Physically consistent simulation of transport of inertial particles in porous media

A new numerical approach is presented for simulating the movement of test particles suspended in an incompressible fluid flowing through a porous matrix. This two-phase particle-laden flow is based on the Navier-Stokes equations for incompressible fluid flow and equations of motion for the individual particles in which Stokes drag is dominant. The Immersed Boundary method is applied to incorporate the geometric complexity of the porous medium. A symmetry-preserving finite volume discretization method in combination with a volume penalization method resolves the flow within the porous material. The new Lagrangian particle tracking is such that for mass-less test particles no (numerical) collision with the coarsely represented porous medium occurs at any spatial resolution

Immersed boundary method predictions of shear stresses for different flow topologies occuring in cerebral aneurysms

A volume-penalizing immersed boundary method is presented that facilitates the computation of incompressible fluid flow in complex flow domains. We apply this method to simulate the flow in cerebral aneurysms, and focus on the accuracy with which the flow field and the corresponding shear stress field are computed. The method is applied to laminar, incompressible flow in curved cylindrical vessels and in a model aneurysm. The time-dependent shear stress distributions over the vessel walls are visualized and interpreted in terms of the flow fields that develop. We compute shear stress levels at two different Reynolds numbers, corresponding to a steady and an unsteady flow. In the latter situation strong fluctuations in the shear stress are observed, that may be connected to raised risk-levels of aneurysm rupture

Simulation of impaction filtration of aerosol droplets in porous media

We report on the development of a method to simulate from first principles the particle filtration efficiency of filters that are composed of structured porous media. We assume that the ratio of particle density to the fluid density is high. We concentrate on the motion of the particles in a laminar flow and quantify the role of inertial effects on the filtration of an ensemble of particles. We adopt the Euler-Lagrange approach, distinguishing a flow field in which the motion of a large number of discrete particles is simulated. We associate filtration with the deterministic collision of inertial particles with solid elements of the structured porous medium. To underpin the physical `consistency' of deterministic particle filtration, we investigate to what extent the particle tracking algorithm ensures that mass-less test-particles will not be captured by the structured porous filter at all. This element of the algorithm is essential in order to distinguish physical filtration by inertial effects from unwanted numerical filtration, due to the finite spatial resolution of the gas flow. We consider filtration of particles whose motion is governed by Stokes drag and determine the filtration efficiency in a range of Stokes relaxation times. An exponential decay of the number of particles with time is observed

Post-intervention Status in Patients With Refractory Myasthenia Gravis Treated With Eculizumab During REGAIN and Its Open-Label Extension

OBJECTIVE: To evaluate whether eculizumab helps patients with anti-acetylcholine receptor-positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension. METHODS: Patients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study. RESULTS: A total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1-4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected. CONCLUSION: Eculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population. CLINICALTRIALSGOV IDENTIFIER: REGAIN, NCT01997229; REGAIN open-label extension, NCT02301624. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo

Application of an immersed boundary method to flow in cerebral aneurysms and porous media

We present the development and application of an immersed boundary (IB) method for the simulation of incompressible flow inside and around complex geometrical shapes and cavities. The IB method is based on a volume-penalization method that is applied throughout the domain, rendering the velocity in stationary solid parts negligibly small, while the flow in the open parts of the domain is governed by the Navier-Stokes equations. The flow solver is based on a skew-symmetric finite-volume discretization in combination with explicit time-stepping for the convective and viscous fluxes, and implicit time-stepping for the IB forcing term. The complex geometry is characterized in terms of a so-called ‘masking function’ which equals unity in the solid parts and zero in the open parts of the domain. The focus is on the accuracy with which gradients of the solution close to solid walls can be approximated using the IB methodology. We investigate this for flow through a model of an aneurysm as may develop in the circle of Willis in a human brain, and to flow in a structured porous medium composed of a regular spatial arrangement of square rods. The shear stress acting on the vessel walls in case of flow through an aneurysm and the permeability of the porous material were analyzed. The computational method converges as a first order method for Poiseuille flow, with a considerable influence derived from the precise definition of the masking function near solid-fluid interfaces. We identify the best masking function strategy and show that for plane Poiseuille flow even second order convergence may be obtained. Qualitatively reliable results are obtained already at modest resolutions of 8-16 grid cells across a characteristic opening in the flow domain, e.g., the vessel diameter or the size of the gap between individual square rods

A new analytical model for the permeability of anisotropic structured porous media

A new analytical model for the permeability of anisotropic porous media composed of a periodic in-line arrangement of long rectangular rods,also referred to as‘fibers’,was developed. This analytical permeability model was based on an approximation of the micro-scopic velocity and pressure fields that develop in the pores of the porous medium. The analytical approximation of the velocity field was assessed by anextensive set of numerical simulations of the microscopic velocity and pressure fields for various solidities and aspect ratios of the rectangular rods.The numerical results were obtained by solving the incompressible Navier–Stokes equations,using a volume-penalizing immersed boundary method in which a binary ‘masking function’was used to represent the inner geometry of the fluid domain. At the pore scale,laminar flow develops,which is dominated by viscous effects. Therefore, an analytical approximation of the microscopic velocity field based on Poiseuille flow through long slender channels of variable width was proposed.This extended Poiseuille model was compared to the numerical simulations in case the pressure gradient was imposed either ‘transverse’ or ‘longitudinal’ to the solid rods that make upthe porous medium. The simulated velocityfields compare quite closely with the Poiseuille model for a range of solidities. Based on the extended Poiseuille flow approximation of the velocity field, ananalytical model for the effective,anisotropic permeability was developed,which can be used in macroscopic simulations of porous transport.This permeability model was found to describe the permeability for the ‘transverse’ and ‘longitudinal’ configurations accurately for viscous, laminar flow(Re[5) at solidities J0.35. The proposed permeability model was found to be more reliable,for the transverse direction,if the fibers were positioned relative to the flow such that the longest side of the cross section of a fiber was aligned with the main flow direction

Safety and efficacy of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis (REGAIN): a phase 3, randomised, double-blind, placebo-controlled, multicentre study

Background Complement is likely to have a role in refractory generalised myasthenia gravis, but no approved therapies specifically target this system. Results from a phase 2 study suggested that eculizumab, a terminal complement inhibitor, produced clinically meaningful improvements in patients with anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis. We further assessed the efficacy and safety of eculizumab in this patient population in a phase 3 trial. Methods We did a phase 3, randomised, double-blind, placebo-controlled, multicentre study (REGAIN) in 76 hospitals and specialised clinics in 17 countries across North America, Latin America, Europe, and Asia. Eligible patients were aged at least 18 years, with a Myasthenia Gravis-Activities of Daily Living (MG-ADL) score of 6 or more, Myasthenia Gravis Foundation of America (MGFA) class II\ue2\u80\u93IV disease, vaccination against Neisseria meningitides, and previous treatment with at least two immunosuppressive therapies or one immunosuppressive therapy and chronic intravenous immunoglobulin or plasma exchange for 12 months without symptom control. Patients with a history of thymoma or thymic neoplasms, thymectomy within 12 months before screening, or use of intravenous immunoglobulin or plasma exchange within 4 weeks before randomisation, or rituximab within 6 months before screening, were excluded. We randomly assigned participants (1:1) to either intravenous eculizumab or intravenous matched placebo for 26 weeks. Dosing for eculizumab was 900 mg on day 1 and at weeks 1, 2, and 3; 1200 mg at week 4; and 1200 mg given every second week thereafter as maintenance dosing. Randomisation was done centrally with an interactive voice or web-response system with patients stratified to one of four groups based on MGFA disease classification. Where possible, patients were maintained on existing myasthenia gravis therapies and rescue medication was allowed at the study physician's discretion. Patients, investigators, staff, and outcome assessors were masked to treatment assignment. The primary efficacy endpoint was the change from baseline to week 26 in MG-ADL total score measured by worst-rank ANCOVA. The efficacy population set was defined as all patients randomly assigned to treatment groups who received at least one dose of study drug, had a valid baseline MG-ADL assessment, and at least one post-baseline MG-ADL assessment. The safety analyses included all randomly assigned patients who received eculizumab or placebo. This trial is registered with ClinicalTrials.gov, number NCT01997229. Findings Between April 30, 2014, and Feb 19, 2016, we randomly assigned and treated 125 patients, 62 with eculizumab and 63 with placebo. The primary analysis showed no significant difference between eculizumab and placebo (least-squares mean rank 56\uc2\ub76 [SEM 4\uc2\ub75] vs 68\uc2\ub73 [4\uc2\ub75]; rank-based treatment difference \ue2\u88\u9211\uc2\ub77, 95% CI \ue2\u88\u9224\uc2\ub73 to 0\uc2\ub796; p=0\uc2\ub70698). No deaths or cases of meningococcal infection occurred during the study. The most common adverse events in both groups were headache and upper respiratory tract infection (ten [16%] for both events in the eculizumab group and 12 [19%] for both in the placebo group). Myasthenia gravis exacerbations were reported by six (10%) patients in the eculizumab group and 15 (24%) in the placebo group. Six (10%) patients in the eculizumab group and 12 (19%) in the placebo group required rescue therapy. Interpretation The change in the MG-ADL score was not statistically significant between eculizumab and placebo, as measured by the worst-rank analysis. Eculizumab was well tolerated. The use of a worst-rank analytical approach proved to be an important limitation of this study since the secondary and sensitivity analyses results were inconsistent with the primary endpoint result; further research into the role of complement is needed. Funding Alexion Pharmaceuticals

Long-term safety and efficacy of eculizumab in generalized myasthenia gravis

Introduction: Eculizumab is effective and well tolerated in patients with antiacetylcholine receptor antibody-positive refractory generalized myasthenia gravis (gMG; REGAIN; NCT01997229). We report an interim analysis of an open-label extension of REGAIN, evaluating eculizumab's long-term safety and efficacy. Methods: Eculizumab (1,200 mg every 2 weeks for 22.7 months [median]) was administered to 117 patients. Results: The safety profile of eculizumab was consistent with REGAIN; no cases of meningococcal infection were reported during the interim analysis period. Myasthenia gravis exacerbation rate was reduced by 75% from the year before REGAIN (P < 0.0001). Improvements with eculizumab in activities of daily living, muscle strength, functional ability, and quality of life in REGAIN were maintained through 3 years; 56% of patients achieved minimal manifestations or pharmacological remission. Patients who had received placebo during REGAIN experienced rapid and sustained improvements during open-label eculizumab (P < 0.0001). Discussion: These findings provide evidence for the long-term safety and sustained efficacy of eculizumab for refractory gMG. Muscle Nerve 2019