the inflammatory rheumatic diseases. Each fact sheet was reviewed by two other experts; 4) Regular updating based on medical literature and post-marketing surveillance data. Results: Four domains were considered relevant: abatacept contraindication s, management of side effects or associated diseases appearing during abatacept treatment, management of "practical situations" such as surgery or pregnancy, physician and patient information. After the literature analysis and discussion during an experts' meeting, a consensus was reached on: - a pre-treatment checklist aimed at searching abatacept contra indications; - a what-to-do document when facing side effects or associated diseases (autoimmune pathology, bacterial or viral infections, cardiovascular diseases, intolerance to abatacept, solid or haematological malignancy) or "practical situations" (surgery, pregnancy, vaccination, travel, drug-drug interactions); - an example of standard information letter to be addressed to the attending physician (rheumatologist and general practitioner); - an example of standard information letter to be addressed to the patient. Conclusion: Based on both an EBM approach and an expert's opinion approach, this abatacept clinical tool guide should provide assistance to all physicians attending patients treated with abatacept. For a better implementation in clinical practice, this tool guide will be available online at www.cri-net.com and regularly updated

IgG subclass distribution of the rheumatoid arthritis-specific autoantibodies to citrullinated fibrin

In the rheumatoid synovium, deiminated (‘citrullinated’) forms of fibrin are the major targets of IgG autoantibodies to citrullinated proteins (ACPA), the most specific serological markers of rheumatoid arthritis (RA). To further the characterization of ACPA, we determined their subclass distribution. From a previously validated highly sensitive and specific enzyme-linked immunosorbent assay (ELISA) onto in vitro deiminated human fibrinogen − antihuman fibrin(ogen) autoantibodies (AhFibA)-ELISA − we derived and calibrated four ELISAs, using monoclonal antibodies to each of the four IgG subclasses, to determine the proportions of AhFibA subclasses in the sera. A series of 186 serum samples from RA patients was analysed. All AhFibA-positive sera contained IgG1-AhFibA, which reached the highest titres and accounted for more than 80% of AhFibA in three-quarters of the sera. One or two other subclasses were associated with IgG1 in 39% of the sera, IgG4-AhFibA being observed much more frequently and at higher titres than IgG3- or IgG2-AhFibA. IgG1 alone or IgG(1 + 4)-AhFibA were the AhFibA subclass profiles found in more than 80% of patients. AhFibA are mainly IgG1 and, to a lesser extent, IgG4. Such IgG subclass profiles may influence the effector phases of the immunological conflict between ACPA and deiminated fibrin that takes place specifically in the rheumatoid synovium and therefore may play a critical role in the self-maintenance of rheumatoid inflammation

Tocilizumab therapy and safety management

International audienceObjectives: To develop fact sheets about tocilizumab, in order to assist physicians in the management of patients with inflammatory joint disease. Methods: 1. selection by a committee of rheumatology experts of the main topics of interest for which fact sheets were desirable; 2. identification and review of publications relevant to each topic; 3. development of fact sheets based on three levels of evidence: evidence-based medicine, official recommendations, and expert opinion. The 20 experts were rheumatologists and invited specialists in other fields, and they had extensive experience with the management of RA. They were members of the CRI (Club Rhumatismes et Inflammation), a section of the Societe Francaise de Rhumatologie. Each fact sheet was revised by several experts and the overall process was coordinated by three experts. Conclusion: These tocilizumab fact sheets built on evidence-based medicine and expert opinion will serve as a practical tool for assisting physicians who manage patients on tocilizumab therapy. They will be available continuously at www.cri-net.com and updated at appropriate intervals