Long-term patency of complex bilobular, bisaccular, and broad-neck aneurysms in the rabbit microsurgical venous pouch bifurcation model

In experimental aneurysm models, long-term patency without spontaneous thrombosis is the most important precondition for analyses of embolization devices. We recently reported the feasibility of creating complex venous pouch bifurcation aneurysms in the rabbit with low morbidity, low mortality, and high short-term aneurysm patency. In order to further evaluate our model, we examined the long-term patency rate.

Clinical outcomes after zotarolimus and everolimus drug eluting stent implantation in coronary artery bifurcation lesions: insights from the RESOLUTE All Comers Trial

OBJECTIVE We investigated clinical outcomes after treatment of coronary bifurcation lesions with second generation drug eluting stents (DES). DESIGN Post hoc analysis of a randomised, multicentre, non-inferiority trial. SETTING Multicentre study. PATIENTS All comers study with minimal exclusion criteria. INTERVENTIONS Patients were treated with either zotarolimus or everolimus eluting stents. The patient population was divided according to treatment of bifurcation or non-bifurcation lesions and clinical outcomes were compared between groups. MAIN OUTCOMES MEASURES Clinical outcomes within 2-year follow-up. RESULTS A total of 2265 patients were included in the present analysis. Two-year follow-up data were available in 2223 patients: 1838 patients in the non-bifurcation group and 385 patients in the bifurcation group. At 2-year follow-up the bifurcation and the non-bifurcation lesion groups showed no significant differences in terms of cardiac death (2.3 vs 2.1, p=0.273), target lesion failure (9.7% vs 13.8%, p=0.255), major adverse cardiac events (11.5% vs 15.1%, p=0.305), target lesion revascularisation (4.7% vs 6.0%, p=0.569), and definite or probable stent thrombosis (1.6% vs 1.8%, p=0.419). CONCLUSIONS The use of second generation DES for the treatment of coronary bifurcation lesions was associated with similar long term mortality and clinical outcomes compared with non-bifurcation lesions.

Dynamics of a minimal model of interlocked positive and negative feedback loops of transcriptional regulation by cAMP-response element binding proteins.

cAMP-response element binding (CREB) proteins are involved in transcriptional regulation in a number of cellular processes (e.g., neural plasticity and circadian rhythms). The CREB family contains activators and repressors that may interact through positive and negative feedback loops. These loops can be generated by auto- and cross-regulation of expression of CREB proteins, via CRE elements in or near their genes. Experiments suggest that such feedback loops may operate in several systems (e.g., Aplysia and rat). To understand the functional implications of such feedback loops, which are interlocked via cross-regulation of transcription, a minimal model with a positive and negative loop was developed and investigated using bifurcation analysis. Bifurcation analysis revealed diverse nonlinear dynamics (e.g., bistability and oscillations). The stability of steady states or oscillations could be changed by time delays in the synthesis of the activator (CREB1) or the repressor (CREB2). Investigation of stochastic fluctuations due to small numbers of molecules of CREB1 and CREB2 revealed a bimodal distribution of CREB molecules in the bistability region. The robustness of the stable HIGH and LOW states of CREB expression to stochastic noise differs, and a critical number of molecules was required to sustain the HIGH state for days or longer. Increasing positive feedback or decreasing negative feedback also increased the lifetime of the HIGH state, and persistence of this state may correlate with long-term memory formation. A critical number of molecules was also required to sustain robust oscillations of CREB expression. If a steady state was near a deterministic Hopf bifurcation point, stochastic resonance could induce oscillations. This comparative analysis of deterministic and stochastic dynamics not only provides insights into the possible dynamics of CREB regulatory motifs, but also demonstrates a framework for understanding other regulatory processes with similar network architecture.

Bifurcation and singularity analysis of a molecular network for the induction of long-term memory.

Withdrawal reflexes of the mollusk Aplysia exhibit sensitization, a simple form of long-term memory (LTM). Sensitization is due, in part, to long-term facilitation (LTF) of sensorimotor neuron synapses. LTF is induced by the modulatory actions of serotonin (5-HT). Pettigrew et al. developed a computational model of the nonlinear intracellular signaling and gene network that underlies the induction of 5-HT-induced LTF. The model simulated empirical observations that repeated applications of 5-HT induce persistent activation of protein kinase A (PKA) and that this persistent activation requires a suprathreshold exposure of 5-HT. This study extends the analysis of the Pettigrew model by applying bifurcation analysis, singularity theory, and numerical simulation. Using singularity theory, classification diagrams of parameter space were constructed, identifying regions with qualitatively different steady-state behaviors. The graphical representation of these regions illustrates the robustness of these regions to changes in model parameters. Because persistent protein kinase A (PKA) activity correlates with Aplysia LTM, the analysis focuses on a positive feedback loop in the model that tends to maintain PKA activity. In this loop, PKA phosphorylates a transcription factor (TF-1), thereby increasing the expression of an ubiquitin hydrolase (Ap-Uch). Ap-Uch then acts to increase PKA activity, closing the loop. This positive feedback loop manifests multiple, coexisting steady states, or multiplicity, which provides a mechanism for a bistable switch in PKA activity. After the removal of 5-HT, the PKA activity either returns to its basal level (reversible switch) or remains at a high level (irreversible switch). Such an irreversible switch might be a mechanism that contributes to the persistence of LTM. The classification diagrams also identify parameters and processes that might be manipulated, perhaps pharmacologically, to enhance the induction of memory. Rational drug design, to affect complex processes such as memory formation, can benefit from this type of analysis.

Dynamics of a minimal model of interlocked positive and negative feedback loops of transcriptional regulation by cAMP-response element binding proteins.

cAMP-response element binding (CREB) proteins are involved in transcriptional regulation in a number of cellular processes (e.g., neural plasticity and circadian rhythms). The CREB family contains activators and repressors that may interact through positive and negative feedback loops. These loops can be generated by auto- and cross-regulation of expression of CREB proteins, via CRE elements in or near their genes. Experiments suggest that such feedback loops may operate in several systems (e.g., Aplysia and rat). To understand the functional implications of such feedback loops, which are interlocked via cross-regulation of transcription, a minimal model with a positive and negative loop was developed and investigated using bifurcation analysis. Bifurcation analysis revealed diverse nonlinear dynamics (e.g., bistability and oscillations). The stability of steady states or oscillations could be changed by time delays in the synthesis of the activator (CREB1) or the repressor (CREB2). Investigation of stochastic fluctuations due to small numbers of molecules of CREB1 and CREB2 revealed a bimodal distribution of CREB molecules in the bistability region. The robustness of the stable HIGH and LOW states of CREB expression to stochastic noise differs, and a critical number of molecules was required to sustain the HIGH state for days or longer. Increasing positive feedback or decreasing negative feedback also increased the lifetime of the HIGH state, and persistence of this state may correlate with long-term memory formation. A critical number of molecules was also required to sustain robust oscillations of CREB expression. If a steady state was near a deterministic Hopf bifurcation point, stochastic resonance could induce oscillations. This comparative analysis of deterministic and stochastic dynamics not only provides insights into the possible dynamics of CREB regulatory motifs, but also demonstrates a framework for understanding other regulatory processes with similar network architecture.

Three-year outcomes of percutaneous coronary intervention with next-generation zotarolimus-eluting stents for de novo coronary bifurcation lesions.

AIMS To investigate the outcomes of percutaneous coronary intervention (PCI) in bifurcation versus non-bifurcation lesions using the next-generation Resolute zotarolimus-eluting stent (R-ZES). METHODS AND RESULTS We analyzed 3-year pooled data from the RESOLUTE All-Comers trial and the RESOLUTE International registry. The R-ZES was used in 2772 non-bifurcation lesion patients and 703 bifurcation lesion patients, of which 482 were treated with a simple-stent technique (1 stent used to treat the bifurcation lesion) and 221 with a complex bifurcation technique (2 or more stents used). The primary endpoint was 3-year target lesion failure (TLF, defined as the composite of death from cardiac causes, target vessel myocardial infarction, or clinically-indicated target lesion revascularization [TLR]), and was 13.3% in bifurcation vs 11.3% in non-bifurcation lesion patients (adjusted P=.06). Landmark analysis revealed that this difference was driven by differences in the first 30 days between bifurcation vs non-bifurcation lesions (TLF, 6.6% vs 2.7%, respectively; adjusted P<.001), which included significant differences in each component of TLF and in-stent thrombosis. Between 31 days and 3 years, TLF, its components, and stent thrombosis did not differ significantly between bifurcation lesions and non-bifurcation lesions (TLF, 7.7% vs 9.0%, respectively; adjusted P=.50). CONCLUSION The 3-year risk of TLF following PCI with R-ZES in bifurcation lesions was not significantly different from non-bifurcation lesions. However, there was an increased risk associated with bifurcation lesions during the first 30 days; beyond 30 days, bifurcation lesions and non-bifurcation lesions yielded similar 3-year outcomes.

Signature, positive Hopf plumbing and the Coxeter transformation

By a theorem of A'Campo, the eigenvalues of certain Coxeter transformations are positive real or lie on the unit circle. By optimally bounding the signature of tree-like positive Hopf plumbings from below by the genus, we prove that at least two thirds of them lie on the unit circle. In contrast, we show that for divide links, the signature cannot be linearly bounded from below by the genus.

The scenario of two-dimensional instabilities of the cylinder wake under EHD forcing: A linear stability analysis

We propose to study the stability properties of an air flow wake forced by a dielectric barrier discharge (DBD) actuator, which is a type of electrohydrodynamic (EHD) actuator. These actuators add momentum to the flow around a cylinder in regions close to the wall and, in our case, are symmetrically disposed near the boundary layer separation point. Since the forcing frequencies, typical of DBD, are much higher than the natural shedding frequency of the flow, we will be considering the forcing actuation as stationary. In the first part, the flow around a circular cylinder modified by EHD actuators will be experimentally studied by means of particle image velocimetry (PIV). In the second part, the EHD actuators have been numerically implemented as a boundary condition on the cylinder surface. Using this boundary condition, the computationally obtained base flow is then compared with the experimental one in order to relate the control parameters from both methodologies. After validating the obtained agreement, we study the Hopf bifurcation that appears once the flow starts the vortex shedding through experimental and computational approaches. For the base flow derived from experimentally obtained snapshots, we monitor the evolution of the velocity amplitude oscillations. As to the computationally obtained base flow, its stability is analyzed by solving a global eigenvalue problem obtained from the linearized Navier–Stokes equations. Finally, the critical parameters obtained from both approaches are compared.

Reentrant and whirling hexagons in non-Boussinesq convection

We review recent computational results for hexagon patterns in non- Boussinesq convection. For sufficiently strong dependence of the fluid parameters on the temperature we find reentrance of steady hexagons, i.e. while near onset the hexagon patterns become unstable to rolls as usually, they become again stable in the strongly nonlinear regime. If the convection apparatus is rotated about a vertical axis the transition from hexagons to rolls is replaced by a Hopf bifurcation to whirling hexagons. For weak non-Boussinesq effects they display defect chaos of the type described by the two-dimensional (2D) complex Ginzburg-andau equation. For stronger non-Boussinesq effects the Hopf bifurcation becomes subcritical and localized bursting of the whirling amplitude is found. In this regime the cou- pling of the whirling amplitude to (small) deformations of the hexagon lattice becomes important. For yet stronger non-Boussinesq effects this coupling breaks up the hexagon lattice and strongly disordered states characterized by whirling and lattice defects are obtained.

Defect chaos and bursts: Hexagonal rotating convection and the complex Ginzburg-Landau equation

We employ numerical computations of the full Navier-Stokes equations to investigate non-Boussinesq convection in a rotating system using water as the working fluid. We identify two regimes. For weak non- Boussinesq effects the Hopf bifurcation from steady to oscillating (whirling) hexagons is supercritical and typical states exhibit defect chaos that is systematically described by the cubic complex Ginzburg-Landau equation. For stronger non-Boussinesq effects the Hopf bifurcation becomes subcritical and the oscil- lations exhibit localized chaotic bursting, which is modeled by a quintic complex Ginzburg-Landau equation.

Bifurcation diagrams for polymer blends with diffuse interfaces in confined and adaptive geometries

Dynamics of binary mixtures such as polymer blends, and fluids near the critical point, is described by the model-H, which couples momentum transport and diffusion of the components [1]. We present an extended version of the model-H that allows to study the combined effect of phase separation in a polymer blend and surface structuring of the film itself [2]. We apply it to analyze the stability of vertically stratified base states on extended films of polymer blends and show that convective transport leads to new mechanisms of instability as compared to the simpler diffusive case described by the Cahn- Hilliard model [3, 4]. We carry out this analysis for realistic parameters of polymer blends used in experimental setups such as PS/PVME. However, geometrically more complicated states involving lateral structuring, strong deflections of the free surface, oblique diffuse interfaces, checkerboard modes, or droplets of a component above of the other are possible at critical composition solving the Cahn Hilliard equation in the static limit for rectangular domains [5, 6] or with deformable free surfaces [6]. We extend these results for off-critical compositions, since balanced overall composition in experiments are unusual. In particular, we study steady nonlinear solutions of the Cahn-Hilliard equation for bidimensional layers with fixed geometry and deformable free surface. Furthermore we distinguished the cases with and without energetic bias at the free surface. We present bifurcation diagrams for off-critical films of polymer blends with free surfaces, showing their free energy, and the L2-norms of surface deflection and the concentration field, as a function of lateral domain size and mean composition. Simultaneously, we look at spatial dependent profiles of the height and concentration. To treat the problem of films with arbitrary surface deflections our calculations are based on minimizing the free energy functional at given composition and geometric constraints using a variational approach based on the Cahn-Hilliard equation. The problem is solved numerically using the finite element method (FEM).

Direct and adjoint global stability analysis of turbulent transonic flows over a NACA0012 profile

In this work, various turbulent solutions of the two-dimensional (2D) and three-dimensional compressible Reynolds averaged Navier?Stokes equations are analyzed using global stability theory. This analysis is motivated by the onset of flow unsteadiness (Hopf bifurcation) for transonic buffet conditions where moderately high Reynolds numbers and compressible effects must be considered. The buffet phenomenon involves a complex interaction between the separated flow and a shock wave. The efficient numerical methodology presented in this paper predicts the critical parameters, namely, the angle of attack and Mach and Reynolds numbers beyond which the onset of flow unsteadiness appears. The geometry, a NACA0012 profile, and flow parameters selected reproduce situations of practical interest for aeronautical applications. The numerical computation is performed in three steps. First, a steady baseflow solution is obtained; second, the Jacobian matrix for the RANS equations based on a finite volume discretization is computed; and finally, the generalized eigenvalue problem is derived when the baseflow is linearly perturbed. The methodology is validated predicting the 2D Hopf bifurcation for a circular cylinder under laminar flow condition. This benchmark shows good agreement with the previous published computations and experimental data. In the transonic buffet case, the baseflow is computed using the Spalart?Allmaras turbulence model and represents a mean flow where the high frequency content and length scales of the order of the shear-layer thickness have been averaged. The lower frequency content is assumed to be decoupled from the high frequencies, thus allowing a stability analysis to be performed on the low frequency range. In addition, results of the corresponding adjoint problem and the sensitivity map are provided for the first time for the buffet problem. Finally, an extruded three-dimensional geometry of the NACA0012 airfoil, where all velocity components are considered, was also analyzed as a Triglobal stability case, and the outcoming results were compared to the previous 2D limited model, confirming that the buffet onset is well detected.