Non-vitamin K antagonist oral anticoagulants in atrial fibrillation accompanying mitral stenosis: the concept for a trial.

Patients at thromboembolic risk with non-valvular atrial fibrillation (AF) can now be managed either with a vitamin K antagonist (VKA) or with a fixed dose of a non-VKA oral anticoagulant (NOAC), while patients with valvular AF have been restricted to VKAs on the basis of a potentially higher risk and different mechanism of thrombosis, and the lack of sufficient data on the efficacy of NOACs. The terms 'non-valvular AF' and 'valvular AF' have not been however consistently defined. 'Valvular' AF has included any valvular disorder, including valve replacement and repair. In AF with rheumatic mitral disease, observational studies strongly suggest that VKA treatment is valuable. These patients have not been included in NOAC trials, but there is also no stringent argument to have excluded them. This is at sharp variance from patients with mechanical valves, also excluded from the pivotal Phase III trial comparing warfarin with NOACs, but in whom a single Phase II trial of dabigatran etexilate against VKA treatment was stopped prematurely because of increased rates of thromboembolism as well as increased bleeding associated with dabigatran. Until more data are available, such patients should be therefore managed with VKAs. We here propose an open-label randomized trial of one of the NOACs against the best of treatment available in regions of the world in which rheumatic heart disease is still highly prevalent, aiming at showing the superiority of the NOAC used against current standard treatment

A matrix product algorithm for stochastic dynamics on networks, applied to non-equilibrium Glauber dynamics

We introduce and apply a novel efficient method for the precise simulation of stochastic dynamical processes on locally tree-like graphs. Networks with cycles are treated in the framework of the cavity method. Such models correspond, for example, to spin-glass systems, Boolean networks, neural networks, or other technological, biological, and social networks. Building upon ideas from quantum many-body theory, the new approach is based on a matrix product approximation of the so-called edge messages -- conditional probabilities of vertex variable trajectories. Computation costs and accuracy can be tuned by controlling the matrix dimensions of the matrix product edge messages (MPEM) in truncations. In contrast to Monte Carlo simulations, the algorithm has a better error scaling and works for both, single instances as well as the thermodynamic limit. We employ it to examine prototypical non-equilibrium Glauber dynamics in the kinetic Ising model. Because of the absence of cancellation effects, observables with small expectation values can be evaluated accurately, allowing for the study of decay processes and temporal correlations.Comment: 5 pages, 3 figures; minor improvements, published versio

The average number of distinct sites visited by a random walker on random graphs

We study the linear large $n$ behavior of the average number of distinct sites $S(n)$ visited by a random walker after $n$ steps on a large random graph. An expression for the graph topology dependent prefactor $B$ in $S(n) = Bn$ is proposed. We use generating function techniques to relate this prefactor to the graph adjacency matrix and then devise message-passing equations to calculate its value. Numerical simulations are performed to evaluate the agreement between the message passing predictions and random walk simulations on random graphs. Scaling with system size and average graph connectivity are also analysed.Comment: 22 pages, 4 figure

Rare events statistics of random walks on networks: localization and other dynamical phase transitions

Rare event statistics for random walks on complex networks are investigated using the large deviations formalism. Within this formalism, rare events are realized as typical events in a suitably deformed path-ensemble, and their statistics can be studied in terms of spectral properties of a deformed Markov transition matrix. We observe two different types of phase transition in such systems: (i) rare events which are singled out for sufficiently large values of the deformation parameter may correspond to {\em localized\/} modes of the deformed transition matrix, (ii) "mode-switching transitions" may occur as the deformation parameter is varied. Details depend on the nature of the observable for which the rare event statistics is studied, as well as on the underlying graph ensemble. In the present letter we report on the statistics of the average degree of the nodes visited along a random walk trajectory in Erd\H{o}s-R\'enyi networks. Large deviations rate functions and localization properties are studied numerically. For observables of the type considered here, we also derive an analytical approximation for the Legendre transform of the large-deviations rate function, which is valid in the large connectivity limit. It is found to agree well with simulations.Comment: 5 pages, 3 figure

Liver involvement in pediatric celiac disease

Celiac disease (CD) is an intestinal inflammatory disease that manifests in genetically susceptible individuals when exposed to dietary gluten. It is a common chronic disorder, with a prevalence of 1% in Europe and North America. Although the disease primarily affects the gut, the clinical spectrum of CD is remarkably varied, and the disease can affect many extraintestinal organs and systems, including the liver. The hepatic dysfunction presenting in CD ranges from asymptomatic liver enzyme elevations or nonspecific reactive hepatitis (cryptogenic liver disorders), to chronic liver disease. In this article, we review the clinical presentations and possible mechanisms of CD-related liver injury to identify strategies for the diagnosis and treatment of these disorders in childhood

Aspirin and the Primary Prevention of Cardiovascular Diseases. An Approach Based on Individualized, Integrated Estimation of Risk

While the use of aspirin in the secondary prevention of cardiovascular (CVD) is well established, aspirin in primary prevention is not systematically recommended because the absolute CV event reduction is similar to the absolute excess in major bleedings. Recently, emerging evidence suggests the possibility that the assumption of aspirin, may also be effective in the prevention of cancer. By adding to the CV prevention benefits the potential beneficial effect of aspirin in reducing the incidence of mortality and cancer could tip the balance between risks and benefits of aspirin therapy in the primary prevention in favour of the latter and broaden the indication for treatment with in populations at average risk. While prospective and randomized study are currently investigating the effect of aspirin in prevention of both cancer and CVD, clinical efforts at the individual level to promote the use of aspirin in global (or total) primary prevention could be already based on a balanced evaluation of the benefit/risk ratio

The edge-disjoint path problem on random graphs by message-passing

We present a message-passing algorithm to solve the edge disjoint path problem (EDP) on graphs incorporating under a unique framework both traffic optimization and path length minimization. The min-sum equations for this problem present an exponential computational cost in the number of paths. To overcome this obstacle we propose an efficient implementation by mapping the equations onto a weighted combinatorial matching problem over an auxiliary graph. We perform extensive numerical simulations on random graphs of various types to test the performance both in terms of path length minimization and maximization of the number of accommodated paths. In addition, we test the performance on benchmark instances on various graphs by comparison with state-of-the-art algorithms and results found in the literature. Our message-passing algorithm always outperforms the others in terms of the number of accommodated paths when considering non trivial instances (otherwise it gives the same trivial results). Remarkably, the largest improvement in performance with respect to the other methods employed is found in the case of benchmarks with meshes, where the validity hypothesis behind message-passing is expected to worsen. In these cases, even though the exact message-passing equations do not converge, by introducing a reinforcement parameter to force convergence towards a sub optimal solution, we were able to always outperform the other algorithms with a peak of 27% performance improvement in terms of accommodated paths. On random graphs, we numerically observe two separated regimes: one in which all paths can be accommodated and one in which this is not possible. We also investigate the behaviour of both the number of paths to be accommodated and their minimum total length.Comment: 14 pages, 8 figure

Clinical experience with apixaban in atrial fibrillation: implications of AVERROES

Raffaele De CaterinaInstitute of Cardiology and Center of Excellence on Aging, G d'Annunzio University, Chieti, G Monasterio Foundation, Pisa, ItalyAbstract: Atrial fibrillation is an extremely common arrhythmia, which substantially increases the risk of stroke and thromboembolism. Prevention of stroke and thromboembolism is therefore an important part of the management of atrial fibrillation. Guidelines until now have recommended that patients with atrial fibrillation receive some form of antithrombotic therapy, ie, a vitamin K antagonist or aspirin, with a preference for anticoagulants in most cases. However, current treatments are suboptimal, and despite the recommendations, many patients do not receive adequate thromboprophylaxis, because they are considered, for various reasons, "unsuitable" to receive a vitamin K antagonist. In this patient population, apixaban, a new oral anticoagulant inhibiting activated coagulation factor X, administered in fixed doses and without anticoagulation monitoring, has undergone testing against aspirin in the recently published AVERROES trial. This paper addresses the strengths and limitations of this trial and the practical relevance of the new clinical information it provides.Keywords: atrial fibrillation, apixaban, thromboprophylaxi