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Microorganism motility often takes place within complex, viscoelastic fluid environments, e.g., sperm in cervicovaginal mucus and bacteria in biofilms. In such complex fluids, strains and stresses generated by the microorganism are stored and relax across a spectrum of length and time scales and the complex fluid can be driven out of its linear response regime. Phenomena not possible in viscous media thereby arise from feedback between the swimmer and the complex fluid, making swimming efficiency co-dependent on the propulsion mechanism and fluid properties. Here we parameterize a flagellar motor and filament properties together with elastic relaxation and nonlinear shear-thinning properties of the fluid in a computational immersed boundary model. We then explore swimming efficiency, defined as a particular flow rate divided by the torque required to spin the motor, over this parameter space. Our findings indicate that motor efficiency (measured by the volumetric flow rate) can be boosted or degraded by relatively moderate or strong shear-thinning of the viscoelastic environment., Competing Interests: Declaration of interests. The authors report no conflict of interest. more...

Cardiac fluid dynamics fundamentally involves interactions between complex blood flows and the structural deformations of the muscular heart walls and the thin valve leaflets. There has been longstanding scientific, engineering, and medical interest in creating mathematical models of the heart that capture, explain, and predict these fluid-structure interactions (FSIs). However, existing computational models that account for interactions among the blood, the actively contracting myocardium, and the valves are limited in their abilities to predict valve performance, capture fine-scale flow features, or use realistic descriptions of tissue biomechanics. Here we introduce and benchmark a comprehensive mathematical model of cardiac FSI in the human heart. A unique feature of our model is that it incorporates biomechanically detailed descriptions of all major cardiac structures that are calibrated using tensile tests of human tissue specimens to reflect the heart's microstructure. Further, it is the first FSI model of the heart that provides anatomically and physiologically detailed representations of all four cardiac valves. We demonstrate that this integrative model generates physiologic dynamics, including realistic pressure-volume loops that automatically capture isovolumetric contraction and relaxation, and that its responses to changes in loading conditions are consistent with the Frank-Starling mechanism. These complex relationships emerge intrinsically from interactions within our comprehensive description of cardiac physiology. Such models can serve as tools for predicting the impacts of medical interventions. They also can provide platforms for mechanistic studies of cardiac pathophysiology and dysfunction, including congenital defects, cardiomyopathies, and heart failure, that are difficult or impossible to perform in patients., (© The Author(s) 2024. Published by Oxford University Press on behalf of National Academy of Sciences.) more...

We present and analyze a series of benchmark tests regarding the application of the immersed boundary (IB) method to viscoelastic flows through and around non-trivial, stationary geometries. The IB method is widely used to simulate biological fluid dynamics and other modeling scenarios in which a structure is immersed in a fluid. Although the IB method has been most commonly used to model systems involving viscous incompressible fluids, it also can be applied to visoelastic fluids, and has enabled the study of a wide variety of dynamical problems including the settling of vesicles and the swimming of elastic filaments in fluids modeled by the Oldroyd-B constitutive equation. In the viscoelastic context, however, relatively little work has explored the accuracy or convergence properties of this numerical scheme. Herein, we present benchmarking results for an IB solver applied to viscoelastic flows in and around non-trivial geometries using either the idealized Oldroyd-B constitutive model or the more physcially realistic, polymer-entanglementbased Rolie-Poly constitutive equations. We use two-dimensional numerical test cases along with results from rheology experiments to benchmark the IB method and compare it to more complex finite element and finite volume viscoelastic flow solvers. Additionally, we analyze different choices of regularized delta function and relative Lagrangian grid spacings which allow us to identify and recommend the key choices of these numerical parameters depending on the present flow regime., Competing Interests: None declared. more...

Laser processing in metals is versatile yet limited by its reliance on phase transformation through heating rather than electronic excitation due to their low absorptivity, attributing from highly ordered structures. Metastable states (i.e., surfaces, glasses, undercooled liquids), however, present a unique platform, both energetically and structurally to enable energy landscape tuning through selective stimuli. Herein, this ansatz is demonstrated by exploiting thin passivating oxides to stabilize an undercooled state, followed by photo-perturbation of the near surface order to induce convective Marangoni flows, edge-coalescence and phase transition into a larger metastable solid bearing asymmetric composition between the near surface and core of the formed structure. The self-terminating nature of the process creates a perfectly contained system which can maintain a high relaxation energy barrier hence deep metastable states for extended periods of time., (© 2023 The Authors. Advanced Materials published by Wiley-VCH GmbH.) more...

Cardiac fluid dynamics fundamentally involves interactions between complex blood flows and the structural deformations of the muscular heart walls and the thin, flexible valve leaflets. There has been longstanding scientific, engineering, and medical interest in creating mathematical models of the heart that capture, explain, and predict these fluid-structure interactions. However, existing computational models that account for interactions among the blood, the actively contracting myocardium, and the cardiac valves are limited in their abilities to predict valve performance, resolve fine-scale flow features, or use realistic descriptions of tissue biomechanics. Here we introduce and benchmark a comprehensive mathematical model of cardiac fluid dynamics in the human heart. A unique feature of our model is that it incorporates biomechanically detailed descriptions of all major cardiac structures that are calibrated using tensile tests of human tissue specimens to reflect the heart's microstructure. Further, it is the first fluid-structure interaction model of the heart that provides anatomically and physiologically detailed representations of all four cardiac valves. We demonstrate that this integrative model generates physiologic dynamics, including realistic pressure-volume loops that automatically capture isovolumetric contraction and relaxation, and predicts fine-scale flow features. None of these outputs are prescribed; instead, they emerge from interactions within our comprehensive description of cardiac physiology. Such models can serve as tools for predicting the impacts of medical devices or clinical interventions. They also can serve as platforms for mechanistic studies of cardiac pathophysiology and dysfunction, including congenital defects, cardiomyopathies, and heart failure, that are difficult or impossible to perform in patients. more...

This paper introduces a sharp-interface approach to simulating fluid-structure interaction (FSI) involving flexible bodies described by general nonlinear material models and across a broad range of mass density ratios. This new flexible-body immersed Lagrangian-Eulerian (ILE) scheme extends our prior work on integrating partitioned and immersed approaches to rigid-body FSI. Our numerical approach incorporates the geometrical and domain solution flexibility of the immersed boundary (IB) method with an accuracy comparable to body-fitted approaches that sharply resolve flows and stresses up to the fluid-structure interface. Unlike many IB methods, our ILE formulation uses distinct momentum equations for the fluid and solid subregions with a Dirichlet-Neumann coupling strategy that connects fluid and solid subproblems through simple interface conditions. As in earlier work, we use approximate Lagrange multiplier forces to treat the kinematic interface conditions along the fluid-structure interface. This penalty approach simplifies the linear solvers needed by our formulation by introducing two representations of the fluid-structure interface, one that moves with the fluid and another that moves with the structure, that are connected by stiff springs. This approach also enables the use of multi-rate time stepping, which allows us to use different time step sizes for the fluid and structure subproblems. Our fluid solver relies on an immersed interface method (IIM) for discrete surfaces to impose stress jump conditions along complex interfaces while enabling the use of fast structured-grid solvers for the incompressible Navier-Stokes equations. The dynamics of the volumetric structural mesh are determined using a standard finite element approach to large-deformation nonlinear elasticity via a nearly incompressible solid mechanics formulation. This formulation also readily accommodates compressible structures with a constant total volume, and it can handle fully compressible solid structures for cases in which at least part of the solid boundary does not contact the incompressible fluid. Selected grid convergence studies demonstrate second-order convergence in volume conservation and in the pointwise discrepancies between corresponding positions of the two interface representations as well as between first and second-order convergence in the structural displacements. The time stepping scheme is also demonstrated to yield second-order convergence. To assess and validate the robustness and accuracy of the new algorithm, comparisons are made with computational and experimental FSI benchmarks. Test cases include both smooth and sharp geometries in various flow conditions. We also demonstrate the capabilities of this methodology by applying it to model the transport and capture of a geometrically realistic, deformable blood clot in an inferior vena cava filter., Competing Interests: Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. more...

Subclinical leaflet thrombosis (SLT) is a potentially serious complication of aortic valve replacement with a bioprosthetic valve in which blood clots form on the replacement valve. SLT is associated with increased risk of transient ischemic attacks and strokes and can progress to clinical leaflet thrombosis. SLT following aortic valve replacement also may be related to subsequent structural valve deterioration, which can impair the durability of the valve replacement. Because of the difficulty in clinical imaging of SLT, models are needed to determine the mechanisms of SLT and could eventually predict which patients will develop SLT. To this end, we develop methods to simulate leaflet thrombosis that combine fluid-structure interaction and a simplified thrombosis model that allows for deposition along the moving leaflets. Additionally, this model can be adapted to model deposition or absorption along other moving boundaries. We present convergence results and quantify the model's ability to realize changes in valve opening and pressures. These new approaches are an important advancement in our tools for modeling thrombosis because they incorporate both adhesion to the surface of the moving leaflets and feedback to the fluid-structure interaction., (© 2023 John Wiley & Sons Ltd.) more...

Objective: To determine the relative efficacy of structured named diet and health behaviour programmes (dietary programmes) for prevention of mortality and major cardiovascular events in patients at increased risk of cardiovascular disease., Design: Systematic review and network meta-analysis of randomised controlled trials., Data Sources: AMED (Allied and Complementary Medicine Database), CENTRAL (Cochrane Central Register of Controlled Trials), Embase, Medline, CINAHL (Cumulative Index to Nursing and Allied Health Literature), and ClinicalTrials.gov were searched up to September 2021., Study Selection: Randomised trials of patients at increased risk of cardiovascular disease that compared dietary programmes with minimal intervention (eg, healthy diet brochure) or alternative programmes with at least nine months of follow-up and reporting on mortality or major cardiovascular events (such as stroke or non-fatal myocardial infarction). In addition to dietary intervention, dietary programmes could also include exercise, behavioural support, and other secondary interventions such as drug treatment., Outcomes and Measures: All cause mortality, cardiovascular mortality, and individual cardiovascular events (stroke, non-fatal myocardial infarction, and unplanned cardiovascular interventions)., Review Methods: Pairs of reviewers independently extracted data and assessed risk of bias. A random effects network meta-analysis was performed using a frequentist approach and grading of recommendations assessment, development and evaluation (GRADE) methods to determine the certainty of evidence for each outcome., Results: 40 eligible trials were identified with 35 548 participants across seven named dietary programmes (low fat, 18 studies; Mediterranean, 12; very low fat, 6; modified fat, 4; combined low fat and low sodium, 3; Ornish, 3; Pritikin, 1). At last reported follow-up, based on moderate certainty evidence, Mediterranean dietary programmes proved superior to minimal intervention for the prevention of all cause mortality (odds ratio 0.72, 95% confidence interval 0.56 to 0.92; patients at intermediate risk: risk difference 17 fewer per 1000 followed over five years), cardiovascular mortality (0.55, 0.39 to 0.78; 13 fewer per 1000), stroke (0.65, 0.46 to 0.93; 7 fewer per 1000), and non-fatal myocardial infarction (0.48, 0.36 to 0.65; 17 fewer per 1000). Based on moderate certainty evidence, low fat programmes proved superior to minimal intervention for prevention of all cause mortality (0.84, 0.74 to 0.95; 9 fewer per 1000) and non-fatal myocardial infarction (0.77, 0.61 to 0.96; 7 fewer per 1000). The absolute effects for both dietary programmes were more pronounced for patients at high risk. There were no convincing differences between Mediterranean and low fat programmes for mortality or non-fatal myocardial infarction. The five remaining dietary programmes generally had little or no benefit compared with minimal intervention typically based on low to moderate certainty evidence., Conclusions: Moderate certainty evidence shows that programmes promoting Mediterranean and low fat diets, with or without physical activity or other interventions, reduce all cause mortality and non-fatal myocardial infarction in patients with increased cardiovascular risk. Mediterranean programmes are also likely to reduce stroke risk. Generally, other named dietary programmes were not superior to minimal intervention., Systematic Review Registration: PROSPERO CRD42016047939., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from Dalhousie University for the submitted work; no other relationships or activities that could appear to have influenced the submitted work. BCJ received a grant from Texas A&M AgriLife Research to fund investigator initiated research related to saturated and polyunsaturated fats. The grant was from Texas A&M AgriLife institutional funds from interest and investment earnings, not a sponsoring organisation, industry, or company., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.) more...

The immersed finite element-finite difference (IFED) method is a computational approach to modeling interactions between a fluid and an immersed structure. The IFED method uses a finite element (FE) method to approximate the stresses, forces, and structural deformations on a structural mesh and a finite difference (FD) method to approximate the momentum and enforce incompressibility of the entire fluid-structure system on a Cartesian grid. The fundamental approach used by this method follows the immersed boundary framework for modeling fluid-structure interaction (FSI), in which a force spreading operator prolongs structural forces to a Cartesian grid, and a velocity interpolation operator restricts a velocity field defined on that grid back onto the structural mesh. With an FE structural mechanics framework, force spreading first requires that the force itself be projected onto the finite element space. Similarly, velocity interpolation requires projecting velocity data onto the FE basis functions. Consequently, evaluating either coupling operator requires solving a matrix equation at every time step. Mass lumping, in which the projection matrices are replaced by diagonal approximations, has the potential to accelerate this method considerably. This paper provides both numerical and computational analyses of the effects of this replacement for evaluating the force projection and for the IFED coupling operators. Constructing the coupling operators also requires determining the locations on the structure mesh where the forces and velocities are sampled. Here we show that sampling the forces and velocities at the nodes of the structural mesh is equivalent to using lumped mass matrices in the IFED coupling operators. A key theoretical result of our analysis is that if both of these approaches are used together, the IFED method permits the use of lumped mass matrices derived from nodal quadrature rules for any standard interpolatory element. This is different from standard FE methods, which require specialized treatments to accommodate mass lumping with higher-order shape functions. Our theoretical results are confirmed by numerical benchmarks, including standard solid mechanics tests and examination of a dynamic model of a bioprosthetic heart valve. more...

Few studies have investigated the effect of a monosaturated diet high in ω-9 on osteoporosis. We hypothesized that omega-9 (ω-9) protects ovariectomized (OVX) mice from a decline in bone microarchitecture, tissue loss, and mechanical strength, thereby serving as a modifiable dietary intervention against osteoporotic deterioration. Female C57BL/6J mice were assigned to sham-ovariectomy, ovariectomy, or ovariectomy + estradiol treatment prior to switching their feed to a diet high in ω-9 for 12 weeks. Tibiae were evaluated using DMA, 3-point-bending, histomorphometry, and microCT. A significant decrease in lean mass ( p = 0.05), tibial area ( p = 0.009), and cross-sectional moment of inertia ( p = 0.028) was measured in OVX mice compared to the control. A trend was seen where OVX bone displayed increased elastic modulus, ductility, storage modulus, and loss modulus, suggesting the ω-9 diet paradoxically increased both stiffness and viscosity. This implies beneficial alterations on the macro-structural, and micro-tissue level in OVX bone, potentially decreasing the fracture risk. Supporting this, no significant differences in ultimate, fracture, and yield stresses were measured. A diet high in ω-9 did not prevent microarchitectural deterioration, nevertheless, healthy tibial strength and resistance to fracture was maintained via mechanisms independent of bone structure/shape. Further investigation of ω-9 as a therapeutic in osteoporosis is warranted. more...

We propose a variational multiscale method stabilization of a linear finite element method for nonlinear poroelasticity. Our approach is suitable for the implicit time integration of poroelastic formulations in which the solid skeleton is anisotropic and incompressible. A detailed numerical methodology is presented for a monolithic formulation that includes both structural dynamics and Darcy flow. Our implementation of this methodology is verified using several hyperelastic and poroelastic benchmark cases, and excellent agreement is obtained with the literature. Grid convergence studies for both anisotropic hyperelastodynamics and poroelastodynamics demonstrate that the method is second-order accurate. The capabilities of our approach are demonstrated using a model of the left ventricle (LV) of the heart derived from human imaging data. Simulations using this model indicate that the anisotropicity of the myocardium has a substantial influence on the pore pressure. Furthermore, the temporal variations of the various components of the pore pressure (hydrostatic pressure and pressure resulting from changes in the volume of the pore fluid) are correlated with the variation of the added mass and dynamics of the LV, with maximum pore pressure being obtained at peak systole. The order of magnitude and the temporal variation of the pore pressure are in good agreement with the literature., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. more...

Transcatheter aortic valve replacement (TAVR) first received FDA approval for high-risk surgical patients in 2011 and has been approved for low-risk surgical patients since 2019. It is now the most common type of aortic valve replacement, and its use continues to accelerate. Computer modeling and simulation (CM&S) is a tool to aid in TAVR device design, regulatory approval, and indication in patient-specific care. This study introduces a computational fluid-structure interaction (FSI) model of TAVR with Medtronic's CoreValve Evolut R device using the immersed finite element-difference (IFED) method. We perform dynamic simulations of crimping and deployment of the Evolut R, as well as device behavior across the cardiac cycle in a patient-specific aortic root anatomy reconstructed from computed tomography (CT) image data. These IFED simulations, which incorporate biomechanics models fit to experimental tensile test data, automatically capture the contact within the device and between the self-expanding stent and native anatomy. Further, we apply realistic driving and loading conditions based on clinical measurements of human ventricular and aortic pressures and flow rates to demonstrate that our Evolut R model supports a physiological diastolic pressure load and provides informative clinical performance predictions., (© 2022. The Author(s).) more...

This paper presents a semi-automatic method for the construction of volumetric models of the aortic valve using computed tomography angiography images. Although the aortic valve typically cannot be segmented directly from a computed tomography angiography image, the method described herein uses manually selected samples of an aortic segmentation derived from this image to inform the construction. These samples capture certain physiologic landmarks and are used to construct a volumetric valve model. As a demonstration of the capabilities of this method, valve models for 25 pediatric patients are created. A selected valve anatomy is used to perform fluid-structure interaction simulations using the immersed finite element/difference method with physiologic driving and loading conditions. Simulation results demonstrate this method creates a functional valve that opens and closes normally and generates pressure and flow waveforms that are similar to those observed clinically., (© 2022. The Author(s) under exclusive licence to Biomedical Engineering Society.) more...

Atrial fibrillation (AF) is the most common arrhythmia encountered clinically, and as the population ages, its prevalence is increasing. Although the CHA 2 DS 2 perscript>- VASc score is the most used risk-stratification system for stroke risk in AF, it lacks personalization. Patient-specific computer models of the atria can facilitate personalized risk assessment and treatment planning. However, a challenge faced in creating such models is the complexity of the atrial muscle arrangement and its influence on the atrial fiber architecture. This work proposes a semi-automated rule-based algorithm to generate the local fiber orientation in the left atrium (LA). We use the solutions of several harmonic equations to decompose the LA anatomy into subregions. Solution gradients define a two-layer fiber field in each subregion. The robustness of our approach is demonstrated by recreating the fiber orientation on nine models of the LA obtained from AF patients who underwent WATCHMAN device implantation. This cohort of patients encompasses a variety of morphology variants of the left atrium, both in terms of the left atrial appendages (LAAs) and the number of pulmonary veins (PVs). We test the fiber construction algorithm by performing electrophysiology (EP) simulations. Furthermore, this study is the first to compare its results with other rule-based algorithms for the LA fiber architecture definition available in the literature. This analysis suggests that a multi-layer fiber architecture is important to capture complex electrical activation patterns. A notable advantage of our approach is the ability to reconstruct the main LA fiber bundles in a variety of morphologies while solving for a small number of harmonic fields, leading to a comparatively straightforward and reproducible approach., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Rossi, Abdala, Woodward, Vavalle, Henriquez and Griffith.) more...

The influence of diet on the development of osteoporosis is significant and not fully understood. This study investigated the effect of diets of varying lipid profiles and ω-3, ω-6 and ω-9 composition on the structural and mechanical properties of bone. The hypothesis studied was that a diet high in saturated fat would induce osteoporosis and produce an overall increased detrimental bony response when compared with a diet high in unsaturated ω-6, or ω-9. Male C57BL/6J mice were fed either a control diet, 50:50 mix (saturated:unsaturated) high in ω-9 (HFD50:50), a diet high in saturated fat (HSF) or a polyunsaturated fat diet high in ω-6 (PUFA) over an 8-week duration. Tibiae were retrieved and evaluated using DMA, 3-point-bending, histomorphometry, and microCT. Mice fed a HSF diet displayed key features characteristic of osteoporosis. The loss tangent was significantly increased in the HFD50:50 diet group compared with control (p = 0.016) and PUFA-fed animals (p = 0.049). HFD50:50-fed mice presented with an increased viscous component, longer tibiae, increased loss modulus (p = 0.009), and ultimate stress, smaller microcracks (p < 0.001), and increased trabecular width (p = 0.002) compared with control animals. A diet high in ω-9 resulted in an overall superior bone response and further analysis of its role in bone health is warranted. more...

The immersed boundary (IB) method is a non-body conforming approach to fluid-structure interaction (FSI) that uses an Eulerian description of the momentum, viscosity, and incompressibility of a coupled fluid-structure system and a Lagrangian description of the deformations, stresses, and resultant forces of the immersed structure. Integral transforms with Dirac delta function kernels couple the Eulerian and Lagrangian variables, and in practice, discretizations of these integral transforms use regularized delta function kernels. Many different kernel functions have been proposed, but prior numerical work investigating the impact of the choice of kernel function on the accuracy of the methodology has often been limited to simplified test cases or Stokes flow conditions that may not reflect the method's performance in applications, particularly at intermediate-to-high Reynolds numbers, or under different loading conditions. This work systematically studies the effect of the choice of regularized delta function in several fluid-structure interaction benchmark tests using the immersed finite element/difference (IFED) method, which is an extension of the IB method that uses a finite element structural discretization combined with a Cartesian grid finite difference method for the incompressible Navier-Stokes equations. Whereas the conventional IB method spreads forces from the nodes of the structural mesh and interpolates velocities to those nodes, the IFED formulation evaluates the regularized delta function on a collection of interaction points that can be chosen to be denser than the nodes of the Lagrangian mesh. This opens the possibility of using structural discretizations with wide node spacings that would produce gaps in the Eulerian force in nodally coupled schemes (e.g., if the node spacing is comparable to or broader than the support of the regularized delta functions). Earlier work with this methodology suggested that such coarse structural meshes can yield improved accuracy for shear-dominated cases and, further, found that accuracy improves when the structural mesh spacing is increased . However, these results were limited to simple test cases that did not include substantial pressure loading on the structure. This study investigates the effect of varying the relative mesh widths of the Lagrangian and Eulerian discretizations in a broader range of tests. Our results indicate that kernels satisfying a commonly imposed even-odd condition require higher resolution to achieve similar accuracy as kernels that do not satisfy this condition. We also find that narrower kernels are more robust, in the sense that they yield results that are less sensitive to relative changes in the Eulerian and Lagrangian mesh spacings, and that structural meshes that are substantially coarser than the Cartesian grid can yield high accuracy for shear-dominated cases but not for cases with large normal forces. We verify our results in a large-scale FSI model of a bovine pericardial bioprosthetic heart valve in a pulse duplicator., Competing Interests: Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. more...

We present a new discretization approach to advection-diffusion problems with Robin boundary conditions on complex, time-dependent domains. The method is based on second order cut cell finite volume methods introduced by Bochkov et al. [8] to discretize the Laplace operator and Robin boundary condition. To overcome the small cell problem, we use a splitting scheme along with a semi-Lagrangian method to treat advection. We demonstrate second order accuracy in the L 1 , L 2 , and L ∞ norms for both analytic test problems and numerical convergence studies. We also demonstrate the ability of the scheme to convert one chemical species to another across a moving boundary., Competing Interests: Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. more...

Objectives: Physical pain is a known symptom in amyotrophic lateral sclerosis (ALS), but no systematically derived prevalence estimate is available. The aim of this study was to determine the pooled prevalence of pain in ALS, relative to its method of measurement and pain characteristics. Methods : A systematic search across multiple databases was conducted on January 16, 2020. Random-effects meta-analyses of single proportions were performed on prevalence data. Heterogeneity was determined using the I 2 statistic. Where available, pain location, intensity, and type or source were compared. Results: 2552 articles were identified. Twenty-one eligible studies were included. All studies used observational designs (14 cross-sectional, 6 cohort, 1 case-control). Pooled prevalence of pain in ALS across all studies was 60% (95% CI = 50-69%), with a high degree of heterogeneity ( I 2 = 94%, p < .001). Studies that used only validated measures had lower heterogeneity ( I 2 = 82%, p  = 0.002), compared to those that used tailored measures, or tailored supplemented with validated measures ( I 2 = 90%, p  < 0.001 and I 2 = 83%, p  < 0.001, respectively). In a subset of studies ( N  = 9), the most commonly reported pain location was the upper limbs including shoulders/extremities (41.5%). A further study subset ( N  = 7) showed moderate-severe intensity pain was most frequently reported. Type of pain was commonly related to cramp or spasm. Conclusions: Experiencing physical pain in ALS occurs with high prevalence. Deriving consensus on which specific tools should be used to assess, monitor and compare symptoms of pain in this population will reduce current heterogeneity in approaches and increase the likelihood of ameliorating distressing experiences more effectively. more...

Amphiphilic phospholipid-iodinated polymer conjugates were designed and synthesized as new macromolecular probes for a highly radiopaque and biocompatible imaging technology. Bioconjugation of PEG 2000-phospholipids and iodinated polyesters by click chemistry created amphiphilic moieties with hydrophobic polyesters and hydrophilic PEG units, which allowed their self-assemblies into vesicles or spiked vesicles. More importantly, the conjugates exhibited high radiopacity and biocompatibility in in vitro X-ray and cell viability measurements. This new type of bioimaging contrast agent with a Mn value of 11 289 g mol-1 was found to have a significant X-ray signal at 3.13 mg mL-1 of iodine equivalent than baseline and no cytotoxicity after 48 hours incubation of with HEK and 3T3 cells at 20 μM (20 picomoles) concentration of conjugates per well. The potential of adopting the described macromolecular probes for bioimaging was demonstrated, which could further promote the development of a field-friendly and highly sensitive bioimaging contrast agent for point-of-care diagnostic applications. more...

This paper focuses on the derivation and simulation of mathematical models describing new plasma fraction in blood for patients undergoing simultaneous extracorporeal membrane oxygenation and therapeutic plasma exchange. Models for plasma exchange with either veno-arterial or veno-venous extracorporeal membrane oxygenation are considered. Two classes of models are derived for each case, one in the form of an algebraic delay equation and another in the form of a system of delay differential equations. In special cases, our models reduce to single compartment ones for plasma exchange that have been validated with experimental data (Randerson et al., 1982, Artif. Organs, 6, 43-49). We also show that the algebraic differential equations are forward Euler discretizations of the delay differential equations, with timesteps equal to transit times through model compartments. Numerical simulations are performed to compare different model types, to investigate the impact of plasma device port switching on the efficiency of the exchange process, and to study the sensitivity of the models to their parameters., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Institute of Mathematics and its Applications. All rights reserved.) more...

Objective: Bioprosthetic heart valves (BHVs) are commonly used in surgical and percutaneous valve replacement. The durability of percutaneous valve replacement is unknown, but surgical valves have been shown to require reintervention after 10 to 15 years. Further, smaller-diameter surgical BHVs generally experience higher rates of prosthesis-patient mismatch, which leads to higher rates of failure. Bioprosthetic aortic valves can flutter in systole, and fluttering is associated with fatigue and failure in flexible structures. The determinants of flutter in BHVs have not been well characterized, despite their potential to influence durability., Methods: We use an experimental pulse duplicator and a computational fluid-structure interaction model of this system to study the role of device geometry on BHV dynamics. The experimental system mimics physiological conditions, and the computational model enables precise control of leaflet biomechanics and flow conditions to isolate the effects of variations in BHV geometry on leaflet dynamics., Results: Both experimental and computational models demonstrate that smaller-diameter BHVs yield markedly higher leaflet fluttering frequencies across a range of conditions. The computational model also predicts that fluttering frequency is directly related to leaflet thickness. A scaling model is introduced that rationalizes these findings., Conclusions: We systematically characterize the influence of BHV diameter and leaflet thickness on fluttering dynamics. Although this study does not determine how flutter influences device durability, increased flutter in smaller-diameter BHVs may explain how prosthesis-patient mismatch could induce BHV leaflet fatigue and failure. Ultimately, understanding the effects of device geometry on leaflet kinematics may lead to more durable valve replacements., Competing Interests: Conflict of Interest Statement Dr Vavalle serves as a consultant for Edwards Lifesciences. All other authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest. more...

Cardiac pacemaker cells (CPCs) rhythmically initiate the electrical impulses that drive heart contraction. CPCs display the highest rate of spontaneous depolarization in the heart despite being subjected to inhibitory electrochemical conditions that should theoretically suppress their activity. While several models have been proposed to explain this apparent paradox, the actual molecular mechanisms that allow CPCs to overcome electrogenic barriers to their function remain poorly understood. Here, we have traced CPC development at single-cell resolution and uncovered a series of cytoarchitectural patterning events that are critical for proper pacemaking. Specifically, our data reveal that CPCs dynamically modulate adherens junction (AJ) engagement to control characteristics including surface area, volume, and gap junctional coupling. This allows CPCs to adopt a structural configuration that supports their overall excitability. Thus, our data have identified a direct role for local cellular mechanics in patterning critical morphological features that are necessary for CPC electrical activity., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.) more...

Background: Diabetes and periodontitis have a bi-directional relationship. And yet, collaborations between primary healthcare practitioners in diabetes and oral health care are minimal. This study explored the views of general practice and oral health professionals on the link between diabetes and periodontitis, and interprofessional diabetes and oral health management. Methods: A sequential mixed-methods exploratory research design was used. General practice and oral health professionals were recruited from four community health centres in Melbourne. Quantitative surveys explored participants' experiences, attitudes and knowledge of diabetes and oral health management and interprofessional collaboration; qualitative follow-up interviews explored survey responses with selected participants. Results: 58 participants completed the online surveys; 22 then participated in semi-structured interviews. Participants generally had strong intentions to collaborate interprofessionally in diabetes and oral health management. Most general practice and oral health professional participants were willing to perform simple screening for periodontitis or diabetes respectively. Themes from the interviews were grouped under three domains: 'a ttitude towards diabetes and oral health management', 'subjective norms' and 'perceived behavioural control'; and an overarching domain to describe participants' 'current practice'. Existing siloed primary healthcare practices and lack of formal referral pathways contribute to poor interprofessional collaboration. Most participants were unsure of each other's responsibilities and roles. Their lack of training in the relationship between general and oral health, compounded by systemic barriers including time constraint, high dental costs, long public dental waiting list and unintegrated health information systems, also impeded interprofessional care. Conclusions: The diabetes and oral health link is not properly recognised or managed collaboratively by relevant primary healthcare professionals in Australia. There is, nonetheless, strong intentions to engage in interprofessional diabetes and oral health care to contribute to improved patient outcomes. Primary healthcare professionals need dedicated and accredited interprofessional training and competencies, formal referral systems and sustainable health policies to facilitate collaboration., Competing Interests: No competing interests were disclosed., (Copyright: © 2021 Lau P et al.) more...

Modern approaches to modelling cardiac perfusion now commonly describe the myocardium using the framework of poroelasticity. Cardiac tissue can be described as a saturated porous medium composed of the pore fluid (blood) and the skeleton (myocytes and collagen scaffold). In previous studies fluid-structure interaction in the heart has been treated in a variety of ways, but in most cases, the myocardium is assumed to be a hyperelastic fibre-reinforced material. Conversely, models that treat the myocardium as a poroelastic material typically neglect interactions between the myocardium and intracardiac blood flow. This work presents a poroelastic immersed finite element framework to model left ventricular dynamics in a three-phase poroelastic system composed of the pore blood fluid, the skeleton, and the chamber fluid. We benchmark our approach by examining a pair of prototypical poroelastic formations using a simple cubic geometry considered in the prior work by Chapelle et al (2010). This cubic model also enables us to compare the differences between system behaviour when using isotropic and anisotropic material models for the skeleton. With this framework, we also simulate the poroelastic dynamics of a three-dimensional left ventricle, in which the myocardium is described by the Holzapfel-Ogden law. Results obtained using the poroelastic model are compared to those of a corresponding hyperelastic model studied previously. We find that the poroelastic LV behaves differently from the hyperelastic LV model. For example, accounting for perfusion results in a smaller diastolic chamber volume, agreeing well with the well-known wall-stiffening effect under perfusion reported previously. Meanwhile differences in systolic function, such as fibre strain in the basal and middle ventricle, are found to be comparatively minor., (© 2021 The Authors. International Journal for Numerical Methods in Biomedical Engineering published by John Wiley & Sons Ltd.) more...

Vascular access connection configurations during tandem extracorporeal membrane oxygenation (ECMO) and therapeutic plasma exchange (TPE) may impact exchange kinetics. In these tandem procedures, typically the TPE inlet line is proximal to the TPE return line with respect to blood flow in the ECMO device, maximizing the opportunity for replacement fluid homogenization within the ECMO circuit. However, if TPE inlet and return line connections are switched, recirculation-a phenomenon in which replacement fluid leaving the TPE return line is prematurely drawn into the TPE inlet line prior to satisfactory homogenization within the ECMO circuit-will occur. Such recirculation could diminish TPE efficacy in patients on ECMO and mitigate therapeutic benefits. Using a mathematical model of recirculation in tandem ECMO and TPE, we demonstrate that the predicted impact of recirculation is negligible and vascular access connection positioning does not appear to be a point of clinical concern with regard to TPE kinetics., (© 2020 Wiley Periodicals LLC.) more...

The immersed boundary method is a mathematical framework for modeling fluid-structure interaction. This formulation describes the momentum, viscosity, and incompressibility of the fluid-structure system in Eulerian form, and it uses Lagrangian coordinates to describe the structural deformations, stresses, and resultant forces. Integral transforms with Dirac delta function kernels connect the Eulerian and Lagrangian frames. The fluid and the structure are both typically treated as incompressible materials. Upon discretization, however, the incompressibility of the structure is only maintained approximately. To obtain an immersed method for incompressible hyperelastic structures that is robust under large structural deformations, we introduce a volumetric energy in the solid region that stabilizes the formulation and improves the accuracy of the numerical scheme. This formulation augments the discrete Lagrange multiplier for the incompressibility constraint, thereby improving the original method's accuracy. This volumetric energy is incorporated by decomposing the strain energy into isochoric and dilatational components, as in standard solid mechanics formulations of nearly incompressible elasticity. We study the performance of the stabilized method using several quasi-static solid mechanics benchmarks, a dynamic fluid-structure interaction benchmark, and a detailed three-dimensional model of esophageal transport. The accuracy achieved by the stabilized immersed formulation is comparable to that of a stabilized finite element method for incompressible elasticity using similar numbers of structural degrees of freedom., Competing Interests: Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. more...

Computer modeling and simulation is a powerful tool for assessing the performance of medical devices such as bioprosthetic heart valves (BHVs) that promises to accelerate device design and regulation. This study describes work to develop dynamic computer models of BHVs in the aortic test section of an experimental pulse-duplicator platform that is used in academia, industry, and regulatory agencies to assess BHV performance. These computational models are based on a hyperelastic finite element extension of the immersed boundary method for fluid-structure interaction (FSI). We focus on porcine tissue and bovine pericardial BHVs, which are commonly used in surgical valve replacement. We compare our numerical simulations to experimental data from two similar pulse duplicators, including a commercial ViVitro system and a custom platform related to the ViVitro pulse duplicator. Excellent agreement is demonstrated between the computational and experimental results for bulk flow rates, pressures, valve open areas, and the timing of valve opening and closure in conditions commonly used to assess BHV performance. In addition, reasonable agreement is demonstrated for quantitative measures of leaflet kinematics under these same conditions. This work represents a step towards the experimental validation of this FSI modeling platform for evaluating BHVs. more...

Rotating disc electrode (RDE) voltammetry has been widely adopted for the study of heterogenized molecular electrocatalysts for multi-step fuel-forming reactions but this tool has never been comprehensively applied to their homogeneous analogues. Here, the utility and limitations of RDE techniques for mechanistic and kinetic analysis of homogeneous molecular catalysts that mediate multi-electron, multi-substrate redox transformations are explored. Using the ECEC' reaction mechanism as a case study, two theoretical models are derived based on the Nernst diffusion layer model and the Hale transformation. Current-potential curves generated by these computational strategies are compared under a variety of limiting conditions to identify conditions under which the more minimalist Nernst Diffusion Layer approach can be applied. Based on this theoretical treatment, strategies for extracting kinetic information from the plateau current and the foot of the catalytic wave are derived. RDEV is applied to a cobaloxime hydrogen evolution reaction (HER) catalyst under non-aqueous conditions in order to experimentally validate this theoretical framework and explore the feasibility of RDE as a tool for studying homogeneous catalysts. Crucially, analysis of the foot-of-the-wave via this theoretical framework provides rate constants for elementary reaction steps that agree with those extracted from stationary voltammetric methods, supporting the application of RDE to study homogeneous fuel-forming catalysts. Finally, obstacles encountered during the kinetic analysis of cobaloxime, along with the voltammetric signatures used to diagnose this reactivity, are discussed with the goal of guiding groups working to improve RDE set-ups and help researchers avoid misinterpretation of RDE data. more...

Fluid-structure systems occur in a range of scientific and engineering applications. The immersed boundary (IB) method is a widely recognized and effective modeling paradigm for simulating fluid-structure interaction (FSI) in such systems, but a difficulty of the IB formulation of these problems is that the pressure and viscous stress are generally discontinuous at fluid-solid interfaces. The conventional IB method regularizes these discontinuities, which typically yields low-order accuracy at these interfaces. The immersed interface method (IIM) is an IB-like approach to FSI that sharply imposes stress jump conditions, enabling higher-order accuracy, but prior applications of the IIM have been largely restricted to numerical methods that rely on smooth representations of the interface geometry. This paper introduces an immersed interface formulation that uses only a C 0 representation of the immersed interface, such as those provided by standard nodal Lagrangian finite element methods. Verification examples for models with prescribed interface motion demonstrate that the method sharply resolves stress discontinuities along immersed boundaries while avoiding the need for analytic information about the interface geometry. Our results also demonstrate that only the lowest-order jump conditions for the pressure and velocity gradient are required to realize global second-order accuracy. Specifically, we demonstrate second-order global convergence rates along with nearly second-order local convergence in the Eulerian velocity field, and between first- and second-order global convergence rates along with approximately first-order local convergence for the Eulerian pressure field. We also demonstrate approximately second-order local convergence in the interfacial displacement and velocity along with first-order local convergence in the fluid traction along the interface. As a demonstration of the method's ability to tackle more complex geometries, the present approach is also used to simulate flow in a patient-averaged anatomical model of the inferior vena cava, which is the large vein that carries deoxygenated blood from the lower extremities back to the heart. Comparisons of the general hemodynamics and wall shear stress obtained by the present IIM and a body-fitted discretization approach show that the present method yields results that are in good agreement with those obtained by the body-fitted approach. more...

Fluid-structure interaction is ubiquitous in nature and occurs at all biological scales. Immersed methods provide mathematical and computational frameworks for modeling fluid-structure systems. These methods, which typically use an Eulerian description of the fluid and a Lagrangian description of the structure, can treat thin immersed boundaries and volumetric bodies, and they can model structures that are flexible or rigid or that move with prescribed deformational kinematics. Immersed formulations do not require body-fitted discretizations and thereby avoid the frequent grid regeneration that can otherwise be required for models involving large deformations and displacements. This article reviews immersed methods for both elastic structures and structures with prescribed kinematics. It considers formulations using integral operators to connect the Eulerian and Lagrangian frames and methods that directly apply jump conditions along fluid-structure interfaces. Benchmark problems demonstrate the effectiveness of these methods, and selected applications at Reynolds numbers up to approximately 20,000 highlight their impact in biological and biomedical modeling and simulation. more...

Current clinical practice for aneurysmatic interventions is often based on the maximum diameter of the vessel and/or on the growth rate, although rupture can occur at any diameter and growth rate, leading to fatality. For 27 medial samples obtained from 12 non-aneurysmatic (control) and 9 aneurysmatic human descending thoracic aortas we examined: the mechanical responses up to rupture using uniaxial extension tests of circumferential and longitudinal specimens; the structure of these tissues using second-harmonic imaging and histology, in particular, the content proportions of collagen, elastic fibers and smooth muscle cells in the media. It was found that the mean failure stresses were higher in the circumferential directions (Control-C 1474kPa; Aneurysmatic-C 1446kPa), than in the longitudinal directions (Aneurysmatic-L 735kPa; Control-L 579kPa). This trend was the opposite to that observed for the mean collagen fiber directions measured from the loading axis (Control-L > Aneurysmatic-L > Aneurysmatic-C > Control-C), thus suggesting that the trend in the failure stress can in part be attributed to the collagen architecture. The difference in the mean values of the out-of-plane dispersion in the radial/longitudinal plane between the control and aneurysmatic groups was significant. The difference in the mean values of the mean fiber angle from the circumferential direction was also significantly different between the two groups. Most specimens showed delamination zones near the ruptured region in addition to ruptured collagen and elastic fibers. This study provides a basis for further studies on the microstructure and the uniaxial failure properties of (aneurysmatic) arterial walls towards realistic modeling and prediction of tissue failure. STATEMENT OF SIGNIFICANCE: A data set relating uniaxial failure properties to the microstructure of non-aneurysmatic and aneurysmatic human thoracic aortic medias under uniaxial extension tests is presented for the first time. It was found that the mean failure stresses were higher in the circumferential directions, than in the longitudinal directions. The general trend for the failure stresses was Control-C > Aneurysmatic-C > Aneurysmatic-L > Control-L, which was the opposite of that observed for the mean collagen fiber direction relative to the loading axis (Control-L > Aneurysmatic-L > Aneurysmatic-C > Control-C) suggesting that the trend in the failure stress can in part be attributed to the collagen architecture. This study provides a first step towards more realistic modeling and prediction of tissue failure., (Copyright © 2019 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.) more...

Ailments of the bladder are often treated via intravesical delivery-direct application of therapeutic into the bladder through a catheter. This technique is employed hundreds of thousands of times every year, but protocol development has largely been limited to empirical determination. Furthermore, the numerical analyses of intravesical delivery performed to date have been restricted to static geometries and have not accounted for bladder deformation. This study uses a finite element analysis approach with biphasic solute transport to investigate several parameters pertinent to intravesical delivery including solute concentration, solute transport properties and instillation volume. The volume of instillation was found to have a substantial impact on the exposure of solute to the deeper muscle layers of the bladder, which are typically more difficult to reach. Indeed, increasing the instillation volume from 50-100 ml raised the muscle solute exposure as a percentage of overall bladder exposure from 60-70% with higher levels achieved for larger instillation volumes. Similar increases were not seen for changes in solute concentration or solute transport properties. These results indicate the role that instillation volume may play in targeting particular layers of the bladder during an intravesical delivery., (© The Author(s) 2018. Published by Oxford University Press on behalf of the Institute of Mathematics and its Applications. All rights reserved.) more...

Reduced weight bearing, and to a lesser extent radiation, during spaceflight have been shown as potential hazards to astronaut joint health. These hazards combined effect to the knee and hip joints are not well defined, particularly with low-dose exposure to radiation. In this study, we examined the individual and combined effects of varying low-dose radiation (≤1 Gy) and reduced weight bearing on the cartilage of the knee and hip joints. C57BL/6J mice (n = 80) were either tail suspended via hindlimb unloading (HLU) or remained full-weight bearing (ground). On day 6, each group was divided and irradiated with 0 Gy (sham), 0.1 Gy, 0.5 Gy or 1.0 Gy (n = 10/group), yielding eight groups: ground-sham; ground-0.1 Gy; ground-0.5 Gy; ground-1.0 Gy; HLU-sham; HLU-0.1 Gy; HLU-0.5 Gy; and HLU-1.0 Gy. On day 30, the hindlimbs, hip cartilage and serum were collected from the mice. Significant differences were identified statistically between treatment groups and the ground-sham control group, but no significant differences were observed between HLU and/or radiation groups. Contrast-enhanced micro-computed tomography (microCECT) demonstrated decrease in volume and thickness at the weight-bearing femoral-tibial cartilage-cartilage contact point in all treatment groups compared to ground-sham. Lower collagen was observed in all groups compared to ground-sham. Circulating serum cartilage oligomeric matrix protein (sCOMP), a biomarker for ongoing cartilage degradation, was increased in all of the irradiated groups compared to ground-sham, regardless of unloading. Mass spectrometry of the cartilage lining the femoral head and subsequent Ingenuity Pathway Analysis (IPA) identified a decrease in cartilage compositional proteins indicative of osteoarthritis. Our findings demonstrate that both individually and combined, HLU and exposure to spaceflight relevant radiation doses lead to cartilage degradation of the knee and hip with expression of an arthritic phenotype. Moreover, early administration of low-dose irradiation (0.1, 0.5 or 1.0 Gy) causes an active catabolic response in cartilage 24 days postirradiation. Further research is warranted with a focus on the prevention of cartilage degradation from long-term periods of reduced weight bearing and spaceflight-relevant low doses and qualities of radiation. more...

Background: Falls are the main cause of death and injury for older adults in the UK. Many of these falls occur within the home as a result of extrinsic falls risk factors such as poor lighting, loose/uneven flooring, and clutter. Falls education plays an important role in self-management education about extrinsic hazards and is typically delivered via information leaflets, falls apps, and educational booklets. Serious games have the potential of delivering an engaging and informative alternative to traditional methods but almost exclusively, these are currently delivered as exergaming applications that focus solely on intrinsic falls risk factors. This study presents 'Falls Sensei' a first-person 3D exploration game that aims to educate older adults about extrinsic falls risk factors within the home environment. After presenting Falls Sensei, game usability and older adults' perceptions and attitudes towards using the game in practice are explored., Methods: This study involved 15 community dwelling older adults. After playing the Falls Sensei game, participants completed a Systems Usability Scale (SUS) questionnaire and post task interview, and follow-up interviews three weeks later. Inductive and deductive thematic template analysis, informed by the Unified Theory of Acceptance and Use of Technology model, was used to analyse the think-aloud, post-task and follow-up interview transcripts. Descriptive statistical analysis and one-sampled t-tests were used to analyse log-file data and SUS responses., Results: Three high-level themes emerged from the analysis of transcriptions: Performance Expectancy; Effort Expectancy; Social Influence. The SUS score was 77.5/100 which indicates 'Good' levels of usability. Interestingly, reported usability of the game increased with participant age. Participants were positive about the usability of the game (p < = 0.05 for 9/10 items). The most memorable fall hazards were those most commonly encountered in the game or those most challenging to participants., Conclusions: The results support the use of serious games as an engaging tool for educating older adults about extrinsic falls risk factors. Awareness of home hazard detection was raised by the game, and some older adults became more aware for the need to adapt their own homes after gameplay. Further research would be needed to draw comparisons with established interventions. more...

We develop a fluid-structure interaction (FSI) model of the mitral valve (MV) that uses an anatomically and physiologically realistic description of the MV leaflets and chordae tendineae. Three different chordae models-complex, 'pseudo-fibre' and simplified chordae-are compared to determine how different chordae representations affect the dynamics of the MV. The leaflets and chordae are modelled as fibre-reinforced hyperelastic materials, and FSI is modelled using an immersed boundary-finite element method. The MV model is first verified under static boundary conditions against the commercial finite element software ABAQUS and then used to simulate MV dynamics under physiological pressure conditions. Interesting flow patterns and vortex formulation are observed in all three cases. To quantify the highly complex system behaviour resulting from FSI, an energy budget analysis of the coupled MV FSI model is performed. Results show that the complex and pseudo-fibre chordae models yield good valve closure during systole but that the simplified chordae model leads to poorer leaflet coaptation and an unrealistic bulge in the anterior leaflet belly. An energy budget analysis shows that the MV models with complex and pseudo-fibre chordae have similar energy distribution patterns but the MV model with the simplified chordae consumes more energy, especially during valve closing and opening. We find that the complex chordae and pseudo-fibre chordae have similar impact on the overall MV function but that the simplified chordae representation is less accurate. Because a pseudo-fibre chordal structure is easier to construct and less computationally intensive, it may be a good candidate for modelling MV dynamics or interaction between the MV and heart in patient-specific applications. more...

Electroanatomical mapping is currently used to provide clinicians with information about the electrophysiological state of the heart and to guide interventions like ablation. These maps can be used to identify ectopic triggers of an arrhythmia such as atrial fibrillation (AF) or changes in the conduction velocity (CV) that have been associated with poor cell to cell coupling or fibrosis. Unfortunately, many factors are known to affect CV, including membrane excitability, pacing rate, wavefront curvature, and bath loading, making interpretation challenging. In this work, we show how endocardial conduction velocities are also affected by the geometrical factors of muscle thickness and wall curvature. Using an idealized three-dimensional strand, we show that transverse conductivities and boundary conditions can slow down or speed up signal propagation, depending on the curvature of the muscle tissue. In fact, a planar wavefront that is parallel to a straight line normal to the mid-surface does not remain normal to the mid-surface in a curved domain. We further demonstrate that the conclusions drawn from the idealized test case can be used to explain spatial changes in conduction velocities in a patient-specific reconstruction of the left atrial posterior wall. The simulations suggest that the widespread assumption of treating atrial muscle as a two-dimensional manifold for electrophysiological simulations will not accurately represent the endocardial conduction velocities in regions of the heart thicker than 0.5 mm with significant wall curvature. more...

The immersed boundary method is an approach to fluid-structure interaction that uses a Lagrangian description of the structural deformations, stresses, and forces along with an Eulerian description of the momentum, viscosity, and incompressibility of the fluid-structure system. The original immersed boundary methods described immersed elastic structures using systems of flexible fibers, and even now, most immersed boundary methods still require Lagrangian meshes that are finer than the Eulerian grid. This work introduces a coupling scheme for the immersed boundary method to link the Lagrangian and Eulerian variables that facilitates independent spatial discretizations for the structure and background grid. This approach uses a finite element discretization of the structure while retaining a finite difference scheme for the Eulerian variables. We apply this method to benchmark problems involving elastic, rigid, and actively contracting structures, including an idealized model of the left ventricle of the heart. Our tests include cases in which, for a fixed Eulerian grid spacing, coarser Lagrangian structural meshes yield discretization errors that are as much as several orders of magnitude smaller than errors obtained using finer structural meshes. The Lagrangian-Eulerian coupling approach developed in this work enables the effective use of these coarse structural meshes with the immersed boundary method. This work also contrasts two different weak forms of the equations, one of which is demonstrated to be more effective for the coarse structural discretizations facilitated by our coupling approach., (© 2017 The Authors International  Journal  for  Numerical  Methods  in  Biomedical  Engineering Published by John Wiley & Sons Ltd.) more...

The Immersed Boundary (IB) method is a mathematical framework for constructing robust numerical methods to study fluid-structure interaction in problems involving an elastic structure immersed in a viscous fluid. The IB formulation uses an Eulerian representation of the fluid and a Lagrangian representation of the structure. The Lagrangian and Eulerian frames are coupled by integral transforms with delta function kernels. The discretized IB equations use approximations to these transforms with regularized delta function kernels to interpolate the fluid velocity to the structure, and to spread structural forces to the fluid. It is well-known that the conventional IB method can suffer from poor volume conservation since the interpolated Lagrangian velocity field is not generally divergence-free, and so this can cause spurious volume changes. In practice, the lack of volume conservation is especially pronounced for cases where there are large pressure differences across thin structural boundaries. The aim of this paper is to greatly reduce the volume error of the IB method by introducing velocity-interpolation and force-spreading schemes with the properties that the interpolated velocity field in which the structure moves is at least C 1 and satisfies a continuous divergence-free condition, and that the force-spreading operator is the adjoint of the velocity-interpolation operator. We confirm through numerical experiments in two and three spatial dimensions that this new IB method is able to achieve substantial improvement in volume conservation compared to other existing IB methods, at the expense of a modest increase in the computational cost. Further, the new method provides smoother Lagrangian forces (tractions) than traditional IB methods. The method presented here is restricted to periodic computational domains. Its generalization to non-periodic domains is important future work. more...

In this work, we extend our previous esophageal transport model using an immersed boundary (IB) method with discrete fiber-based structural model, to one using a continuum mechanics-based model that is approximated based on finite elements (IB-FE). To deal with the leakage of flow when the Lagrangian mesh becomes coarser than the fluid mesh, we employ adaptive interaction quadrature points to deal with Lagrangian-Eulerian interaction equations based on a previous work (Griffith and Luo [1]). In particular, we introduce a new anisotropic adaptive interaction quadrature rule. The new rule permits us to vary the interaction quadrature points not only at each time-step and element but also at different orientations per element. This helps to avoid the leakage issue without sacrificing the computational efficiency and accuracy in dealing with the interaction equations. For the material model, we extend our previous fiber-based model to a continuum-based model. We present formulations for general fiber-reinforced material models in the IB-FE framework. The new material model can handle non-linear elasticity and fiber-matrix interactions, and thus permits us to consider more realistic material behavior of biological tissues. To validate our method, we first study a case in which a three-dimensional short tube is dilated. Results on the pressure-displacement relationship and the stress distribution matches very well with those obtained from the implicit FE method. We remark that in our IB-FE case, the three-dimensional tube undergoes a very large deformation and the Lagrangian mesh-size becomes about 6 times of Eulerian mesh-size in the circumferential orientation. To validate the performance of the method in handling fiber-matrix material models, we perform a second study on dilating a long fiber-reinforced tube. Errors are small when we compare numerical solutions with analytical solutions. The technique is then applied to the problem of esophageal transport. We use two fiber-reinforced models for the esophageal tissue: a bi-linear model and an exponential model. We present three cases on esophageal transport that differ in the material model and the muscle fiber architecture. The overall transport features are consistent with those observed from the previous model. We remark that the continuum-based model can handle more realistic and complicated material behavior. This is demonstrated in our third case where a spatially varying fiber architecture is included based on experimental study. We find that this unique muscle fiber architecture could generate a so-called pressure transition zone, which is a luminal pressure pattern that is of clinical interest. This suggests an important role of muscle fiber architecture in esophageal transport. more...

In standard models of cardiac electrophysiology, including the bidomain and monodomain models, local perturbations can propagate at infinite speed. We address this unrealistic property by developing a hyperbolic bidomain model that is based on a generalization of Ohm's law with a Cattaneo-type model for the fluxes. Further, we obtain a hyperbolic monodomain model in the case that the intracellular and extracellular conductivity tensors have the same anisotropy ratio. In one spatial dimension, the hyperbolic monodomain model is equivalent to a cable model that includes axial inductances, and the relaxation times of the Cattaneo fluxes are strictly related to these inductances. A purely linear analysis shows that the inductances are negligible, but models of cardiac electrophysiology are highly nonlinear, and linear predictions may not capture the fully nonlinear dynamics. In fact, contrary to the linear analysis, we show that for simple nonlinear ionic models, an increase in conduction velocity is obtained for small and moderate values of the relaxation time. A similar behavior is also demonstrated with biophysically detailed ionic models. Using the Fenton-Karma model along with a low-order finite element spatial discretization, we numerically analyze differences between the standard monodomain model and the hyperbolic monodomain model. In a simple benchmark test, we show that the propagation of the action potential is strongly influenced by the alignment of the fibers with respect to the mesh in both the parabolic and hyperbolic models when using relatively coarse spatial discretizations. Accurate predictions of the conduction velocity require computational mesh spacings on the order of a single cardiac cell. We also compare the two formulations in the case of spiral break up and atrial fibrillation in an anatomically detailed model of the left atrium, and we examine the effect of intracellular and extracellular inductances on the virtual electrode phenomenon. more...

Understanding the interaction between the valves and walls of the heart is important in assessing and subsequently treating heart dysfunction. This study presents an integrated model of the mitral valve (MV) coupled to the left ventricle (LV), with the geometry derived from in vivo clinical magnetic resonance images. Numerical simulations using this coupled MV-LV model are developed using an immersed boundary/finite element method. The model incorporates detailed valvular features, left ventricular contraction, nonlinear soft tissue mechanics, and fluid-mediated interactions between the MV and LV wall. We use the model to simulate cardiac function from diastole to systole. Numerically predicted LV pump function agrees well with in vivo data of the imaged healthy volunteer, including the peak aortic flow rate, the systolic ejection duration, and the LV ejection fraction. In vivo MV dynamics are qualitatively captured. We further demonstrate that the diastolic filling pressure increases significantly with impaired myocardial active relaxation to maintain a normal cardiac output. This is consistent with clinical observations. The coupled model has the potential to advance our fundamental knowledge of mechanisms underlying MV-LV interaction, and help in risk stratification and optimisation of therapies for heart diseases., (Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.) more...

Each year, approximately 300,000 heart valve repair or replacement procedures are performed worldwide, including approximately 70,000 aortic valve replacement surgeries in the United States alone. Computational platforms for simulating cardiovascular devices such as prosthetic heart valves promise to improve device design and assist in treatment planning, including patient-specific device selection. This paper describes progress in constructing anatomically and physiologically realistic immersed boundary (IB) models of the dynamics of the aortic root and ascending aorta. This work builds on earlier IB models of fluid-structure interaction (FSI) in the aortic root, which previously achieved realistic hemodynamics over multiple cardiac cycles, but which also were limited to simplified aortic geometries and idealized descriptions of the biomechanics of the aortic valve cusps. By contrast, the model described herein uses an anatomical geometry reconstructed from patient-specific computed tomography angiography (CTA) data, and employs a description of the elasticity of the aortic valve leaflets based on a fiber-reinforced constitutive model fit to experimental tensile test data. The resulting model generates physiological pressures in both systole and diastole, and yields realistic cardiac output and stroke volume at physiological Reynolds numbers. Contact between the valve leaflets during diastole is handled automatically by the IB method, yielding a fully competent valve model that supports a physiological diastolic pressure load without regurgitation. Numerical tests show that the model is able to resolve the leaflet biomechanics in diastole and early systole at practical grid spacings. The model is also used to examine differences in the mechanics and fluid dynamics yielded by fresh valve leaflets and glutaraldehyde-fixed leaflets similar to those used in bioprosthetic heart valves. Although there are large differences in the leaflet deformations during diastole, the differences in the open configurations of the valve models are relatively small, and nearly identical hemodynamics are obtained in all cases considered., (Copyright © 2017 IPEM. Published by Elsevier Ltd. All rights reserved.) more...

A service learning outreach was undertaken to assess the feasibility of adapting the Preconception Peer Educator (PPE) program to Bahamian youth. By focusing on preconception health, the PPE program is a logical step toward ensuring age sensitive and developmentally appropriate education to improve potential birth outcomes and decrease infant mortality rates (IMR) associated with the complex societal problems on Grand Bahama. Concerned with the prevalence of adolescent pregnancy, lack of social support, depression, and failure to complete high school, a nurse midwife invited PPEs from a School of Nursing to meet with stakeholders to introduce the PPE program to Bahamian youth. Mentored by a faculty advisor, the PPEs assumed a leadership role and determined that the primary needs of Grand Bahamian adolescents were messages of self-empowerment and proactive life planning within a cultural context. Positive responses from stakeholders and the promise of a partnership between a School of Nursing and a Caribbean community encouraged the PPEs to adapt their PPE program to the cultural climate and needs of the island of Grand Bahama. The experience informed students' practice and leadership ability by enhancing cultural awareness and sensitivity, expanding world-views, and instilling an ethic of social responsibility., (Copyright © 2016 Elsevier Inc. All rights reserved.) more...

Objective: The research evaluated the perceived quality of librarian-mediated literature searching services at one of Canada's largest acute care teaching hospitals for the purpose of continuous quality improvement and investigation of relationships between variables that can impact user satisfaction., Methods: An online survey was constructed using evidence-based methodologies. A systematic sample of staff and physicians requesting literature searches at London Health Sciences Centre were invited to participate in the study over a one-year period. Data analyses included descriptive statistics of closed-ended questions and coding of open-ended questions., Results: A range of staff including clinicians, researchers, educators, leaders, and analysts submitted a total of 137 surveys, representing a response rate of 71%. Staff requested literature searches for the following "primary" purposes: research or publication (34%), teaching or training (20%), informing a policy or standard practice (16%), patient care (15%), and "other" purposes (15%). While the majority of staff (76%) submitted search requests using methods of written communication, including email and search request forms, staff using methods of verbal communication, including face-to-face and telephone conversations, were significantly more likely to be extremely satisfied with the librarian's interpretation of the search request ( p =0.004) and to rate the perceived quality of the search results as excellent ( p =0.005). In most cases, librarians followed up with staff to clarify the details of their search requests (72%), and these staff were significantly more likely to be extremely satisfied with the librarian's interpretation of the search request ( p =0.002)., Conclusions: Our results demonstrate the limitations of written communication in the context of librarian-mediated literature searching and suggest a multifaceted approach to quality improvement efforts. more...

The smallest flying insects commonly possess wings with long bristles. Little quantitative information is available on the morphology of these bristles, and their functional importance remains a mystery. In this study, we (1) collected morphological data on the bristles of 23 species of Mymaridae by analyzing high-resolution photographs and (2) used the immersed boundary method to determine via numerical simulation whether bristled wings reduced the force required to fling the wings apart while still maintaining lift. The effects of Reynolds number, angle of attack, bristle spacing and wing-wing interactions were investigated. In the morphological study, we found that as the body length of Mymaridae decreases, the diameter and gap between bristles decreases and the percentage of the wing area covered by bristles increases. In the numerical study, we found that a bristled wing experiences less force than a solid wing. The decrease in force with increasing gap to diameter ratio is greater at higher angles of attack than at lower angles of attack, suggesting that bristled wings may act more like solid wings at lower angles of attack than they do at higher angles of attack. In wing-wing interactions, bristled wings significantly decrease the drag required to fling two wings apart compared with solid wings, especially at lower Reynolds numbers. These results support the idea that bristles may offer an aerodynamic benefit during clap and fling in tiny insects., (© 2016. Published by The Company of Biologists Ltd.) more...

Rupture of aneurysms and acute dissection of the thoracic aorta are life-threatening events which affect tens of thousands of people per year. The underlying mechanisms remain unclear and the aortic wall is known to lose its structural integrity, which in turn affects its mechanical response to the loading conditions. Hence, research on such aortic diseases is an important area in biomechanics. The present study investigates the mechanical properties of aneurysmatic and dissected human thoracic aortas via triaxial shear and uniaxial tensile testing with a focus on the former. In particular, ultimate stress values from triaxial shear tests in different orientations regarding the aorta׳s orthotropic microstructure, and from uniaxial tensile tests in radial, circumferential and longitudinal directions were determined. In total, 16 human thoracic aortas were investigated from which it is evident that the aortic media has much stronger resistance to rupture under 'out-of-plane' than under 'in-plane' shear loadings. Under different shear loadings the aortic tissues revealed anisotropic failure properties with higher ultimate shear stresses and amounts of shear in the longitudinal than in the circumferential direction. Furthermore, the aortic media decreased its tensile strength as follows: circumferential direction >longitudinaldirection> radial direction. Anisotropic and nonlinear tissue properties are apparent from the experimental data. The results clearly showed interspecimen differences influenced by the anamnesis of the donors such as aortic diseases or connective tissue disorders, e.g., dissected specimens exhibited on average a markedly lower mechanical strength than aneurysmatic specimens. The rupture data based on the combination of triaxial shear and uniaxial extension testing are unique and build a good basis for developing a 3D failure criterion of diseased human thoracic aortic media. This is a step forward to more realistic modeling of mechanically induced tissue failure i.e. rupture of aneurysms or progression of aortic dissections., (Copyright © 2016 Elsevier Ltd. All rights reserved.) more...

It has long been recognized that aortic root elasticity helps to ensure efficient aortic valve closure, but our understanding of the functional importance of the elasticity and geometry of the aortic root continues to e-volve as increasingly detailed in vivo imaging data become available. Herein, we describe a fluid-structure interaction model of the aortic root, including the aortic valve leaflets, the sinsuses of Valsalva, the aortic annulus, and the sinotubular junction, that employs a version of Peskin's immersed boundary (IB) method with a finite element (FE) description of the structural elasticity. As in earlier work, we use a fiber-based model of the valve leaflets, but this study extends earlier IB models of the aortic root by employing an incompressible hyperelastic model of the mechanics of the sinuses and ascending aorta using a constitutive law fit to experimental data from human aortic root tissue. In vivo pressure loading is accounted for by a backward displacement method that determines the unloaded configurations of the root model. Our model yields realistic cardiac output at physiological pressures, with low transvalvular pressure differences during forward flow, minimal regurgitation during valve closure, and realistic pressure loads when the valve is closed during diastole. Further, results from high-resolution computations indicate that although the detailed leaflet and root kinematics show some grid sensitivity, our IB model of the aortic root nonetheless produces essentially grid-converged flow rates and pressures at practical grid spacings for the high-Reynolds number flows of the aortic root. These results thereby clarify minimum grid resolutions required by such models when used as stand-alone models of the aortic valve as well as when used to provide models of the outflow valves in models of left ventricular fluid dynamics. more...