Moving Beyond Simulation: Data-Driven Quantitative Photoacoustic Imaging Using Tissue-Mimicking Phantoms.

Accurate measurement of optical absorption coefficients from photoacoustic imaging (PAI) data would enable direct mapping of molecular concentrations, providing vital clinical insight. The ill-posed nature of the problem of absorption coefficient recovery has prohibited PAI from achieving this goal in living systems due to the domain gap between simulation and experiment. To bridge this gap, we introduce a collection of experimentally well-characterised imaging phantoms and their digital twins. This first-of-a-kind phantom data set enables supervised training of a U-Net on experimental data for pixel-wise estimation of absorption coefficients. We show that training on simulated data results in artefacts and biases in the estimates, reinforcing the existence of a domain gap between simulation and experiment. Training on experimentally acquired data, however, yielded more accurate and robust estimates of optical absorption coefficients. We compare the results to fluence correction with a Monte Carlo model from reference optical properties of the materials, which yields a quantification error of approximately 20%. Application of the trained U-Nets to a blood flow phantom demonstrated spectral biases when training on simulated data, while application to a mouse model highlighted the ability of both learning-based approaches to recover the depth-dependent loss of signal intensity. We demonstrate that training on experimental phantoms can restore the correlation of signal amplitudes measured in depth. While the absolute quantification error remains high and further improvements are needed, our results highlight the promise of deep learning to advance quantitative PAI.

'I Had It. I Don't Think I Have It But I Do Feel It Will Come Back Somewhere': A Qualitative Investigation of the Experience of People With Non-Muscle Invasive Bladder Cancer.

Very little is known about the impact of living with non-muscle invasive bladder cancer (NMIBC). NMIBC patients' experiences of their illness-in terms of their perceptions, coping strategies and psychological wellbeing-were explored. This study describes an interpretative phenomenological analysis (IPA) of individuals' accounts of living with NMIBC while on routine surveillance for cancer recurrence. Ten individuals took part in face-to-face semi-structured interviews. Three superordinate themes were derived from the data. The first theme, Being Diagnosed and Treated for NMIBC, concerned the observation that participants considered the physical implications, timeline and practicalities of their illness of primary importance and focused less on its psychological aspects. The second theme, Grappling with the Illness, outlined the impact of the doctor-patient relationship. The final theme, 'I don't treat it as a problem. I treat it as an issue', delineated how participants managed difficult emotions in the context of the illness. Findings from this study demonstrated that participants generally found effective ways to cope with their illness and experience of ongoing surveillance, though delay of emotional responses was common. Clinical implications for healthcare professionals are outlined including the importance of high-quality communication with the urology team.

The decline in transurethral resection of the prostate gland in Irish public hospitals between 2005 and 2021.

BACKGROUND: Lower urinary tract symptoms due to an enlarged prostate is a common condition. Transurethral resection of the prostate gland (TURP) has been the gold standard treatment. The objective of this study was to assess the trends in the prevalence of TURP procedures in Irish public hospitals within the period of 2005-2021. In addition, we explore the attitudes and practices of urologist in Ireland on this topic. METHODS: An analysis using the Hospital In-Patient Enquiry (HIPE) system using code 37203-00 was undertaken. 16,176 discharges contained the code of interest and had undergone a TURP procedure. The data from this cohort was further analysed. In addition, members of the Irish Society of Urology undertook a bespoke questionnaire to understand the TURP surgery practices. RESULTS: There has been a substantial decline in the prevalence of TURP procedures in Irish public hospitals from 2005 to 2021. The number of patients discharged from Irish hospitals with a TURP procedure was 66% less in 2021 compared to 2005. 75% (n = 36) of urologist surveyed felt that the declining TURP numbers were due to lack of resources, access to theatre/inpatient beds and outsourcing. 91.5% (n = 43) felt that the declining TURP numbers would result in a lack of training opportunities for trainees, 83% (39) felt this has increased morbidity for patients. CONCLUSIONS: TURP procedures in Irish public hospitals has declined over the 16-year period studied. This decline is a concern for patient morbidity and urology training.

Performance evaluation of mesoscopic photoacoustic imaging.

Photoacoustic mesoscopy visualises vascular architecture at high-resolution up to ~3 mm depth. Despite promise in preclinical and clinical imaging studies, with applications in oncology and dermatology, the accuracy and precision of photoacoustic mesoscopy is not well established. Here, we evaluate a commercial photoacoustic mesoscopy system for imaging vascular structures. Typical artefact types are first highlighted and limitations due to non-isotropic illumination and detection are evaluated with respect to rotation, angularity, and depth of the target. Then, using tailored phantoms and mouse models, we investigate system precision, showing coefficients of variation (COV) between repeated scans [short term (1 h): COV= 1.2%; long term (25 days): COV= 9.6%], from target repositioning (without: COV=1.2%, with: COV=4.1%), or from varying in vivo user experience (experienced: COV=15.9%, unexperienced: COV=20.2%). Our findings show robustness of the technique, but also underscore general challenges of limited-view photoacoustic systems in accurately imaging vessel-like structures, thereby guiding users when interpreting biologically-relevant information.

Heterogeneity in biological assemblages and exposure in chemical risk assessment: Exploring capabilities and challenges in methodology with two landscape-scale case studies.

Chemical exposure concentrations and the composition of ecological receptors (e.g., species) vary in space and time, resulting in landscape-scale (e.g. catchment) heterogeneity. Current regulatory, prospective chemical risk assessment frameworks do not directly address this heterogeneity because they assume that reasonably worst-case chemical exposure concentrations co-occur (spatially and temporally) with biological species that are the most sensitive to the chemical's toxicity. Whilst current approaches may parameterise fate models with site-specific data and aim to be protective, a more precise understanding of when and where chemical exposure and species sensitivity co-occur enables risk assessments to be better tailored and applied mitigation more efficient. We use two aquatic case studies covering different spatial and temporal resolution to explore how geo-referenced data and spatial tools might be used to account for landscape heterogeneity of chemical exposure and ecological assemblages in prospective risk assessment. Each case study followed a stepwise approach: i) estimate and establish spatial chemical exposure distributions using local environmental information and environmental fate models; ii) derive toxicity thresholds for different taxonomic groups and determine geo-referenced distributions of exposure-toxicity ratios (i.e., potential risk); iii) overlay risk data with the ecological status of biomonitoring sites to determine if relationships exist. We focus on demonstrating whether the integration of relevant data and potential approaches is feasible rather than making comprehensive and refined risk assessments of specific chemicals. The case studies indicate that geo-referenced predicted environmental concentration estimations can be achieved with available data, models and tools but establishing the distribution of species assemblages is reliant on the availability of a few sources of biomonitoring data and tools. Linking large sets of geo-referenced exposure and biomonitoring data is feasible but assessment of risk will often be limited by the availability of ecotoxicity data. The studies highlight the important influence that choices for aggregating data and for the selection of statistical metrics have on assessing and interpreting risk at different spatial scales and patterns of distribution within the landscape. Finally, we discuss approaches and development needs that could help to address environmental heterogeneity in chemical risk assessment.

Quantification of vascular networks in photoacoustic mesoscopy.

Mesoscopic photoacoustic imaging (PAI) enables non-invasive visualisation of tumour vasculature. The visual or semi-quantitative 2D measurements typically applied to mesoscopic PAI data fail to capture the 3D vessel network complexity and lack robust ground truths for assessment of accuracy. Here, we developed a pipeline for quantifying 3D vascular networks captured using mesoscopic PAI and tested the preservation of blood volume and network structure with topological data analysis. Ground truth data of in silico synthetic vasculatures and a string phantom indicated that learning-based segmentation best preserves vessel diameter and blood volume at depth, while rule-based segmentation with vesselness image filtering accurately preserved network structure in superficial vessels. Segmentation of vessels in breast cancer patient-derived xenografts (PDXs) compared favourably to ex vivo immunohistochemistry. Furthermore, our findings underscore the importance of validating segmentation methods when applying mesoscopic PAI as a tool to evaluate vascular networks in vivo.

Assessment of intrinsic aquifer vulnerability at continental scale through a critical application of the drastic framework: The case of South America.

An assessment of the intrinsic aquifer vulnerability of South America is presented. The outcomes represent the potential sensitivity of natural aquifers to leaching of dissolved compounds from the land surface. The study, developed at continental scale but retaining regionally a high resolution, is based on a critical application of the DRASTIC method. The biggest challenge in performing such a study in South America was the scattered and irregular nature of environmental datasets. Accordingly, the most updated information on soil, land use, geology, hydrogeology, and climate at continental, national, and regional scale were selected from international and local databases. To avoid spatial discrepancy and inconsistency, data were integrated, harmonized, and accurately cross-checked, using local professional knowledge where information was missing. The method was applied in a GIS environment to allow spatial analysis of raw data along with the overlaying and rating of maps. The application of the DRASTIC method allows to classify South America into five vulnerability classes, from very low to very high, and shows an overall medium to low vulnerability at continental scale. The Amazon region, coastal aquifers, colluvial Andean valleys, and alluvial aquifers of main rivers were the areas classified as highly vulnerable. Moreover, countries with the largest areas with high aquifer vulnerability were those characterized by extended regions of rainforest. In addition, a single parameter sensitivity analysis showed depth to water table to be the most significant factor, while a cross-validation using existing vulnerability assessments and observed concentrations of compounds in groundwater confirmed the reliability of the proposed assessment, even at regional scale. Overall, although additional field surveys and detailed works at local level are needed to develop effective water management plans, the present DRASTIC map represents an essential common ground towards a more sustainable land-use and water management in the whole territory of South America.

Patient reported factors influencing the decision-making process of men with localised prostate cancer when considering Active Surveillance-A systematic review and thematic synthesis.

OBJECTIVES: Outcomes for men with localised prostate cancer managed with Active Surveillance (AS) are similar to outcomes for men who have received Active Treatment. This review explore men's perceptions of the factors that influence their decision-making process when considering AS. METHOD: A systematic review of studies was conducted up to May 2021, including qualitative studies which explored the decision making of men with localised prostate cancer when considering AS. Evidence was analysed using thematic synthesis. RESULTS: Thirteen papers, including 426 men, met inclusion criteria and were analysed in the review. Approximately half of the men had chosen AS and half had chosen Active Treatment. The choice of AS was not a one-off decision but rather an ongoing behaviour. Four themes were identified and considered within a temporal model: pre-diagnosis representations of cancer and treatment; experience of testing and diagnosis; patient decision making; and emotional adjustment to AS. Key barriers and facilitators to men choosing AS were identified. In deciding whether or not to choose AS, men balanced a desire for quality of life against fear of cancer progression. CONCLUSIONS: Both cognitive representations and emotional arousal influence how men decided whether or not to opt for AS. Interventions tailored to elicit and address emotional appraisals of risk, and increase trust in AS protocols, may be of value in helping men to make decisions around treatment for localised prostate cancer.

A mathematical investigation into the uptake kinetics of nanoparticles in vitro.

Nanoparticles have the potential to increase the efficacy of anticancer drugs whilst reducing off-target side effects. However, there remain uncertainties regarding the cellular uptake kinetics of nanoparticles which could have implications for nanoparticle design and delivery. Polymersomes are nanoparticle candidates for cancer therapy which encapsulate chemotherapy drugs. Here we develop a mathematical model to simulate the uptake of polymersomes via endocytosis, a process by which polymersomes bind to the cell surface before becoming internalised by the cell where they then break down, releasing their contents which could include chemotherapy drugs. We focus on two in vitro configurations relevant to the testing and development of cancer therapies: a well-mixed culture model and a tumour spheroid setup. Our mathematical model of the well-mixed culture model comprises a set of coupled ordinary differential equations for the unbound and bound polymersomes and associated binding dynamics. Using a singular perturbation analysis we identify an optimal number of ligands on the polymersome surface which maximises internalised polymersomes and thus intracellular chemotherapy drug concentration. In our mathematical model of the spheroid, a multiphase system of partial differential equations is developed to describe the spatial and temporal distribution of bound and unbound polymersomes via advection and diffusion, alongside oxygen, tumour growth, cell proliferation and viability. Consistent with experimental observations, the model predicts the evolution of oxygen gradients leading to a necrotic core. We investigate the impact of two different internalisation functions on spheroid growth, a constant and a bond dependent function. It was found that the constant function yields faster uptake and therefore chemotherapy delivery. We also show how various parameters, such as spheroid permeability, lead to travelling wave or steady-state solutions.

Screening for Obstructive Sleep Apnea in an Atrial Fibrillation Population: What's the Best Test?

BACKGROUND: Among individuals with nonvalvular atrial fibrillation (AF), the prevalence of obstructive sleep apnea (OSA) can be as high as 85%. Continuous positive airway pressure treatment for moderate or severe OSA might improve AF outcomes and quality of life, so early identification of OSA might be of value. However, screening questionnaires for OSA are suboptimal because they are weighted toward tiredness and loud snoring, which might be absent in AF patients. NoSAS (Neck, Obesity, Snoring, Age, Sex) is a new OSA questionnaire that excludes these parameters. Acoustic pharyngometry (AP) is a potential novel screening technique that measures pharyngeal cross-sectional area, which is reduced in patients with OSA. METHODS: We prospectively compared the accuracy of the NoSAS, the STOP-BANG questionnaire (Snoring, Tiredness, Observed apnea, blood Pressure, Body mass index, Age, Neck circumference and Gender), and AP with home sleep apnea testing (HSAT) in consecutive patients with nonvalvular AF. RESULTS: Of 188 participants, 86% had OSA and 49% had moderate or severe OSA. Mean Epworth Sleepiness Scale scores were low; 5.9 (SD, 3.9), indicating that most participants were not sleepy. Receiver operating characteristic curves for comparisons of screening tests with HSAT showed suboptimal accuracy. For moderate plus severe and severe only groups respectively, the area under the curve was 0.50 (95% confidence interval [CI], 0.42-0.58) and 0.42 (95% CI, 0.34-0.52) for AP, 0.65 (95% CI, 0.58-0.73) and 0.63 (95% CI, 0.52-0.74) for the STOP-BANG questionnaire, and 0.68 (95% CI, 0.60-0.75) and 0.69 (95% CI, 0.59-0.80) for the NoSAS. CONCLUSIONS: AP and NoSAS are not sufficiently accurate for screening AF patients for OSA. Because of the high rates of OSA in this cohort, the potential benefits of OSA treatment, and the suboptimal accuracy of current screening questionnaires, cardiologists should consider HSAT for AF patients.

CONTEXTE: Chez les sujets présentant une fibrillation auriculaire (FA) non valvulaire, la prévalence de l'apnée obstructive du sommeil (AOS) peut atteindre 85 %. En cas d'AOS modérée ou sévère, un traitement par ventilation spontanée en pression positive continue peut améliorer les résultats liés à la FA et la qualité de vie du patient; un diagnostic précoce d'AOS pourrait donc être utile. Les questionnaires de dépistage de l'AOS ne sont toutefois pas optimaux parce qu'ils accordent une grande importance à la fatigue et aux ronflements sonores, des symptômes qui ne se manifestent pas nécessairement en cas de FA. Le questionnaire NoSAS (de l'anglais Neck, Obesity, Snoring, Age, Sex) est un nouvel outil d'évaluation de l'AOS qui ne tient pas compte de ces paramètres. La pharyngométrie acoustique (PA) pourrait aussi constituer une nouvelle technique de dépistage; elle mesure l'aire de section transversale du pharynx, qui est réduite chez les patients souffrant d'AOS. MÉTHODOLOGIE: Nous avons comparé de façon prospective la précision du score au questionnaire NoSAS, du score au questionnaire STOP-BANG (de l'anglais Snoring, Tiredness, Observed apnea, blood Pressure, Body mass index, Age, Neck circumference and Gender) et des résultats de la PA à celle du test d'apnée du sommeil à domicile (TASD) chez des patients consécutifs présentant une FA non valvulaire. RÉSULTATS: Sur les 188 participants, 86 % présentaient une AOS et 49 % souffraient d'AOS modérée ou sévère. Le score moyen sur l'échelle de somnolence d'Epworth était faible et se situait à 5,9 (écart-type : 3,9), ce qui indique que la plupart des participants ne ressentaient pas de somnolence. La comparaison entre les questionnaires de dépistage et le TASD effectuée au moyen des courbes caractéristiques de la performance des tests a révélé une précision sous-optimale. Dans les groupes souffrant d'AOS modérée ou sévère et d'AOS sévère seulement, les aires sous la courbe étaient respectivement de 0,50 (intervalle de confiance [IC] à 95 % : de 0,42 à 0,58) et de 0,42 (IC à 95 % : de 0,34 à 0,52) pour la PA, de 0,65 (IC à 95 % : de 0,58 à 0,73) et de 0,63 (IC à 95 % : de 0,52 à 0,74) pour le questionnaire STOP-BANG, et de 0,68 (IC à 95 % : de 0,60 à 0,75) et de 0,69 (IC à 95 % : de 0,59 à 0,80) pour le questionnaire NoSAS. CONCLUSIONS: La PA et le questionnaire NoSAS ne sont pas suffisamment précis pour dépister l'AOS chez les patients présentant une FA. Compte tenu de la forte prévalence de l'AOS dans cette cohorte, des bienfaits potentiels d'un traitement de l'AOS et de la précision sous-optimale des questionnaires de dépistage actuels, il conviendrait d'envisager un TASD chez les patients présentant une FA.

Regulatory groundwater monitoring: Realistic residues of pinoxaden and metabolites at vulnerable locations.

A bespoke groundwater monitoring programme was designed to generate a database of pinoxaden and metabolite concentrations in shallow groundwater at agricultural locations across Europe. The data generated from this programme represent a higher tier refinement of modelled exposure estimates and provide realistic information on groundwater quality at vulnerable locations which will aid plant protection product (PPP) assessment in Europe in relation to Regulation (EC) No. 1107/2009. The Regulatory GeoPEARL_3.3.3 model developed by RIVM was used to estimate the vulnerability of cereal growing regions to leaching of two pinoxaden metabolites across the entire EU at a 1 km2 level using 20 years of daily weather data (MARS, EU JRC). Seventy sites located within the upper 50th percentile of leaching vulnerability from this modelling exercise, crop density and shallow groundwater were selected for monitoring groundwater. Retrospective and prospective pinoxaden product applications at candidate sites were recorded and these data used to place sites in the distribution for Europe. The 70 sites all fulfil the site assessment criteria and have no confining layers which may prevent or delay leaching. All sites equipped with groundwater wells had a minimum of two pinoxaden applications in the preceding four years to cereal crops. A total of 1326 samples were analysed from up to 90 down hydraulic gradient wells at 70 locations between June 2015 and July 2018. Results indicate that pinoxaden and pinoxaden metabolites are very unlikely to reach shallow groundwater at concentrations greater than 0.1 µg/L for relevant metabolites, or 10 µg/L for non-relevant metabolites, respectively (Sanco/221/2000-rev.10). Over 38 months of groundwater monitoring the annual average and 90th percentile for pinoxaden or its metabolites never exceeded 0.1 µg/L and it is proposed that these data infer that exposure to these metabolites is minimal.

A knowledge-based approach to designing control strategies for agricultural pests.

Chemical control of insect pests remains vital to agricultural productivity, but limited mechanistic understanding of the interactions between crop, pest and chemical control agent have restricted our capacity to respond to challenges such as the emergence of resistance and demands for tighter environmental regulation. Formulating effective control strategies that integrate chemical and non-chemical management for soil-dwelling pests is particularly problematic owing to the complexity of the soil-root-pest system and the variability that occurs between sites and between seasons. Here, we present a new concept, termed COMPASS, that integrates ecological knowledge on pest development and behaviour together with crop physiology and mechanistic understanding of chemical distribution and toxic action within the rhizosphere. The concept is tested using a two-dimensional systems model (COMPASS-Rootworm) that simulates root damage in maize from the corn rootworm Diabrotica spp. We evaluate COMPASS-Rootworm using 119 field trials that investigated the efficacy of insecticidal products and placement strategies at four sites in the USA over a period of ten years. Simulated root damage is consistent with measurements for 109 field trials. Moreover, we disentangle factors influencing root damage and pest control, including pest pressure, weather, insecticide distribution, and temporality between the emergence of crop roots and pests. The model can inform integrated pest management, optimize pest control strategies to reduce environmental burdens from pesticides, and improve the efficiency of insecticide development.

A Novel Simulated Training Platform and Study of Performance Among Different Levels of Learners in Flexible Cystoscopy.

INTRODUCTION: The aims of this study were to test a novel simulation platform suitable for flexible cystoscopy using a standard scope, to assess the platform's proposed use as a training tool for flexible cystoscopy, and to assess the user experience through surveyed response. METHODS: Thirty-one urologists (11 novices, 20 experts) were evaluated using a novel light-based bladder model and standard flexible cystoscope. Time to complete full inspection of the simulated bladder was measured, and the scope trajectory was recorded. Participants also completed a survey of the training platform. RESULTS: Thirty participants completed a simulated inspection of a portable bladder model with a mean ± SD time for 153.1 ± 76.1 seconds. One participant failed to complete. Novice urologists (defined as those having completed less than 50 flexible cystoscopies in clinic) had a mean ± SD time of 176.9 ± 95.8 seconds, whereas with experts, this decreased to 139.3 ± 60.7 seconds. Dynamic trajectory maps identified "blind spots" within each user's cystoscopy performance. In a poststudy follow-up, 27 participants considered the tool valuable or extremely valuable for training, whereas 19 participants considered that the tool either very well or excellently replicated the clinical setting. All participants ranked the tool as very good or excellent for overall quality of training. DISCUSSION: Advances in electronic technology make portable low-cost models a potential low-cost alternative to endourology training platforms. In providing a quantifiable measure of user performance, the tool may shorten the learning curve in flexible cystoscopy and, potentially, reduce clinical errors and provide quantifiable measures for further clinical training.

A four-compartment multiscale model of fluid and drug distribution in vascular tumours.

The subtle relationship between vascular network structure and mass transport is vital to predict and improve the efficacy of anticancer treatments. Here, mathematical homogenisation is used to derive a new multiscale continuum model of blood and chemotherapy transport in the vasculature and interstitium of a vascular tumour. This framework enables information at a range of vascular hierarchies to be fed into an effective description on the length scale of the tumour. The model behaviour is explored through a demonstrative case study of a simplified representation of a dorsal skinfold chamber, to examine the role of vascular network architecture in influencing fluid and drug perfusion on the length scale of the chamber. A single parameter, P, is identified that relates tumour-scale fluid perfusion to the permeability and density of the capillary bed. By fixing the topological and physiological properties of the arteriole and venule networks, an optimal value for P is identified, which maximises tumour fluid transport and is thus hypothesised to benefit chemotherapy delivery. We calculate the values for P for eight explicit network structures; in each case, vascular intervention by either decreasing the permeability or increasing the density of the capillary network would increase fluid perfusion through the cancerous tissue. Chemotherapeutic strategies are compared and indicate that single injection is consistently more successful compared with constant perfusion, and the model predicts optimal timing of a second dose. These results highlight the potential of computational modelling to elucidate the link between vascular architecture and fluid, drug distribution in tumours.

A hybrid discrete-continuum approach for modelling microcirculatory blood flow.

In recent years, biological imaging techniques have advanced significantly and it is now possible to digitally reconstruct microvascular network structures in detail, identifying the smallest capillaries at sub-micron resolution and generating large 3D structural data sets of size >106 vessel segments. However, this relies on ex vivo imaging; corresponding in vivo measures of microvascular structure and flow are limited to larger branching vessels and are not achievable in three dimensions for the smallest vessels. This suggests the use of computational modelling to combine in vivo measures of branching vessel architecture and flows with ex vivo data on complete microvascular structures to predict effective flow and pressures distributions. In this paper, a hybrid discrete-continuum model to predict microcirculatory blood flow based on structural information is developed and compared with existing models for flow and pressure in individual vessels. A continuum-based Darcy model for transport in the capillary bed is coupled via point sources of flux to flows in individual arteriolar vessels, which are described explicitly using Poiseuille's law. The venular drainage is represented as a spatially uniform flow sink. The resulting discrete-continuum framework is parameterized using structural data from the capillary network and compared with a fully discrete flow and pressure solution in three networks derived from observations of the rat mesentery. The discrete-continuum approach is feasible and effective, providing a promising tool for extracting functional transport properties in situations where vascular branching structures are well defined.

Multiple Scale Homogenisation of Nutrient Movement and Crop Growth in Partially Saturated Soil.

In this paper, we use multiple scale homogenisation to derive a set of averaged macroscale equations that describe the movement of nutrients in partially saturated soil that contains growing potato tubers. The soil is modelled as a poroelastic material, which is deformed by the growth of the tubers, where the growth of each tuber is dependent on the uptake of nutrients via a sink term within the soil representing root nutrient uptake. Special attention is paid to the reduction in void space, resulting change in local water content and the impact on nutrient diffusion within the soil as the tubers increase in size. To validate the multiple scale homogenisation procedure, we compare the system of homogenised equations to the original set of equations and find that the solutions between the two models differ by [Formula: see text]. However, we find that the computation time between the two sets of equations differs by several orders of magnitude. This is due to the combined effects of the complex three-dimensional geometry and the implementation of a moving boundary condition to capture tuber growth.

Modelling the transport of fluid through heterogeneous, whole tumours in silico.

Cancers exhibit spatially heterogeneous, unique vascular architectures across individual samples, cell-lines and patients. This inherently disorganised collection of leaky blood vessels contribute significantly to suboptimal treatment efficacy. Preclinical tools are urgently required which incorporate the inherent variability and heterogeneity of tumours to optimise and engineer anti-cancer therapies. In this study, we present a novel computational framework which incorporates whole, realistic tumours extracted ex vivo to efficiently simulate vascular blood flow and interstitial fluid transport in silico for validation against in vivo biomedical imaging. Our model couples Poiseuille and Darcy descriptions of vascular and interstitial flow, respectively, and incorporates spatially heterogeneous blood vessel lumen and interstitial permeabilities to generate accurate predictions of tumour fluid dynamics. Our platform enables highly-controlled experiments to be performed which provide insight into how tumour vascular heterogeneity contributes to tumour fluid transport. We detail the application of our framework to an orthotopic murine glioma (GL261) and a human colorectal carcinoma (LS147T), and perform sensitivity analysis to gain an understanding of the key biological mechanisms which determine tumour fluid transport. Finally we mimic vascular normalization by modifying parameters, such as vascular and interstitial permeabilities, and show that incorporating realistic vasculatures is key to modelling the contrasting fluid dynamic response between tumour samples. Contrary to literature, we show that reducing tumour interstitial fluid pressure is not essential to increase interstitial perfusion and that therapies should seek to develop an interstitial fluid pressure gradient. We also hypothesise that stabilising vessel diameters and permeabilities are not key responses following vascular normalization and that therapy may alter interstitial hydraulic conductivity. Consequently, we suggest that normalizing the interstitial microenvironment may provide a more effective means to increase interstitial perfusion within tumours.

Insights into cerebral haemodynamics and oxygenation utilising in vivo mural cell imaging and mathematical modelling.

The neurovascular mechanisms underpinning the local regulation of cerebral blood flow (CBF) and oxygen transport remain elusive. In this study we have combined novel in vivo imaging of cortical microvascular and mural cell architecture with mathematical modelling of blood flow and oxygen transport, to provide new insights into CBF regulation that would be inaccessible in a conventional experimental context. Our study indicates that vasoconstriction of smooth muscle actin-covered vessels, rather than pericyte-covered capillaries, induces stable reductions in downstream intravascular capillary and tissue oxygenation. We also propose that seemingly paradoxical observations in the literature around reduced blood velocity in response to arteriolar constrictions might be caused by a propagation of constrictions to upstream penetrating arterioles. We provide support for pericytes acting as signalling conduits for upstream smooth muscle activation, and erythrocyte deformation as a complementary regulatory mechanism. Finally, we caution against the use of blood velocity as a proxy measurement for flow. Our combined imaging-modelling platform complements conventional experimentation allowing cerebrovascular physiology to be probed in unprecedented detail.

Computational fluid dynamics with imaging of cleared tissue and of in vivo perfusion predicts drug uptake and treatment responses in tumours.

Understanding the uptake of a drug by diseased tissue, and the drug's subsequent spatiotemporal distribution, are central factors in the development of effective targeted therapies. However, the interaction between the pathophysiology of diseased tissue and individual therapeutic agents can be complex, and can vary across tissue types and across subjects. Here, we show that the combination of mathematical modelling, high-resolution optical imaging of intact and optically cleared tumour tissue from animal models, and in vivo imaging of vascular perfusion predicts the heterogeneous uptake, by large tissue samples, of specific therapeutic agents, as well as their spatiotemporal distribution. In particular, by using murine models of colorectal cancer and glioma, we report and validate predictions of steady-state blood flow and intravascular and interstitial fluid pressure in tumours, of the spatially heterogeneous uptake of chelated gadolinium by tumours, and of the effect of a vascular disrupting agent on tumour vasculature.

Evaluation of a novel test design to determine uptake of chemicals by plant roots.

A new hydroponic study design to determine uptake of chemicals by plant roots was tested by (i) investigating uptake of [14C]-1,2,4-triazole by wheat plants in a ring test with ten laboratory organizations and (ii) studying uptake of ten other radiolabelled chemicals by potato, tomato or wheat plants in two laboratories. Replicate data from the ring test were used to calculate plant uptake factor (PUF) values (uptake into roots and shoots) and transpiration stream concentration factor (TSCF) values (uptake into shoots). Average PUF for 1,2,4-triazole was 0.73 (n=39, 95% confidence interval (CI): 0.64, 0.82) and the corresponding TSCF value was 1.03 (n=49, 95% CI: 0.76, 1.3). Boxplots and subsequent classification tree analysis of PUF and TSCF values showed that potential outlier values were >1.38 and were observed for PUF replicates with low biomass increase (ratio of final to initial biomass ≤1.739) and small initial biomass (≤1.55g) and for TSCF replicates with an increase in biomass of <0.67g over a period of eight days. Considering only valid replicate data, average values of PUF and TSCF were 0.65 (n=33, 95% CI: 0.57, 0.73) and 0.64 (n=39, 95% CI: 0.58, 0.70). The additional experiments with ten chemicals and three plant species showed that uptake was low for polar substances of high molecular weight (≥394g/mol) and that TSCF values increased with log Kow values of the tested chemicals ranging from -1.54 to 1.88 (polynomial equation with R2=0.64). A cluster analysis for three of the compounds that were tested on wheat and tomato indicated that the plant uptake was mainly determined by the substance. Overall, the findings show that the hydroponic study design allows for reliable quantification of plant uptake over a range of compound/crop combinations.