Differential effects of mechano-electric feedback mechanisms on whole-heart activation, repolarization, and tension.

The human heart is subject to highly variable amounts of strain during day-to-day activities and needs to adapt to a wide range of physiological demands. This adaptation is driven by an autoregulatory loop that includes both electrical and the mechanical components. In particular, mechanical forces are known to feed back into the cardiac electrophysiology system, which can result in pro- and anti-arrhythmic effects. Despite the widespread use of computational modelling and simulation for cardiac electrophysiology research, the majority of in silico experiments ignore this mechano-electric feedback entirely due to the high computational cost associated with solving cardiac mechanics. In this study, we therefore use an electromechanically coupled whole-heart model to investigate the differential and combined effects of electromechanical feedback mechanisms with a focus on their physiological relevance during sinus rhythm. In particular, we consider troponin-bound calcium, the effect of deformation on the tissue diffusion tensor, and stretch-activated channels. We found that activation of the myocardium was only significantly affected when including deformation into the diffusion term of the monodomain equation. Repolarization, on the other hand, was influenced by both troponin-bound calcium and stretch-activated channels and resulted in steeper repolarization gradients in the atria. The latter also caused afterdepolarizations in the atria. Due to its central role for tension development, calcium bound to troponin affected stroke volume and pressure. In conclusion, we found that mechano-electric feedback changes activation and repolarization patterns throughout the heart during sinus rhythm and lead to a markedly more heterogeneous electrophysiological substrate. KEY POINTS: The electrophysiological and mechanical function of the heart are tightly interrelated by excitation-contraction coupling (ECC) in the forward direction and mechano-electric feedback (MEF) in the reverse direction. While ECC is considered in many state-of-the-art computational models of cardiac electromechanics, less is known about the effect of different MEF mechanisms. Accounting for calcium bound to troponin increases stroke volume and delays repolarization. Geometry-mediated MEF leads to more heterogeneous activation and repolarization with steeper gradients. Both effects combine in an additive way. Non-selective stretch-activated channels as an additional MEF mechanism lead to heterogeneous diastolic transmembrane voltage, higher developed tension and delayed repolarization or afterdepolarizations in highly stretched parts of the atria. The differential and combined effects of these three MEF mechanisms during sinus rhythm activation in a human four-chamber heart model may have implications for arrhythmogenesis, both in terms of substrate (repolarization gradients) and triggers (ectopy).

Human sodium current voltage-dependence at physiological temperature measured by coupling a patch-clamp experiment to a mathematical model.

Voltage-gated Na+ channels are crucial to action potential propagation in excitable tissues. Because of the high amplitude and rapid activation of the Na+ current, voltage-clamp measurements are very challenging and are usually performed at room temperature. In this study, we measured Na+ current voltage-dependence in stem cell-derived cardiomyocytes at physiological temperature. While the apparent activation and inactivation curves, measured as the dependence of current amplitude on voltage, fall within the range reported in previous studies, we identified a systematic error in our measurements. This error is caused by the deviation of the membrane potential from the command potential of the amplifier. We demonstrate that it is possible to account for this artifact using computer simulation of the patch-clamp experiment. We obtained surprising results through patch-clamp model optimization: a half-activation of -11.5 mV and a half-inactivation of -87 mV. Although the half-activation deviates from previous research, we demonstrate that this estimate reproduces the conduction velocity dependence on extracellular potassium concentration. KEY POINTS: Voltage-gated Na+ currents play a crucial role in excitable tissues including neurons, cardiac and skeletal muscle. Measurement of Na+ current is challenging because of its high amplitude and rapid kinetics, especially at physiological temperature. We have used the patch-clamp technique to measure human Na+ current voltage-dependence in human induced pluripotent stem cell-derived cardiomyocytes. The patch-clamp data were processed by optimization of the model accounting for voltage-clamp experiment artifacts, revealing a large difference between apparent parameters of Na+ current and the results of the optimization. We conclude that actual Na+ current activation is extremely depolarized in comparison to previous studies. The new Na+ current model provides a better understanding of action potential propagation; we demonstrate that it explains propagation in hyperkalaemic conditions.

Do lead (Pb) content of lipsticks expose a health risk to children? A risk assessment study.

BACKGROUND: Lead (Pb) content in lipsticks and potential life-long exposure of which might cause severe effects in consumers are an important concern for public. Thus, studies emphasize that lead exposure has no safe levels. METHODS: From 10 different brands, in total, 25 solid, gloss and creamy lipsticks are deployed from Turkish markets that are also categorized in two different price ranges. In order to evaluate the blood Pb levels in children, the United States Environmental Protection Agency's 'Exposure Uptake Biokinetic Model' is utilized. To assess the health risk of chronic usage both for children and adults, oral daily systemic exposure levels are calculated with the worst-case scenario and are compared with Maximum Allowable Dose Level for lipsticks. For lifetime risk assessment, exposure is assumed to start by age 7, and four different exposure scenarios have been deployed. RESULTS: The mean lead content of lipsticks shows significant statistical differences between the high- and low-priced lipstick groups. Daily level and total risk for lifetime Pb exposure from deployed lipsticks are below the acceptable risk levels but long-worn usage of products with routine monitoring of metal content is crucial for sensitive and unintended exposure groups.

Comparing Video Analysis to Computerized Detection of Limb Position for the Diagnosis of Movement Control during Back Squat Exercise with Overload.

Incorrect limb position while lifting heavy weights might compromise athlete success during weightlifting performance, similar to the way that it increases the risk of muscle injuries during resistance exercises, regardless of the individual's level of experience. However, practitioners might not have the necessary background knowledge for self-supervision of limb position and adjustment of the lifting position when improper movement occurs. Therefore, the computerized analysis of movement patterns might assist people in detecting changes in limb position during exercises with different loads or enhance the analysis of an observer with expertise in weightlifting exercises. In this study, hidden Markov models (HMMs) were employed to automate the detection of joint position and barbell trajectory during back squat exercises. Ten volunteers performed three lift movements each with a 0, 50, and 75% load based on body weight. A smartphone was used to record the movements in the sagittal plane, providing information for the analysis of variance and identifying significant position changes by video analysis (p < 0.05). Data from individuals performing the same movements with no added weight load were used to train the HMMs to identify changes in the pattern. A comparison of HMMs and human experts revealed between 40% and 90% agreement, indicating the reliability of HMMs for identifying changes in the control of movements with added weight load. In addition, the results highlighted that HMMs can detect changes imperceptible to the human visual analysis.

Deep skin homogeneity and light diffusion: An accelerated Monte Carlo model for in vivo skin characterization and consumer perception.

The appearance of healthy and youthful skin is related to many factors of the skin optical properties as perceived by our visual sense. The optics of light travelling through human tissues has been extensively investigated in the field of biomedical applications, including the experimental characterization and modelling of skin optics and the propagation of light such as lasers through the layers. This work presents an innovative approach to probe deep skin by means of spectrally and spatially resolved light diffusion in the different layers of skin. Dual hyperspectral measurements of the panellist's skin are performed in vivo on subjects to obtain reflectance and light diffusion spectra. Both are simultaneously fitted by a GPU-accelerated Monte Carlo model to obtain skin optical parameters as a function of depth. The results show a clear correlation between deep skin light diffusion at wavelengths above 590 nm and the subject age, which indicates a progressive degradation of skin homogeneity with age. The effect of this orange-red light diffusion background is to alter the colour tone of the skin. A skincare product is used to show that the warmer skin colour tone is clearly perceivable to consumers when evaluating facial images with and without the product. The product effect also correlates well with hyperspectral measurements. Lastly, this innovative approach demonstrates a first step in real-time skin characterization for consumers and opens the door to customized cosmetic solutions for individual needs.

L'aspect jeune et en bonne santé de la peau est lié à de nombreux facteurs des propriétés de la peau perçues par notre sens visuel. L'optique de la lumière qui traverse les tissus humains a fait l'objet de recherches approfondies dans le domaine des applications biomédicales, notamment la caractérisation expérimentale, la modélisation de l'optique cutanée et la propagation de la lumière telle que les lasers à travers ses couches. Ce travail présente une approche innovante permettant de sonder la peau profonde au moyen d'une diffusion de la lumière résolue spectralement et spatialement dans les différentes couches de la peau. Des mesures hyperspectrales doubles de la peau du panéliste sont effectuées in vivo sur des sujets pour obtenir des spectres de réflectance et de diffusion de la lumière. Les deux sont simultanément ajustés par un modèle Monte Carlo accéléré par processeur graphique afin d'obtenir les paramètres optiques de la peau comme fonction de sa profondeur. Les résultats montrent une corrélation claire entre la diffusion de la lumière de la peau profonde à des longueurs d'onde supérieures à 590 nm et l'âge du sujet, ce qui indique une dégradation progressive de l'homogénéité de la peau avec l'âge. L'effet de ce fond de diffusion de la lumière rouge­orangée est l'altération de la couleur de la peau. Un produit de soin de la peau a été utilisé pour montrer que le teint plus chaud de la peau était clairement perceptible par les consommateurs évaluant des images du visage avec ou sans produit. L'effet du produit est aussi bien corrélé avec les mesures hyperspectrales. Cette approche innovante démontre enfin une première étape dans la caractérisation de la peau en temps réel pour les consommateurs et ouvre la voie à une solution cosmétique personnalisée selon les besoins individuels.

Preparation and efficacy verification of three-dimensional printed partitioned multi-effect precision-care gel facial mask.

OBJECTIVE: A partition multi-effect precision-care gel facial mask conforming to facial skin characteristics was prepared using three-dimensional (3D) printing technology. METHODS: First, the hydrogel matrix and humectant of a 3D-printed gel for facial masks were screened, and three 3D-printed gels of arbutin, hexapeptide, and salicylic acid were prepared with whitening, wrinkle removal, and oil control functions, respectively. Skin irritation tests were performed on the gels. Physicochemical properties such as pH, heat and cold tolerance were evaluated. The efficacy of three 3D-printed gels was assessed by measuring melanin value, wrinkle depression score, and oil secretion. Finally, the facial mask model design and printing parameters were studied, and a partition multi-effect precision-care gel facial mask was printed in line with facial skin characteristics. RESULTS: For the 3D-printed facial mask, the gel prescription with 2% hydroxyethyl cellulose gel as matrix and 7% glycerol as humectant was the best. The prepared 3D-printed gel did not irritate the human skin, and its physicochemical properties met the Chinese facial mask industry standard (QB/T2872-2017). We showed that three types of 3D-printed gels containing arbutin, hexapeptide, and salicylic acid could be applied to the corresponding parts of the face to solve different problems, such as facial skin dullness, wrinkles, and oil secretion. Therefore, according to facial physiological characteristics, the facial mask model was designed for the forehead and nasolabial fold, which needs to be anti-wrinkled; the cheek, which needs to be whitened; and the nose and chin, which need oil control. The optimal printing parameters were 0.26 mm nozzle diameter, 90 mm/s printing speed, 30% filling density, 140% wire extrusion ratio, and 0.25 mm layer height. Different skin care effects can be achieved using a three-nozzle printer to print arbutin, hexapeptide, or salicylic acid gel on the mask's forehead and nasolabial fold, cheek, and nose and chin, respectively. CONCLUSION: The 3D-printed partition multi-effect care gel facial mask prepared according to the skin features of different parts of the face can overcome the problem of the single skincare effect of the mass-produced facial masks.

OBJECTIF: Un masque facial de soin de précision en gel à effets multiples, adapté aux caractéristiques de la peau du visage, a été préparé à l'aide de la technologie d'impression tridimensionnelle (3D). MÉTHODES: Tout d'abord, la matrice d'hydrogel et l'humectant d'un gel imprimé en 3D pour les masques faciaux ont été sélectionnés, et trois gels imprimés en 3D d'arbutine, d'hexapeptide et d'acide salicylique ont été préparés avec des fonctions de blanchiment, d'élimination des rides et de contrôle du sébum, respectivement. Des tests d'irritation cutanée ont été réalisés sur les gels. Les propriétés physicochimiques telles que le pH et la tolérance à la chaleur et au froid ont été évaluées. L'efficacité des trois gels imprimés en 3D a été évaluée en mesurant la valeur de la mélanine, le score de dépression des rides et la sécrétion de sébum. Enfin, la conception du modèle de masque facial et les paramètres d'impression ont été étudiés, et un masque facial de gel de soin de précision à effets multiples a été imprimé en fonction des caractéristiques de la peau du visage. RÉSULTATS: Pour le masque facial imprimé en 3D, la prescription de gel avec 2 % de gel d'hydroxyéthylcellulose comme matrice et 7 % de glycérol comme humectant était la meilleure. Le gel imprimé en 3D n'a pas irrité la peau humaine et ses propriétés physicochimiques sont conformes à la norme industrielle chinoise relative aux masques faciaux (QB/T2872­2017). Nous avons montré que trois types de gels imprimés en 3D contenant de l'arbutine, de l'hexapeptide et de l'acide salicylique pouvaient être appliqués aux parties correspondantes du visage pour résoudre différents problèmes, tels que l'aspect terne de la peau du visage, les rides et la sécrétion de sébum. Par conséquent, en fonction des caractéristiques physiologiques du visage, le modèle de masque facial a été conçu pour le front et le sillon nasogénien, qui doivent être antirides, la joue, qui doit être blanchie, et le nez et le menton, qui ont besoin d'un contrôle du sébum. Les paramètres d'impression optimaux étaient les suivants : diamètre de buse de 0,26 mm, vitesse d'impression de 90 mm/s, densité de remplissage de 30 %, rapport d'extrusion du fil de 140 % et hauteur de couche de 0,25 mm. Différents effets de soin de la peau peuvent être obtenus en utilisant une imprimante à trois buses pour imprimer de l'arbutine, de l'hexapeptide ou du gel d'acide salicylique sur le front et le sillon nasogénien, la joue, le nez et le menton du masque, respectivement. CONCLUSION: Le masque facial en gel de soin à effets multiples imprimé en 3D et préparé en fonction des caractéristiques de la peau des différentes parties du visage peut résoudre le problème de l'effet de soin unique des masques faciaux produits en masse.

SCAWA scales: A new digital tool for wrinkles clinical grading based on AI.

OBJECTIVE: Clinical assessment of wrinkle depth is essential for efficacy evaluations of anti-ageing products. Standardized photographic scales, representative of different wrinkle depths are often used by experts to assign subjects reliable grades. These tools, based on real pictures, usually exist as hard copies (printed books or sheets) for in vivo gradings. Our project aims at developing a methodology to create digital standardized computer-generated scales, allowing photograph and real-life gradings, and providing raters with greater comfort, accessibility, and flexibility in their construction, thanks to the artificial intelligence significative contribution. METHODS: A completely new approach, based on machine learning, allows the creation of Standardized ColorFace® AI-based Wrinkle Assessment (SCAWA) scales. Instead of using real photographs, the scale images are computer-generated. A generative adversarial network (GAN) is trained to create realistic wrinkle samples that are finely controllable by exploring the GAN latent space. Finally, the scale images are selected among hundreds of artificial images depicting natural wrinkle appearances, such as the illustrated wrinkle evolution is well-detailed (small gaps between grades), morphologically stable, and mathematically linear according to a criterion of wrinkle conspicuous depth. RESULTS: The created 12-point scale for crow's feet wrinkle evaluation on ColorFace® pictures is proven to be realistic, linear, and robustly and accurately usable for photograph assessments. The scale coherence in terms of image ranking has been validated, as well as its reliability and acceptability in real conditions of use. Additionally, the wrinkle grades obtained by the SCAWA scale are well correlated (R = 0.94) with the ones obtained by the Skin Aging Atlas on the same pictures. The AI methodology and digital format brought also interesting side results, such as an enhanced harmonization between experts and a higher representativeness, that is, a decrease of out-of-range pictures. CONCLUSION: SCAWA scale makes the most of machine learning to provide an innovative digital tool to ease wrinkles in visual assessment of pictures, while optimizing linearity, homogeneity, and accuracy aspects. The experts' enthusiastic feedback about the scale format and quality is promising regarding the adaptation of the methodology to other signs and a larger distribution of this tool in the market of cosmetic product efficacy assessment.

OBJECTIF: L'évaluation clinique de la profondeur des rides est essentielle pour les évaluations de l'efficacité des produits anti­âge. Des échelles photographiques standardisées, représentatives de différentes profondeurs de rides, sont souvent utilisées par les experts pour attribuer des notes fiables aux sujets. Ces outils, basés sur des images réelles, existent généralement sous forme de copies papier (livres ou feuilles imprimées) pour les notations in vivo. Notre projet vise à développer une méthodologie pour créer des échelles numériques normalisées générées par ordinateur, permettant des évaluations sur photographies et des évaluations en contexte de vie réelle, ce qui offrirait aux évaluateurs un plus grand confort, une meilleure accessibilité et davantage de flexibilité dans leur construction, grâce à la contribution significative de l'intelligence artificielle. MÉTHODES: Une approche totalement nouvelle, basée sur l'apprentissage automatique, permet de créer des échelles standardisées d'évaluation des rides fondées sur l'IA ColorFace® (Standardised ColorFace® AI­based Wrinkle Assessment, SCAWA). Au lieu d'utiliser de vraies photographies, les images de l'échelle sont générées par ordinateur. Un réseau génératif antagoniste (generative adversarial network, GAN) est formé pour créer des échantillons de rides réalistes qui sont finement contrôlables en étudiant l'espace latent GAN. Enfin, les images de l'échelle sont sélectionnées parmi des centaines d'images artificielles représentant des aspects de rides naturelles, où l'illustration de l'évolution des rides est bien détaillée (petits écarts entre les grades), morphologiquement stable et mathématiquement linéaire selon un critère de profondeur visible des rides. RÉSULTATS: L'échelle à 12 points créée pour l'évaluation des pattes­d'oie sur les images ColorFace® s'est avérée réaliste, linéaire, robuste et précise pour les évaluations photographiques. La cohérence de l'échelle en termes de classement des images a été validée, ainsi que sa fiabilité et son acceptabilité en conditions réelles d'utilisation. En outre, les grades de rides obtenus par l'échelle SCAWA sont bien corrélés (R = 0,94) avec ceux obtenus pour les mêmes images par l'Atlas du vieillissement de la peau. La méthodologie de l'IA et le format numérique ont également apporté des résultats intéressants, tels qu'une meilleure harmonisation entre les experts et une représentativité plus élevée, c.­à­d. une diminution des images en dehors de la plage. CONCLUSION: L'échelle SCAWA tire le meilleur parti de l'apprentissage automatique pour fournir un outil numérique innovant visant à faciliter l'évaluation visuelle des rides sur les images, tout en optimisant les aspects de linéarité, d'homogénéité et de précision. Les avis enthousiastes des experts sur le format et la qualité de l'échelle sont prometteurs en ce qui concerne l'adaptation de la méthodologie à d'autres signes et une plus grande distribution de cet outil sur le marché de l'évaluation de l'efficacité des produits cosmétiques.

Artificial intelligence system for automatic maxillary sinus segmentation on cone beam computed tomography images.

OBJECTIVES: The study aims to develop an artificial intelligence (AI) model based on nnU-Net v2 for automatic maxillary sinus (MS) segmentation in cone beam computed tomography (CBCT) volumes and to evaluate the performance of this model. METHODS: In 101 CBCT scans, MS were annotated using the CranioCatch labelling software (Eskisehir, Turkey) The dataset was divided into 3 parts: 80 CBCT scans for training the model, 11 CBCT scans for model validation, and 10 CBCT scans for testing the model. The model training was conducted using the nnU-Net v2 deep learning model with a learning rate of 0.00001 for 1000 epochs. The performance of the model to automatically segment the MS on CBCT scans was assessed by several parameters, including F1-score, accuracy, sensitivity, precision, area under curve (AUC), Dice coefficient (DC), 95% Hausdorff distance (95% HD), and Intersection over Union (IoU) values. RESULTS: F1-score, accuracy, sensitivity, precision values were found to be 0.96, 0.99, 0.96, 0.96, respectively for the successful segmentation of maxillary sinus in CBCT images. AUC, DC, 95% HD, IoU values were 0.97, 0.96, 1.19, 0.93, respectively. CONCLUSIONS: Models based on nnU-Net v2 demonstrate the ability to segment the MS autonomously and accurately in CBCT images.

Trace metal speciation trends in Mazowe dam, Zimbabwe, a typical sub-tropical dam ecosystem impacted by gold mining and agriculture.

The present study aimed to assess trace metal speciation trends in the water and sediments of Mazowe Dam, a typical sub-tropical dam ecosystem impacted by gold mining and agriculture in Zimbabwe. The elements studied include Al, As, Cd, Co, Cr, Cu, Hg, Fe, Mn, Ni, Pb, and Zn. Elemental speciation in the water column was determined using Visual MINTEQ version 3.1 geochemical computer modelling, while speciation in the sediment phase was determined using sequential extraction techniques. For each element, the data obtained were subjected to extensive correlation analysis to identify intra- and inter-metal species interactions in the water column and the sediment phase, as well as across the water-sediment interface. Possible mechanisms to account for the observed species interactions are proposed. In the water column, Co was predicted to have the highest number of chemical species (9), Cd and Zn (8), Mn and Fe (7), Ni (6), Pb (5), Al and Cu (3), Cr, Hg, and As have the least (2). In the sediment, Al, As, Co, Cr, Cu, Fe, Ni and Fe mainly exist in the residual fraction, while Zn and Mn concentrations in fractions vary per sampling site, with no fraction that is dominant across the sampling sites. Equilibrium exchange reactions across the water-sediment interface were observed e.g., for Cd species /FA2Cd (aq) and Co species /FACo+2G (aq), and /FA2Co (aq). This study is valuable in highlighting trace metal speciation in a tropical dam ecosystem in Africa and adds to the growing knowledge about the behaviour of trace metals in aquatic ecosystems in the region and globally.

Graft-host coupling changes can lead to engraftment arrhythmia: a computational study.

After myocardial infarction (MI), a significant portion of heart muscle is replaced with scar tissue, progressively leading to heart failure. Human pluripotent stem cell-derived cardiomyocytes (hPSC-CM) offer a promising option for improving cardiac function after MI. However, hPSC-CM transplantation can lead to engraftment arrhythmia (EA). EA is a transient phenomenon arising shortly after transplantation then spontaneously resolving after a few weeks. The underlying mechanism of EA is unknown. We hypothesize that EA may be explained partially by time-varying, spatially heterogeneous, graft-host electrical coupling. Here, we created computational slice models derived from histological images that reflect different configuration of grafts in the infarcted ventricle. We ran simulations with varying degrees of connection imposed upon the graft-host perimeter to assess how heterogeneous electrical coupling affected EA with non-conductive scar, slow-conducting scar and scar replaced by host myocardium. We also quantified the effect of variation in intrinsic graft conductivity. Susceptibility to EA initially increased and subsequently decreased with increasing graft-host coupling, suggesting the waxing and waning of EA is regulated by progressive increases in graft-host coupling. Different spatial distributions of graft, host and scar yielded markedly different susceptibility curves. Computationally replacing non-conductive scar with host myocardium or slow-conducting scar, and increasing intrinsic graft conductivity both demonstrated potential means to blunt EA vulnerability. These data show how graft location, especially relative to scar, along with its dynamic electrical coupling to host, can influence EA burden; moreover, they offer a rational base for further studies aimed to define the optimal delivery of hPSC-CM injection. KEY POINTS: Human pluripotent stem cell-derived cardiomyocytes (hPSC-CM) hold great cardiac regenerative potential but can also cause engraftment arrhythmias (EA). Spatiotemporal evolution in the pattern of electrical coupling between injected hPSC-CMs and surrounding host myocardium may explain the dynamics of EA observed in large animal models. We conducted simulations in histology-derived 2D slice computational models to assess the effects of heterogeneous graft-host electrical coupling on EA propensity, with or without scar tissue. Our findings suggest spatiotemporally heterogeneous graft-host coupling can create an electrophysiological milieu that favours graft-initiated host excitation, a surrogate metric of EA susceptibility. Removing scar from our models reduced but did not abolish the propensity for this phenomenon. Conversely, reduced intra-graft electrical connectedness increased the incidence of graft-initiated host excitation. The computational framework created for this study can be used to generate new hypotheses, targeted delivery of hPSC-CMs.

Haemodynamic effects of hypertension and type 2 diabetes: Insights from a 4D flow MRI-based personalized cardiovascular mathematical model.

Type 2 diabetes (T2D) and hypertension increase the risk of cardiovascular diseases mediated by whole-body changes to metabolism, cardiovascular structure and haemodynamics. The haemodynamic changes related to hypertension and T2D are complex and subject-specific, however, and not fully understood. We aimed to investigate the haemodynamic mechanisms in T2D and hypertension by comparing the haemodynamics between healthy controls and subjects with T2D, hypertension, or both. For all subjects, we combined 4D flow magnetic resonance imaging data, brachial blood pressure and a cardiovascular mathematical model to create a comprehensive subject-specific analysis of central haemodynamics. When comparing the subject-specific haemodynamic parameters between the four groups, the predominant haemodynamic difference is impaired left ventricular relaxation in subjects with both T2D and hypertension compared to subjects with only T2D, only hypertension and controls. The impaired relaxation indicates that, in this cohort, the long-term changes in haemodynamic load of co-existing T2D and hypertension cause diastolic dysfunction demonstrable at rest, whereas either disease on its own does not. However, through subject-specific predictions of impaired relaxation, we show that altered relaxation alone is not enough to explain the subject-specific and group-related differences; instead, a combination of parameters is affected in T2D and hypertension. These results confirm previous studies that reported more adverse effects from the combination of T2D and hypertension compared to either disease on its own. Furthermore, this shows the potential of personalized cardiovascular models in providing haemodynamic mechanistic insights and subject-specific predictions that could aid in the understanding and treatment planning of patients with T2D and hypertension. KEY POINTS: The combination of 4D flow magnetic resonance imaging data and a cardiovascular mathematical model allows for a comprehensive analysis of subject-specific haemodynamic parameters that otherwise cannot be derived non-invasively. Using this combination, we show that diastolic dysfunction in subjects with both type 2 diabetes (T2D) and hypertension is the main group-level difference between controls, subjects with T2D, subjects with hypertension, and subjects with both T2D and hypertension. These results suggest that, in this relatively healthy population, the additional load of both hypertension and T2D affects the haemodynamic function of the left ventricle, whereas each disease on its own is not enough to cause significant effects under resting conditions. Finally, using the subject-specific model, we show that the haemodynamic effects of diastolic dysfunction alone are not sufficient to explain all the observed haemodynamic differences. Instead, additional subject-specific variations in cardiac and vascular function combine to explain the complex haemodynamics of subjects affected by hypertension and/or T2D.

Electrophysiological effects of stretch-activated ion channels: a systematic computational characterization.

Cardiac electrophysiology and mechanics are strongly interconnected. Their interaction is, among others, mediated by mechano-electric feedback through stretch-activated ion channels (SACs). The electrophysiological changes induced by SACs may contribute to arrhythmogenesis, but the precise SAC-induced electrophysiological changes remain incompletely understood. Here, we provide a systematic characterization of stretch effects through three distinguished SACs on cardiac electrophysiology using computational modelling. We implemented potassium-selective, calcium-selective and non-selective SACs in the Tomek-Rodriguez-O'Hara-Rudy model of human ventricular electrophysiology. The model was calibrated to experimental data from isolated cardiomyocytes undergoing stretch, considering inter-species differences, and disease-related remodelling of SACs. SAC-mediated effects on the action potential (AP) were analysed by varying stretch amplitude, application timing and/or duration. Afterdepolarizations of different amplitudes were observed with transient 10-ms stretch stimuli of 15-18% applied during phase 4, while stretch ≥18% during phase 4 elicited triggered APs. Longer stimuli shifted the threshold of AP trigger during phase 4 to lower amplitudes, while shorter stimuli increased it. Continuous stretch provoked electrophysiological remodelling. Furthermore, stretch shortened duration or changed morphology of a subsequent electrically evoked AP, and, if applied during a vulnerable time window with sufficient amplitude, prevented its occurrence because of stretch-induced modulation of sodium and L-type calcium channel gating. These effects were more pronounced with disease-related SAC remodelling due to increased stretch sensitivity of diseased hearts. We showed that SACs may induce afterdepolarizations and triggered activities, and prevent subsequent AP generation or change its morphology. These effects depend on cardiomyocyte stretch characteristics and disease-related SACs remodelling and may contribute to cardiac arrhythmogenesis. KEY POINTS: The interplay between cardiac electrophysiology and mechanics is mediated by mechano-electric feedback through stretch-activated ion channels (SACs). These channels may be pro-arrhythmic, but their precise effect on electrophysiology remains unclear. Here we present a systematic in silico characterization of stretch effects through three SACs by implementing inter-species differences as well as disease-related remodelling of SACs in a novel computational model of human ventricular cardiomyocyte electrophysiology. Our simulations showed that, at the cellular level, SACs may provoke electrophysiological remodelling, afterdepolarizations, triggered activities, change the morphology or shorten subsequent electrically evoked action potentials. The model further suggests that a vulnerable window exists in which stretch prevents the following electrically triggered beat occurrence. The pro-arrhythmic effects of stretch strongly depend on disease-related SAC remodelling as well as on stretch characteristics, such as amplitude, time of application and duration. Our study helps in understanding the role of stretch in cardiac arrhythmogenesis and revealing the underlying cellular mechanisms.

Evaluation of a deep learning-enabled automated computational heart modelling workflow for personalized assessment of ventricular arrhythmias.

Personalized, image-based computational heart modelling is a powerful technology that can be used to improve patient-specific arrhythmia risk stratification and ventricular tachycardia (VT) ablation targeting. However, most state-of-the-art methods still require manual interactions by expert users. The goal of this study is to evaluate the feasibility of an automated, deep learning-based workflow for reconstructing personalized computational electrophysiological heart models to guide patient-specific treatment of VT. Contrast-enhanced computed tomography (CE-CT) images with expert ventricular myocardium segmentations were acquired from 111 patients across five cohorts from three different institutions. A deep convolutional neural network (CNN) for segmenting left ventricular myocardium from CE-CT was developed, trained and evaluated. From both CNN-based and expert segmentations in a subset of patients, personalized electrophysiological heart models were reconstructed and rapid pacing was used to induce VTs. CNN-based and expert segmentations were more concordant in the middle myocardium than in the heart's base or apex. Wavefront propagation during pacing was similar between CNN-based and original heart models. Between most sets of heart models, VT inducibility was the same, the number of induced VTs was strongly correlated, and VT circuits co-localized. Our results demonstrate that personalized computational heart models reconstructed from deep learning-based segmentations even with a small training set size can predict similar VT inducibility and circuit locations as those from expertly-derived heart models. Hence, a user-independent, automated framework for simulating arrhythmias in personalized heart models could feasibly be used in clinical settings to aid VT risk stratification and guide VT ablation therapy. KEY POINTS: Personalized electrophysiological heart modelling can aid in patient-specific ventricular tachycardia (VT) risk stratification and VT ablation targeting. Current state-of-the-art, image-based heart models for VT prediction require expert-dependent, manual interactions that may not be accessible across clinical settings. In this study, we develop an automated, deep learning-based workflow for reconstructing personalized heart models capable of simulating arrhythmias and compare its predictions with that of expert-generated heart models. The number and location of VTs was similar between heart models generated from the deep learning-based workflow and expert-generated heart models. These results demonstrate the feasibility of using an automated computational heart modelling workflow to aid in VT therapeutics and has implications for generalizing personalized computational heart technology to a broad range of clinical centres.

Gamma Radiation-Induced Degradation of Acetohydroxamic Acid (AHA) in Aqueous Nitrate and Nitric Acid Solutions Evaluated by Multiscale Modelling.

Acetohydroxamic acid (AHA) has been proposed for inclusion in advanced, single-cycle, used nuclear fuel reprocessing solvent systems for the reduction and complexation of plutonium and neptunium ions. For this application, a detailed description of the fundamental degradation of AHA in dilute aqueous nitric acid is required. To this end, we present a comprehensive, multiscale computer model for the coupled radiolytic and hydrolytic degradation of AHA in aqueous sodium nitrate and nitric acid solutions. Rate coefficients for the reactions of AHA and hydroxylamine (HA) with the oxidizing nitrate radical were measured for the first time using electron pulse radiolysis and used as inputs for the kinetic model. The computer model results are validated by comparison to experimental data from steady-state gamma ray irradiations, for which the agreement is excellent. The presented model accurately predicts the yields of the major degradation products of AHA: acetic acid, HA, nitrous oxide, and molecular hydrogen.

Anterior vs. posterior position of dispersive patch during radiofrequency catheter ablation: insights from in silico modelling.

AIMS: To test the hypothesis that the dispersive patch (DP) location does not significantly affect the current distribution around the catheter tip during radiofrequency catheter ablation (RFCA) but may affect lesions size through differences in impedance due to factors far from the catheter tip. METHODS: An in silico model of RFCA in the posterior left atrium and anterior right ventricle was created using anatomic measurements from patient thoracic computed tomography scans and tested the effect of anterior vs. posterior DP locations on baseline impedance, myocardial power delivery, radiofrequency current path, and predicted lesion size. RESULTS: For posterior left atrium ablation, the baseline impedance, total current delivered, current distribution, and proportion of power delivered to the myocardium were all similar with both anterior and posterior DP locations, resulting in similar RFCA lesion sizes (< 0.2 mm difference). For anterior right ventricular (RV) ablation, an anterior DP location resulted in slightly higher proportion of power delivered to the myocardium and lower baseline impedance leading to slightly larger RFCA lesions (0.6 mm deeper and 0.8 mm wider). CONCLUSIONS: An anterior vs. posterior DP location will not meaningfully affect RFCA for posterior left atrial ablation, and the slightly larger lesions predicted with anterior DP location for anterior RV ablation are of unclear clinical significance.

Wavefront directionality and decremental stimuli synergistically improve identification of ventricular tachycardia substrate: insights from personalized computational heart models.

AIMS: Multiple wavefront pacing (MWP) and decremental pacing (DP) are two electroanatomic mapping (EAM) strategies that have emerged to better characterize the ventricular tachycardia (VT) substrate. The aim of this study was to assess how well MWP, DP, and their combination improve identification of electrophysiological abnormalities on EAM that reflect infarct remodelling and critical VT sites. METHODS AND RESULTS: Forty-eight personalized computational heart models were reconstructed using images from post-infarct patients undergoing VT ablation. Paced rhythms were simulated by delivering an initial (S1) and an extra-stimulus (S2) from one of 100 locations throughout each heart model. For each pacing, unipolar signals were computed along the myocardial surface to simulate substrate EAM. Six EAM features were extracted and compared with the infarct remodelling and critical VT sites. Concordance of S1 EAM features between different maps was lower in hearts with smaller amounts of remodelling. Incorporating S1 EAM features from multiple maps greatly improved the detection of remodelling, especially in hearts with less remodelling. Adding S2 EAM features from multiple maps decreased the number of maps required to achieve the same detection accuracy. S1 EAM features from multiple maps poorly identified critical VT sites. However, combining S1 and S2 EAM features from multiple maps paced near VT circuits greatly improved identification of critical VT sites. CONCLUSION: Electroanatomic mapping with MWP is more advantageous for characterization of substrate in hearts with less remodelling. During substrate EAM, MWP and DP should be combined and delivered from locations proximal to a suspected VT circuit to optimize identification of the critical VT site.

Virtual pacing of a patient's digital twin to predict left ventricular reverse remodelling after cardiac resynchronization therapy.

AIMS: Identifying heart failure (HF) patients who will benefit from cardiac resynchronization therapy (CRT) remains challenging. We evaluated whether virtual pacing in a digital twin (DT) of the patient's heart could be used to predict the degree of left ventricular (LV) reverse remodelling post-CRT. METHODS AND RESULTS: Forty-five HF patients with wide QRS complex (≥130 ms) and reduced LV ejection fraction (≤35%) receiving CRT were retrospectively enrolled. Echocardiography was performed before (baseline) and 6 months after CRT implantation to obtain LV volumes and 18-segment longitudinal strain. A previously developed algorithm was used to generate 45 DTs by personalizing the CircAdapt model to each patient's baseline measurements. From each DT, baseline septal-to-lateral myocardial work difference (MWLW-S,DT) and maximum rate of LV systolic pressure rise (dP/dtmax,DT) were derived. Biventricular pacing was then simulated using patient-specific atrioventricular delay and lead location. Virtual pacing-induced changes ΔMWLW-S,DT and ΔdP/dtmax,DT were correlated with real-world LV end-systolic volume change at 6-month follow-up (ΔLVESV). The DT's baseline MWLW-S,DT and virtual pacing-induced ΔMWLW-S,DT were both significantly associated with the real patient's reverse remodelling ΔLVESV (r = -0.60, P < 0.001 and r = 0.62, P < 0.001, respectively), while correlation between ΔdP/dtmax,DT and ΔLVESV was considerably weaker (r = -0.34, P = 0.02). CONCLUSION: Our results suggest that the reduction of septal-to-lateral work imbalance by virtual pacing in the DT can predict real-world post-CRT LV reverse remodelling. This DT approach could prove to be an additional tool in selecting HF patients for CRT and has the potential to provide valuable insights in optimization of CRT delivery.

Eukaryotic Cell Membranes: Structure, Composition, Research Methods and Computational Modelling.

This paper deals with the problems encountered in the study of eukaryotic cell membranes. A discussion on the structure and composition of membranes, lateral heterogeneity of membranes, lipid raft formation, and involvement of actin and cytoskeleton networks in the maintenance of membrane structure is included. Modern methods for the study of membranes and their constituent domains are discussed. Various simplified models of biomembranes and lipid rafts are presented. Computer modelling is considered as one of the most important methods. This is stated that from the study of the plasma membrane structure, it is desirable to proceed to the diverse membranes of all organelles of the cell. The qualitative composition and molar content of individual classes of polar lipids, free sterols and proteins in each of these membranes must be considered. A program to create an open access electronic database including results obtained from the membrane modelling of individual cell organelles and the key sites of the membranes, as well as models of individual molecules composing the membranes, has been proposed.

Non-Antigenic Modulation of Antigen Receptor (TCR) Cß-FG Loop Modulates Signalling: Implications of External Factors Influencing T-Cell Responses.

T-cell recognition of antigens is complex, leading to biochemical and cellular events that impart both specific and targeted immune responses. The end result is an array of cytokines that facilitate the direction and intensity of the immune reaction-such as T-cell proliferation, differentiation, macrophage activation, and B-cell isotype switching-all of which may be necessary and appropriate to eliminate the antigen and induce adaptive immunity. Using in silico docking to identify small molecules that putatively bind to the T-cell Cß-FG loop, we have shown in vitro using an antigen presentation assay that T-cell signalling is altered. The idea of modulating T-cell signalling independently of antigens by directly targeting the FG loop is novel and warrants further study.

Repurposing consumer sunscreen habits and practices survey data to guide the development of UV filter environmental exposure models and risk assessments.

OBJECTIVE: A key factor that is deficient in most environmental emissions assessments for UV filters is a keen understanding of consumer habits and practices that can inform realistic exposure assessments. This study utilized a large volunteer survey (>11 000 persons) that captured many factors that affect consumer-based loadings to aquatic environments. The purpose of this study was to utilize this large survey to identify factors that affect the amount of sunscreen products used by consumers. METHODS: Correlations among more than 20 variables were used to provide an understanding of the overall dataset and identify factors that may be related to the amount of sunscreen product applied to the body (i.e., application thickness). Forward multiple linear regressions were used to identify the relative importance of each of these factors alone and in combination with others in predicting the amount of applied sunscreen. RESULTS: The proportion of body surface area (BSA) covered by sunscreen was the primary factor related to application thickness, followed by body surface area of the survey participant, seasonal usage, Fitzpatrick skin type and the sun protection factor, respectively. Each of the five regression models examined was statistically highly significant. CONCLUSIONS: Comparisons to recommendations from the National Academies of Science, Engineering and Medicine parameters illustrated sufficient differences so as to encourage the development of future consumer habits and practice surveys that include factors beyond the scope of this study (e.g., activities, time of day, year, location, etc.) that can lead to improved exposure and risk assessments.

OBJECTIF: Un facteur clé qui est insuffisant dans la plupart des évaluations des émissions environnementales pour les filtres UV est une bonne compréhension des habitudes et pratiques des consommateurs qui peuve informer sur les évaluations réalistes de l'exposition. Cette étude a utilisé une vaste enquête auprès de volontaires (> 11 000 personnes) qui a pris en compte de nombreux facteurs affectant les habitudes des consommateurs dans des environnements aquatiques. L'objectif de cette étude était d'utiliser cette vaste enquête pour identifier les facteurs qui affectent la quantité de produit d'écran solaire utilisée par les consommateurs. MÉTHODES: Des corrélations entre plus de vingt variables ont été utilisées pour fournir une compréhension de l'ensemble des données et identifier les facteurs qui peuvent être liés à la quantité de produit d'écran solaire appliqué sur le corps (c.-à-d., épaisseur d'application). Des régressions linéaires multiples ont été utilisées pour identifier l'importance relative de chacun de ces facteurs seuls et en association avec d'autres pour prédire la quantité d'écran solaire appliqué. RÉSULTATS: La proportion de la surface corporelle (SC) couverte par l'écran solaire était le facteur principal lié à l'épaisseur de l'application, suivie de la surface corporelle du participant à l'enquête, de l'utilisation saisonnière, du type de peau (Fitzpatrick) et du facteur de protection solaire, respectivement. Chacun des cinq modèles de régression examinés était hautement significatif statistiquement. CONCLUSIONS: Les comparaisons avec les recommandations des Académies nationales de la science, de l'ingénierie et de la médecine ont mis en évidence des différences suffisantes pour encourager le développement de futures enquêtes sur les habitudes et les pratiques des consommateurs qui incluent des facteurs dépassant le champ d'application de cette étude (ex., activités, moment de la journée, année, lieu, etc.) qui peuvent conduire à une amélioration de l'exposition et des évaluations des risques.