Three-dimensional virtual histology of the rat uterus musculature using micro-computed tomography.

Contractions of the uterus play an important role in menstruation and fertility, and contractile dysfunction can lead to chronic diseases such as endometriosis. However, the structure and function of the uterus are difficult to interrogate in humans, and thus animal studies are often employed to understand its function. In rats, anatomical studies of the uterus have typically been based on histological assessment, have been limited to small segments of the uterine structure, and have been time-consuming to reconstruct at the organ scale. This study used micro-computed tomography imaging to visualise the muscle structures in the entire non-pregnant rat uterus and assess its use for 3D virtual histology. An assessment of the rodent uterus is presented to (i) quantify muscle thickness variations along the horns, (ii) identify predominant fibre orientations of the muscles and (iii) demonstrate how the anatomy of the uterus can be mapped to 3D volumetric meshes via virtual histology. Micro-computed tomography measurements were validated against measurements from histological sections. The average thickness of the myometrium was found to be 0.33 ± 0.11 mm and 0.31 ± 0.09 mm in the left and right horns, respectively. The micro-computed tomography and histology thickness calculations were found to correlate strongly at different locations in the uterus: at the cervix, r = 0.87, and along the horn from the cervical end to the ovarian end, respectively, r = 0.77, r = 0.89 and r = 0.54, with p < 0.001 in every location. This study shows that micro-computed tomography can be used to quantify the musculature in the whole non-pregnant uterus and can be used for 3D virtual histology.

Evaluating the role of sex-related structure-function differences on airway aerosol transport and deposition.

Several experimental studies have found that females have higher deposition of particles in the airways compared with males. This has implications for the delivery of aerosolized therapeutics and for understanding sex differences in respiratory system response to environmental exposures. This study evaluates several factors that potentially contribute to sex differences in particle deposition, using scale-specific structure-function models of 1D ventilation distribution, particle transport, and deposition. The impact of gravity, inhalation flow rate, and dead space are evaluated in 12 structure-based models (seven female; five male). Females were found to have significantly higher total, bronchial, and alveolar deposition than males across a particle size range from 0.01 to 10 . Results suggest that higher deposition fraction in females is due to higher alveolar deposition for smaller particle sizes, and higher bronchial deposition for larger particles. Females had higher alveolar deposition in the lower lobes, and slightly lower particle concentration in the left upper lobe. Males were found to be more sensitive to changes due to gravity, showing greater reduction in bronchial deposition fraction. Males were also more sensitive to change in inhalation flow rate, and to scaling of dead space due to the larger male baseline airway size. Predictions of sex differences in particle deposition - that are consistent with the literature - suggest that sex-based characteristics of lung and airway size interacting with particle size gives rise to differences in regional deposition.

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 [means (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.NEW & NOTEWORTHY Mapping of rat gastric slow waves showed regional variations in their organization. In some subjects, separate wavefronts propagated near the lesser and greater curvatures with a loosely coupled region near the midline, between the wavefronts, having a varying slow-wave origin. Furthermore, simultaneous intracellular and extracellular recordings were concordant and independent of movement artifacts, indicating that extracellular recordings can be interpreted in terms of their intracellular counterparts when intracellular recording is not possible.

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.

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.

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.

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.

Cervical Vagus Nerve Stimulation Disrupts Gastric Slow Wave Activity in Rats.

Cervical vagus nerve stimulation (cVNS) is a promising neuromodulation therapy for treating symptoms of disease in peripheral organs. The rat is a common animal model for studying and trialing new applications of cVNS therapy, but the stomach and its activity in rats is less well characterized than other animals, such as pigs. We sought to investigate the effects of acute, in vivo cVNS on gastric bioelectrical activity as an intermediate step to computational modeling of the effects of cVNS on gastric smooth muscle electromechanical coupling. Here we show a method of detecting bioelectrical gastric slow wave events using a non-linear energy operator. The marked events are compared to the underlying bioelectrical slow wave activity.The mean propagation velocity before stimulation was 0.79 ± 0.31 mm s-1, and the mean interval was 17.4 ± 1.4 s. During cVNS, there was a significant increase in velocity (1.02 ± 0.69 mm s-1; p < 0.001), and decrease in interval (15.4 ± 2.9 s; p = 0.0196). At stimulation onset, premature slow waves were induced at an ectopic pacemaker location and waves originating at the ectopic and initial pacemaker sites continued to collide following the cessation of cVNS.This work forms the basis for more thorough investigation of the effects of cVNS on gastric bioelectrical slow wave activity and consequential smooth muscle contractions in rats. A better understanding of the effects of cVNS on gastric function will allow the refinement of cVNS therapy to target the stomach, and avoid off-target effects on the stomach.Clinical relevance- This work presents a signal processing and analysis approach for the investigation of cervical vagus nerve stimulation on gastric bioelectrical activity in rats. Vagus nerve stimulation may enable the control and amelioration of hunger, gastric emptying, or functional gastric disorders.

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.

Maternal Cardiovascular Responses to Position Change in Pregnancy.

The maternal cardiovascular-circulatory system undergoes profound changes almost from the conception of a pregnancy until the postpartum period to support the maternal adaptions required for pregnancy and lactation. Maintenance of cardiovascular homeostasis requires changes in the cardiovascular autonomic responses. Here, we present a longitudinal study of the maternal cardiovascular autonomic responses to pregnancy and maternal position. Over a normal gestation, in the left lateral position there are significant changes in both time and frequency domain parameters reflecting heart rate variability. We show that cardiovascular autonomic responses to physiological stressors (standing and supine positions in late pregnancy) became significantly different with advancing gestation. In the third trimester, 60% of the subjects had an unstable heart rate response on standing, and these subjects had a significantly reduced sample entropy evident in their heart rate variability data. By 6 weeks, postpartum function returned to near the non-pregnant state, but there were consistent differences in high-frequency power when compared to nulligravid cases. Finally, we review complementary evidence, in particular from magnetic resonance imaging, that provides insights into the maternal and fetal impacts of positioning in pregnancy. This demonstrates a clear relationship between supine position and maternal hemodynamic parameters, which relates to compression of the inferior vena cava (p = 0.05). Together, these studies demonstrate new understanding of the physiology of physiological stressors related to position.

A review of feto-placental vasculature flow modelling.

The placenta provides the vital nutrients and removal of waste products required for fetal growth and development. Understanding and quantifying the differences in structure and function between a normally functioning placenta compared to an abnormal placenta is vital to provide insights into the aetiology and treatment options for fetal growth restriction and other placental disorders. Computational modelling of blood flow in the placenta allows a new understanding of the placental circulation to be obtained. This structured review discusses multiple recent methods for placental vascular model development including analysis of the appearance of the placental vasculature and how placental haemodynamics may be simulated at multiple length scales.

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.

Digital Technologies for Women's Pelvic Floor Muscle Training to Manage Urinary Incontinence Across Their Life Course: Scoping Review.

BACKGROUND: Women with urinary incontinence (UI) may consider using digital technologies (DTs) to guide pelvic floor muscle training (PFMT) to help manage their symptoms. DTs that deliver PFMT programs are readily available, yet uncertainty exists regarding whether they are scientifically valid, appropriate, and culturally relevant and meet the needs of women at specific life stages. OBJECTIVE: This scoping review aims to provide a narrative synthesis of DTs used for PFMT to manage UI in women across their life course. METHODS: This scoping review was conducted in accordance with the Joanna Briggs Institute methodological framework. A systematic search of 7 electronic databases was conducted, and primary quantitative and qualitative research and gray literature publications were considered. Studies were eligible if they focused on women with or without UI who had engaged with DTs for PFMT, reported on outcomes related to the use of PFMT DTs for managing UI, or explored users' experiences of DTs for PFMT. The identified studies were screened for eligibility. Data on the evidence base for and features of PFMT DTs using the Consensus on Exercise Reporting Template for PFMT, PFMT DT outcomes (eg, UI symptoms, quality of life, adherence, and satisfaction), life stage and culture, and the experiences of women and health care providers (facilitators and barriers) were extracted and synthesized by ≥2 independent reviewers. RESULTS: In total, 89 papers were included (n=45, 51% primary and n=44, 49% supplementary) involving studies from 14 countries. A total of 28 types of DTs were used in 41 primary studies, including mobile apps with or without a portable vaginal biofeedback or accelerometer-based device, a smartphone messaging system, internet-based programs, and videoconferencing. Approximately half (22/41, 54%) of the studies provided evidence for or testing of the DTs, and a similar proportion of PFMT programs were drawn from or adapted from a known evidence base. Although PFMT parameters and program compliance varied, most studies that reported on UI symptoms showed improved outcomes, and women were generally satisfied with this treatment approach. With respect to life stage, pregnancy and the postpartum period were the most common focus, with more evidence needed for women of various age ranges (eg, adolescent and older women), including their cultural context, which is a factor that is rarely considered. Women's perceptions and experiences are often considered in the development of DTs, with qualitative data highlighting factors that are usually both facilitators and barriers. CONCLUSIONS: DTs are a growing mechanism for delivering PFMT, as evidenced by the recent increase in publications. This review highlighted the heterogeneity in types of DTs, PFMT protocols, the lack of cultural adaptations of most of the DTs reviewed, and a paucity in the consideration of the changing needs of women across their life course.

From fetus to neonate: A review of cardiovascular modeling in early life.

Computational modeling has well-established utility in the study of cardiovascular hemodynamics, with applications in medical research and, increasingly, in clinical settings to improve the diagnosis and treatment of cardiovascular diseases. Most cardiovascular models developed to date have been of the adult circulatory system; however, the perinatal period is unique as cardiovascular physiology undergoes drastic changes from the fetal circulation, during the birth transition, and into neonatal life. There may also be further complications in this period: for example, preterm birth (defined as birth before 37 completed weeks of gestation) carries risks of short-term cardiovascular instability and is associated with increased lifetime cardiovascular risk. Here, we review computational models of the cardiovascular system in early life, their applications to date and potential improvements and enhancements of these models. We propose a roadmap for developing an open-source cardiovascular model that spans the fetal, perinatal, and postnatal periods. This article is categorized under: Cardiovascular Diseases > Computational Models Cardiovascular Diseases > Biomedical Engineering Congenital Diseases > Computational Models.

Improved Electrical Impedance Tomography Reconstruction via a Bayesian Approach With an Anatomical Statistical Shape Model.

OBJECTIVE: electrical impedance tomography (EIT) is a promising technique for rapid and continuous bedside monitoring of lung function. Accurate and reliable EIT reconstruction of ventilation requires patient-specific shape information. However, this shape information is often not available and current EIT reconstruction methods typically have limited spatial fidelity. This study sought to develop a statistical shape model (SSM) of the torso and lungs and evaluate whether patient-specific predictions of torso and lung shape could enhance EIT reconstructions in a Bayesian framework. METHODS: torso and lung finite element surface meshes were fitted to computed tomography data from 81 participants, and a SSM was generated using principal component analysis and regression analyses. Predicted shapes were implemented in a Bayesian EIT framework and were quantitatively compared to generic reconstruction methods. RESULTS: Five principal shape modes explained 38% of the cohort variance in lung and torso geometry, and regression analysis yielded nine total anthropometrics and pulmonary function metrics that significantly predicted these shape modes. Incorporation of SSM-derived structural information enhanced the accuracy and reliability of the EIT reconstruction as compared to generic reconstructions, demonstrated by reduced relative error, total variation, and Mahalanobis distance. CONCLUSION: As compared to deterministic approaches, Bayesian EIT afforded more reliable quantitative and visual interpretation of the reconstructed ventilation distribution. However, no conclusive improvement of reconstruction performance using patient specific structural information was observed as compared to the mean shape of the SSM. SIGNIFICANCE: The presented Bayesian framework builds towards a more accurate and reliable method for ventilation monitoring via EIT.

Roadmap for an imaging and modelling paediatric study in rural NZ.

Our study methodology is motivated from three disparate needs: one, imaging studies have existed in silo and study organs but not across organ systems; two, there are gaps in our understanding of paediatric structure and function; three, lack of representative data in New Zealand. Our research aims to address these issues in part, through the combination of magnetic resonance imaging, advanced image processing algorithms and computational modelling. Our study demonstrated the need to take an organ-system approach and scan multiple organs on the same child. We have pilot tested an imaging protocol to be minimally disruptive to the children and demonstrated state-of-the-art image processing and personalized computational models using the imaging data. Our imaging protocol spans brain, lungs, heart, muscle, bones, abdominal and vascular systems. Our initial set of results demonstrated child-specific measurements on one dataset. This work is novel and interesting as we have run multiple computational physiology workflows to generate personalized computational models. Our proposed work is the first step towards achieving the integration of imaging and modelling improving our understanding of the human body in paediatric health and disease.

Pulmonary vessel volume in idiopathic pulmonary fibrosis compared with healthy controls aged > 50 years.

Idiopathic pulmonary fibrosis (IPF) is characterised by progressive fibrosing interstitial pneumonia with an associated irreversible decline in lung function and quality of life. IPF prevalence increases with age, appearing most frequently in patients aged > 50 years. Pulmonary vessel-like volume (PVV) has been found to be an independent predictor of mortality in IPF and other interstitial lung diseases, however its estimation can be impacted by artefacts associated with image segmentation methods and can be confounded by adjacent fibrosis. This study compares PVV in IPF patients (N = 21) with PVV from a healthy cohort aged > 50 years (N = 59). The analysis includes a connected graph-based approach that aims to minimise artefacts contributing to calculation of PVV. We show that despite a relatively low extent of fibrosis in the IPF cohort (20% of the lung volume), PVV is 2-3 times higher than in controls. This suggests that a standardised method to calculate PVV that accounts for tree connectivity could provide a promising tool to provide early diagnostic or prognostic information in IPF patients and other interstitial lung 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.

Modeling and experimental approaches for elucidating multi-scale uterine smooth muscle electro- and mechano-physiology: A review.

The uterus provides protection and nourishment (via its blood supply) to a developing fetus, and contracts to deliver the baby at an appropriate time, thereby having a critical contribution to the life of every human. However, despite this vital role, it is an under-investigated organ, and gaps remain in our understanding of how contractions are initiated or coordinated. The uterus is a smooth muscle organ that undergoes variations in its contractile function in response to hormonal fluctuations, the extreme instance of this being during pregnancy and labor. Researchers typically use various approaches to studying this organ, such as experiments on uterine muscle cells, tissue samples, or the intact organ, or the employment of mathematical models to simulate the electrical, mechanical and ionic activity. The complexity exhibited in the coordinated contractions of the uterus remains a challenge to understand, requiring coordinated solutions from different research fields. This review investigates differences in the underlying physiology between human and common animal models utilized in experiments, and the experimental interventions and computational models used to assess uterine function. We look to a future of hybrid experimental interventions and modeling techniques that could be employed to improve the understanding of the mechanisms enabling the healthy function of the uterus.