Investigating the effect of drug release on in-stent restenosis: A hybrid continuum – agent-based modelling approach

Background and objective: In-stent restenosis (ISR) following percutaneous coronary intervention with drug-eluting stent (DES) implantation remains an unresolved issue, with ISR rates up to 10%. The use of antiproliferative drugs on DESs has significantly reduced ISR. However, a complete knowledge of the mechanobiological processes underlying ISR is still lacking. Multiscale agent-based modelling frameworks, integrating continuum- and agent-based approaches, have recently emerged as promising tools to decipher the mechanobiological events driving ISR at different spatiotemporal scales. However, the integration of sophisticated drug models with an agent-based model (ABM) of ISR has been under-investigated. The aim of the present study was to develop a novel multiscale agent-based modelling framework of ISR following DES implantation. Methods: The framework consisted of two bi-directionally coupled modules, namely (i) a drug transport module, simulating drug transport through a continuum-based approach, and (ii) a tissue remodelling module, simulating cellular dynamics through an ABM. Receptor saturation (RS), defined as the fraction of target receptors saturated with drug, is used to mediate cellular activities in the ABM, since RS is widely regarded as a measure of drug efficacy. Three studies were performed to investigate different scenarios in terms of drug mass (DM), drug release profiles (RP), coupling schemes and idealized vs. patient-specific artery geometries. Results: The studies demonstrated the versatility of the framework and enabled exploration of the sensitivity to different settings, coupling modalities and geometries. As expected, changes in the DM, RP and coupling schemes illustrated a variation in RS over time, in turn affecting the ABM response. For example, combined small DM – fast RP led to similar ISR degrees as high DM – moderate RP (lumen area reduction of ∼13/17% vs. ∼30% without drug). The use of a patient-specific geometry with non-equally distributed struts resulted in a heterogeneous RS map, but did not remarkably impact the ABM response. Conclusion: The application to a patient-specific geometry highlights the potential of the framework to address complex realistic scenarios and lays the foundations for future research, including calibration and validation on patient datasets and the investigation of the effects of different plaque composition on the arterial response to DES

Coupling Tumor Necrosis Factor-α with αV Integrin Ligands Improves Its Antineoplastic Activity

Despite the impressive results obtained in animal models, the clinical use of tumor necrosis factor-α (TNF) as an anticancer drug is limited by severe toxicity. We have shown previously that targeted delivery of TNF to aminopeptidase N (CD13), a marker of angiogenic vessels, improved the therapeutic index of this cytokine in tumor-bearing mice. To assess whether the vascular-targeting approach could be extended to other markers of tumor blood vessels, in this work, we have fused TNF with the ACDCRGDCFCG peptide, a ligand of αV integrins by recombinant DNA technology. We have found that subnanogram doses of this conjugate are sufficient to induce antitumor effects in tumor-bearing mice when combined with melphalan, a chemotherapeutic drug. Cell adhesion assays and competitive binding experiments with anti-integrin antibodies showed that the Arg-Gly-Asp moiety interacts with cell adhesion receptors, including αVβ3 integrin, as originally postulated. In addition, ACGDRGDCFCG-mouse TNF conjugate induced cytotoxic effects in standard cytolytic assays, implying that ACGDRGDCFCG-mouse TNF conjugate can also bind TNF receptors and trigger death signals. These results indicate that coupling TNF with αV integrin ligands improves its antineoplastic activity and supports the concept that vascular targeting is a strategy potentially applicable to different endothelial markers, not limited to CD13

Rediscovery of a population of the Balearic lizard Podarcis lilfordi (Squamata, Lacertidae) on Menorca (Balearic Islands)

Abstract not availabl

A cross-sectional study of the individual, social, and built environmental correlates of pedometer-based physical activity among elementary school children

Background: Children who participate in regular physical activity obtain health benefits. Preliminary pedometerbased cut-points representing sufficient levels of physical activity among youth have been established; however limited evidence regarding correlates of achieving these cut-points exists. The purpose of this study was to identify correlates of pedometer-based cut-points among elementary school-aged children.Method: A cross-section of children in grades 5-7 (10-12 years of age) were randomly selected from the most (n = 13) and least (n = 12) &lsquo;walkable&rsquo; public elementary schools (Perth, Western Australia), stratified by socioeconomic status. Children (n = 1480; response rate = 56.6%) and parents (n = 1332; response rate = 88.8%) completed a survey, and steps were collected from children using pedometers. Pedometer data were categorized to reflect the sex-specific pedometer-based cut-points of &ge;15000 steps/day for boys and &ge;12000 steps/day for girls. Associations between socio-demographic characteristics, sedentary and active leisure-time behavior, independent mobility, active transportation and built environmental variables - collected from the child and parent surveys - and meeting pedometer-based cut-points were estimated (odds ratios: OR) using generalized estimating equations.Results: Overall 927 children participated in all components of the study and provided complete data. On average, children took 11407 &plusmn; 3136 steps/day (boys: 12270 &plusmn; 3350 vs. girls: 10681 &plusmn; 2745 steps/day; p &lt; 0.001) and 25.9% (boys: 19.1 vs. girls: 31.6%; p &lt; 0.001) achieved the pedometer-based cut-points. After adjusting for all other variables and school clustering, meeting the pedometer-based cut-points was negatively associated (p &lt; 0.05) with being male (OR = 0.42), parent self-reported number of different destinations in the neighborhood (OR 0.93), and a friend&rsquo;s (OR 0.62) or relative&rsquo;s (OR 0.44, boys only) house being at least a 10-minute walk from home. Achieving the pedometer-based cut-points was positively associated with participating in screen-time &lt; 2 hours/day (OR 1.88), not being driven to school (OR 1.48), attending a school located in a high SES neighborhood (OR 1.33), the average number of steps among children within the respondent&rsquo;s grade (for each 500 step/day increase: OR 1.29), and living further than a 10-minute walk from a relative&rsquo;s house (OR 1.69, girls only).Conclusions: Comprehensive multi-level interventions that reduce screen-time, encourage active travel to/from school and foster a physically active classroom culture might encourage more physical activity among children.<br /

A fully coupled computational fluid dynamics – agent-based model of atherosclerotic plaque development: Multiscale modeling framework and parameter sensitivity analysis

Background: Peripheral Artery Disease (PAD) is an atherosclerotic disorder that leads to impaired lumen patency through intimal hyperplasia and the build-up of plaques, mainly localized in areas of disturbed flow. Computational models can provide valuable insights in the pathogenesis of atherosclerosis and act as a predictive tool to optimize current interventional techniques. Our hypothesis is that a reliable predictive model must include the atherosclerosis development history. Accordingly, we developed a multiscale modeling framework of atherosclerosis that replicates the hemodynamic-driven arterial wall remodeling and plaque formation. Methods: The framework was based on the coupling of Computational Fluid Dynamics (CFD) simulations with an Agent-Based Model (ABM). The CFD simulation computed the hemodynamics in a 3D artery model, while 2D ABMs simulated cell, Extracellular Matrix (ECM) and lipid dynamics in multiple vessel cross-sections. A sensitivity analysis was also performed to evaluate the oscillation of the ABM output to variations in the inputs and to identify the most influencing ABM parameters. Results: Our multiscale model qualitatively replicated both the physiologic and pathologic arterial configuration, capturing histological-like features. The ABM outputs were mostly driven by cell and ECM dynamics, largely affecting the lumen area. A subset of parameters was found to affect the final lipid core size, without influencing cell/ECM or lumen area trends. Conclusion: The fully coupled CFD-ABM framework described atherosclerotic morphological and compositional changes triggered by a disturbed hemodynamics

Is the neighbourhood environment associated with sedentary behaviour outside of school hours among children?

Background Little is known about neighbourhood environments and children&rsquo;s sedentary behaviour outside school hours.Purpose This study aims to examine the associations between public open spaces (POS), parent perceptions of the neighbourhood and children&rsquo;s sedentary behaviours.Methods Parents reported their child&rsquo;s television viewing and computer/electronic game time and their perceptions of the physical and social neighbourhood. Children&rsquo;s sedentarytime was objectively assessed. The closest POS was audited.Results Cross-sectionally, living near a POS with a water feature and greater parental satisfactionwith POS quality were negatively associated with computer/e-games; greater POS area was negatively associated with TV viewing. Longitudinally, living in a cul-de-sac and greater satisfaction with POS quality were negatively associated with computer/e-games and TV viewing, respectively. Awalking path in the POS was positively associated with computer/e-games.Conclusion Neighbourhood features appear to positively and negatively influence children&rsquo;s sedentary behaviours, highlighting the complexity of urban planning on behaviour. Further age- and context-specific studies are required.<br /

An agent-based model of cardiac allograft vasculopathy: toward a better understanding of chronic rejection dynamics

Cardiac allograft vasculopathy (CAV) is a coronary artery disease affecting 50% of heart transplant (HTx) recipients, and it is the major cause of graft loss. CAV is driven by the interplay of immunological and non-immunological factors, setting off a cascade of events promoting endothelial damage and vascular dysfunction. The etiology and evolution of tissue pathology are largely unknown, making disease management challenging. So far, in vivo models, mostly mouse-based, have been widely used to study CAV, but they are resource-consuming, pose many ethical issues, and allow limited investigation of time points and important biomechanical measurements. Recently, agent-based models (ABMs) proved to be valid computational tools for deciphering mechanobiological mechanisms driving vascular adaptation processes at the cell/tissue level, augmenting cost-effective in vivo lab-based experiments, at the same time guaranteeing richness in observation time points and low consumption of resources. We hypothesize that integrating ABMs with lab-based experiments can aid in vivo research by overcoming those limitations. Accordingly, this work proposes a bidimensional ABM of CAV in a mouse coronary artery cross-section, simulating the arterial wall response to two distinct stimuli: inflammation and hemodynamic disturbances, the latter considered in terms of low wall shear stress (WSS). These stimuli trigger i) inflammatory cell activation and ii) exacerbated vascular cell activities. Moreover, an extensive analysis was performed to investigate the ABM sensitivity to the driving parameters and inputs and gain insights into the ABM working mechanisms. The ABM was able to effectively replicate a 4-week CAV initiation and progression, characterized by lumen area decrease due to progressive intimal thickening in regions exposed to high inflammation and low WSS. Moreover, the parameter and input sensitivity analysis highlighted that the inflammatory-related events rather than the WSS predominantly drive CAV, corroborating the inflammatory nature of the vasculopathy. The proof-of-concept model proposed herein demonstrated its potential in deepening the pathology knowledge and supporting the in vivo analysis of CAV

Neighbourhood physical activity environments and adiposity in children and mothers : a three-year longitudinal study

Background Although neighbourhood environments are often blamed for contributing to rising levels of obesity, current evidence is based predominantly on cross-sectional samples. This study examined associations between objectively-measured environmental characteristics of neighbourhoods and adiposity cross-sectionally and longitudinally over three years in children and their female carers.Methods Longitudinal study of 140 5-6 year-old and 269 10-12 year-old children and their female carers (n = 369). At baseline (2001) and follow-up (2004), height and weight were measured among children and self-reported among female carers, and were used to compute BMI z-scores and BMI, respectively. A Geographic Information System determined access to destinations (public open spaces, sports options, walking/cycling tracks), road connectivity (density of cul-de-sacs and intersections, proportion of 4-way intersections, length of \u27access\u27 paths (overpasses, access lanes, throughways between buildings)) and traffic exposure (length of \u27busy\u27 and \u27local\u27 roads) within 800 m and 2 km of home. Univariate and multivariable linear regression analyses examined associations between environmental characteristics and BMI/BMI z-scores at baseline and change in BMI/BMI z-scores over the three years.Results Cross-sectionally, BMI z-score was inversely associated with length (km) of access paths within 800 m (b = -0.50) and 2 km (b = -0.16) among younger and number of sport/recreation public open spaces (b = -0.14) and length (km) of \u27access\u27 paths (b = -0.94) within 800 m and length of local roads within 2 km (b = -0.01) among older children. Among female carers, BMI was associated with length (km) of walking/cycling tracks (b = 0.17) and busy roads (b = -0.34) within 800 m. Longitudinally, the proportion of intersections that were 4-way (b = -0.01) within 800 m of home was negatively associated with change in BMI z-score among younger children, while length (km) of access paths (b = 0.18) within 800 m was significant among older children. Among female carers, options for aerobics/fitness and swimming within 2 km were associated with change in BMI (B = -0.42).Conclusion A small number of neighbourhood environment features were associated with adiposity outcomes. These differed by age group and neighbourhood scale (800 m and 2 km) and were inconsistent between cross-sectional and longitudinal findings. However, the results suggest that improvements to road connectivity and slowing traffic and provision of facilities for leisure activities popular among women may support obesity prevention efforts.<br /

A natural experiment to examine the impact of park renewal on park-use and park-based physical activity in a disadvantaged neighbourhood: the REVAMP study methods

Background: Modifying the built environment by improving parks is potentially a sustainable way to increase population level physical activity. Despite considerable investment in parks and park renovations, few natural experiments on the impact of improving amenities on park use and park-based physical activity have been conducted. REVAMP is a natural experiment that aims to examine whether park improvement increases overall park usage, park-based physical activity and active travel to and from the park in the intervention compared with the control park over a two-year period; and to identify which specific aspects of the park refurbishment attracts park visitors and encourages park users to be more active. This paper describes the methods of the REVAMP study. Methods. The intervention park is a large regional park (329 hectares) located in a low socio-economic status (SES) area in the north-eastern suburbs of Melbourne, Australia. The control park is a regional park (120 hectares) located in a high SES area in the eastern suburbs of Melbourne. Multiple methodologies to evaluate the impact of the park renovation are being employed including: cross-sectional surveys of local residents living near the two parks, direct observations of park users, intercept surveys with park users, and electronic monitoring of path usage and car traffic within the parks. Baseline measures were conducted in April-May 2013 (T1), and an innovative play space suitable for children of all ages and abilities was installed at the intervention park between September 2013 and February 2014. Follow-up measures will be repeated in April-May 2014 (T2) and April-May 2015 (T3). All methodologies will be completed at both the intervention and control parks at all three time-points, with the exception of the cross-sectional survey of local residents which will only be conducted at T1 and T3. Conclusion: This research will inform future park developments, and will contribute to creating an evidence ba

Challenges in conducting natural experiments in parks - lessons from the REVAMP study

Experimental evidence on the role of the built environment for promoting physical activity is important for informing how to create cities that promote active living. Parks provide opportunities for physical activity, however, there is little robust evidence on the impact of park refurbishment. Government agencies often modify parks, providing opportunities for natural experiment studies of these interventions. Such an opportunity was provided by the modification of a large park in Victoria, Australia in 2013 when the Recording and EValuating Activity in a Modified Park (REVAMP) study was established. Based on insights from the REVAMP study, this paper discusses challenges involved in conducting natural experiments in park settings, focussing on issues that may help design more effective future evaluations of the impact of park refurbishment. Natural experiments offer unique opportunities to evaluate the impact of large-scale changes to the built environment. They provide valuable data that might not otherwise be possible to gather, because of the costs associated with modification of the environment. However, factors beyond the control of the study team contribute to the complexity of both organising and conducting natural experiments, with potential flow-on effects to the quality of data. Therefore many extraneous factors need to be considered when designing, costing and conducting natural experiments, studies should identify opportunities to include key partners from the inception of the project, be flexible yet robust, and allow sufficient funding to accommodate unexpected changes in the research protocol