Empty vein ablation (EVA) technique: an in-vivo animal model to assess the effects of sclerosing agent concentration and wall contact time on intima and media tunicae structure.

BACKGROUND: Sclerotherapy is a cornerstone of the treatment of chronic venous disease, despite some technical aspects (e.g., sclerosant liquid agent concentration [SLAC] and contact time between sclerosant agent and vein wall [ctSA/VW]) to maximize outcomes remain an unsolved problem and a source of debate. An innovative three-balloon catheter has been developed to allow sclerotherapy in empty vein conditions (Empty Vein Ablation technique, EVA), revolutionizing the definition of SLAC and ctSA/VW. Aim of this experimental study is to analyze EVA effects on intima and media vessel tunicae using different SLAC and ctSA/VW in an in-vivo animal model. METHODS: Two adult sheep were treated by EVA using jugular and common iliac vein axes (eight vein segments). Different SLAC (polidocanol 0.5% or 1%) and different ctSA/VW (3 or 5 minutes) were combined for testing residual circumferential intima percentage and media thickness after EVA. RESULTS: Intact circumferential residual intima after the treatment was 21.3±4.9%, 18.2±7.4%, 15.7±2.4% and 8.9±2.0% using 0.5% (3 min), 0.5% (5 min), 1% (3 min) and 1% (5 min), respectively (R2=0.945; control sample: 97.6%). Media thickness after the treatment was 121.6±35.3 µm, 110.9±7.8 µm, 96.1±30.4 µm and 79.1±34.1 µm using 0.5% (3 min), 0.5% (5 min), 1% (3 min) and 1% (5 min), respectively (R2=0.990; control sample 125.7 µm). No significant modifications were detected analyzing the adventitia in all samples. CONCLUSIONS: EVA proved to be effective in venous wall destruction even with a very low SLAC and ctSA/VW (0.5% in 3 minutes), in quite large caliber veins. Direct comparisons with foam/liquid sclerotherapy should be done to confirm therapeutic effectiveness of these results, despite EVA has provided a maximized and controlled SA/VW contact time and ratio.

Density Dependent Gauge Field Inducing Emergent Su-Schrieffer-Heeger Physics, Solitons, and Condensates in a Discrete Nonlinear Schrödinger Equation.

We investigate a discrete nonlinear Schrödinger equation with dynamical, density-difference-dependent gauge fields. We find a ground-state transition from a plane wave condensate to a localized soliton state as the gauge coupling is varied. Interestingly we find a regime in which the condensate and soliton are both stable. We identify an emergent chiral symmetry, which leads to the existence of a symmetry-protected zero-energy edge mode. The emergent chiral symmetry relates low and high energy solitons. These states indicate that the interaction acts both repulsively and attractively.

Dynamical self-trapping of two-dimensional binary solitons in cross-combined linear and nonlinear optical lattices.

Dynamical and self-trapping properties of two-dimensional (2D) binary mixtures of Bose-Einstein condensates in cross-combined lattices, consisting of a one-dimensional (1D) linear optical lattice (LOL) in the x direction for the first component and a 1D nonlinear optical lattice (NOL) in the y direction for the second component, are analytically and numerically investigated. The existence and stability of 2D binary matter wave solitons in these settings are demonstrated both by variational analysis and by direct numerical integration of the coupled Gross-Pitaevskii equations. We find that in the absence of the NOL, binary solitons, stabilized by the action of the 1D LOL and by the attractive intercomponent interaction, can freely move in the y direction. In the presence of the NOL, we find, quite remarkably, the existence of threshold curves in the parameter space separating regions where solitons can move from regions where the solitons become dynamically self-trapped. The mechanism underlying the dynamical self-trapping phenomenon (DSTP) is qualitatively understood in terms of a dynamical barrier induced by the NOL, similar to the Peirls-Nabarro barrier of solitons in discrete lattices. DSTP is numerically demonstrated for binary solitons that are put in motion both by phase imprinting and by the action of external potentials applied in the y direction. In the latter case, we show that the trapping action of the NOL allows one to maintain a 2D binary soliton at rest in a nonequilibrium position of a parabolic trap or to prevent it from falling under the action of gravity. Possible applications of the results are also briefly discussed.

Empty vein ablation innovative technique for chronic venous disease treatment: proof of concept and ex-vivo analysis.

BACKGROUND: Sclerotherapy is among the mainstays of chronic venous disease treatment, yet its occlusion rate remains suboptimal compared to thermal tumescent techniques. An innovative three-balloons catheter has been developed to allow sclerotherapy in empty vein conditions (empty vein ablation technique, EVA). Aim of this investigation was to describe the EVA technical aspects and related ex-vivo effects on vein wall. METHODS: Two samples from jugular veins of an adult sheep were treated by EVA or foam sclerotherapy (FS, Tessari method). Primary outcome was the percentage of circumferential intima treated by EVA or FS; secondary outcomes were intima and media thickness modifications after treatment. RESULTS: Intact circumferential residual intima were 6.07±2.94% and 16.55±0.70% after EVA and FS, respectively (P=0.020). Despite the average intima and media thickness did not differ between treatments, EVA demonstrated a homogenous damage throughout the vein segment, while FS effect was less destructive distally to the injection site, because moving away from the injection site and floating, it has a less contact with internal surface of the vein. CONCLUSIONS: EVA seems to overcome chemical ablation limits as flushing effect and the increases vein wall/sclerosant agent contact effect compared to FS. Ex-vivo encouraging results need in-vivo validation to evaluate other points like deactivation of sclerosing agent by blood protein and the contact time control between SA and the vein wall. If we have further confirmations in vivo we might think we have a potential higher occlusion rate compared to FS, paving the way for future clinical trials.

An innovative application of event structure analysis (ESA).

This paper presents an innovative application of event structure analysis (ESA). The key improvements incorporated on the method are: (i) a robust system for coding events; (ii) the use of causal process tracing tests for inferring necessary connections; (iii) the combination of ESA with network analyses. Finally, we propose five types of analysis for event network models (i.e., critical elements, critical associations, critical connections, critical specific happenings, and critical antecedents) and exemplify some of them in a causal case study about the process of capability construction for open innovation management in an Industrial Electronic Manufacturer.•ESA can be combined with process-tracing tests to ground counterfactual causal inferences.•ESA can be combined with network analysis to explore quantitative patterns in event structures.•ESA is an outstanding method to conduct process research in management and engineering.

FNS allows efficient event-driven spiking neural network simulations based on a neuron model supporting spike latency.

Neural modelling tools are increasingly employed to describe, explain, and predict the human brain's behavior. Among them, spiking neural networks (SNNs) make possible the simulation of neural activity at the level of single neurons, but their use is often threatened by the resources needed in terms of processing capabilities and memory. Emerging applications where a low energy burden is required (e.g. implanted neuroprostheses) motivate the exploration of new strategies able to capture the relevant principles of neuronal dynamics in reduced and efficient models. The recent Leaky Integrate-and-Fire with Latency (LIFL) spiking neuron model shows some realistic neuronal features and efficiency at the same time, a combination of characteristics that may result appealing for SNN-based brain modelling. In this paper we introduce FNS, the first LIFL-based SNN framework, which combines spiking/synaptic modelling with the event-driven approach, allowing us to define heterogeneous neuron groups and multi-scale connectivity, with delayed connections and plastic synapses. FNS allows multi-thread, precise simulations, integrating a novel parallelization strategy and a mechanism of periodic dumping. We evaluate the performance of FNS in terms of simulation time and used memory, and compare it with those obtained with neuronal models having a similar neurocomputational profile, implemented in NEST, showing that FNS performs better in both scenarios. FNS can be advantageously used to explore the interaction within and between populations of spiking neurons, even for long time-scales and with a limited hardware configuration.

The Interplay between Phase Separation and Gene-Enhancer Communication: A Theoretical Study.

The phase separation occurring in a system of mutually interacting proteins that can bind on specific sites of a chromatin fiber is investigated here. This is achieved by means of extensive molecular dynamics simulations of a simple polymer model that includes regulatory proteins as interacting spherical particles. Our interest is particularly focused on the role played by phase separation in the formation of molecule aggregates that can join distant regulatory elements, such as gene promoters and enhancers, along the DNA. We find that the overall equilibrium state of the system resulting from the mutual interplay between binding molecules and chromatin can lead, under suitable conditions that depend on molecules concentration, molecule-molecule, and molecule-DNA interactions, to the formation of phase-separated molecular clusters, allowing robust contacts between regulatory sites. Vice versa, the presence of regulatory sites can promote the phase-separation process. Different dynamical regimes can generate the enhancer-promoter contact, either by cluster nucleation at binding sites or by bulk spontaneous formation of the mediating cluster to which binding sites are successively attracted. The possibility that such processes can explain experimental live-cell imaging data measuring distances between regulatory sites during time is also discussed.

On the Turbulence Modeling of Blood Flow in a Stenotic Vessel.

Blood flow dynamics in a stenosed, subject-specific carotid bifurcation is numerically simulated using direct numerical simulation (DNS) and Reynolds-averaged Navier-Stokes (RANS) equations closed with turbulence models. DNS is meant to provide a term of comparison for the RANS calculations, which include classic two-equations models (k-ε and k-ω) as well as a transitional three-equations eddy-viscosity model (kT-kL-ω). Pulsatile inlet conditions based on in vivo ultrasound measurements of blood velocity are used. The blood is modeled as a Newtonian fluid, and the vessel walls are rigid. The main purpose of this work is to highlight the problems related to the use of classic RANS models in the numerical simulation of such flows. The time-averaged DNS results, interpreted in view of their finite-time averaging error, are used to demonstrate the superiority of the transitional RANS model, which is found to provide results closer to DNS than those of conventional models. The transitional model shows better predictive capabilities in terms of turbulence intensity, temporal evolution of the pressure along the cardiac cycle, and the oscillatory shear index (OSI). Indeed, DNS brings to light the locally transitional or weakly turbulent state of the blood flow, which presents velocity and pressure fluctuations only in the poststenotic region of the internal carotid artery during systole, while the flow is laminar during diastole.

Dissipative solitons in the discrete Ginzburg-Landau equation with saturable nonlinearity.

The modulational instability of nonlinear plane waves and the existence of periodic and localized dissipative solitons and waves of the discrete Ginzburg-Landau equation with saturable nonlinearity are investigated. Explicit analytic expressions for periodic solutions with a zero and a finite background are derived and their stability properties investigated by means of direct numerical simulations. We find that while discrete periodic waves and solitons on a zero background are stable under time evolution, they may become modulationally unstable on finite backgrounds. The effects of a linear ramp potential on stable localized dissipative solitons are also briefly discussed.

Patent portfolio management: literature review and a proposed model.

INTRODUCTION: Patents and patent portfolios are gaining attention in the last decades, from the called 'pro-patent era' to the recent billionaire transactions involving patent portfolios. The field is growing in importance, both theoretically and practically and despite having substantial literature on new product development portfolio management, we have not found an article relating this theory to patent portfolios. AREAS COVERED: The paper develops a systematic literature review on patent portfolio management to organize the evolution and tendencies of patent portfolio management, highlighting distinctive features of patent portfolio management. Interview with IP manager of three life sciences companies, including a leading multinational group provided relevant information about patent portfolio management. EXPERT OPINION: Based on the systematic literature review on portfolio management, more specifically, on new product development portfolio theory, and interview the paper proposes the paper proposes a reference model to manage patent portfolios. The model comprises four stages aligned with the three goals of the NPD portfolio management: 1 - Linking strategy of the Company's NPD Portfolio to Patent Portfolio; 2 - Balancing the portfolio in buckets; 3 - Patent Valuation (maximizing valuation); 4 - Regularly reviewing the patent portfolio.

Biofármacos no Brasil: características, importância e delineamento de políticas públicas para seu desenvolvimento

O texto discute possibilidades de políticas públicas para o desenvolvimento de biofármacos no Brasil, com ênfase em anticorpos monoclonais. Num primeiro momento, é feita a exposição dos conceitos básicos sobre biotecnologia, biofármacos e anticorpos monoclonais, de forma a sustentar o desenvolvimento posterior do trabalho. Em seguida, é focalizada a evolução da indústria farmacêutica mundial, com ênfase em biofármacos, sua cadeia de valor e principais desafios gerais da indústria. Após isso, discute-se o cenário brasileiro, enfatizando-se a estrutura da indústria, a demanda, principalmente do Sistema Único de Saúde (SUS), a regulação e os atores envolvidos na cadeia ou rede de valor. Finalizando o texto, faz-se uma reflexão sobre possibilidades e alternativas para o desenvolvimento de políticas públicas que ajudem a alavancar o desenvolvimento dessa relevante indústria.

Optimal transport and von Neumann entropy in a Heisenberg XXZ chain out of equilibrium.

In this paper we investigate the spin currents and the von Neumann entropy (vNE) of a Heisenberg XXZ chain in contact with twisted XY-boundary magnetic reservoirs by means of the Lindblad master equation. Exact solutions for the stationary reduced density matrix are explicitly constructed for chains of small sizes by using a quantum symmetry operation of the system. These solutions are then used to investigate the optimal transport in the chain in terms of the vNE. As a result we show that the maximal spin current always occurs in the proximity of minima of the vNE and for particular choices of parameters (coupling with reservoirs and anisotropy) it can exactly coincide with them. As the coupling is increased, current reversals may occur and in the limit of strong coupling we show that minima of the vNE tend to zero, meaning that the maximal transport is achieved in this case with states that are very close to pure states.

Behavior of magnetic currents in anisotropic Heisenberg spin chains out of equilibrium.

The behavior of the magnetic currents in one-dimensional Heisenberg XXZ spin chains kept out of equilibrium by boundary driving fields is investigated. In particular, the dependence of the spin currents on the anisotropy parameter Δ and on the boundary fields is studied both analytically and numerically in the framework of the Lindblad master equation formalism. We show that the spin current can be maximized with appropriate choices of the boundary fields, and for odd system sizes, N, we demonstrate the existence of additional symmetries that cause the current to be an odd function of Δ. From direct numerical integrations of the quantum master equation, we find that for an arbitrary N the current J(z)(N) vanishes for Δ=0, while for Δ negative it alternates its sign with the system size. In the gapless critical region |Δ|<1, the scaling of the current is shown to be J(z)(N)∼1/N while in the gapped region |Δ|>1 we find that J(z)(N)∼exp(-αN). A simple mean-field approach, which predicts rather well the values of J(z)(N) for the gapped region and the values of the absolute current maxima in the critical region, is developed. The existence of two different stationary solutions for the mean-field density matrix in the whole parameter range is also demonstrated.

Linear superpositions of gap solitons in periodic Kerr media.

The existence of a type of soliton in periodic Kerr media constructed as a superposition of noninteracting gap solitons of different kinds (bright, dark, and periodic) is first demonstrated. The periodic modulation of the nonlinearity is used to suppress the cross-phase modulation between component solitons to allow the superimposed beam to propagate for long distances.

Hierarchy of boundary-driven phase transitions in multispecies particle systems.

Interacting systems with K driven particle species on an open chain or chains that are coupled at the ends to boundary reservoirs with fixed particle densities are considered. We classify discontinuous and continuous phase transitions that are driven by adiabatic change of boundary conditions. We build minimal paths along which any given boundary-driven phase transition (BDPT) is observed and we reveal kinetic mechanisms governing these transitions. Combining minimal paths, we can drive the system from a stationary state with all positive characteristic speeds to a state with all negative characteristic speeds, by means of adiabatic changes of the boundary conditions. We show that along such composite paths, one generically encounters Z discontinuous and 2(K-Z) continuous BDPT's, with Z taking values 0≥Z≥K depending on the path. As model examples, we consider solvable exclusion processes with product measure states and K=1,2,3 particle species and a nonsolvable two-way traffic model. Our findings are confirmed by numerical integration of hydrodynamic limit equations and by Monte Carlo simulations. Results extend straightforwardly to a wide class of driven diffusive systems with several conserved particle species.

Reduced-density-matrix spectrum and block entropy of permutationally invariant many-body systems.

Spectral properties of the reduced density matrix (RDM) of permutational invariant quantum many-body systems are investigated. The RDM block diagonalization which accounts for all symmetries of the Hamiltonian is achieved. The analytical expression of the RDM spectrum is provided for arbitrary parameters and rigorously proved in the thermodynamical limit. The existence of several sum rules and recurrence relations among RDM eigenvalues is also demonstrated and the distribution function of RDM eigenvalues (including degeneracies) characterized. In particular, we prove that the distribution function approaches a two-dimensional Gaussian in the limit of large subsystem sizes n>>1. As a physical application we discuss the von Neumann entropy (VNE) of a block of size n for a system of hard-core bosons on a complete graph, as a function of n and of the temperature T. The occurrence of a crossover of VNE from purely logarithmic behavior at T=0 to a purely linear behavior in n for T≥Tc, is demonstrated.

[Prevention of sudden death in heart failure patients: cardiac resynchronization therapy with or without defibrillation back-up]. / Prevenzione della morte improvvisa nel paziente con insufficienza cardiaca: terapia di resincronizzazione cardiaca con o senza back-up di defibrillazione.

The prevalence and incidence of heart failure are progressively increasing in both Europe and the United States. Despite many advances in diagnosis and therapy, morbidity and mortality remain high and long-term prognosis is still poor in most heart failure patients. The use of implantable devices, cardiac resynchronization therapy and implantable cardioverter-defibrillators plays a pivotal role in the treatment of heart failure. Cardiac resynchronization therapy improves survival and reduces cardiac mortality due to either sudden or non-sudden death. In clinical practice, patients with an indication for cardiac resynchronization therapy should be carefully evaluated in view of a potential concomitant indication for defibrillator implantation. The combination of the two therapies may have maximal beneficial effects on prognosis.

Asymmetric simple exclusion process with periodic boundary driving.

We consider the asymmetric simple exclusion process (ASEP) on a semi-infinite chain which is coupled at the end to a reservoir with a particle density that changes periodically in time. It is shown that the density profile assumes a time-periodic sawtoothlike shape. This shape does not depend on initial conditions and is found analytically in the hydrodynamic limit. In a finite system, the stationary state is shown to be governed by effective boundary densities and the extremal flux principle. Effective boundary densities are determined numerically via Monte Carlo simulations and compared with those given by mean-field approach and numerical integration of the hydrodynamic limit equation which is the Burgers equation. Our results extend straightforwardly beyond the ASEP to a wide class of driven diffusive systems with one conserved particle species.

[Risk stratification for sudden cardiac death: from the electrophysiological study to T-wave alternans]. / Stratificazione del rischio di morte improvvisa: dallo studio elettrofisiologico all'alternanza dell'onda T.

T-wave alternans is a change, in the microvolt range, of T-wave amplitude on an ABABAB sequence. At present, various groups of patients have been evaluated, including those with myocardial infarction, congestive heart failure, implantable cardioverter-defibrillators and a clinical indication for programmed ventricular stimulation. In all clinical conditions analyzed, T-wave alternans analysis demonstrated a good diagnostic accuracy, suggesting a possible clinical use of the test in these settings.