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The overexpression of the ecotropic viral integration site-1 gene (EVI1/MECOM) marks the most lethal acute myeloid leukemia (AML) subgroup carrying chromosome 3q26 abnormalities. By taking advantage of the intersectionality of high-throughput cell-based and gene expression screens selective and pan-histone deacetylase inhibitors (HDACis) emerge as potent repressors of EVI1. To understand the mechanism driving on-target anti-leukemia activity of this compound class, here we dissect the expression dynamics of the bone marrow leukemia cells of patients treated with HDACi and reconstitute the EVI1 chromatin-associated co-transcriptional complex merging on the role of proliferation-associated 2G4 (PA2G4) protein. PA2G4 overexpression rescues AML cells from the inhibitory effects of HDACis, while genetic and small molecule inhibition of PA2G4 abrogates EVI1 in 3q26 AML cells, including in patient-derived leukemia xenografts. This study positions PA2G4 at the crosstalk of the EVI1 leukemogenic signal for developing new therapeutics and urges the use of HDACis-based combination therapies in patients with 3q26 AML.

Although the two-layer quasi-geostrophic equations (2QGE) are a simplified model for the dynamics of a stratified, wind-driven ocean, their numerical simulation is still plagued by the need for high resolution to capture the full spectrum of turbulent scales. Since such high resolution would lead to unreasonable computational times, it is typical to resort to coarse low-resolution meshes combined with the so-called eddy viscosity parameterization to account for the diffusion mechanisms that are not captured due to mesh under-resolution. We propose to enable the use of further coarsened meshes by adding a (linear or nonlinear) differential low-pass to the 2QGE, without changing the eddy viscosity coefficient. While the linear filter introduces constant (additional) artificial viscosity everywhere in the domain, the nonlinear filter relies on an indicator function to determine where and how much artificial viscosity is needed. Through several numerical results for a double-gyre wind forcing benchmark, we show that with the nonlinear filter we obtain accurate results with very coarse meshes, thereby drastically reducing the computational time (speed up ranging from 30 to 300)., Comment: 34 pages, 13 figures

We develop, and implement in a Finite Volume environment, a density-based approach for the Euler equations written in conservative form using density, momentum, and total energy as variables. Under simplifying assumptions, these equations are used to describe non-hydrostatic atmospheric flow. The well-balancing of the approach is ensured by a local hydrostatic reconstruction updated in runtime during the simulation to keep the numerical error under control. To approximate the solution of the Riemann problem, we consider four methods: Roe-Pike, HLLC, AUSM+-up and HLLC-AUSM. We assess our density-based approach and compare the accuracy of these four approximated Riemann solvers using two two classical benchmarks, namely the smooth rising thermal bubble and the density current., Comment: 22 pages

We present a comparative computational study of two stabilized Reduced Order Models (ROMs) for the simulation of convection-dominated incompressible flow (Reynolds number of the order of a few thousands). Representative solutions in the parameter space, which includes either time only or time and Reynolds number, are computed with a Finite Volume method and used to generate a reduced basis via Proper Orthogonal Decomposition (POD). Galerkin projection of the Navier-Stokes equations onto the reduced space is used to compute the ROM solution. To ensure computational efficiency, the number of POD modes is truncated and ROM solution accuracy is recovered through two stabilization methods: i) adding a global constant artificial viscosity to the reduced dimensional model, and ii) adding a different value of artificial viscosity for the different POD modes. We test the stabilized ROMs for fluid flow in an idealized medical device consisting of a conical convergent, a narrow throat, and a sudden expansion. Both stabilization methods significantly improve the ROM solution accuracy over a standard (non-stabilized) POD-Galerkin model.

The paper studies a scalar auxiliary variable (SAV) method to solve the Cahn-Hilliard equation with degenerate mobility posed on a smooth closed surface {\Gamma}. The SAV formulation is combined with adaptive time stepping and a geometrically unfitted trace finite element method (TraceFEM), which embeds {\Gamma} in R3. The stability is proven to hold in an appropriate sense for both first- and second-order in time variants of the method. The performance of our SAV method is illustrated through a series of numerical experiments, which include systematic comparison with a stabilized semi-explicit method., Comment: 23 pages, 12 figures

We present a filter stabilization technique for the mildly compressible Euler equations that relies on a linear or nonlinear indicator function to identify the regions of the domain where artificial viscosity is needed and determine its amount. For the realization of this technique, we adopt a three step algorithm called Evolve-Filter-Relax (EFR), which at every time step evolves the solution (i.e., solves the Euler equations on a coarse mesh), then filters the computed solution, and finally performs a relaxation step to combine the filtered and non-filtered solutions. We show that the EFR algorithm is equivalent to an eddy-viscosity model in Large Eddy Simulation. Three indicator functions are considered: a constant function (leading to a linear filter), a function proportional to the norm of the velocity gradient (recovering a Smagorinsky-like model), and a function based on approximate deconvolution operators. Through well-known benchmarks for atmospheric flow, we show that the deconvolution-based filter yields stable solutions that are much less dissipative than the linear filter and the Samgorinsky-like model and we highlight the efficiency of the EFR algorithm.

Dynamical encounters of stellar-mass black holes (BHs) in a disc of compact objects around a supermassive BH (SMBH) can accelerate the formation and coalescence of BH binaries. It has been proposed that binary-single encounters among BHs in such discs can lead to an excess of highly-eccentric BH mergers. However, previous studies have neglected how the disc velocity dispersion and the SMBH's tidal field affect the 3-body dynamics. We investigate the outcomes of binary-single encounters considering different values of the disc velocity dispersion, and examine the role of the SMBH's tidal field. We then demonstrate how their inclusion affects the properties of merging BH binaries. We perform simulations of 4-body encounters (i.e. with the SMBH as fourth particle) using the highly-accurate, regularized code TSUNAMI, which includes post-Newtonian corrections up to order 3.5PN. The disc velocity dispersion controls how orbits in the disc are aligned and circular, and determines the relative velocity of the binary-single pair before the encounter. As the velocity dispersion decreases, the eccentricity of post-encounter binaries transitions from thermal to superthermal, and binaries experience enhanced hardening. The transition between these two regimes happens at disc eccentricities and inclinations of order e ~ i ~ 10^-4. These distinct regimes correspond to a disc dominated by random motions, and one dominated by the Keplerian shear. The inclusion of the SMBH's tidal field and the disc velocity dispersion can significantly affect the number of GW mergers, and especially the number of highly-eccentric inspirals. These can be up to ~2 times higher at low velocity dispersion, and ~12 times lower at high velocity dispersions. The spin-orbit alignment is influenced by the tidal field exclusively at high velocity dispersions, effectively inhibiting the formation of anti-aligned binary BHs., Comment: 12 pages, 7 figures, accepted for publication in Astronomy & Astrophysics

This paper studies the fusogenicity of cationic liposomes in relation to their surface distribution of cationic lipids and utilizes membrane phase separation to control this surface distribution. It is found that concentrating the cationic lipids into small surface patches on liposomes, through phase-separation, can enhance liposome's fusogenicity. Further concentrating these lipids into smaller patches on the surface of liposomes led to an increased level of fusogenicity. These experimental findings are supported by numerical simulations using a mathematical model for phase-separated charged liposomes. Findings of this study may be used for design and development of highly fusogenic liposomes with minimal level of toxicity.

We propose a regularization for Reduced Order Models (ROMs) of the quasi-geostrophic equations (QGE) to increase accuracy when the Proper Orthogonal Decomposition (POD) modes retained to construct the reduced basis are insufficient to describe the system dynamics. Our regularization is based on the so-called BV-alpha model, which modifies the nonlinear term in the QGE and adds a linear differential filter for the vorticity. To show the effectiveness of the BV-alpha model for ROM closure, we compare the results computed by a POD-Galerkin ROM with and without regularization for the classical double-gyre wind forcing benchmark. Our numerical results show that the solution computed by the regularized ROM is more accurate, even when the retained POD modes account for a small percentage of the eigenvalue energy. Additionally, we show that, although computationally more expensive that the ROM with no regularization, the regularized ROM is still a competitive alternative to full order simulations of the QGE., Comment: 19 pages, 4 tables, 9 figures

We consider an optimal flow control problem in a patient-specific coronary artery bypass graft with the aim of matching the blood flow velocity with given measurements as the Reynolds number varies in a physiological range. Blood flow is modelled with the steady incompressible Navier-Stokes equations. The geometry consists in a stenosed left anterior descending artery where a single bypass is performed with the right internal thoracic artery. The control variable is the unknown value of the normal stress at the outlet boundary, which is need for a correct set-up of the outlet boundary condition. For the numerical solution of the parametric optimal flow control problem, we develop a data-driven reduced order method that combines proper orthogonal decomposition (POD) with neural networks. We present numerical results showing that our data-driven approach leads to a substantial speed-up with respect to a more classical POD-Galerkin strategy proposed in [59], while having comparable accuracy.

We investigate various data-driven methods to enhance projection-based model reduction techniques with the aim of capturing bifurcating solutions. To show the effectiveness of the data-driven enhancements, we focus on the incompressible Navier-Stokes equations and different types of bifurcations. To recover solutions past a Hopf bifurcation, we propose an approach that combines proper orthogonal decomposition with Hankel dynamic mode decomposition. To approximate solutions close to a pitchfork bifurcation, we combine localized reduced models with artificial neural networks. Several numerical examples are shown to demonstrate the feasibility of the presented approaches.

We present a Large Eddy Simulation (LES) approach based on a nonlinear differential low-pass filter for the simulation of two-dimensional barotropic flows with under-refined meshes. For the implementation of such model, we choose a segregated three-step algorithm combined with a computationally efficient Finite Volume method. We assess the performance of our approach on the classical double-gyre wind forcing benchmark. The numerical experiments we present demonstrate that our nonlinear filter is an improvement over a linear filter since it is able to recover the four-gyre pattern of the time-averaged stream function even with extremely coarse meshes. In addition, our LES approach provides an average kinetic energy that compares well with the one computed with a Direct Numerical Simulation., Comment: 16 pages, 11 figures

This work introduces a novel approach for data-driven model reduction of time-dependent parametric partial differential equations. Using a multi-step procedure consisting of proper orthogonal decomposition, dynamic mode decomposition and manifold interpolation, the proposed approach allows to accurately recover field solutions from a few large-scale simulations. Numerical experiments for the Rayleigh-B\'{e}nard cavity problem show the effectiveness of such multi-step procedure in two parametric regimes, i.e.~medium and high Grashof number. The latter regime is particularly challenging as it nears the onset of turbulent and chaotic behaviour. A major advantage of the proposed method in the context of time-periodic solutions is the ability to recover frequencies that are not present in the sampled data.

We develop a Proper Orthogonal Decomposition (POD)-Galerkin based Reduced Order Model (ROM) for the efficient numerical simulation of the parametric Navier-Stokes equations in the stream function-vorticity formulation. Unlike previous works, we choose different reduced coefficients for the vorticity and stream function fields. In addition, for parametric studies we use a global POD basis space obtained from a database of time dependent full order snapshots related to sample points in the parameter space. We test the performance of our ROM strategy with the vortex merger benchmark. Accuracy and efficiency are assessed for both time reconstruction and physical parametrization., Comment: 19 pages, 18 figures

Liposomes that achieve a heterogeneous and spatially organized surface through phase separation have been recognized to be a promising platform for delivery purposes. However, their design and optimization through experimentation can be expensive and time-consuming. To assist with the design and reduce the associated cost, we propose a computational platform for modeling membrane coarsening dynamics based on the principles of continuum mechanics and thermodynamics. This model couples phase separation to lateral flow and accounts for different membrane fluidity within the different phases, which is known to affect the coarsening dynamics on lipid membranes. The simulation results are in agreement with the experimental data in terms of liquid ordered domains area fraction, total domains perimeter over time and total number of domains over time for two different membrane compositions (DOPC:DPPC with a 1:1 molar ratio with 15% Chol and DOPC:DPPC with a 1:2 molar ratio with 25% Chol) that yield opposite and nearly inverse phase behavior. This quantitative validation shows that the developed platform can be a valuable tool in complementing experimental practice. Keywords: Multicomponent Membranes; Membrane fluidity; Membrane Phase Separation; Computational Modeling; Fluorescence Microscopy; Liposomes, Comment: 21 pages, 13 figures

We consider phase-field models with and without lateral flow for the numerical simulation of lateral phase separation and coarsening in lipid membranes. For the numerical solution of these models, we apply an unfitted finite element method that is flexible in handling complex and possibly evolving shapes in the absence of an explicit surface parametrization. Through several numerical tests, we investigate the effect of the presence of lateral flow on the evolution of phases. In particular, we focus on understanding how variable line tension, viscosity, membrane composition, and surface shape affect the pattern formation. Keywords: Lateral phase separation, surface Cahn-Hilliard equation, lateral flow, surface Navier-Stokes-Cahn-Hilliard system, TraceFEM, Comment: 21 pages, 12 figures

We develop a Reduced Order Model (ROM) for a Large Eddy Simulation (LES) approach that combines a three-step algorithm called Evolve-Filter-Relax (EFR) with a computationally efficient finite volume method. The main novelty of our ROM lies in the use within the EFR algorithm of a nonlinear, deconvolution-based indicator function that identifies the regions of the domain where the flow needs regularization. The ROM we propose is a hybrid projection/data-driven strategy: a classical Proper Orthogonal Decomposition Galerkin projection approach for the reconstruction of the velocity and the pressure fields and a data-driven reduction method to approximate the indicator function used by the nonlinear differential filter. This data-driven technique is based on interpolation with Radial Basis Functions. We test the performance of our ROM approach on two benchmark problems: 2D and 3D unsteady flow past a cylinder at Reynolds number 0 <= Re <= 100. The accuracy of the ROM is assessed against results obtained with the full order model for velocity, pressure, indicator function and time evolution of the aerodynamics coefficients., Comment: 27 pages, 19 figures, 4 tables. arXiv admin note: text overlap with arXiv:2009.13593

We focus on the modeling and simulation of an infectious disease spreading in a medium size population occupying a confined environment, such as an airport terminal, for short periods of time. Because of the size of the crowd and venue, we opt for a kinetic type model. The paper is divided into two parts. In the first part, we adopt the simplifying assumption that people's walking speed and direction are given. The resulting kinetic model features a variable that denotes the level of exposure to people spreading the disease, a parameter describing the contagion interaction strength, and a kernel function that is a decreasing function of the distance between a person and a spreading individual. Such model is tested on problems involving a small crowd in a square walkable domain. In the second part, ideas from the simplified model are used to incorporate disease spreading in a kinetic theory approach for crowd dynamics, i.e. the walking speed and direction result from interaction with other people and the venue., Comment: 20 pages, 7 figures. arXiv admin note: substantial text overlap with arXiv:2103.15151

We present a stabilized POD-Galerkin reduced order method (ROM) for a Leray model. For the implementation of the model, we combine a two-step algorithm called Evolve-Filter (EF) with a computationally efficient finite volume method. In both steps of the EF algorithm, velocity and pressure fields are approximated using different POD basis and coefficients. To achieve pressure stabilization, we consider and compare two strategies: the pressure Poisson equation and the supremizer enrichment of the velocity space. We show that the evolve and filtered velocity spaces have to be enriched with the supremizer solutions related to both evolve and filter pressure fields in order to obtain stable and accurate solutions with the supremizer enrichment method. We test our ROM approach on 2D unsteady flow past a cylinder at Reynolds number 0 <= Re <= 100. We find that both stabilization strategies produce comparable errors in the reconstruction of the lift and drag coefficients, with the pressure Poisson equation method being more computationally efficient., Comment: 18 pages, 4 figures, 3 tables. arXiv admin note: substantial text overlap with arXiv:2009.13593

This paper studies a model of two-phase flow with an immersed material viscous interface and a finite element method for numerical solution of the resulting system of PDEs. The interaction between the bulk and surface media is characterized by no-penetration and slip with friction interface conditions. The system is shown to be dissipative and a model stationary problem is proved to be well-posed. The finite element method applied in this paper belongs to a family of unfitted discretizations. The performance of the method when model and discretization parameters vary is assessed. Moreover, an iterative procedure based on the splitting of the system into bulk and surface problems is introduced and studied numerically.

The paper considers a thermodynamically consistent phase-field model of a two-phase flow of incompressible viscous fluids. The model allows for a non-linear dependence of fluid density on the phase-field order parameter. Driven by applications in biomembrane studies, the model is written for tangential flows of fluids constrained to a surface and consists of (surface) Navier-Stokes-Cahn-Hilliard type equations. We apply an unfitted finite element method to discretize the system and introduce a fully discrete time-stepping scheme with the following properties: (i) the scheme decouples the fluid and phase-field equation solvers at each time step, (ii) the resulting two algebraic systems are linear, and (iii) the numerical solution satisfies the same stability bound as the solution of the original system under some restrictions on the discretization parameters. Numerical examples are provided to demonstrate the stability, accuracy, and overall efficiency of the approach. Our computational study of several two-phase surface flows reveals some interesting dependencies of flow statistics on the geometry., Comment: 22 pages, 5 figures, 1 table

We present some ideas on how to extend a kinetic type model for crowd dynamics to account for an infectious disease spreading. We focus on a medium size crowd occupying a confined environment where the disease is easily spread. The kinetic theory approach we choose uses tools of game theory to model the interactions of a person with the surrounding people and the environment and it features a parameter to represent the level of stress. It is known that people choose different walking strategies when subjected to fear or stressful situations. To demonstrate that our model for crowd dynamics could be used to reproduce realistic scenarios, we simulate passengers in one terminal of Hobby Airport in Houston. In order to model disease spreading in a walking crowd, we introduce a variable that denotes the level of exposure to people spreading the disease. In addition, we introduce a parameter that describes the contagion interaction strength and a kernel function that is a decreasing function of the distance between a person and a spreading individual. We test our contagion model on a problem involving a small crowd walking through a corridor., Comment: 27 pages, 12 figures. arXiv admin note: text overlap with arXiv:1901.07620

The goal of this paper is to test solids4Foam, the fluid-structure interaction (FSI) toolbox developed for foam-extend (a branch of OpenFOAM), and assess its flexibility in handling more complex flows. For this purpose, we consider the interaction of an incompressible fluid described by a Leray model with a hyperelastic structure modeled as a Saint Venant-Kirchhoff material. We focus on a strongly coupled, partitioned fluid-structure interaction (FSI) solver in a finite volume environment, combined with an arbitrary Lagrangian-Eulerian approach to deal with the motion of the fluid domain. For the implementation of the Leray model, which features a nonlinear differential low-pass filter, we adopt a three-step algorithm called Evolve-Filter-Relax. We validate our approach against numerical data available in the literature for the 3D cross flow past a cantilever beam at Reynolds number 100 and 400., Comment: 18 pages, 4 figures, 3 tables

We present an isoparametric unfitted finite element approach of the CutFEM or Nitsche-XFEM family for the simulation of two-phase Stokes problems with slip between phases. For the unfitted generalized Taylor--Hood finite element pair $\mathbf{P}_{k+1}-P_k$, $k\ge1$, we show an inf-sup stability property with a stability constant that is independent of the viscosity ratio, slip coefficient, position of the interface with respect to the background mesh and, of course, mesh size. In addition, we prove stability and optimal error estimates that follow from this inf-sup property. We provide numerical results in two and three dimensions to corroborate the theoretical findings and demonstrate the robustness of our approach with respect to the contrast in viscosity, slip coefficient value, and position of the interface relative to the fixed computational mesh.

The Thermodynamics of Advanced Fuels – International Database (TAF-ID) was developed using the Calphad method to provide a computational tool to perform thermodynamic calculations on nuclear fuel materials under normal and off-normal conditions. Different kinds of fuels are considered: oxide, metallic, carbide and nitride fuels. Many fission products are introduced as well as structural materials (e.g., zirconium, steel, concrete, SiC) and absorbers (e.g., B4C), in order to investigate the thermochemistry of irradiated fuels and to predict their chemical interaction with the surrounding materials. The approach to develop the database and the models implemented in the database are described. Examples of models for key chemical systems are presented. Finally, a few examples of application calculations on severe accidents with UO2 fuels, irradiated fuel chemistry of MOX and metallic fuels and metallic fuel/cladding interaction show how this tool can be used. To validate the database, the calculations are compared to the available experimental data. A good agreement is obtained which gives confidence in the maturity degree and quality of the TAF-ID database. The working version is only accessible to the participants of the TAF-ID project (Canada, France, Japan, the Netherlands, Republic of Korea, United Kingdom, USA). A public version is accessible by all the NEA countries. The current version contains models on the Am–Fe, Am–Np, Am-O-Pu, Am–U, Am–Zr, C–O–U-Pu, Cr–U, Np–U, Np–Zr, O–U–Zr, Re–U, Ru–U, Si–U, Ti–U, U-Pu-Zr, U–W systems. It is progressively extended with our published assessments. Information on how to join the project is available on the website: https://www.oecd-nea.org/science/taf-id/., Accepted Author Manuscript, RST/Reactor Physics and Nuclear Materials

Membrane phase-separation is a mechanism that biological membranes often use to locally concentrate specific lipid species in order to organize diverse membrane processes. Phase separation has also been explored as a tool for the design of liposomes with heterogeneous and spatially organized surfaces. These "patchy" liposomes are promising platforms for delivery purposes, however their design and optimization through experimentation can be expensive and time-consuming. We developed a computationally efficient method based on the surface Cahn-Hilliard phase-field model to complement experimental investigations in the design of patchy liposomes. The method relies on thermodynamic considerations to set the initial state for numerical simulations. We show that our computational approach delivers not only qualitative pictures, but also accurate quantitative information about the dynamics of the membrane organization. In particular, the computational and experimental results are in excellent agreement in terms of raft area fraction, total raft perimeter over time and total number of rafts over time for two different membrane compositions (DOPC:DPPC with a 2:1 molar ratio with 20% Chol and DOPC:DPPC with a 3:1 molar ratio with 20% Chol). Thus, the computational phase-field model informed by experiments has a considerable potential to assist in the design of liposomes with spatially organized surfaces, thereby containing the cost and time required by the design process.

The goal of this work is to study an infectious disease spreading in a medium size population occupying a confined environment. For this purpose, we consider a kinetic theory approach to model crowd dynamics in bounded domains and couple it to a kinetic equation to model contagion. The interactions of a person with other pedestrians and the environment are modeled by using tools of game theory. The pedestrian dynamics model allows to weight between two competing behaviors: the search for less congested areas and the tendency to follow the stream unconsciously in a panic situation. Each person in the system has a contagion level that is affected by their neighborhood. For the numerical solution of the coupled problem, we propose a numerical algorithm that at every time step solves one crowd dynamics problem and one contagion problem, i.e. with no subiterations between the two. We test our coupled model on a problem involving a small crowd walking through a corridor., Comment: arXiv admin note: substantial text overlap with arXiv:1901.07620

In this paper, we present a computational modeling approach for the dynamics of human crowds, where the spreading of an emotion (specifically fear) has an influence on the pedestrians' behavior. Our approach is based on the methods of the kinetic theory of active particles. The model allows us to weight between two competing behaviors depending on fear level: the search for less congested areas and the tendency to follow the stream unconsciously (herding). The fear level of each pedestrian influences her walking speed and is influenced by the fear levels of her neighbors. Numerically, we solve our pedestrian model with emotional contagion using an operator splitting scheme. We simulate evacuation scenarios involving two groups of interacting pedestrians to assess how domain geometry and the details of fear propagation impact evacuation dynamics. Further, we reproduce the evacuation dynamics of an experimental study involving distressed ants., Comment: 26 pages, 10 figures. arXiv admin note: text overlap with arXiv:1901.07620

This paper focuses on reduced-order models (ROMs) built for the efficient treatment of PDEs having solutions that bifurcate as the values of multiple input parameters change. First, we consider a method called local ROM that uses k-means algorithm to cluster snapshots and construct local POD bases, one for each cluster. We investigate one key ingredient of this approach: the local basis selection criterion. Several criteria are compared and it is found that a criterion based on a regression artificial neural network (ANN) provides the most accurate results for a channel flow problem exhibiting a supercritical pitchfork bifurcation. The same benchmark test is then used to compare the local ROM approach with the regression ANN selection criterion to an established global projection-based ROM and a recently proposed ANN based method called POD-NN. We show that our local ROM approach gains more than an order of magnitude in accuracy over the global projection-based ROM. However, the POD-NN provides consistently more accurate approximations than the local projection-based ROM.

We propose a Proper Orthogonal Decomposition (POD)-Galerkin based Reduced Order Model (ROM) for a Leray model. For the implementation of the model, we combine a two-step algorithm called Evolve-Filter (EF) with a computationally efficient finite volume method. The main novelty of the proposed approach relies in applying spatial filtering both for the collection of the snapshots and in the reduced order model, as well as in considering the pressure field at reduced level. In both steps of the EF algorithm, velocity and pressure fields are approximated by using different POD basis and coefficients. For the reconstruction of the pressures fields, we use a pressure Poisson equation approach. We test our ROM on two benchmark problems: 2D and 3D unsteady flow past a cylinder at Reynolds number 0 <= Re <= 100. The accuracy of the reduced order model is assessed against results obtained with the full order model. For the 2D case, a parametric study with respect to the filtering radius is also presented., Comment: 29 pages, 16 figures, 9 tables

Background: ICU patients must be kept conscious, calm, and cooperative even during the critical phases of illness. Enteral administration of sedative drugs might avoid over sedation, and would be as adequate as intravenous administration in patients who are awake, with fewer side effects and lower costs. This study compares two sedation strategies, for early achievement and maintenance of the target light sedation. Methods: This was a multicenter, single-blind, randomized and controlled trial carried out in 12 Italian ICUs, involving patients with expected mechanical ventilation duration > 72 h at ICU admission and predicted mortality > 12% (Simplified Acute Physiology Score II > 32 points) during the first 24 h on ICU. Patients were randomly assigned to receive intravenous (midazolam, propofol) or enteral (hydroxyzine, lorazepam, and melatonin) sedation. The primary outcome was percentage of work shifts with the patient having an observed Richmond Agitation-Sedation Scale (RASS) = target RASS ±1. Secondary outcomes were feasibility, delirium-free and coma-free days, costs of drugs, length of ICU and hospital stay, and ICU, hospital, and one-year mortality. Results: There were 348 patients enrolled. There were no differences in the primary outcome: enteral 89.8% (74.1-100), intravenous 94.4% (78-100), p = 0.20. Enteral-treated patients had more protocol violations: n = 81 (46.6%) vs 7 (4.2%), p < 0.01; more self-extubations: n = 14 (8.1%) vs 4 (2.4%), p = 0.03; a lighter sedative target (RASS = 0): 93% (71-100) vs 83% (61-100), p < 0.01; and lower total drug costs: 2.39 (0.75-9.78) vs 4.15 (1.20-20.19) €/day with mechanical ventilation (p = 0.01). Conclusions: Although enteral sedation of critically ill patients is cheaper and permits a lighter sedation target, it is not superior to intravenous sedation for reaching the RASS target. Trial registration: ClinicalTrials.gov, NCT01360346. Registered on 25 March 2011.

Background: ICU patients must be kept conscious, calm, and cooperative even during the critical phases of illness. Enteral administration of sedative drugs might avoid over sedation, and would be as adequate as intravenous administration in patients who are awake, with fewer side effects and lower costs. This study compares two sedation strategies, for early achievement and maintenance of the target light sedation. Methods: This was a multicenter, single-blind, randomized and controlled trial carried out in 12 Italian ICUs, involving patients with expected mechanical ventilation duration > 72 h at ICU admission and predicted mortality > 12% (Simplified Acute Physiology Score II > 32 points) during the first 24 h on ICU. Patients were randomly assigned to receive intravenous (midazolam, propofol) or enteral (hydroxyzine, lorazepam, and melatonin) sedation. The primary outcome was percentage of work shifts with the patient having an observed Richmond Agitation-Sedation Scale (RASS) = target RASS ±1. Secondary outcomes were feasibility, delirium-free and coma-free days, costs of drugs, length of ICU and hospital stay, and ICU, hospital, and one-year mortality. Results: There were 348 patients enrolled. There were no differences in the primary outcome: enteral 89.8% (74.1-100), intravenous 94.4% (78-100), p = 0.20. Enteral-treated patients had more protocol violations: n = 81 (46.6%) vs 7 (4.2%), p < 0.01; more self-extubations: n = 14 (8.1%) vs 4 (2.4%), p = 0.03; a lighter sedative target (RASS = 0): 93% (71-100) vs 83% (61-100), p < 0.01; and lower total drug costs: 2.39 (0.75-9.78) vs 4.15 (1.20-20.19) €/day with mechanical ventilation (p = 0.01). Conclusions: Although enteral sedation of critically ill patients is cheaper and permits a lighter sedation target, it is not superior to intravenous sedation for reaching the RASS target. Trial registration: ClinicalTrials.gov, NCT01360346. Registered on 25 March 2011.

The paper presents a model of lateral phase separation in a two component material surface. The resulting fourth order nonlinear PDE can be seen as a Cahn-Hilliard equation posed on a time-dependent surface. Only elementary tangential calculus and the embedding of the surface in $\mathbb{R}^3$ are used to formulate the model, thereby facilitating the development of a fully Eulerian discretization method to solve the problem numerically. A hybrid method, finite difference in time and trace finite element in space, is introduced and stability of its semi-discrete version is proved. The method avoids any triangulation of the surface and uses a surface-independent background mesh to discretize the equation. Thus, the method is capable of solving the Cahn-Hilliard equation numerically on implicitly defined surfaces and surfaces undergoing strong deformations and topological transitions. We assess the approach on a set of test problems and apply it to model spinodal decomposition and pattern formation on colliding surfaces. Finally, we consider the phase separation on a sphere splitting into two droplets.

We propose a computationally efficient framework to treat nonlinear partial differential equations having bifurcating solutions as one or more physical control parameters are varied. Our focus is on steady bifurcations. Plotting a bifurcation diagram entails computing multiple solutions of a parametrized, nonlinear problem, which can be extremely expensive in terms of computational time. In order to reduce these demanding computational costs, our approach combines a continuation technique and Newton's method with a Reduced Order Modeling (ROM) technique, suitably supplemented with a hyper-reduction method. To demonstrate the effectiveness of our ROM approach, we trace the steady solution branches of a nonlinear Schr\"{o}dinger equation, called Gross-Pitaevskii equation, as one or two physical parameters are varied. In the two parameter study, we show that our approach is 60 times faster in constructing a bifurcation diagram than a standard Full Order Method., Comment: 17 pages, 10 figures

We consider the Navier-Stokes equations in a channel with a narrowing and walls of varying curvature. By applying the empirical interpolation method to generate an affine parameter dependency, the offline-online procedure can be used to compute reduced order solutions for parameter variations. The reduced order space is computed from the steady-state snapshot solutions by a standard POD procedure. The model is discretised with high-order spectral element ansatz functions, resulting in 4752 degrees of freedom. The proposed reduced order model produces accurate approximations of steady-state solutions for a wide range of geometries and kinematic viscosity values. The application that motivated the present study is the onset of asymmetries (i.e., symmetry breaking bifurcation) in blood flow through a regurgitant mitral valve, depending on the Reynolds number and the valve shape. Through our computational study, we found that the critical Reynolds number for the symmetry breaking increases as the wall curvature increases., Comment: arXiv admin note: text overlap with arXiv:1812.11051

Background: ICU patients must be kept conscious, calm, and cooperative even during the critical phases of illness. Enteral administration of sedative drugs might avoid over sedation, and would be as adequate as intravenous administration in patients who are awake, with fewer side effects and lower costs. This study compares two sedation strategies, for early achievement and maintenance of the target light sedation. Methods: This was a multicenter, single-blind, randomized and controlled trial carried out in 12 Italian ICUs, involving patients with expected mechanical ventilation duration > 72 h at ICU admission and predicted mortality > 12% (Simplified Acute Physiology Score II > 32 points) during the first 24 h on ICU. Patients were randomly assigned to receive intravenous (midazolam, propofol) or enteral (hydroxyzine, lorazepam, and melatonin) sedation. The primary outcome was percentage of work shifts with the patient having an observed Richmond Agitation-Sedation Scale (RASS) = target RASS ±1. Secondary outcomes were feasibility, delirium-free and coma-free days, costs of drugs, length of ICU and hospital stay, and ICU, hospital, and one-year mortality. Results: There were 348 patients enrolled. There were no differences in the primary outcome: enteral 89.8% (74.1-100), intravenous 94.4% (78-100), p = 0.20. Enteral-treated patients had more protocol violations: n = 81 (46.6%) vs 7 (4.2%), p < 0.01; more self-extubations: n = 14 (8.1%) vs 4 (2.4%), p = 0.03; a lighter sedative target (RASS = 0): 93% (71-100) vs 83% (61-100), p < 0.01; and lower total drug costs: 2.39 (0.75-9.78) vs 4.15 (1.20-20.19) €/day with mechanical ventilation (p = 0.01). Conclusions: Although enteral sedation of critically ill patients is cheaper and permits a lighter sedation target, it is not superior to intravenous sedation for reaching the RASS target. Trial registration: ClinicalTrials.gov, NCT01360346. Registered on 25 March 2011.

We consider a kinetic theory approach to model the evacuation of a crowd from bounded domains. The interactions of a person with other pedestrians and the environment, which includes walls, exits, and obstacles, are modeled by using tools of game theory and are transferred to the crowd dynamics. The model allows to weight between two competing behaviors: the search for less congested areas and the tendency to follow the stream unconsciously in a panic situation. For the numerical approximation of the solution to our model, we apply an operator splitting scheme which breaks the problem into two pure advection problems and a problem involving the interactions. We compare our numerical results against the data reported in a recent empirical study on evacuation from a room with two exits. For medium and medium-to-large groups of people we achieve good agreement between the computed average people density and flow rate and the respective measured quantities. Through a series of numerical tests we also show that our approach is capable of handling evacuation from a room with one or more exits with variable size, with and without obstacles, and can reproduce lane formation in bidirectional flow in a corridor., Comment: 30 pages, 18 figures

Severe accident facilities for European safety targets (SAFEST) is a European project networking the European experimental laboratories focused on the investigation of a nuclear power plant (NPP) severe accident (SA) with reactor core melting and formation of hazardous material system known as corium. The main objective of the project is to establish coordinated activities, enabling the development of a common vision and severe accident research roadmaps for the next years, and of the management structure to achieve these goals. In this frame, a European roadmap on severe accident experimental research has been developed to define research challenges to contribute to further reinforcement of Gen II and III NPP safety. The roadmap takes into account different SA phenomena and issues identified and prioritized in the analyses of severe accidents at commercial NPPs and in the results of the recent European stress tests carried out after the Fukushima accident. Nineteen relevant issues related to reactor core meltdown accidents have been selected during these efforts. These issues have been compared to a survey of the European SA research experimental facilities and corium analysis laboratories. Finally, the coherence between European infrastructures and R&D needs has been assessed and a table linking issues and infrastructures has been derived. The comparison shows certain important lacks in SA research infrastructures in Europe, especially in the domains of core late reflooding impact on source term, reactor pressure vessel failure and molten core release modes, spent fuel pool (SFP) accidents, as well as the need for a large-scale experimental facility operating with up to 500 kg of chemically prototypic corium melt., QC 20180530

BACKGROUND: International guidelines recommend systematic assessment of pain, agitation/sedation and delirium with validated scales for all ICU patients. However, these evaluations are often not done. We have created an e-learning training platform for the continuous medical education, and assessed its efficacy in increasing the use of validated tools by all medical and nursing staff of the participating ICUs during their daily practice. METHODS: Multicenter, randomized, before and after study. The eight participating centers were randomized in two groups, and received training at different times. The use of validated tools (Verbal Numeric Rating or Behavioral Pain Scale for pain; Richmond Agitation-Sedation Scale for agitation; Confusion Assessment Method for the ICU for delirium) was evaluated from clinical data recorded in medical charts during a week, with follow-up up to six months after the training. All the operators were invited to complete a questionnaire, at baseline and after the training. RESULTS : Among the 374 nurses and physicians involved, 140 (37.4%) completed at least one of the three courses. The assessment of pain (38.1 vs. 92.9%, P<0.01) and delirium (0 vs. 78.6%, P<0.01) using validated tools significantly increased after training. Observation in the follow-up showed further improvement in delirium monitoring, with no signs of extinction for pain and sedation/agitation measurements. CONCLUSIONS: This e-learning program shows encouraging effectiveness, and the increase in the use of validated tools for neurological monitoring in critically ill patients lasts over time.

Objectives: The optimal repair of functional mitral regurgitation is still debated. No device is able to simultaneously abolish mitral regurgitation and replicate natural mitral annular dynamics. We have tested a fully elastic mitral ring in an acute animal study with the purpose of evaluating (1) ring design and implantation technique, (2) elastic performance, and (3) acute effects on the native mitral annulus. Methods: Ten healthy sheep underwent surgical implantation of mitral devices, the elastic component of which is represented by a helicoid metallic spring. Preimplantation and postimplantation echocardiographic parameter measurements to evaluate annular dynamics and ventricular function comprise mitral annular motion, systolic tissue Doppler imaging peak wave, transmitral pressure gradient, peak transmitral flow velocity, and ejection fraction. Postimplantation angiographic analysis allowed measurement of the mitral annular area and perimeter variations by means of segmentation of the radiopaque mitral device contour. Results: No significant difference in terms of ejection fraction (P = .13) and systolic tissue Doppler imaging peak wave (P = .87) was found before and after implantation. Mitral annular motion (1.16 cm) was preserved. The percentage of systolic annular reduction derived from angiographic analysis was 14.1% ( range, 7.7%-19.7%) in terms of area and 7.2% (range, 4.9%-10.0%) in terms of perimeter. Conclusions: A mitral elastic ring, implantable by using a standard technique, acutely preserves mitral annular dynamics, allowing area and perimeter changes. Further chronic study is needed to verify the biocompatibility and durability of the device.

Objectives: We hypothesize that the implantation of an endoventricular elastic ring at the left ventricle (LV) equatorial site will positively affect the cardiac mechanics in an experimental model of acute LV dysfunction. Background: Changes in the elastic properties of LV occur in the dilated and failing heart, contributing to overall cardiac mechanical dysfunction. No interventions are as yet specifically designed to improve LV elasticity in failing hearts. Methods: Acute LV enlargement and dysfunction was induced in 13 healthy sheep via the insertion of a large Dacron patch into the lateral wall. In 6 of these sheep, a customized elastic ring was implanted at the inner surface of the LV equator (ring group), and the remaining 7 served as control subjects (dysfunction group). Systolic and diastolic function was evaluated using echocardiography and pressure-volume (P-V) analysis. Results: In the ring group, both the maximum rate of pressure increase and the slope of end-systolic P-V relationship were significantly different from those without ring (1,718 ± 726 vs. 1,049 ± 269 and 1.25 ± 0.30 vs. 0.88 ± 0.19; both p < 0.05). Preload recruitable stroke work changed even more prominently (33 ± 11 vs. 17 ± 5; p = 0.005), along with stroke volume, ejection fraction, and stroke work. Although ring implantation had no effect on end-diastolic P-V relationship, it positively affected the active component of diastole: the maximum rate of pressure decrease declined significantly (p = 0.037). The time constant of relaxation tended to decrease (37 ± 8 vs. 44 ± 6; p = 0.088). Conclusions: Improving the elastic component of the LV at its equatorial site substantially augments contractility and early relaxation in acute systodiastolic LV dysfunction.

Heart failure of different etiologies is due to changes in cardiac structure and function. During normal diastolic filling, the passive stretch of the ventricular myocardium is modulated by titin, a giant elastic protein that acts as a molecular spring and leads to the recapitulation of single cell mechanics at global ventricular level. The mechanics of a dilated failing heart are at least partially determined by variations in the passive filling properties of the myocardium that impair contraction. Current volume reduction surgery is based on Laplace's law and obtained by rigid means that may impair diastolic function. We postulate that inserting one or more elastic elements at different levels of a failing ventricle (the mitral annulus, equator and apex) could improve cardiac performance. We describe our invention for the first time by presenting the results of two animal experiments. © 2006 Italian Federation of Cardiology.

Background. Stentless bioprostheses and homografts show better hemodynamic profiles compared with conventional stented bioprostheses and mechanical valves. Few data are available on stentless aortic valve implantation for patients with severe left ventricular dysfunction. The aim of this retrospective study was to assess the potential benefits of stentless aortic valve implantation for patients undergoing isolated aortic valve replacement with left ventricular ejection fraction ≤ 35%. Methods. From November 1988 through March 2000, 53 patients (45 men and 8 women, aged 64.2 ± 15.2 years) with a LVEF ≤ 35% (mean EF, 28.7 ± 5.4%) underwent isolated, primary aortic valve replacement for chronic aortic valve disease. Twenty patients received stentless aortic valves and 33 patients received conventional stented bioprostheses and mechanical valves. Predictive factors for LVEF recovery at echocardiographic follow-up (36.2 ± 32.1 months) were analyzed by simple and multiple regression analysis. Results. There were no significant differences between groups in early and late mortality. Stentless aortic valve implantation required a longer aortic cross-clamp time (p = 0.037). The stentless aortic valve group showed a better LVEF recovery (p = 0.016). Stentless aortic valves had a larger indexed effective orifice area compared with conventional stented bioprostheses and mechanical valves (p < 0.0001). A smaller indexed effective orifice area (p = 0.0008), chronic obstructive pulmonary disease (p = 0.015), and implantation of a conventional stented bioprosthesis or mechanical valve (p = 0.016) were related to reduced LVEF recovery by univariate analysis. A larger indexed effective orifice area (p = 0.024) was an independent predictive factor for a better LVEF recovery by multivariate analysis. Conclusions. Stentless aortic valve implantation for patients with severe left ventricular dysfunction, even if technically more demanding, is a safe procedure that warrants a larger in

We present a numerical study of laminar incompressible flows in two-dimensional and three-dimensional contraction-expansion channels. The aim is to understand the causes of the so-called Coanda effect (i.e., the tendency of a fluid jet to be attracted to a surface) in order to reproduce wall-hugging jets in a mock heart chamber constructed to improve the diagnosis of mitral valve regurgitation. First, we validate the critical Reynolds number for the onset of the Coanda effect (also known as symmetry-Ureaking bifurcation) given by our computations against the values found in the literature. Excellent agreement is found. Then, we considered flow in a section of the mock heart chamber and showed how a pronounced Coanda effect is possible only with some modifications of the contraction channel geometry. Finally, we propose a 3mathrm{D} mock heart chamber in which quasi-2D flow is possible, thereby allowing the Coanda effect at the low Reynolds numbers for which it is observed in 2mathrm{D}.

SAFEST (Severe Accident Facilities for European Safety Targets) is a European project networking the European corium experimental laboratories with the objective to establish coordination activities, enabling the development of a common vision and research roadmaps for the next years, and of the management structure to achieve these goals. In this frame, a European roadmap on corium experimental research has been written to define research challenges to contribute to further reinforcement of Gen II and III NPP safety. It is based on the research priorities deteimined by SARNET SARP group as well as those from the recently formulated in the NUGENIA Roadmap for severe accidents and the recently published NUGENIA Global Vision report. It also takes into account issues identified in the analysis of the European stress tests and from the interpretation of the Fukushima accident. 19 relevant issues related to corium have been selected during these prioritization efforts. These issues have been compared to a survey of the European corium experimental facilities and corium analysis laboratories. Finally, the coherence between European infrastructures and R&D needs has been assessed and a table linking issues and infrastructures has been derived. It shows a few lacks in EU corium infrastructures, especially in the domains of core late reflooding impact on source term, Reactor Pressure Vessel failure and corium release, Spent Fuel Pool accidents, as well as the need for a large mass (100500 kg) prototypic corium facility., QC 20170118

Six cases of combined heart and kidney transplantation with organs from the same donor are reported. All six patients suffered from primary end- stage kidney disease, two chronic glomerulonephritis, two glomerulosclerosis, one chronic pyelonephritis and one with unknown etiology. Four patients were undergoing hemodialysis. Three patients had the diagnosis of ischemic heart disease, one dilated cardiomyopathy secondary to congenital heart disease, two idiopathic dilated cardiomyopathy. Five were males and one female. Ages ranged from 38 to 54 years. On-site or short-distance young donors with normal renal function and good cardiac function necessitating low inotropic support were selected. ABO compatibility was used exclusively. Orthotopic heart transplantation was performed first. During cardiopulmonary bypass, hemofiltration was used in four cases. Kidney transplantation was performed immediately after the closure of the chest. Diuresis was immediate in all cases. No cardiac rejection was documented at EMB. Renal function normalized within few clays with no signs of kidney rejection. All six patients are alive and well with normal cardiac and renal function at a mean follow-up of 43 months. Patients and donors selection associated with a proper surgical strategy and prompt immunosuppressive therapy administration make the combined heart and kidney transplantation an effective therapeutic option

The high-temperature phase diagram of the UO2–ThO2 system has been experimentally revisited in the present study for the first time since 1970, using a laser heating approach combined with fast pyrometry in a thermal arrest method. The melting/solidification temperature, which is of fundamental information for a reactor design was studied here. It was found that low addition of ThO2 to UO2 would result in a slight decrease of the solidification temperature. A minimum was found at 3098 K around a composition of 5 mol% ThO2. The solid/liquid transition temperature was then observed to increase again with increasing ThO2 fraction. The literature value of pure ThO2 (around 3630 K) was well reproduced here. Important experimental difficulties, stemming from the high temperatures reached during the measurements, as well as a complete investigation with electron microscopy, Raman spectroscopy and powder X-ray diffraction, are extensively discussed. These results show the importance of the high-temperature oxygen chemistry in this actinide oxide compound., RST/Radiation, Science and Technology, Applied Sciences