Mapping the rat gastric slow wave conduction pathway: Bridging in vitro and in vivo methods, revealing a loosely-coupled region in the distal stomach.

Rhythmic electrical events, termed slow waves, govern the timing and amplitude of phasic contractions of the gastric musculature. Extracellular multielectrode measurement of gastric slow waves can be a biomarker for phenotypes of motility dysfunction. However, a gastric slow wave conduction pathway for the rat, a common animal model, is unestablished. In this study, the validity of extracellular recording was demonstrated in vitro with simultaneous intracellular and extracellular recordings and by pharmacological inhibition of slow waves. The conduction pathway was determined by in vivo extracellular recordings while considering the effect of motion. Slow wave characteristics (mean (SD)) varied regionally, having higher amplitude in the antrum than the distal corpus (1.03 (0.12) mV vs 0.75 (0.31) mV; n = 7; p = 0.025 paired t-test) and faster propagation near the greater curvature than the lesser curvature (1.00 (0.14) mm s-1 vs 0.74 (0.14) mm s-1; n = 9 GC, 7 LC; p = 0.003 unpaired t-test). Notably, in some subjects, separate wavefronts propagated near the lesser and greater curvatures with a loosely-coupled region occurring in the area near the distal corpus midline, at the interface of the two wavefronts. This region had either the greater or lesser curvature wavefront propagating through it in a time-varying manner. The conduction pattern suggests that slow waves in the rat stomach form annular wavefronts in the antrum and not the corpus. This study has implications for interpretation of the relationship between slow waves, the interstitial cells of Cajal network structure, smooth muscles, and gastric motility.

Steady-state approximations for Hodgkin-Huxley cell models: Reduction of order for uterine smooth muscle cell model.

Multi-scale mathematical bioelectrical models of organs such as the uterus, stomach or heart present challenges both for accuracy and computational tractability. These multi-scale models are typically founded on models of biological cells derived from the classic Hodkgin-Huxley (HH) formalism. Ion channel behaviour is tracked with dynamical variables representing activation or inactivation of currents that relax to steady-state dependencies on cellular membrane voltage. Timescales for relaxation may be orders of magnitude faster than companion ion channel variables or phenomena of physiological interest for the entire cell (such as bursting sequences of action potentials) or the entire organ (such as electromechanical coordination). Exploiting these time scales with steady-state approximations for relatively fast-acting systems is a well-known but often overlooked approach as evidenced by recent published models. We thus investigate feasibility of an extensive reduction of order for an HH-type cell model with steady-state approximations to the full dynamical activation and inactivation ion channel variables. Our effort utilises a published comprehensive uterine smooth muscle cell model that encompasses 19 ordinary differential equations and 105 formulations overall. The numerous ion channel submodels in the published model exhibit relaxation times ranging from order 10-1 to 105 milliseconds. Substitution of the faster dynamic variables with steady-state formulations demonstrates both an accurate reproduction of the full model and substantial improvements in time-to-solve, for test cases performed. Our demonstration here of an effective and relatively straightforward reduction method underlines the particular importance of considering time scales for model simplification before embarking on large-scale computations or parameter sweeps. As a preliminary complement to more intensive reduction of order methods such as parameter sensitivity and bifurcation analysis, this approach can rapidly and accurately improve computational tractability for challenging multi-scale organ modelling efforts.

Pregnancy-specific uterine vascular reactivity: a data-driven computational model of shear-dependent, myogenic, and mechanical radial artery features.

`The entire maternal circulation adapts to pregnancy, and this adaption is particularly extensive in the uterine circulation where the major vessels double in size to facilitate an approximately 15-fold increase in blood supply to this organ over the course of pregnancy. Several factors may play a role in both the remodeling and biomechanical function of the uterine vasculature including the paracrine microenvironment, passive properties of the vessel wall, and active components of vascular function (incorporating the myogenic response and response to shear stress induced by intravascular blood flow). However, the interplay between these factors and how this plays out in an organ-specific manner to induce the extent of remodeling observed in the uterus is not well understood. Here we present an integrated assessment of the uterine radial arteries, likely rate limiters to the flow of oxygenated maternal blood to the placental surface, via computational modeling and pressure myography. We show that uterine radial arteries behave differently to other systemic vessels (higher compliance and shear-mediated constriction) and that their properties change with the adaptation to pregnancy (higher myogenic tone, higher compliance, and ability to tolerate higher flow rates before constricting). Together, this provides a useful tool to improve our understanding of the role of uterine vascular adaptation in normal and abnormal pregnancies and highlights the need for vascular bed-specific investigations of vascular function in health and disease.NEW & NOTEWORTHY To our knowledge, this is the first data-driven computational model of autoregulation of uterine radial arteries, likely rate limiters of maternal blood flow to the placenta. The study demonstrates that uterine radial arteries behave differently from systemic vessels (higher compliance, shear-mediated constriction) and change in pregnancy (higher myogenic tone, higher compliance, tolerance of higher flow rates). This pregnancy-specific mathematical model of vascular reactivity allows interrogation of the functional significance of incomplete vascular adaption in pathology.

The effect of respiration and body position on terminal thoracic duct diameter and the lymphovenous junction: An exploratory ultrasound study.

The thoracic duct (TD) drains most of the body's lymph back to the venous system via its lymphovenous junction (LVJ), playing a pivotal role in fluid homeostasis, fat absorption and the systemic immune response. The respiratory cycle is thought to assist with lymph flow, but the precise mechanism underpinning terminal TD lymph flow into the central veins is not well understood. The aim of this study was to use ultrasonography (US) to explore the relationship between terminal TD lymph flow, the respiratory cycle, and gravity. The left supraclavicular fossa was scanned in healthy non-fasted volunteers using high-resolution (13-5 MHz) US to identify the terminal TD and the presence of a lymphovenous valve (LVV). The TD's internal diameter was measured in relation to respiration (inspiration vs. expiration) and body positioning (supine vs. Trendelenburg). The terminal TD was visualized in 20/33 (61%) healthy volunteers. An LVV was visualized in only 4/20 (20%) cases. The mean terminal TD diameter in the supine position was 1.7 mm (range 0.8-3.1 mm); this increased in full inspiration (mean 1.8 mm, range 0.9-3.2 mm, p < 0.05), and in the Trendelenburg position (mean 1.8 mm, range 1.2-3.1 mm, p < 0.05). The smallest mean terminal TD diameter occurred in full expiration (1.6 mm, range 0.7-3.1 mm, p < 0.05). Respiration and gravity impact the terminal TD diameter. Due to the challenges of visualizing the TD and LVJ, other techniques such as dynamic magnetic resonance imaging will be required to fully understand the factors governing TD lymph flow.

Something old, something new: digital quantification of uterine vascular remodelling and trophoblast plugging in historical collections provides new insight into adaptation of the utero-placental circulation.

STUDY QUESTION: What is the physiological extent of vascular remodelling in and trophoblast plugging of the uterine circulation across the first half of pregnancy? SUMMARY ANSWER: All levels of the uterine vascular tree (arcuate, radial and spiral arteries (SAs)) dilate ∼2.6- to 4.3-fold between 6 and 20 weeks of gestation, with significant aggregates of trophoblasts persisting in the decidual and myometrial parts of SAs beyond the first trimester. WHAT IS KNOWN ALREADY: In early pregnancy, endovascular trophoblasts form 'plugs' in the SAs, transiently inhibiting blood flow to the placenta, whilst concurrently the uterine vasculature undergoes significant adaption to facilitate increased blood delivery to the placenta later in gestation. These processes are impaired in pregnancy disorders, but quantitative understanding of the anatomical changes even in normal pregnancy is poor. STUDY DESIGN, SIZE, DURATION: Serial sections of normal placentae in situ (n = 22) of 6.1-20.5 weeks of gestation from the Boyd collection and Dixon collection (University of Cambridge, UK) were digitalized using a slide scanner or Axio Imager.A1 microscope. PARTICIPANTS/MATERIALS, SETTING, METHODS: Spiral (n = 45), radial (n = 40) and arcuate (n = 39) arteries were manually segmented. Using custom-written scripts for Matlab® software, artery dimensions (Feret diameters; major axes; luminal/wall area) and endovascular trophoblast plug/aggregate (n = 24) porosities were calculated. Diameters of junctional zone SAs within the myometrium (n = 35) were acquired separately using a micrometre and light microscope. Decidual thickness and trophoblast plug depth was measured using ImageJ. MAIN RESULTS AND THE ROLE OF CHANCE: By all measures, radial and arcuate artery dimensions progressively increased from 6.1 to 20.5 weeks (P < 0.01). The greatest increase in SA calibre occurred after 12 weeks of gestation. Trophoblast aggregates were found to persist within decidual and myometrial parts of SA lumens beyond the first trimester, and up to 18.5 weeks of gestation, although those present in the second trimester did not appear to prevent the passage of red blood cells to the intervillous space. Trophoblasts forming these aggregates became more compact (decreased in porosity) over gestation, whilst channel size between cells increased (P = 0.01). Decidual thickness decreased linearly over gestation (P = 0.0003), meaning plugs occupied an increasing proportion of the decidua (P = 0.02). LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: Although serial sections were assessed, two-dimensional images cannot completely reflect the three-dimensional properties and connectivity of vessels and plugs/aggregates. Immersion-fixation of the specimens means that vessel size may be under-estimated. WIDER IMPLICATIONS OF THE FINDINGS: Uterine vascular remodelling and trophoblast plug dispersion is a progressive phenomenon that is not completed by the end of the first trimester. Our quantitative findings support the concept that radial arteries present a major site of resistance until mid-gestation. Their dimensional increase at 10-12 weeks of gestation may explain the rapid increase in blood flow to the placenta observed by others at ∼13 weeks. Measured properties of trophoblast plugs suggest that they will impact on the resistance, shear stress and nature of blood flow within the utero-placental vasculature until mid-gestation. The presence of channels within plugs will likely lead to high velocity flow streams and thus increase shear stress experienced by the trophoblasts forming the aggregates. Quantitative understanding of utero-placental vascular adaptation gained here will improve in silico modelling of utero-placental haemodynamics and provide new insights into pregnancy disorders, such as fetal growth restriction. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by a Royal Society Te Aparangi Marsden Grant [18-UOA-135]. A.R.C. is supported by a Rutherford Discovery Fellowship [14-UOA-019]. The authors have no conflict of interest to declare.

Structure-function relationships in the feto-placental circulation from in silico interpretation of micro-CT vascular structures.

A well-functioning placenta is critical for healthy fetal development, as the placenta brings fetal blood in close contact with nutrient rich maternal blood, enabling exchange of nutrients and waste between mother and fetus. The feto-placental circulation forms a complex branching structure, providing blood to fetal capillaries, which must receive sufficient blood flow to ensure effective exchange, but at a low enough pressure to prevent damage to placental circulatory structures. The branching structure of the feto-placental circulation is known to be altered in complications such as fetal growth restriction, and the presence of regions of vascular dysfunction (such as hypovascularity or thrombosis) are proposed to elevate risk of placental pathology. Here we present a methodology to combine micro-computed tomography and computational model-based analysis of the branching structure of the feto-placental circulation in ex vivo placentae from normal term pregnancies. We analyse how vascular structure relates to function in this key organ of pregnancy; demonstrating that there is a 'resilience' to placental vascular structure-function relationships. We find that placentae with variable chorionic vascular structures, both with and without a Hyrtl's anastomosis between the umbilical arteries, and those with multiple regions of poorly vascularised tissue are able to function with a normal vascular resistance. Our models also predict that by progressively introducing local heterogeneity in placental vascular structure, large increases in feto-placental vascular resistances are induced. This suggests that localised heterogeneities in placental structure could potentially provide an indicator of increased risk of placental dysfunction.

Could automated analysis of chest X-rays detect early bronchiectasis in children?

Non-cystic fibrosis bronchiectasis is increasingly described in the paediatric population. While diagnosis is by high-resolution chest computed tomography (CT), chest X-rays (CXRs) remain a first-line investigation. CXRs are currently insensitive in their detection of bronchiectasis. We aim to determine if quantitative digital analysis allows CT features of bronchiectasis to be detected in contemporaneously taken CXRs. Regions of radiologically (A) normal, (B) severe bronchiectasis, (C) mild airway dilation and (D) other parenchymal abnormalities were identified in CT and mapped to corresponding CXR. An artificial neural network (ANN) algorithm was used to characterise regions of classes A, B, C and D. The algorithm was then tested in 13 subjects and compared to CT scan features. Structural changes in CT were reflected in CXR, including mild airway dilation. The areas under the receiver operator curve for ANN feature detection were 0.74 (class A), 0.71 (class B), 0.76 (class C) and 0.86 (class D). CXR analysis identified CT measures of abnormality with a better correlation than standard radiological scoring at the 99% confidence level.Conclusion: Regional abnormalities can be detected by digital analysis of CXR, which may provide a low-cost and readily available tool to indicate the need for diagnostic CT and for ongoing disease monitoring. What is Known: • Bronchiectasis is a severe chronic respiratory disorder increasingly recognised in paediatric populations. • Diagnostic computed tomography imaging is often requested only after several chest X-ray investigations. What is New: • We show that a digital analysis of chest X-ray could provide more accurate identification of bronchiectasis features.

Ventilation/Perfusion Matching: Of Myths, Mice, and Men.

Despite a huge range in lung size between species, there is little measured difference in the ability of the lung to provide a well-matched air flow (ventilation) to blood flow (perfusion) at the gas exchange tissue. Here, we consider the remarkable similarities in ventilation/perfusion matching between species through a biophysical lens and consider evidence that matching in large animals is dominated by gravity but in small animals by structure.

Feeding Your Baby In Utero: How the Uteroplacental Circulation Impacts Pregnancy.

The utero-placental circulation links the maternal and fetal circulations during pregnancy, ensuring adequate gas and nutrient exchange, and consequently fetal growth. However, our understanding of this circulatory system remains incomplete. Here, we discuss how the utero-placental circulation is established, how it changes dynamically during pregnancy, and how this may impact on pregnancy success, highlighting how we may address knowledge gaps through advances in imaging and computational modeling approaches.

Trophoblast plugs: impact on utero-placental haemodynamics and spiral artery remodelling.

STUDY QUESTION: How does trophoblast plugging impact utero-placental haemodynamics? SUMMARY ANSWER: Physiological trophoblast plug structures are dense enough to restrict flow of oxygenated blood to the intervillous space (IVS) in the first trimester, and result in a shear stress environment upstream of the plugs that promotes spiral artery remodelling. WHAT IS KNOWN ALREADY: Trophoblast plugging of the uterine spiral arteries is thought to be the dominant factor restricting the flow of oxygenated maternal blood to the placenta in the first trimester of pregnancy. However, the extent of plugging, the timing of plug break up, and the impact of plug structure on pregnancy outcomes is debated. STUDY DESIGN, SIZE, DURATION: A computational model of the uterine radial and spiral arteries, incorporating arteriovenous anastomoses was developed. The model was parameterized with our own histological data and previous literature descriptions of the dimensions of the spiral arteries, and the structural properties (porosity) of trophoblast plugs. PARTICIPANTS/MATERIALS, SETTING, METHODS: Structural data were acquired from the literature, and supplemented by images of the spiral arteries acquired by standard thin-section 2D immunohistochemistry, and whole mount immunohistochemistry imaged in 3D by micro-CT. Computational models were solved using Matlab software, via custom written scripts. MAIN RESULTS AND THE ROLE OF CHANCE: We confirm that physiological lengths (>0.1 mm) and porosities (0.2-0.6) of trophoblast plugs are sufficient to restrict the flow of oxygenated maternal blood flow to the placental surface. Trophoblast plugs also have important haemodynamic consequences upstream in the spiral arteries by generating shear stress conditions of <2 dyne/cm2 that promote trophoblast-induced spiral artery remodelling. Structural changes in plugs as they dislodge are likely to result in rapid increases in blood flow to the IVS, and it is likely at this stage of gestation that the major source of resistance in the utero-placental circulation transitions from the spiral arteries to the radial arteries, which then act as a the 'rate-limiting' step to IVS flow. LIMITATIONS, REASONS FOR CAUTION: Structural descriptions of the spiral arteries, radial arteries and trophoblast plugs largely rely on 2D histological sections, or historical measurements. Increased focus on quantitatively assessing the 3D structure of the uterine arteries using more modern imaging technologies in the future will strengthen model predictions. WIDER IMPLICATIONS OF THE FINDINGS: Our work suggests that trophoblast plugs play a previously under-appreciated role in regulating spiral artery remodelling in the first trimester of human pregnancy. This creates the possibility that inadequate trophoblast plugging in the first trimester may contribute to the inadequate artery remodelling observed in pregnancy pathologies such as pre-eclampsia. The incorporation of arteriovenous anastomoses in our model highlights the important influence that shunted blood can play in utero-placental haemodynamics, and together with the emerging role of radial arteries in regulating blood flow to the placenta, the influence of arteriovenous anastomoses on radial artery haemodynamics in normal and pathological pregnancies warrants further investigation. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by a Royal Society of New Zealand Marsden Fund award (13-UOA-032). A.R.C. is supported by a Royal Society of New Zealand Rutherford Discovery Fellowship (14-UOA-019). R.S. was supported by a Gravida (National Centre for Growth and Development) postgraduate scholarship. The authors have no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

Association of Placental Jets and Mega-Jets With Reduced Villous Density.

Spiral arteries (SAs) lie at the interface between the uterus and placenta, and supply nutrients to the placental surface. Maternal blood circulation is separated from the fetal circulation by structures called villous trees. SAs are transformed in early pregnancy from tightly coiled vessels to large high-capacity channels, which is believed to facilitate an increased maternal blood flow throughout pregnancy with minimal increase in velocity, preventing damage to delicate villous trees. Significant maternal blood flow velocities have been theorized in the space surrounding the villi (the intervillous space, IVS), particularly when SA conversion is inadequate, but have only recently been visualized reliably using pulsed wave Doppler ultrasonography. Here, we present a computational model of blood flow from SA openings, allowing prediction of IVS properties based on jet length. We show that jets of flow observed by ultrasound are likely correlated with increased IVS porosity near the SA mouth and propose that observed mega-jets (flow penetrating more than half the placental thickness) are only possible when SAs open to regions of the placenta with very sparse villous structures. We postulate that IVS tissue density must decrease at the SA mouth through gestation, supporting the hypothesis that blood flow from SAs influences villous tree development.

A multiscale model of placental oxygen exchange: The effect of villous tree structure on exchange efficiency.

The placenta is critical to fetal health during pregnancy as it supplies oxygen and nutrients to maintain life. It has a complex structure, and alterations to this structure across spatial scales are associated with several pregnancy complications, including intrauterine growth restriction (IUGR). The relationship between placental structure and its efficiency as an oxygen exchanger is not well understood in normal or pathological pregnancies. Here we present a computational framework that predicts oxygen transport in the placenta which accounts for blood and oxygen transport in the space around a placental functional unit (the villous tree). The model includes the well-defined branching structure of the largest villous tree branches, as well as a smoothed representation of the small terminal villi that comprise the placenta's gas exchange interfaces. The model demonstrates that oxygen exchange is sensitive to villous tree geometry, including the villous branch length and volume, which are seen to change in IUGR. This is because, to be an efficient exchanger, the architecture of the villous tree must provide a balance between maximising the surface area available for exchange, and the opposing condition of allowing sufficient maternal blood flow to penetrate into the space surrounding the tree. The model also predicts an optimum oxygen exchange when the branch angle is 24 °, as villous branches and TBs are spread out sufficiently to channel maternal blood flow deep into the placental tissue for oxygen exchange without being shunted directly into the DVs. Without concurrent change in the branch length and angles, the model predicts that the number of branching generations has a small influence on oxygen exchange. The modelling framework is presented in 2D for simplicity but is extendible to 3D or to incorporate the high-resolution imaging data that is currently evolving to better quantify placental structure.

Quantifying normal geometric variation in human pulmonary lobar geometry from high resolution computed tomography.

Previous studies of the ex vivo lung have suggested significant intersubject variability in lung lobe geometry. A quantitative description of normal lung lobe shape would therefore have value in improving the discrimination between normal population variability in shape and pathology. To quantify normal human lobe shape variability, a principal component analysis (PCA) was performed on high resolution computed tomography (HRCT) imaging of the lung at full inspiration. Volumetric imaging from 22 never-smoking subjects (10 female and 12 male) with normal lung function was included in the analysis. For each subject, an initial finite element mesh geometry was generated from a group of manually selected nodes that were placed at distinct anatomical locations on the lung surface. Each mesh used cubic shape functions to describe the surface curvilinearity, and the mesh was fitted to surface data for each lobe. A PCA was performed on the surface meshes for each lobe. Nine principal components (PCs) were sufficient to capture >90% of the normal variation in each of the five lobes. The analysis shows that lobe size can explain between 20% and 50% of intersubject variability, depending on the lobe considered. Diaphragm shape was the next most significant intersubject difference. When the influence of lung size difference is removed, the angle of the fissures becomes the most significant shape difference, and the variability in relative lobe size becomes important. We also show how a lobe from an independent subject can be projected onto the study population's PCs, demonstrating potential for abnormalities in lobar geometry to be defined in a quantitative manner.

3D Single Vessel Fractional Moving Blood Volume (3D-svFMBV): Fully Automated Tissue Perfusion Estimation Using Ultrasound.

Power Doppler ultrasound (PD-US) is the ideal modality to assess tissue perfusion as it is cheap, patient-friendly and does not require ionizing radiation. However, meaningful inter-patient comparison only occurs if differences in tissue-attenuation are corrected for. This can be done by standardizing the PD-US signal to a blood vessel assumed to have 100% vascularity. The original method to do this is called fractional moving blood volume (FMBV). We describe a novel, fully-automated method combining image processing, numerical modelling, and deep learning to estimate three-dimensional single vessel fractional moving blood volume (3D-svFMBV). We map the PD signals to a characteristic intensity profile within a single large vessel to define the standardization value at the high shear vessel margins. This removes the need for mathematical correction for background signal which can introduce error. The 3D-svFMBV was first tested on synthetic images generated using the characteristics of uterine artery and physiological ultrasound noise levels, demonstrating prediction of standardization value close to the theoretical ideal. Clinical utility was explored using 143 first-trimester placental ultrasound volumes. More biologically plausible perfusion estimates were obtained, showing improved prediction of pre-eclampsia compared with those generated with the semi-automated original 3D-FMBV technique. The proposed 3D-svFMBV method overcomes the limitations of the original technique to provide accurate and robust placental perfusion estimation. This not only has the potential to provide an early pregnancy screening tool but may also be used to assess perfusion of different organs and tumors.

Multichannel mapping of in vivo rat uterine myometrium exhibits both high and low frequency electrical activity in non-pregnancy.

The uterus exhibits intermittent electrophysiological activity in vivo. Although most active during labor, the non-pregnant uterus can exhibit activity of comparable magnitude to the early stages of labor. In this study, two types of flexible electrodes were utilized to measure the electrical activity of uterine smooth muscle in vivo in anesthetized, non-pregnant rats. Flexible printed circuit electrodes were placed on the serosal surface of the uterine horn of six anesthetized rats. Electrical activity was recorded for a duration of 20-30 min. Activity contained two components: high frequency activity (bursts) and an underlying low frequency 'slow wave' which occurred concurrently. These components had dominant frequencies of 6.82 ± 0.63 Hz for the burst frequency and 0.032 ± 0.0055 Hz for the slow wave frequency. There was a mean burst occurrence rate of 0.76 ± 0.23 bursts per minute and mean burst duration of 20.1 ± 6.5 s. The use of multiple high-resolution electrodes enabled 2D mapping of the initiation and propagation of activity along the uterine horn. This in vivo approach has the potential to provide the organ level detail to help interpret non-invasive body surface recordings.

Neural regulation of slow waves and phasic contractions in the distal stomach: a mathematical model.

Objective.Neural regulation of gastric motility occurs partly through the regulation of gastric bioelectrical slow waves (SWs) and phasic contractions. The interaction of the tissues and organs involved in this regulatory process is complex. We sought to infer the relative importance of cellular mechanisms in inhibitory neural regulation of the stomach by enteric neurons and the interaction of inhibitory and excitatory electrical field stimulation.Approach.A novel mathematical model of gastric motility regulation by enteric neurons was developed and scenarios were simulated to determine the mechanisms through which enteric neural influence is exerted. This model was coupled to revised and extended electrophysiological models of gastric SWs and smooth muscle cells (SMCs).Main results.The mathematical model predicted that regulation of contractile apparatus sensitivity to intracellular calcium in the SMC was the major inhibition mechanism of active tension development, and that the effect on SW amplitude depended on the inhibition of non-specific cation currents more than the inhibition of calcium-activated chloride current (kiNSCC= 0.77 vs kiAno1= 0.33). The model predicted that the interaction between inhibitory and excitatory neural regulation, when applied with simultaneous and equal intensity, resulted in an inhibition of contraction amplitude almost equivalent to that of inhibitory stimulation (79% vs 77% decrease), while the effect on frequency was overall excitatory, though less than excitatory stimulation alone (66% vs 47% increase).Significance.The mathematical model predicts the effects of inhibitory and excitatory enteric neural stimulation on gastric motility function, as well as the effects when inhibitory and excitatory enteric neural stimulation interact. Incorporation of the model into organ-level simulations will provide insights regarding pathological mechanisms that underpin gastric functional disorders, and allow forin silicotesting of the effects of clinical neuromodulation protocols for the treatment of these disorders.

Evaluating Tissue Heterogeneity in the Radiologically Normal-Appearing Tissue in IPF Compared to Healthy Controls.

RATIONALE AND OBJECTIVES: Idiopathic Pulmonary Fibrosis (IPF) is a progressive interstitial lung disease characterised by heterogeneously distributed fibrotic lesions. The inter- and intra-patient heterogeneity of the disease has meant that useful biomarkers of severity and progression have been elusive. Previous quantitative computed tomography (CT) based studies have focussed on characterising the pathological tissue. However, we hypothesised that the remaining lung tissue, which appears radiologically normal, may show important differences from controls in tissue characteristics. MATERIALS AND METHODS: Quantitative metrics were derived from CT scans in IPF patients (N = 20) and healthy controls with a similar age (N = 59). An automated quantitative software (CALIPER, Computer-Aided Lung Informatics for Pathology Evaluation and Rating) was used to classify tissue as normal-appearing, fibrosis, or low attenuation area. Densitometry metrics were calculated for all lung tissue and for only the normal-appearing tissue. Heterogeneity of lung tissue density was quantified as coefficient of variation and by quadtree. Associations between measured lung function and quantitative metrics were assessed and compared between the two cohorts. RESULTS: All metrics were significantly different between controls and IPF (p < 0.05), including when only the normal tissue was evaluated (p < 0.04). Density in the normal tissue was 14% higher in the IPF participants than controls (p < 0.001). The normal-appearing tissue in IPF had heterogeneity metrics that exhibited significant positive relationships with the percent predicted diffusion capacity for carbon monoxide. CONCLUSION: We provide quantitative assessment of IPF lung tissue characteristics compared to a healthy control group of similar age. Tissue that appears visually normal in IPF exhibits subtle but quantifiable differences that are associated with lung function and gas exchange.

Quantitative Analysis of Lung Shape in Idiopathic Pulmonary Fibrosis: Insights Into Disease- and Age-Associated Patterns.

RATIONALE AND OBJECTIVES: Fibrotic scarring in idiopathic pulmonary fibrosis (IPF) typically develops first in the posterior-basal lung tissue before advancing to involve more of the lung. The complexity of lung shape in the costo-diaphragmatic region has been proposed as a potential factor in this regional development. Intrinsic and disease-related shape could therefore be important for understanding IPF risk and its staging. We hypothesized that lung and lobe shape in IPF would have important differences from controls. MATERIALS AND METHODS: A principal component (PC) analysis was used to derive a statistical shape model (SSM) of the lung for a control cohort aged > 50 years (N = 39), using segmented lung and fissure surface data from CT imaging. Individual patient shape models derived for baseline (N = 18) and follow-up (N = 16) CT scans in patients with IPF were projected to the SSM to describe shape as the sum of the SSM average and weighted PC modes. Associations between the first four PC shape modes, lung function, percentage of fibrosis (fibrosis%) and pulmonary vessel-related structures (PVRS%), and other tissue metrics were assessed and compared between the two cohorts. RESULTS: Shape was different between IPF and controls (P < 0.05 for all shape modes), with IPF shape forming a distinct shape cluster. Shape had a negative relationship with age in controls (P = 0.013), but a positive relationship with age in IPF (P = 0.026). Some features of shape changed on follow-up. Shape in IPF was associated with fibrosis% (P < 0.05) and PVRS% (P < 0.05). CONCLUSION: Quantitative comparison of lung and lobe shape in IPF with controls of a similar age reveals shape differences that are strongly associated with age and percent fibrosis. The clustering of IPF cohort shape suggests that it could be an important feature to describe disease.

Multi-scale Modelling of Shear Stress on the Syncytiotrophoblast: Could Maternal Blood Flow Impact Placental Function Across Gestation?

The placenta is a critical fetal exchange organ, with a complex branching tree-like structure. Its surface is covered by a single multinucleated cell, the syncytiotrophoblast, which bathes in maternal blood for most of pregnancy. Mechanosensing protein expression by the syncytiotrophoblast at term suggests that shear stress exerted by maternal blood flow may modulate placental development and function. However, it is not known how the mechanosensitive capacity of the syncytiotrophoblast, or the shear stress it experiences, change across gestation. Here, we show that the syncytiotrophoblast expresses both mechanosensitive ion channels (Piezo 1, Polycystin 2, TRPV6) and motor proteins associated with primary cilia (Dynein 1, IFT88, Kinesin 2), with higher staining for all these proteins seen in late first trimester placentae than at term. MicroCT imaging of placental tissue was then used to inform computational models of blood flow at the placentone scale (using a porous media model), and at the villous scale (using explicit flow simulations). These two models are then linked to produce a combined model that allows the variation of shear stress across both these scales simultaneously. This combined model predicts that the range of shear stress on the syncytiotrophoblast is higher in the first-trimester than at term (0.8 dyne/cm2 median stress compared to 0.04 dyne/cm2) when considering both these scales. Together, this suggests that the nature of blood flow through the intervillous space, and the resulting shear stress on the syncytiotrophoblast have important influences on placental morphogenesis and function from early in pregnancy.

Atrous spatial pyramid pooling and multi-image data fusion for smooth muscle segmentation in upper gastrointestinal sphincters.

Gastrointestinal (GI) sphincters provide critical roles in regulating the transport of contents along the GI tract. Dysfunctions of GI sphincters are associated with a range of major digestive disorders. Despite their importance, the microstructures of GI sphincters are not well investigated. While micro-computed tomography (µ-CT) provides detailed 3D images, conventional segmentation methods rely on manual correction, which is both time-consuming and prone to human error. This study proposes a segmentation method using atrous spatial pyramid pooling (ASPP), which helps in capturing different effective fields of view from a given input feature map, thereof providing finer local and global information for a given pixel. Additionally, we explored the use of multi-species data fusion to make the model more generalized. The proposed segmentation network incorporating ASPP and multi-species data fusion improved the segmentation of sphincter muscle images. Specifically, it increased the dice score and Jaccard index by 3.7% and 5.8%, respectively, while reducing the variance compared to conventional methods.Clinical relevance- Techniques developed in this study will inform µ-CT segmentation of human upper GI sphincters for detailed structural analysis of muscular dysfunction.