Massively parallel simulations of coupled arterial cells : Ca2+ dynamics and atherosclerosis.

Ischaemic heart disease (IHD) is the most common cardiovascular disease, and is a major cause of mortality globally. The underlying process of IHD involves the development of atherosclerotic plaques on the arterial wall. These plaques can subsequently rupture and release thrombogenic species into circulation, or can occlude the vessel downstream following detachment. Such complications result in ischaemia—a restriction of blood supply to tissue that results in a shortage of vital cellular nutrients, such as oxygen and glucose. Recent publications hypothesise that cellular ionised calcium (Ca2+) concentrations play an important role in atherogenesis. There has been a significant amount of research on cardiovascular disease within multiple sub areas, including: in vivo and in vitro experimental work, computational fluid dynamics (CFD) simulations, and computational modelling of pathological behaviour. However, a combination of these fields will provide a greater understanding of the conditions that promote plaque development. The research presented in this thesis consists primarily of massively parallel simulations of arterial bifurcations which used CFD to generate the input agonist maps for each arterial mesh. Micro-scale dynamics of coupled endothelial cells (ECs) and smooth muscle cells (SMCs) were modelled in bifurcation surfaces containing over one million cells. In particular, the effect bifurcation angulation may have on atherosclerosis development was investigated. A number of improvements were introduced to the original coupled cells model to perform these simulations. A surface-mesh generation pipeline capable of creating geometrically varying 3-D surfaces, including EC and SMC layers, was implemented. These surfaces were used in CFD simulations to generate agonist input maps, and to define the EC and SMC layers on which the dynamics in our simulations are mapped. A detailed inositol triphosphate (IP3) pathway and gap-junction currents were introduced to the coupled cells model. These additions were to ensure our simulations present physiologically accurate results when compared to related experimental research and computational modelling. Finally, the parallel implementation that enabled our simulations to be conducted at the macro scale was improved by the introduction of Open-Multi-Processing (OpenMP). The massively parallel simulations displayed propagating Ca2+ waves in SMCs and steady-state concentrations of Ca2+ in ECs. Particularly complex SMC Ca2+ behaviour was observed in the lateral regions where the main stem meets the branches. Waves propagated in a slower, sporadic manner, and over significantly shorter distances. Further, we observed lower time-averaged Ca2+ concentrations in arterial geometries with wider bifurcation angles compared to those with narrower bifurcation angles. The regions of low EC and SMC Ca2+ concentrations correspond to the sites re- search utilising CFD agrees are those most likely to experience plaque development due to flow detachment. Furthermore, we noted the low Ca2+ concentrations in these areas are more prominent in arterial geometries with wider bifurcation angles. These results suggest bifurcation angulation may have a significant effect on the susceptibility of arterial regions to atherosclerosis development

Coronary Smooth Muscle Cell Calcium Dynamics: Effects of Bifurcation Angle on Atheroprone Conditions

This work investigates the effect of arterial bifurcation angulation on atherosclerosis development through in-silico simulations of coupled cell dynamics. The computational model presented here combines cellular pathways, fluid dynamics, and physiologically-realistic vessel geometries as observed in the human vasculature. The coupled cells model includes endothelial cells (ECs) and smooth muscle cells (SMCs) with ion dynamics, hetero and homotypic coupling, as well as electro-diffusive coupling. Three arterial bifurcation surface models were used in the coupled cells simulations. All three simulations showed propagating waves of Ca2+ in both the SMC and EC layers, following the introduction of a luminal agonist, in this case ATP. Immediately following the introduction of ATP concentration Ca2+ waves propagate from the area of high ATP toward the areas of low ATP concentration, forming complex patterns where waves interact with eachother, collide and fade. These dynamic phenomena are repeated with a series of waves of slower velocity. The underlying motivation of this research was to examine the macro-scale phenomena, given that the characteristic length scales of atherosclerotic plaques are much larger than a single cell. The micro-scale dynamics were modeled on macro-scale arterial bifurcation surfaces containing over one million cells. The results of the simulations presented here suggest that susceptibility to atherosclerosis development depends on the bifurcation angulation. In conjunction with findings reported in the literature, the simulation results demonstrate that arterial bifurcations containing wider angles have a more prominent influence on the coupled cells pathways associated with the development of atherosclerosis, by means of disturbed flow and lower SMC Ca2+ concentrations. The discussion of the results considers the findings of this research within the context of the potential link between information transport through frequency encoding of Ca2+ wave dynamics and development of atheroprone conditions

Community Nurses' Judgement for the Management of Venous Leg Ulceration: A Judgement Analysis

Background: Nurses caring for the large numbers of people with leg ulceration play a key role in promoting quality in health via their diagnostic and treatment clinical judgements. In the UK, audit evidence suggests that the quality of these judgements is often sub optimal. Misdiagnosis and incorrect treatment choices are likely to affect healing rates, patients’ quality of life, patient safety and healthcare costs. Objectives: To explore the diagnostic judgements and treatment choices of UK community nurses managing venous leg ulceration. Design: A judgement analysis based on Brunswik's psychological Lens Model theory. Setting: UK community and primary care nursing services. Participants: 18 community generalist nurses working in district (home) nursing teams and general practitioner services and 18 community tissue viability specialist nurses. Methods: During 2011 and 2012, 36 nurses made diagnostic judgements and treatment choices in response to 110 clinical scenarios. Scenarios were generated from real patient cases and presented online using text and wound photographs. The consensus judgements of a panel of nurses with advanced knowledge of leg ulceration judged the same scenarios and provided a standard against which to compare the participants. Correlations and logistic regression models were constructed to generate various indices of judgement and decision “performance”: accuracy (Ra), consistency (Rs) and information use (G) and uncertainty (Re). Results: Taking uncertainty into account, nurses could theoretically have achieved a diagnostic level of accuracy of 0.63 but the nurses only achieved an accuracy of 0.48. For the treatment judgement (whether applying high compression was warranted) nurses could have achieved an accuracy of 0.88 but achieved only an accuracy of 0.49. This may have been due to the nurses giving insufficient weight to the diagnostic cues of medical history and appearance of the leg and ulcer and insufficient weight to the treatment cues of type of leg ulcer and pain. Conclusion: Clinical judgements and decisions made by nurses managing leg ulceration are complex and uncertain and some of the variability in judgements and choices can be explained by the ways in which nurses process the information and handle the uncertainties, present in clinical encounters

What is the 'dominant model' of British policymaking? Comparing majoritarian and policy community ideas

The aim of this article is to help identify the fundamental characteristics of the British policymaking system. It highlights an enduring conflict of interpretation within the literature. On the one hand, most contemporary analysts argue that the ‘Westminster model' is outmoded and that it has been replaced by modern understandings based on ‘governance'. On the other, key ideas associated with the Westminster model, regarding majoritarian government and policy imposition, are still in good currency in the academic literature, which holds firm to Lijphart's description of the United Kingdom as a majoritarian democracy. These very different understandings of British government are both commonly cited, but without much recognition that their conclusions may be mutually incompatible. To address this lack of comparison of competing narratives, the article outlines two main approaches to describe and explain the ‘characteristic and durable' ways of doing things in Britain: the ‘policy styles' literature initiated by Richardson in Policy Styles in Western Europe and the Lijphart account found in Democracies and revised in 1999 as Patterns of Democracy. The article encourages scholars to reject an appealing compromise between majoritarian and governance accounts

Establishing a primary care audit and feedback implementation laboratory: a consensus study

Background: There is a significant variation among individual primary care providers in prescribing of potentially problematic, low-value medicines which cause avoidable patient harm. Audit and feedback is generally effective at improving prescribing. However, progress has been hindered by research waste, leading to unanswered questions about how to include audit and feedback for specific problems and circumstances. Trials of different ways of providing audit and feedback in implementation laboratories have been proposed as a way of improving population healthcare while generating robust evidence on feedback effects. However, there is limited experience in their design and delivery. Aim: To explore priorities, feasibility, and ethical challenges of establishing a primary care prescribing audit and feedback implementation laboratory. Design and setting: Two-stage Delphi consensus process involving primary care pharmacy leads, audit and feedback researchers, and patient and public. Method: Participants initially scored statements relating to priorities, feasibility, and ethical considerations for an implementation laboratory. These covered current feedback practice, priority topics for feedback, usefulness of feedback in improving prescribing and different types of prescribing data, acceptability and desirability of different organization levels of randomization, options for trial consent, different methods of delivering feedback, and interest in finding out how effective different ways of presenting feedback would be. After receiving collated results, participants then scored the items again. The consensus was defined using the GRADE criteria. The results were analyzed by group and overall score. Results: Fourteen participants reached consensus for 38 out of 55 statements. Addressing antibiotic and opioid prescribing emerged as the highest priorities for action. The panel supported statements around addressing highpriority prescribing issues, taking an “opt-out” approach to practice consent if waiving consent was not permitted, and randomizing at lower rather than higher organizational levels. Participants supported patient-level prescribing data and further research evaluating most of the different feedback methods we presented them with. Conclusions: There is a good level of support for evaluating a wide range of potential enhancements to improve the effects of feedback on prescribing. The successful design and delivery of a primary care audit and feedback implementation laboratory depend on identifying shared priorities and addressing practical and ethical considerations

Topography of features machined into bisphenol A polycarbonate using closed thick film flowing filtered water immersed KrF excimer laser ablation

Laser micromachining with the use of liquid immersion allows debris control. Use of an immersion technique potentially modifies the ablation mechanism when compared to laser material interactions in a medium of ambient air. Equipment has been developed to allow feature machining under a controllable liquid film and thereby elucidate and quantify and changes in feature topography caused. The findings of this study revealed that immersion of bisphenol A polycarbonate samples in closed thick film flowing filtered water during KrF excimer laser ablation markedly altered feature geometry, waviness and roughness laser machining in ambient air. Feature geometry definition improved with flow velocity. Waviness was found to be less regular and less predictable and roughness became fluence dependant. Variation of flow velocity during immersion resulted in modification of the surface waviness: an optimum flow velocity exists, producing maximum waviness. Surface roughness displayed a power law relationship with flow velocity. These observed effects are explained through examination of the flow – plume interaction: closed thick film flowing filtered water immersion caused a combination of photomechanical etching promoted by plume confinement, laser etching and plume distortion by rapid flow velocity. Furthermore, the influence each of these interactions varied depending on the flow velocity. This is not an eventuality possible when using an open thin film immersed laser ablation technique: film rupture and splashing limited the plume etching contribution to the confined laser ablation process. It is apparent that the changes to feature geometry, waviness and roughness observed when KrF excimer laser machining under closed thick film flowing filtered water were brought about directly by the immersion, rather than by variations in fluence level

Topography of features machined into bisphenol A polycarbonate using closed thick film flowing filtered water immersed KrF excimer laser ablation

Laser micromachining with the use of liquid immersion allows debris control. Use of an immersion technique potentially modifies the ablation mechanism when compared to laser material interactions in a medium of ambient air. Equipment has been developed to allow feature machining under a controllable liquid film and thereby elucidate and quantify and changes in feature topography caused. The findings of this study revealed that immersion of bisphenol A polycarbonate samples in closed thick film flowing filtered water during KrF excimer laser ablation markedly altered feature geometry, waviness and roughness laser machining in ambient air. Feature geometry definition improved with flow velocity. Waviness was found to be less regular and less predictable and roughness became fluence dependant. Variation of flow velocity during immersion resulted in modification of the surface waviness: an optimum flow velocity exists, producing maximum waviness. Surface roughness displayed a power law relationship with flow velocity. These observed effects are explained through examination of the flow – plume interaction: closed thick film flowing filtered water immersion caused a combination of photomechanical etching promoted by plume confinement, laser etching and plume distortion by rapid flow velocity. Furthermore, the influence each of these interactions varied depending on the flow velocity. This is not an eventuality possible when using an open thin film immersed laser ablation technique: film rupture and splashing limited the plume etching contribution to the confined laser ablation process. It is apparent that the changes to feature geometry, waviness and roughness observed when KrF excimer laser machining under closed thick film flowing filtered water were brought about directly by the immersion, rather than by variations in fluence level.</p

Ductile failure X-prize.

Fracture or tearing of ductile metals is a pervasive engineering concern, yet accurate prediction of the critical conditions of fracture remains elusive. Sandia National Laboratories has been developing and implementing several new modeling methodologies to address problems in fracture, including both new physical models and new numerical schemes. The present study provides a double-blind quantitative assessment of several computational capabilities including tearing parameters embedded in a conventional finite element code, localization elements, extended finite elements (XFEM), and peridynamics. For this assessment, each of four teams reported blind predictions for three challenge problems spanning crack initiation and crack propagation. After predictions had been reported, the predictions were compared to experimentally observed behavior. The metal alloys for these three problems were aluminum alloy 2024-T3 and precipitation hardened stainless steel PH13-8Mo H950. The predictive accuracies of the various methods are demonstrated, and the potential sources of error are discussed