On the Sensitivity Analysis of Porous Finite Element Models for Cerebral Perfusion Estimation.

Computational physiological models are promising tools to enhance the design of clinical trials and to assist in decision making. Organ-scale haemodynamic models are gaining popularity to evaluate perfusion in a virtual environment both in healthy and diseased patients. Recently, the principles of verification, validation, and uncertainty quantification of such physiological models have been laid down to ensure safe applications of engineering software in the medical device industry. The present study sets out to establish guidelines for the usage of a three-dimensional steady state porous cerebral perfusion model of the human brain following principles detailed in the verification and validation (V&V 40) standard of the American Society of Mechanical Engineers. The model relies on the finite element method and has been developed specifically to estimate how brain perfusion is altered in ischaemic stroke patients before, during, and after treatments. Simulations are compared with exact analytical solutions and a thorough sensitivity analysis is presented covering every numerical and physiological model parameter. The results suggest that such porous models can approximate blood pressure and perfusion distributions reliably even on a coarse grid with first order elements. On the other hand, higher order elements are essential to mitigate errors in volumetric blood flow rate estimation through cortical surface regions. Matching the volumetric flow rate corresponding to major cerebral arteries is identified as a validation milestone. It is found that inlet velocity boundary conditions are hard to obtain and that constant pressure inlet boundary conditions are feasible alternatives. A one-dimensional model is presented which can serve as a computationally inexpensive replacement of the three-dimensional brain model to ease parameter optimisation, sensitivity analyses and uncertainty quantification. The findings of the present study can be generalised to organ-scale porous perfusion models. The results increase the applicability of computational tools regarding treatment development for stroke and other cerebrovascular conditions.

Uncertainty quantification patterns for multiscale models.

Uncertainty quantification (UQ) is a key component when using computational models that involve uncertainties, e.g. in decision-making scenarios. In this work, we present uncertainty quantification patterns (UQPs) that are designed to support the analysis of uncertainty in coupled multi-scale and multi-domain applications. UQPs provide the basic building blocks to create tailored UQ for multiscale models. The UQPs are implemented as generic templates, which can then be customized and aggregated to create a dedicated UQ procedure for multiscale applications. We present the implementation of the UQPs with multiscale coupling toolkit Multiscale Coupling Library and Environment 3. Potential speed-up for UQPs has been derived as well. As a proof of concept, two examples of multiscale applications using UQPs are presented. This article is part of the theme issue 'Reliability and reproducibility in computational science: implementing verification, validation and uncertainty quantification in silico'.

Haemodynamic flow conditions at the initiation of high-shear platelet aggregation: a combined in vitro and cellular in silico study.

The influence of the flow environment on platelet aggregation is not fully understood in high-shear thrombosis. The objective of this study is to investigate the role of a high shear rate in initial platelet aggregation. The haemodynamic conditions in a microfluidic device are studied using cell-based blood flow simulations. The results are compared with in vitro platelet aggregation experiments performed with porcine whole blood (WB) and platelet-rich-plasma (PRP). We studied whether the cell-depleted layer in combination with high shear and high platelet flux can account for the distribution of platelet aggregates. High platelet fluxes at the wall were found in silico. In WB, the platelet flux was about twice as high as in PRP. Additionally, initial platelet aggregation and occlusion were observed in vitro in the stenotic region. In PRP, the position of the occlusive thrombus was located more downstream than in WB. Furthermore, the shear rates and stresses in cell-based and continuum simulations were studied. We found that a continuum simulation is a good approximation for PRP. For WB, it cannot predict the correct values near the wall.

A porous circulation model of the human brain for in silico clinical trials in ischaemic stroke.

The advancement of ischaemic stroke treatment relies on resource-intensive experiments and clinical trials. In order to improve ischaemic stroke treatments, such as thrombolysis and thrombectomy, we target the development of computational tools for in silico trials which can partially replace these animal and human experiments with fast simulations. This study proposes a model that will serve as part of a predictive unit within an in silico clinical trial estimating patient outcome as a function of treatment. In particular, the present work aims at the development and evaluation of an organ-scale microcirculation model of the human brain for perfusion prediction. The model relies on a three-compartment porous continuum approach. Firstly, a fast and robust method is established to compute the anisotropic permeability tensors representing arterioles and venules. Secondly, vessel encoded arterial spin labelling magnetic resonance imaging and clustering are employed to create an anatomically accurate mapping between the microcirculation and large arteries by identifying superficial perfusion territories. Thirdly, the parameter space of the problem is reduced by analysing the governing equations and experimental data. Fourthly, a parameter optimization is conducted. Finally, simulations are performed with the tuned model to obtain perfusion maps corresponding to an open and an occluded (ischaemic stroke) scenario. The perfusion map in the occluded vessel scenario shows promising qualitative agreement with computed tomography images of a patient with ischaemic stroke caused by large vessel occlusion. The results highlight that in the case of vessel occlusion (i) identifying perfusion territories is essential to capture the location and extent of underperfused regions and (ii) anisotropic permeability tensors are required to give quantitatively realistic estimation of perfusion change. In the future, the model will be thoroughly validated against experiments.

Fatty Acid and Carnitine Metabolism Are Dysregulated in Systemic Sclerosis Patients.

Systemic sclerosis (SSc) is a rare chronic disease of unknown pathogenesis characterized by fibrosis of the skin and internal organs, vascular alteration, and dysregulation of the immune system. In order to better understand the immune system and its perturbations leading to diseases, the study of the mechanisms regulating cellular metabolism has gained a widespread interest. Here, we have assessed the metabolic status of plasma and dendritic cells (DCs) in patients with SSc. We identified a dysregulated metabolomic signature in carnitine in circulation (plasma) and intracellularly in DCs of SSc patients. In addition, we confirmed carnitine alteration in the circulation of SSc patients in three independent plasma measurements from two different cohorts and identified dysregulation of fatty acids. We hypothesized that fatty acid and carnitine alterations contribute to potentiation of inflammation in SSc. Incubation of healthy and SSc dendritic cells with etoposide, a carnitine transporter inhibitor, inhibited the production of pro-inflammatory cytokines such as IL-6 through inhibition of fatty acid oxidation. These findings shed light on the altered metabolic status of the immune system in SSc patients and opens up for potential novel avenues to reduce inflammation.

A particle-based model for endothelial cell migration under flow conditions.

Endothelial cells (ECs) play a major role in the healing process following angioplasty to inhibit excessive neointima. This makes the process of EC healing after injury, in particular EC migration in a stented vessel, important for recovery of normal vessel function. In that context, we present a novel particle-based model of EC migration and validate it against in vitro experimental data. We have developed a particle-based model of EC migration under flow conditions in an in vitro vessel with obstacles. Cell movement in the model is a combination of random walks and directed movement along the local flow velocity vector. For model calibration, a set of experimental data for cell migration in a similarly shaped channel has been used. We have calibrated the model for a baseline case of a channel with no obstacles and then applied it to the case of a channel with ridges on the bottom surface, representative of stent strut geometry. We were able to closely reproduce the cell migration speed and angular distribution of their movement relative to the flow direction reported in vitro. The model also reproduces qualitative aspects of EC migration, such as entrapment of cells downstream from the flow-disturbing ridge. The model has the potential, after more extensive in vitro validation, to study the effect of variation in strut spacing and shape, through modification of the local flow, on EC migration. The results of this study support the hypothesis that EC migration is strongly affected by the direction and magnitude of local wall shear stress.

Identifying the start of a platelet aggregate by the shear rate and the cell-depleted layer.

Computer simulations were performed to study the transport of red blood cells and platelets in high shear flows, mimicking earlier published in vitro experiments in microfluidic devices with high affinity for platelet aggregate formation. The goal is to understand and predict where thrombus formation starts. Additionally, the need of cell-based modelling in these microfluidic devices is demonstrated by comparing our results with macroscopic models, wherein blood is modelled as a continuous fluid. Hemocell, a cell-based blood flow simulation framework is used to investigate the transport physics in the microfluidic devices. The simulations show an enlarged cell-depleted layer at the site where a platelet aggregate forms in the experiments. In this enlarged cell-depleted layer, the probability to find a platelet is higher than in the rest of the microfluidic device. In addition, the shear rates are sufficiently high to allow for the von Willebrand factor to elongate in this region. We hypothesize that the enlarged cell-depleted layer combined with a sufficiently large platelet flux and sufficiently high shear rates result in an haemodynamic environment that is a preferred location for initial platelet aggregation.

Location-Specific Comparison Between a 3D In-Stent Restenosis Model and Micro-CT and Histology Data from Porcine In Vivo Experiments.

BACKGROUND: Coronary artery restenosis is an important side effect of percutaneous coronary intervention. Computational models can be used to better understand this process. We report on an approach for validation of an in silico 3D model of in-stent restenosis in porcine coronary arteries and illustrate this approach by comparing the modelling results to in vivo data for 14 and 28 days post-stenting. METHODS: This multiscale model includes single-scale models for stent deployment, blood flow and tissue growth in the stented vessel, including smooth muscle cell (SMC) proliferation and extracellular matrix (ECM) production. The validation procedure uses data from porcine in vivo experiments, by simulating stent deployment using stent geometry obtained from micro computed tomography (micro-CT) of the stented vessel and directly comparing the simulation results of neointimal growth to histological sections taken at the same locations. RESULTS: Metrics for comparison are per-strut neointimal thickness and per-section neointimal area. The neointimal area predicted by the model demonstrates a good agreement with the detailed experimental data. For 14 days post-stenting the relative neointimal area, averaged over all vessel sections considered, was 20 ± 3% in vivo and 22 ± 4% in silico. For 28 days, the area was 42 ± 3% in vivo and 41 ± 3% in silico. CONCLUSIONS: The approach presented here provides a very detailed, location-specific, validation methodology for in silico restenosis models. The model was able to closely match both histology datasets with a single set of parameters. Good agreement was obtained for both the overall amount of neointima produced and the local distribution. It should be noted that including vessel curvature and ECM production in the model was paramount to obtain a good agreement with the experimental data.

Prolonged use of pegylated liposomal doxorubicin in gynecologic malignancies.

Pegylated liposomal doxorubicin (PLD) is a palliative treatment option for patients with recurrent gynecologic malignancies. It has an appealing toxicity profile and responses can be prolonged. There is no consensus as to the level of cardiac toxicity. Current label warnings, National Comprehensive Cancer Network (NCCN) guidelines, and extrapolation of prescribing guidelines from doxorubicin, may limit PLD's use in patients with baseline cardiac comorbidities, limit the lifetime dosing of an effective palliative treatment, or lead to over-use of unnecessary cardiac testing. This case series describes the experience of 18 patients using prolonged courses of PLD for gynecologic malignancies with no cardiac toxicity.

Semi-intrusive multiscale metamodelling uncertainty quantification with application to a model of in-stent restenosis.

We explore the efficiency of a semi-intrusive uncertainty quantification (UQ) method for multiscale models as proposed by us in an earlier publication. We applied the multiscale metamodelling UQ method to a two-dimensional multiscale model for the wound healing response in a coronary artery after stenting (in-stent restenosis). The results obtained by the semi-intrusive method show a good match to those obtained by a black-box quasi-Monte Carlo method. Moreover, we significantly reduce the computational cost of the UQ. We conclude that the semi-intrusive metamodelling method is reliable and efficient, and can be applied to such complex models as the in-stent restenosis ISR2D model. This article is part of the theme issue 'Multiscale modelling, simulation and computing: from the desktop to the exascale'.

Water scarcity alleviation through water footprint reduction in agriculture: The effect of soil mulching and drip irrigation.

Water scarcity has received global attention in the last decade as it challenges food security in arid and semi-arid regions, particularly in the Middle East and North Africa. This research assesses the possible alleviation of water scarcity by reducing the water footprint in crop production through the application of soil mulching and drip irrigation. The study is the first to do so at catchment scale, taking into account various crops, multi-cropping, cropping patterns, and spatial differences in climate, soil, and field management factors, using field survey and local data. The AquaCrop-OS model and the global water footprint assessment (WFA) standard were used to assess the green and blue water footprint (WF) of ten major crops in the Upper Litani Basin (ULB) in Lebanon. The blue water saving and blue water scarcity reduction under these two alternative practices were compared to the current situation. The results show that the WF of crop production is more sensitive to climate than soil type. The annual blue WF of summer crops was largest when water availability was lowest. Mulching reduced the blue WF by 3.6% and mulching combined with drip irrigation reduced it by 4.7%. The blue water saving from mulching was estimated about 6.3 million m3/y and from mulching combined with drip irrigation about 8.3 million m3/y. This is substantial but by far not sufficient to reduce the overall blue WF in summer to a sustainable level at catchment scale.

Cell-resolved blood flow simulations of saccular aneurysms: effects of pulsatility and aspect ratio.

We study the effect of pulsatile flow on the transport of red blood cells (RBCs) and platelets into aneurysm geometries with varying dome-to-neck aspect ratios (AR). We use a validated two-dimensional lattice Boltzmann model for blood plasma with a discrete element method for both RBCs and platelets coupled by the immersed boundary method. Flow velocities and vessel diameters were matched with measurements of cerebral perforating arteries and flow was driven by a synthetic heartbeat curve typical for such vessel sizes. We observe a flow regime change as the aspect ratio increases from a momentum-driven regime in the small aspect ratio to a shear-driven regime in the larger aspect ratios. In the small aspect ratio case, we see the development of a re-circulation zone that exhibits a layering of high (greater than or equal to 7 s) and low (less than 7 s) residence cells. In the shear-driven regime, we see high and low residence cells well mixed, with an increasing population of cells that are trapped inside the aneurysm as the aspect ratio increases. In all cases, we observe aneurysms that are platelet-rich and red blood cell-poor when compared with their respective parental vessel populations. Pulsatility also plays a role in the small aspect ratio as we observe a smaller population of older trapped cells along the aneurysm wall in the pulsatile case when compared with a steady flow case. Pulsatility does not have a significant effect in shear-driven regime aspect ratios.

Cervical cancer in women over 65: An analysis of screening.

OBJECTIVE: Evaluate the characteristics and screening history of patients diagnosed with cervical cancer over age 65. METHODS: A retrospective review of 34 patients who were diagnosed with cervical cancer after the age of 65 at a single community cancer center between 2006 and 2016 was performed. Data collected included screening history, method of detection, stage, and survival. RESULTS: Between 2006 and 2016, 346 women were diagnosed with cervical cancer at a single community cancer center, 34 (9.8%) of them were over 65 years old. 30 had known screening histories and could be evaluated. 15 women had adequate screening prior to being diagnosed with cervical cancer, indicating that 50% of women who developed cervical cancer after age 65 in this population followed screening guidelines and still developed disease. CONCLUSIONS: Women over 65 make up a significant portion of women diagnosed with cervical cancer. As many as half of all cervical cancers over age 65 occur in women who get recommended screening, and some of these may be prevented or detected early if screening was extended beyond age 65.

National water, food, and trade modeling framework: The case of Egypt.

This paper introduces a modeling framework for the analysis of real and virtual water flows at national scale. The framework has two components: (1) a national water model that simulates agricultural, industrial and municipal water uses, and available water and land resources; and (2) an international virtual water trade model that captures national virtual water exports and imports related to trade in crops and animal products. This National Water, Food & Trade (NWFT) modeling framework is applied to Egypt, a water-poor country and the world's largest importer of wheat. Egypt's food and water gaps and the country's food (virtual water) imports are estimated over a baseline period (1986-2013) and projected up to 2050 based on four scenarios. Egypt's food and water gaps are growing rapidly as a result of steep population growth and limited water resources. The NWFT modeling framework shows the nexus of the population dynamics, water uses for different sectors, and their compounding effects on Egypt's food gap and water self-sufficiency. The sensitivity analysis reveals that for solving Egypt's water and food problem non-water-based solutions like educational, health, and awareness programs aimed at lowering population growth will be an essential addition to the traditional water resources development solution. Both the national and the global models project similar trends of Egypt's food gap. The NWFT modeling framework can be easily adapted to other nations and regions.

Physical water scarcity metrics for monitoring progress towards SDG target 6.4: An evaluation of indicator 6.4.2 "Level of water stress".

Target 6.4 of the recently adopted Sustainable Development Goals (SDGs) deals with the reduction of water scarcity. To monitor progress towards this target, two indicators are used: Indicator 6.4.1 measuring water use efficiency and 6.4.2 measuring the level of water stress (WS). This paper aims to identify whether the currently proposed indicator 6.4.2 considers the different elements that need to be accounted for in a WS indicator. WS indicators compare water use with water availability. We identify seven essential elements: 1) both gross and net water abstraction (or withdrawal) provide important information to understand WS; 2) WS indicators need to incorporate environmental flow requirements (EFR); 3) temporal and 4) spatial disaggregation is required in a WS assessment; 5) both renewable surface water and groundwater resources, including their interaction, need to be accounted for as renewable water availability; 6) alternative available water resources need to be accounted for as well, like fossil groundwater and desalinated water; 7) WS indicators need to account for water storage in reservoirs, water recycling and managed aquifer recharge. Indicator 6.4.2 considers many of these elements, but there is need for improvement. It is recommended that WS is measured based on net abstraction as well, in addition to currently only measuring WS based on gross abstraction. It does incorporate EFR. Temporal and spatial disaggregation is indeed defined as a goal in more advanced monitoring levels, in which it is also called for a differentiation between surface and groundwater resources. However, regarding element 6 and 7 there are some shortcomings for which we provide recommendations. In addition, indicator 6.4.2 is only one indicator, which monitors blue WS, but does not give information on green or green-blue water scarcity or on water quality. Within the SDG indicator framework, some of these topics are covered with other indicators.

Epithelioid angiosarcoma of the vulva: A case report.

•Vulvar angiosarcoma in a patient with pelvic radiation and chronic lymphedema•Epithelioid histologic staining positive for vimentin, ERG, CD31•Gross appearance of violaceous hyperpigmentation of the mons pubis.

BOARD-INVITED REVIEW: Quantifying water use in ruminant production.

The depletion of water resources, in terms of both quantity and quality, has become a major concern both locally and globally. Ruminants, in particular, are under increased public scrutiny due to their relatively high water use per unit of meat or milk produced. Estimating the water footprint of livestock production is a relatively new field of research for which methods are still evolving. This review describes the approaches used to quantify water use in ruminant production systems as well as the methodological and conceptual issues associated with each approach. Water use estimates for the main products from ruminant production systems are also presented, along with possible management strategies to reduce water use. In the past, quantifying water withdrawal in ruminant production focused on the water demand for drinking or operational purposes. Recently, the recognition of water as a scarce resource has led to the development of several methodologies including water footprint assessment, life cycle assessment, and livestock water productivity to assess water use and its environmental impacts. These methods differ with respect to their target outcome (efficiency or environmental impacts), geographic focus (local or global), description of water sources (green, blue, and gray), handling of water quality concerns, the interpretation of environmental impacts, and the metric by which results are communicated (volumetric units or impact equivalents). Ruminant production is a complex activity where animals are often reared at different sites using a range of resources over their lifetime. Additional water use occurs during slaughter, product processing, and packaging. Estimating water use at the various stages of meat and milk production and communicating those estimates will help producers and other stakeholders identify hotspots and implement strategies to improve water use efficiency. Improvements in ruminant productivity (i.e., BW and milk production) and reproductive efficiency can also reduce the water footprint per unit product. However, given that feed production makes up the majority of water use by ruminants, research and development efforts should focus on this area. More research and clarity are needed to examine the validity of assumptions and possible trade-offs between ruminants' water use and other sustainability indicators.

A cell-based mechanical model of coronary artery tunica media.

A three-dimensional cell-based mechanical model of coronary artery tunica media is proposed. The model is composed of spherical cells forming a hexagonal close-packed lattice. Tissue anisotropy is taken into account by varying interaction forces with the direction of intercellular connection. Several cell-centre interaction potentials for repulsion and attraction are considered, including the Hertz contact model and its neo-Hookean extension, the Johnson-Kendall-Roberts model of adhesive contact, and a wormlike chain model. The model is validated against data from in vitro uni-axial tension tests performed on dissected strips of tunica media. The wormlike chain potential in combination with the neo-Hookean Hertz contact model produces stress-stretch curves which represent the experimental data very well.

Revisiting the use of the immersed-boundary lattice-Boltzmann method for simulations of suspended particles.

The immersed-boundary lattice-Boltzmann method (IB-LBM) is increasingly being used in simulations of dense suspensions. These systems are computationally very expensive and can strongly benefit from lower resolutions that still maintain the desired accuracy for the quantities of interest. IB-LBM has a number of free parameters that have to be defined, often without exact knowledge of the tradeoffs, since their behavior in low resolutions is not well understood. Such parameters are the lattice constant Δx, the number of vertices N_{v}, the interpolation kernel ϕ, and the LBM relaxation time τ. We investigate the effect of these IB-LBM parameters on a number of straightforward but challenging benchmarks. The systems considered are (a) the flow of a single sphere in shear flow, (b) the collision of two spheres in shear flow, and (c) the lubrication interaction of two spheres. All benchmarks are performed in three dimensions. The first two systems are used for determining two effective radii: the hydrodynamic radius r_{hyd} and the particle interaction radius r_{inter}. The last system is used to establish the numerical robustness of the lubrication forces, used to probe the hydrodynamic interactions in the limit of small gaps. Our results show that lower spatial resolutions result in larger hydrodynamic and interaction radii, while surface densities should be chosen above two vertices per LU^{2} result to prevent fluid penetration in underresolved meshes. Underresolved meshes also failed to produce the migration of particles toward the center of the domain due to lift forces in Couette flow, mostly noticeable for IBM-kernel ϕ_{2}. Kernel ϕ_{4}, despite being more robust toward mesh resolution, produces a notable membrane thickness, leading to the breakdown of the lubrication forces in larger gaps, and its use in dense suspensions where the mean particle distances are small can result in undesired behavior. r_{hyd} is measured to be different from r_{inter}, suggesting that there is no consistent measure to recalibrate the radius of the suspended particle.

Effect of holding a racket on propulsion technique of wheelchair tennis players.

The purpose of this study was to determine possible differences in propulsion technique between propelling the wheelchair with and without a racket in the hand. Eight experienced wheelchair tennis players performed three submaximal exercise tests and six sprint tests on a wheelchair ergometer. Torque and velocity were measured during the tests and power output and timing variables were calculated. Differences between the conditions with and without racket were analyzed. When propelling with the racket, the racket side showed a significantly lower push time (P = 0.03), lower percentage push time (P = 0.001), shorter contact angle (P < 0.001), more power loss before (P = 0.006) and after (P = 0.001) the push, a higher peak (P = 0.009) and mean (P = 0.005) power output during the push, and a lower mean overall velocity (P = 0.03). When the same hand is compared when propelling with and without racket or when the sprint data were analyzed, similar significant differences were found. Propelling the wheelchair while holding a racket has negative effects on the propulsion technique and may lead to injuries of the upper extremity. The longer time needed to couple the hand with the racket to the rim leads to higher power losses and subsequently higher power output generation during the shorter push phase.