Articoli di riviste sul tema "Stroke-based rendering"

Vector graphics includes both filled and stroked paths as the main primitives. While there are many techniques for rendering filled paths on GPU, stroked paths have proved more elusive. This paper presents a technique for performing stroke expansion, namely the generation of the outline representing the stroke of the given input path. Stroke expansion is a global problem, with challenging constraints on continuity and correctness. Nonetheless, we implement it using a fully parallel algorithm suitable for execution in a GPU compute shader, with minimal preprocessing. The output of our method can be either line or circular arc segments, both of which are well suited to GPU rendering, and the number of segments is minimal. We introduce several novel techniques, including an encoding of vector graphics primitives suitable for parallel processing, and an Euler spiral based method for computing approximations to parallel curves and evolutes.

The automatic style translation of Chinese characters (CH-Char) is a challenging problem. Different from English or general artistic style transfer, Chinese characters contain a large number of glyphs with the complicated content and characteristic style. Early methods on CH-Char synthesis are inefficient and require manual intervention. Recently some GAN-based methods are proposed for font generation. The supervised GAN-based methods require numerous image pairs, which is difficult for many chirography styles. In addition, unsupervised methods often cause the blurred and incorrect strokes. Therefore, in this work, we propose a three-stage Generative Adversarial Network (GAN) architecture for multi-chirography image translation, which is divided into skeleton extraction, skeleton transformation and stroke rendering with unpaired training data. Specifically, we first propose a fast skeleton extraction method (ENet). Secondly, we utilize the extracted skeleton and the original image to train a GAN model, RNet (a stroke rendering network), to learn how to render the skeleton with stroke details in target style. Finally, the pre-trained model RNet is employed to assist another GAN model, TNet (a skeleton transformation network), to learn to transform the skeleton structure on the unlabeled skeleton set. We demonstrate the validity of our method on two chirography datasets we established.

We present a new non-photorealistic rendering (NPR) algorithm for rendering photographs in an impasto painterly style. We observe that most existing image-based NPR algorithms operate in a spatially local manner, typically as non-linear image filters seeking to preserve edges and other high-frequency content. By contrast, we argue that figurative artworks are salience maps, and develop a novel painting algorithm that uses a genetic algorithm (GA) to search the space of possible paintings for a given image, so approaching an "optimal" artwork in which salient detail is conserved and non-salient detail is attenuated. Differential rendering styles are also possible by varying stroke style according to the classification of salient artifacts encountered, for example edges or ridges. We demonstrate the results of our technique on a wide range of images, illustrating both the improved control over level of detail due to our salience adaptive painting approach, and the benefits gained by subsequent relaxation of the painting using the GA.

<span lang="EN-US"><span>The present study aimed to investigate the metacognitive ability of students using e-portfolio assessment in project-based learning classes. The projects were a set out a critical analysis based on the selected references (project 1) and set out of field activities based on the selected theme content (project 2). Student metacognitive ability consists of three phases, planning, implementation, and evaluation abilities that were assessed through e-portfolio assignments. There were 87 participants who divided into groups consisted of four to five students, conducted the projects, and submitted the progress of their projects in every decided step into online report assignments. The rubric of metacognition was used to acquire the quantitative score of skill that was separated into six levels category: not yet, at risk, not-really, developing, OK, and super. The result revealed that 44.83% of the students belong to the last three of those levels and the rest are otherwise. The lowest and highest metacognitive ability of the student is “not really” and “developing” respectively. Student metacognitive ability through conducting the project 2 activities is higher than project 1. The findings showed that project-based learning (PBL) enables to foster the student metacognitive ability that developed through e-portfolio-based documents that student conducted during fulfilling all projects assignments.</span>The aim of present study was to investigate the metacognitive ability of student using e-portfolio assessment in the project-based learning classes. The projects were the set out a critical analysis based on the selected references (project 1) and the set out of field activities based on the selected theme content (project 2). Student metacognitive ability consists of three phases, planning, implementation and evaluation abilities that were assessed through e-portfolio assignments. Eighty-seven participants divided into groups consisted of four to five students, conducted the projects, and submitted the progress of their projects in every decided step into online report assignments. The rubric of metacognition was used to acquire the quantitative score of skill that was separated into six levels category; not yet, at risk, not really, developing, OK, and super. The result revealed that 44.83% of the students belong to the last three of those levels and the rest are otherwise. The lowest and highest metacognitive ability of student is "not really" and "developing” respectively. Student metacognitive ability through conducting the project 2 activities is higher than the project 1. The findings showed that PjBl enable to foster the student metacognitive ability that developed through e-portfolio-based documents that student conducted during fulfilling all projects assignments.</span><div class="ms-editor-squiggler" style="color: initial; font: initial; font-feature-settings: initial; font-kerning: initial; font-optical-sizing: initial; font-variation-settings: initial; forced-color-adjust: initial; text-orientation: initial; text-rendering: initial; -webkit-font-smoothing: initial; -webkit-locale: initial; -webkit-text-orientation: initial; -webkit-writing-mode: initial; writing-mode: initial; zoom: initial; place-content: initial; place-items: initial; place-self: initial; alignment-baseline: initial; animation: initial; appearance: initial; aspect-ratio: initial; backdrop-filter: initial; backface-visibility: initial; background: initial; background-blend-mode: initial; baseline-shift: initial; block-size: initial; border-block: initial; border: initial; border-radius: initial; 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x: initial; y: initial; z-index: initial;"> </div><div class="ms-editor-squiggler" style="color: initial; font: initial; font-feature-settings: initial; font-kerning: initial; font-optical-sizing: initial; font-variation-settings: initial; forced-color-adjust: initial; text-orientation: initial; text-rendering: initial; -webkit-font-smoothing: initial; -webkit-locale: initial; -webkit-text-orientation: initial; -webkit-writing-mode: initial; writing-mode: initial; zoom: initial; place-content: initial; place-items: initial; place-self: initial; alignment-baseline: initial; animation: initial; appearance: initial; aspect-ratio: initial; backdrop-filter: initial; backface-visibility: initial; background: initial; background-blend-mode: initial; baseline-shift: initial; block-size: initial; border-block: initial; border: initial; border-radius: initial; border-collapse: initial; border-end-end-radius: initial; border-end-start-radius: initial; border-inline: initial; border-start-end-radius: initial; 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grid-area: initial; height: 0px; hyphens: initial; image-orientation: initial; image-rendering: initial; inline-size: initial; inset-block: initial; inset-inline: initial; isolation: initial; letter-spacing: initial; lighting-color: initial; line-break: initial; list-style: initial; margin-block: initial; margin: initial; margin-inline: initial; marker: initial; mask: initial; mask-type: initial; max-block-size: initial; max-height: initial; max-inline-size: initial; max-width: initial; min-block-size: initial; min-height: initial; min-inline-size: initial; min-width: initial; mix-blend-mode: initial; object-fit: initial; object-position: initial; offset: initial; opacity: initial; order: initial; origin-trial-test-property: initial; orphans: initial; outline: initial; outline-offset: initial; overflow-anchor: initial; overflow-wrap: initial; overflow: initial; overscroll-behavior-block: initial; overscroll-behavior-inline: initial; overscroll-behavior: initial; padding-block: initial; padding: initial; padding-inline: initial; page: initial; page-orientation: initial; paint-order: initial; perspective: initial; perspective-origin: initial; pointer-events: initial; position: initial; quotes: initial; r: initial; resize: initial; ruby-position: initial; rx: initial; ry: initial; scroll-behavior: initial; scroll-margin-block: initial; scroll-margin: initial; scroll-margin-inline: initial; scroll-padding-block: initial; scroll-padding: initial; scroll-padding-inline: initial; scroll-snap-align: initial; scroll-snap-stop: initial; scroll-snap-type: initial; shape-image-threshold: initial; shape-margin: initial; shape-outside: initial; shape-rendering: initial; size: initial; speak: initial; stop-color: initial; stop-opacity: initial; stroke: initial; stroke-dasharray: initial; stroke-dashoffset: initial; stroke-linecap: initial; stroke-linejoin: initial; stroke-miterlimit: initial; stroke-opacity: initial; stroke-width: initial; tab-size: initial; table-layout: initial; text-align: initial; text-align-last: initial; text-anchor: initial; text-combine-upright: initial; text-decoration: initial; text-decoration-skip-ink: initial; text-indent: initial; text-overflow: initial; text-shadow: initial; text-size-adjust: initial; text-transform: initial; text-underline-offset: initial; text-underline-position: initial; touch-action: initial; transform: initial; transform-box: initial; transform-origin: initial; transform-style: initial; transition: initial; user-select: initial; vector-effect: initial; vertical-align: initial; visibility: initial; -webkit-app-region: initial; border-spacing: initial; -webkit-border-image: initial; -webkit-box-align: initial; -webkit-box-decoration-break: initial; -webkit-box-direction: initial; -webkit-box-flex: initial; -webkit-box-ordinal-group: initial; -webkit-box-orient: initial; -webkit-box-pack: initial; -webkit-box-reflect: initial; -webkit-highlight: initial; -webkit-hyphenate-character: initial; -webkit-line-break: initial; -webkit-line-clamp: initial; -webkit-mask-box-image: initial; -webkit-mask: initial; -webkit-mask-composite: initial; -webkit-perspective-origin-x: initial; -webkit-perspective-origin-y: initial; -webkit-print-color-adjust: initial; -webkit-rtl-ordering: initial; -webkit-ruby-position: initial; -webkit-tap-highlight-color: initial; -webkit-text-combine: initial; -webkit-text-decorations-in-effect: initial; -webkit-text-emphasis: initial; -webkit-text-emphasis-position: initial; -webkit-text-fill-color: initial; -webkit-text-security: initial; -webkit-text-stroke: initial; -webkit-transform-origin-x: initial; -webkit-transform-origin-y: initial; -webkit-transform-origin-z: initial; -webkit-user-drag: initial; -webkit-user-modify: initial; white-space: initial; widows: initial; width: initial; will-change: initial; word-break: initial; word-spacing: initial; x: initial; y: initial; z-index: initial;"> </div>

We propose a novel image-to-pencil translation method that could not only generate high-quality pencil sketches but also offer the drawing process. Existing pencil sketch algorithms are based on texture rendering rather than the direct imitation of strokes, making them unable to show the drawing process but only a final result. To address this challenge, we first establish a pencil stroke imitation mechanism. Next, we develop a framework with three branches to guide stroke drawing: the first branch guides the direction of the strokes, the second branch determines the shade of the strokes, and the third branch enhances the details further. Under this framework's guidance, we can produce a pencil sketch by drawing one stroke every time. Our method is fully interpretable. Comparison with existing pencil drawing algorithms shows that our method is superior to others in terms of texture quality, style, and user evaluation. Our code and supplementary material are now available at: https://github.com/TZYSJTU/Sketch-Generation-withDrawing-Process-Guided-by-Vector-Flow-and-Grayscale

Rapid advance of location acquisition technologies boosts the generation of trajectory data, which track the traces of moving objects. A trajectory is typically represented by a sequence of timestamped geographical locations. Data visualization is an efficient means to represent distributions and structures of datasets and reveal hidden patterns in the data. In this paper, we explore a cloud model-based method for the generation of stylized renderings of trajectory data. The artistic visualizations of the proposed method do not have the goal to allow for data mining tasks or others but instead show the aesthetic effect of the traces of moving objects in a distorted manner. The techniques used to create the images of traces of moving objects include the uncertain line using extended cloud model, stroke-based rendering of geolocation in varying styles, and stylistic shading with aesthetic effects for print or electronic displays, as well as various parameters to be further personalized. The influence of different parameters on the aesthetic qualities of various painted images is investigated, including step size, types of strokes, colour modes, and quantitative comparisons using four aesthetic measures are also involved into the experiment. The experimental results suggest that the proposed method is with advantages of uncertainty, simplicity and effectiveness, and it would inspire professional graphic designers and amateur users who may be interested in playful and creative exploration of artistic visualization of trajectory data.

There is a myriad of methodologies to assess driving performance after a stroke. These include psychometric tests, driving simulation, questionnaires, and/or road tests. Research-based driving simulators have emerged as a safe, convenient way to assess driving performance after a stroke. Such traditional research simulators are useful in recreating street traffic scenarios, but are often expensive, with limited physics models and graphics rendering. In contrast, racing simulators developed for motorsport professionals and enthusiasts offer high levels of realism, run on consumer-grade hardware, and can provide rich telemetric data. However, most offer limited simulation of traffic scenarios. This pilot study compares the feasibility of research simulation and racing simulation in a sample with minor stroke. We determine that the racing simulator is tolerated well in subjects with a minor stroke. There were correlations between research and racing simulator outcomes with psychometric tests associated with driving performance, such as the Trails Making Test Part A, Snellgrove Maze Task, and the Motricity Index. We found correlations between measures of driving speed on a complex research simulator scenario and racing simulator lap time and maximum tires off track. Finally, we present two models, using outcomes from either the research or racing simulator, predicting road test failure as linked to a previously published fitness-to-drive calculator that uses psychometric screening.

Histology is a long standing and well-established gold standard for pathological characterizations. In recent years however, synchrotron radiation-based micro-computed tomography (SRμCT) has become a tool for extending the imaging of two-dimensional thin sections into three-dimensional imaging of tissue blocks, enabling so-called virtual histology with arbitrary clipping planes, volumetric rendering and automatic segmentation. In this study, we present a thorough characterization of human carotid plaques after endarterectomy of patients with stroke or transient ischemic attack (TIA), investigating several different pathologic structures using both SRμCT and histology. Phase-contrast SRμCT was performed with two different magnifications (voxel sizes 6.5 μm and 0.65 μm, respectively), and histology was performed with multiple different stainings (Alpha-actin, Glycophorin A, von Kossa, Movat, CD68). The 0.65 μm high-resolution SRμCT was performed on selected areas with plaque typical relevant morphology, identified on the 6.5 μm low-resolution SRμCT. The tomography datasets were reconstructed with additional 3D volume rendering and compared to histology. In total, nine different regions with typical pathologic structures were identified and imaged with high-resolution SRμCT. The results show many characteristics typical for advanced atherosclerotic plaques, clinically relevant, namely ruptures with thrombosis, neo-vascularization, inflammatory infiltrates in shoulder regions, lipid rich necrotic cores (LRNC), thin fibrous cap, calcifications, lumen irregularities, and changes in vessel wall structures such as the internal elastic membrane. This method’s non-destructive nature renders details of micro-structures with an excellent visual likeness to histology, with the additional strength of multiplanar and 3D visualization and the possibility of multiple re-scans.

Histology is a long standing and well-established gold standard for pathological characterizations. In recent years however, synchrotron radiation-based micro-computed tomography (SRμCT) has become a tool for extending the imaging of two-dimensional thin sections into three-dimensional imaging of tissue blocks, enabling so-called virtual histology with arbitrary clipping planes, volumetric rendering and automatic segmentation. In this study, we present a thorough characterization of human carotid plaques after endarterectomy of patients with stroke or transient ischemic attack (TIA), investigating several different pathologic structures using both SRμCT and histology. Phase-contrast SRμCT was performed with two different magnifications (voxel sizes 6.5 μm and 0.65 μm, respectively), and histology was performed with multiple different stainings (Alpha-actin, Glycophorin A, von Kossa, Movat, CD68). The 0.65 μm high-resolution SRμCT was performed on selected areas with plaque typical relevant morphology, identified on the 6.5 μm low-resolution SRμCT. The tomography datasets were reconstructed with additional 3D volume rendering and compared to histology. In total, nine different regions with typical pathologic structures were identified and imaged with high-resolution SRμCT. The results show many characteristics typical for advanced atherosclerotic plaques, clinically relevant, namely ruptures with thrombosis, neo-vascularization, inflammatory infiltrates in shoulder regions, lipid rich necrotic cores (LRNC), thin fibrous cap, calcifications, lumen irregularities, and changes in vessel wall structures such as the internal elastic membrane. This method’s non-destructive nature renders details of micro-structures with an excellent visual likeness to histology, with the additional strength of multiplanar and 3D visualization and the possibility of multiple re-scans.

Histology is a long standing and well-established gold standard for pathological characterizations. In recent years however, synchrotron radiation-based micro-computed tomography (SRμCT) has become a tool for extending the imaging of two-dimensional thin sections into three-dimensional imaging of tissue blocks, enabling so-called virtual histology with arbitrary clipping planes, volumetric rendering and automatic segmentation. In this study, we present a thorough characterization of human carotid plaques after endarterectomy of patients with stroke or transient ischemic attack (TIA), investigating several different pathologic structures using both SRμCT and histology. Phase-contrast SRμCT was performed with two different magnifications (voxel sizes 6.5 μm and 0.65 μm, respectively), and histology was performed with multiple different stainings (Alpha-actin, Glycophorin A, von Kossa, Movat, CD68). The 0.65 μm high-resolution SRμCT was performed on selected areas with plaque typical relevant morphology, identified on the 6.5 μm low-resolution SRμCT. The tomography datasets were reconstructed with additional 3D volume rendering and compared to histology. In total, nine different regions with typical pathologic structures were identified and imaged with high-resolution SRμCT. The results show many characteristics typical for advanced atherosclerotic plaques, clinically relevant, namely ruptures with thrombosis, neo-vascularization, inflammatory infiltrates in shoulder regions, lipid rich necrotic cores (LRNC), thin fibrous cap, calcifications, lumen irregularities, and changes in vessel wall structures such as the internal elastic membrane. This method’s non-destructive nature renders details of micro-structures with an excellent visual likeness to histology, with the additional strength of multiplanar and 3D visualization and the possibility of multiple re-scans.

AbstractSubarachnoid haemorrhage (SAH) is a consistent presentation of haemorrhagic stroke of significance to clinicians in neurocritical care, inducing consequent effects on non-neurological systems, while at the same time, rendering the brain vulnerable to secondary physiological insult modifying neurological outcome, despite control of the original point of haemorrhage. Coordinated treatment depends on comprehensive evaluation of both cerebral and systemic physiology, identifying and treating impaired function. The presence of a dedicated neurocritical care team can benefit outcome. Protocols of care have evolved to meet evidence-based challenges, discarding potentially deleterious components of hypervolaemia and haemodilution, while maintaining pressure-guided perfusion. Treatment targets have also evolved with a shift in focus away from SAH-associated vasospasm, towards actual ischaemic outcome – illustrated by lack of effectiveness of pharmaceutical treatments of vasospasm. Clinicians must consequently review pathophysiological mechanisms of injury and devise new treatment opportunities.

In this paper, we put forward an improved non-photorealistic rendering method for generating a colored pencil drawing from digital image. First, to make sure the result can retain the original color information, we use the original pixel value instead of the black dot which generated by the traditional white-noise generating method. Second, we added a ratio for the Kirsch operator to be suitable for different images with different details. Third, we present a new approach which extruded form the luminance of the original image to determine the stroke orientation. Based on our methods, the quality of traditional pencil illustration can be guaranteed to a certain extent, and an effective and convenient tool is provided to generate the same drawings in style with artists and illustrations even for the users that have not been trained professionally.

Abstract Post-stroke cognitive and linguistic impairments are debilitating conditions, with limited therapeutic options. Domain-general brain networks play an important role in stroke recovery and characterizing their residual function with functional MRI has the potential to yield biomarkers capable of guiding patient-specific rehabilitation. However, this is challenging as such detailed characterization requires testing patients on multitudes of cognitive tasks in the scanner, rendering experimental sessions unfeasibly lengthy. Thus, the current status quo in clinical neuroimaging research involves testing patients on a very limited number of tasks, in the hope that it will reveal a useful neuroimaging biomarker for the whole cohort. Given the great heterogeneity among stroke patients and the volume of possible tasks this approach is unsustainable. Advancing task-based functional MRI biomarker discovery requires a paradigm shift in order to be able to swiftly characterize residual network activity in individual patients using a diverse range of cognitive tasks. Here, we overcome this problem by leveraging neuroadaptive Bayesian optimization, an approach combining real-time functional MRI with machine-learning, by intelligently searching across many tasks, this approach rapidly maps out patient-specific profiles of residual domain-general network function. We used this technique in a cross-sectional study with 11 left-hemispheric stroke patients with chronic aphasia (four female, age ± standard deviation: 59 ± 10.9 years) and 14 healthy, age-matched control subjects (eight female, age ± standard deviation: 55.6 ± 6.8 years). To assess intra-subject reliability of the functional profiles obtained, we conducted two independent runs per subject, for which the algorithm was entirely reinitialized. Our results demonstrate that this technique is both feasible and robust, yielding reliable patient-specific functional profiles. Moreover, we show that group-level results are not representative of patient-specific results. Whereas controls have highly similar profiles, patients show idiosyncratic profiles of network abnormalities that are associated with behavioural performance. In summary, our study highlights the importance of moving beyond traditional ‘one-size-fits-all’ approaches where patients are treated as one group and single tasks are used. Our approach can be extended to diverse brain networks and combined with brain stimulation or other therapeutics, thereby opening new avenues for precision medicine targeting a diverse range of neurological and psychiatric conditions.

In this paper, inertial sensing is used to identify a swimming stance and analyze its swimming stance data. A wireless monitoring device based on a nine-axis microinertial sensor is designed for the characteristics of swimming motion, and measurement experiments are conducted for different intensities and stances of swimming motion. By comparing and analyzing the motion characteristics of various swimming stances, the basis for performing stroke identification is proposed, and the monitoring data characteristics of the experimental results match with it. The stance reconstruction technology is studied, PC-based OpenGL multithreaded data synchronization and stance following reconstruction are designed to reconstruct the joint association data of multiple nodes in a constrained set, and the reconstruction results are displayed through graphic image rendering. For the whole system, each key technology is organically integrated to design a wearable wireless sensing network-based pose resolution analysis and reconstruction recognition system. Inertial sensors inevitably suffer from drift after a long period of position trajectory tracking. The proposed fusion algorithm corrects the drift of position estimation using the measurement of the visual sensor, and the measurement of the inertial sensor complements the missing measurement of the visual sensor for the case of occlusion of the visual sensor and fast movement of the upper limb. An experimental platform for upper-limb position estimation based on the fusion of inertial and visual sensors is built to verify the effectiveness of the proposed method. Finally, the full paper is summarized, and an outlook for further research is provided.

Robot-Assisted Rehabilitation (RAR) is relevant for treating patients affected by nervous system injuries (e.g., stroke and spinal cord injury). The accurate estimation of the joint angles of the patient limbs in RAR is critical to assess the patient improvement. The economical prevalent method to estimate the patient posture in Exoskeleton-based RAR is to approximate the limb joint angles with the ones of the Exoskeleton. This approximation is rough since their kinematic structures differ. Motion capture systems (MOCAPs) can improve the estimations, at the expenses of a considerable overload of the therapy setup. Alternatively, the Extended Inverse Kinematics Posture Estimation (EIKPE) computational method models the limb and Exoskeleton as differing parallel kinematic chains. EIKPE has been tested with single DOF movements of the wrist and elbow joints. This paper presents the assessment of EIKPE with elbow-shoulder compound movements (i.e., object prehension). Ground-truth for estimation assessment is obtained from an optical MOCAP (not intended for the treatment stage). The assessment shows EIKPE rendering a good numerical approximation of the actual posture during the compound movement execution, especially for the shoulder joint angles. This work opens the horizon for clinical studies with patient groups, Exoskeleton models, and movements types.

Based on current guidelines, 15% to 20% of patients undergoing mitral valve repair for regurgitation develop left ventricular dysfunction (ejection fraction < 50%–55%) despite a normal baseline. Two schools of thought have been debated: preexisting myocardial disease or suboptimal intraoperative myocardial protection. In our view, they could be reconciled. It is well recognized that left ventricular ejection fraction with a standard cut off at 50%–55% has limited sensitivity in detecting early systolic impairment in mitral regurgitation patients. Mitral regurgitation also leads to mitochondrial oxidative stress, thus rendering the myocardium more susceptible to ischemia-reperfusion injury and precipitating postoperative cardiac dysfunction. The fall in left ventricular ejection fraction early after mitral valve repair was shown to be caused by the reduction in both myocardial contractility and left ventricular stroke volume. To mitigate the risk to myocardial reperfusion injury, appropriate cardioplegia volume and distribution and well-defined surgical repair processes are equally important. We use transesophageal echocardiography-guided cardioplegia delivery, imaging the intramyocardial flow and ensuring adequate protection of the subendocardium during mitral valve repair. Mild aortic regurgitation on a beating heart often leads to left ventricular dilatation with diminished cardioplegia flow in the myocardium, thus requiring direct ostia cardioplegia. Systematic transesophageal echocardiography assessment before surgery is essential for establishing the mitral regurgitation mechanisms and translating them into precise surgical repair strategies. The benefits of transesophageal echocardiography-guided cardioplegia delivery warrant further clinical trials in order to evolve into part of a high surgical standard.

Introduction Haemorrhage is a leading cause of death following traumatic injury and the early detection of hypovolaemia is critical to effective management. However, accurate assessment of circulating blood volume is challenging when using traditional vital signs such as blood pressure. We conducted a study to compare the stroke volume (SV) recorded using two devices, trans-thoracic electrical bioimpedance (TEB) and supra-sternal Doppler (SSD), against a reference standard using trans- thoracic echocardiography (TTE). Methods A lower body negative pressure (LBNP) model was used to simulate hypovolaemia and in half of the study sessions lower limb tourniquets were applied as these are common in military practice and can potentially affect some haemodynamic monitoring systems. In order to provide a clinically relevant comparison we constructed an error grid alongside more traditional measures of agreement. Results 21 healthy volunteers aged 18–40 were enrolled and underwent 2 sessions of LBNP, with and without lower limb tourniquets. With respect to absolute SV values Bland Altman analysis showed significant bias in both non-tourniquet and tourniquet strands for TEB (-42.5 / -49.6 ml), rendering further analysis impossible. For SSD bias was minimal but percentage error was unacceptably high (35% / 48%). Degree of agreement for dynamic change in SV, assessed using 4 quadrant plots showed a seemingly acceptable concordance rate for both TEB (86% / 93%) and SSD (90% / 91%). However, when results were plotted on an error grid, constructed based on expert clinical opinion, a significant minority of measurement errors were identified that had potential to lead to moderate or severe patient harm. Conclusion Thoracic bioimpedance and suprasternal Doppler both demonstrated measurement errors that had the potential to lead to clinical harm and caution should be applied in interpreting the results in the detection of early hypovolaemia following traumatic injury.

This paper presents an interactive method of using ink diffusion, and gradually approaching simulation brush character with style of Chinese painting and calligraphy. Try to use materials based on the Chinese ink painting: ink and rice paper, according to their characteristics to build the diffusion rules to simulate text ink. Although the initial can show the phenomenon of ink rendering, they can only show diffusion of the ink with black lines, Can not rendering a complete ink diffusion behavior, it is difficult to form a sense of artistic calligraphy. It proposes Interactive model to amend the power of the brush pen and puts forward a binding behavior of ink broken down. The results show that based on the pratice physical meaning, considering the interaction of the two materials(ink and rice paper), appropriate to improve the mathematical equation model to render the calligraphy image more in line with Chinese ink painting style.

The visualization of cerebral microvessels is essential for understanding brain remodeling after stroke. Injection of dyes allows for the evaluation of perfused vessels, but has limitations related either to incomplete microvascular filling or leakage. In conventional histochemistry, the analysis of microvessels is limited to 2D structures, with apparent limitations regarding the interpretation of vascular circuits. Herein, we developed a straight-forward technique to visualize microvessels in the whole ischemic mouse brain, combining the injection of a fluorescent-labeled low viscosity hydrogel conjugate with 3D solvent clearing followed by automated light sheet microscopy. We performed transient middle cerebral artery occlusion in C57Bl/6j mice and acquired detailed 3D vasculature images from whole brains. Subsequent image processing, rendering and fitting of blood vessels to a filament model was employed to calculate vessel length density, resulting in 0.922 ± 0.176 m/mm3 in healthy tissue and 0.329 ± 0.131 m/mm3 in ischemic tissue. This analysis showed a marked loss of capillaries with a diameter ≤ 10 µm and a more moderate loss of microvessels in the range > 10 and ≤ 20 µm, whereas vessels > 20 µm were unaffected by focal cerebral ischemia. We propose that this protocol is highly suitable for studying microvascular injury and remodeling post-stroke.

Background. Haptic robots allow the exploitation of known motorlearning mechanisms, representing a valuable option for motor treatment after stroke. The aim of this feasibility multicentre study was to test the clinical efficacy of a haptic prototype, for the recovery of hand function after stroke.Methods. A prospective pilot clinical trial was planned on 15 consecutive patients enrolled in 3 rehabilitation centre in Italy. All the framework features of the haptic robot (e.g., control loop, external communication, and graphic rendering for virtual reality) were implemented into a real-time MATLAB/Simulink environment, controlling a five-bar linkage able to provide forces up to 20 [N] at the end effector, used for finger and hand rehabilitation therapies. Clinical (i.e., Fugl-Meyer upper extremity scale; nine hold pegboard test) and kinematics (i.e., time; velocity; jerk metric; normalized jerk of standard movements) outcomes were assessed before and after treatment to detect changes in patients' motor performance. Reorganization of cortical activation was detected in one patient by fMRI.Results and Conclusions. All patients showed significant improvements in both clinical and kinematic outcomes. Additionally, fMRI results suggest that the proposed approach may promote a better cortical activation in the brain.

OBJECTIVES/SPECIFIC AIMS: Infants with single ventricle congenital heart disease (CHD) who undergo staged surgical reconstruction are among the pediatric patients at highest risk for thrombotic complications. Despite improvements in survival due to medical and surgical advancements, thrombotic complications are common and lead to increased morbidity and mortality, especially during the first two stages of surgical reconstruction. The burden of disease caused by thrombosis is not fully known, and the risk factors associated with thrombosis are not clear. Due to this knowledge gap, prevention of thrombosis with medication, a strategy called thromboprophylaxis, has not been standardized, leading to inadequate prevention of thrombosis. In order to understand the burden of thrombosis and then provide targeted thromboprophylaxis for thrombosis prevention, better characterization of thrombotic complications and the associated factors is needed. Hypothesis: I hypothesize that in infants with single ventricle CHD, the incidence of thrombosis will be more frequent after stage I Versus stage II reconstruction, despite the type of shunt used. Specific demographic, clinical, and surgical variables will be associated with an increased risk for thrombotic complications, and a model to predict which subset of infants is at increased risk will be developed. Specific Aim 1: Characterize the incidence of thrombotic complications at different time points from stage I through stage II of the single ventricle reconstruction (SVR) pathway and determine the demographic, clinical, and surgical factors associated with thrombosis in infants with single ventricle CHD. (1) Determine the incidence of thrombosis in infants with single ventricle CHD. (2) Compare the rate of thrombotic complications between the 2 most commonly used approaches for stage I reconstruction for the group of patients with hypoplastic left heart type of anatomy [modified Blalock-Taussig shunt (MBTS) vs. right ventricle to pulmonary artery shunt (RVPAS)]. (3) Determine the factors (demographic, clinical, and surgical) associated with thrombosis in infants with single ventricle CHD. Specific Aim 2: Determine which subset of infants with single ventricle CHD is at increased risk of developing thrombotic complications across the first 2 stages of surgical reconstruction. (1) Test the identified demographic, clinical, and surgical variables including, but not limited to, gestational age, sex, CHD diagnosis, baseline oxygen saturation, stage of reconstruction, shunt type, and other clinical data available in a univariable and multivariable analysis and study their potential interactions to construct a novel risk predictive model specific for single ventricle CHD. METHODS/STUDY POPULATION: To address the specific aims, I will utilize data from the SVR clinical trial public use data set. This data set includes a prospective cohort of infants, 0–14 months of age, enrolled from any of the 15 participating clinical centers from the years 2005 to 2009. Inclusion criteria for enrollment were diagnosis of hypoplastic left heart syndrome or related single, morphologic right systemic ventricle anomaly, planned Norwood procedure, and informed consent of parent or legal guardian. No additional subjects outside of this data set will be included. Exclusion criteria were a diagnosis of single, morphologic left ventricle anomaly, preoperative identification of anatomy rendering the MBTS or RVPAS technically impossible, and any other major abnormality or acquired extra-cardiac disorder that could independently affect the likelihood of the subject meeting the primary endpoint. The complication of stroke will be excluded from the analyses of factors associated with thrombosis. The complication of thrombosis as defined in this dataset is a composite of events that include arterial or venous thrombosis, thromboembolism, and pulmonary embolism. The data was collected in such a way that it will not be possible to separate these sub-types of thrombosis. Additional thrombotic events of interest are superior vena cava occlusion and inferior vena cava occlusion. Specific Aim 1: Patient data will be extracted from the SVR clinical trial public use dataset to characterize the incidence of thrombotic complications at different time points from stage I through stage II of the SVR pathway and determine the demographic, clinical, and surgical factors associated with thrombosis in infants with single ventricle CHD. In addition, I will compare the rates of thrombotic complications between the 2 most commonly used approaches for stage I palliation for the group of patients with hypoplastic left heart type of anatomy (MBTS vs. RVPAS) and will test the hypothesis that the risk of thrombotic complications is associated with the stage of palliative surgery (stage I vs. stage II). Specific Aim 2: We will test identified demographic, clinical, surgical, and newly identified variables in a univariable and multivariable analysis and study their potential interactions to construct a novel risk predictive model specific for single ventricle CHD. RESULTS/ANTICIPATED RESULTS: To determine feasibility for adequate numbers to be able to address the research aims, a preliminary analysis dataset was performed using a dataset from the Pediatric Heart Network. The PHN is a collaborative group of hospitals that participates in clinical research studies in children with CHD. For the SVR clinical trial, the PHN conducted a randomized clinical trial at 15 centers in North America between 2005 and 2009, prospectively enrolling infants with HLHS or single right ventricle anomalies who were to undergo the Stage I Norwood procedure. A total of 920 newborns were screened; 664 were medically eligible and 549 patients were randomized. The primary aim of the trial was to compare survival of infants randomized to receive either the Norwood procedure with the MBTS or the RVPAS. These patients were followed at specific time points, including from baseline (pre-Norwood), at the time of the Norwood procedure, between stage I and II, following stage II reconstruction, and at 14 months of age. At these time points, data were collected that includes demographic, radiologic, clinical, and surgical outcomes. Included in the clinical outcomes are complications, such a thrombosis. There was no screening process to assess for asymptomatic thromboses, suggesting that most, if not all, discovered thromboses were due to clinically relevant effects. A newer iteration of this study (SVRIII) expands the monitoring of this cohort until the Fontan stage at 2–6 years of age, but these data have not yet been released in the public use data set. A descriptive analysis of the frequency of thrombotic complications was assessed at each time point, as well as in aggregate. Data were extracted from the specific time periods of interest, identified as Pre-Norwood, during Norwood Hospitalization, in-between visits, and during Stage II Hospitalization. There were 549 infants who were randomized with available data to analyze. During the Norwood hospitalization, 37 infants had a thrombotic complication. Between Stage I and Stage II outpatient visits, 8 infants had a thrombotic complication. During Stage II hospitalization, 16 infants had a thrombus. Overall, 61 individual patients (11%) had a thrombotic complication. DISCUSSION/SIGNIFICANCE OF IMPACT: This study utilizing data from the Pediatric Heart will be the largest cohort ever utilized for characterizing thrombotic complications and determining the factors associated with thrombosis across the first and second stages of surgical reconstruction. More than 500 (n=549) subject’s data will be analyzed through the first two stages of reconstruction, while the largest analysis before this proposed analysis only included a total of 195 children. Notably, these prior studies did not include a comparison between the 2 shunt types in stage I reconstruction, leaving a gap in knowledge regarding the incidence of thrombosis comparing these groups. The analysis will be the first to address this gap and update the current literature. Preliminary data show that the overall incidence of thrombosis across the first 2 stages of surgical reconstruction was 11%, which is lower than the previously reported overall rates of 40%–50%. Despite the continued lack of evidence-based guidelines for thromboprophylaxis methods, the decreased overall rate is most likely due to more widespread practice of anticoagulation in general. Determining the factors associated with thrombosis across the first and second stages of surgical reconstruction will help identify those at risk. An innovative aspect of this analysis will be the use of disease-specific factors to develop a model to predict thrombosis. Unique factors include cardiac variables like ejection fraction, baseline oxygen saturation, shunt type (MBTS vs. RVPAS), and other echocardiographic parameters. While the use of thromboprophylaxis has been associated with decreased risk of thrombosis, there is no general consensus to guide thromboprophylaxis in this population, which can be burdensome and costly. Determining which subset of infants with single ventricle CHD are at increased risk of developing thrombotic complications will allow for the development of a prediction model to predict those at highest risk of developing a thrombotic complication. Developing a predictive model will be a novel way to identify patients at risk for thrombosis and will set the stage for targeted prevention of thrombosis.

AbstractIt is a challenging task to teach machines to paint like human artists in a stroke-by-stroke fashion. Despite advances in stroke-based image rendering and deep learning-based image rendering, existing painting methods have limitations: they (i) lack flexibility to choose different art-style strokes, (ii) lose content details of images, and (iii) generate few artistic styles for paintings. In this paper, we propose a stroke-style generative adversarial network, called Stroke-GAN, to solve the first two limitations. Stroke-GAN learns styles of strokes from different stroke-style datasets, so can produce diverse stroke styles. We design three players in Stroke-GAN to generate pure-color strokes close to human artists’ strokes, thereby improving the quality of painted details. To overcome the third limitation, we have devised a neural network named Stroke-GAN Painter, based on Stroke-GAN; it can generate different artistic styles of paintings. Experiments demonstrate that our artful painter can generate various styles of paintings while well-preserving content details (such as details of human faces and building textures) and retaining high fidelity to the input images.

Vision transformer architectures attract widespread interest due to their robust representation capabilities of global features. Transformer-based methods as the encoder achieve superior performance compared to convolutional neural networks and other popular networks in many segmentation tasks for medical images. Due to the complex structure of the brain and the approximate grayscale of healthy tissue and lesions, lesion segmentation suffers from over-smooth boundaries or inaccurate segmentation. Existing methods, including the transformer, utilize stacked convolutional layers as the decoder to uniformly treat each pixel as a grid, which is convenient for feature computation. However, they often neglect the high-frequency features of the boundary and focus excessively on the region features. We propose an effective method for lesion boundary rendering called TransRender, which adaptively selects a series of important points to compute the boundary features in a point-based rendering way. The transformer-based method is selected to capture global information during the encoding stage. Several renders efficiently map the encoded features of different levels to the original spatial resolution by combining global and local features. Furthermore, the point-based function is employed to supervise the render module generating points, so that TransRender can continuously refine the uncertainty region. We conducted substantial experiments on different stroke lesion segmentation datasets to prove the efficiency of TransRender. Several evaluation metrics illustrate that our method can automatically segment the stroke lesion with relatively high accuracy and low calculation complexity.

AbstractAlthough digital painting has advanced much in recent years, there is still a significant divide between physically drawn paintings and purely digitally drawn paintings. These differences arise due to the physical interactions between the brush, ink, and paper, which are hard to emulate in the digital domain. Most ink painting approaches have focused on either using heuristics or physical simulation to attempt to bridge the gap between digital and analog, however, these approaches are still unable to capture the diversity of painting effects, such as ink fading or blotting, found in the real world. In this work, we propose a data‐driven approach to generate ink paintings based on a semi‐automatically collected high‐quality real‐world ink painting dataset. We use a multi‐camera robot‐based setup to automatically create a diversity of ink paintings, which allows for capturing the entire process in high resolution, including capturing detailed brush motions and drawing results. To ensure high‐quality capture of the painting process, we calibrate the setup and perform occlusion‐aware blending to capture all the strokes in high resolution in a robust and efficient way. Using our new dataset, we propose a recursive deep learning‐based model to reproduce the ink paintings stroke by stroke while capturing complex ink painting effects such as bleeding and mixing. Our results corroborate the fidelity of the proposed approach to real hand‐drawn ink paintings in comparison with existing approaches. We hope the availability of our dataset will encourage new research on digital realistic ink painting techniques.

AbstractIn this paper, a method of stroke‐based rendering is proposed for image representation and reconstruction. The proposed method involves compositing a set of ellipses that greatly vary in location, size, rotation angle, color, and opacity. This study proves that alpha compositing is differentiable if a two‐dimensional Gaussian function is used to draw a solid ellipse. The gradient method can then be employed for automatically identifying the parameters of each ellipse such that the difference between the input image and the composited image is minimized. Experimental results indicate that the proposed method can represent various types of images including portraits, landscapes, buildings, street scenes, artificial objects, medical images etc. The proposed method can particularly render the most details and significant features of an input image with fewer strokes compared to other stroke‐based rendering algorithms. This study also demonstrates that the proposed method can be applied in painting style simulation and sparse‐view computed tomography imaging.

Stroke survivors are commonly affected by somatosensory impairment, hampering their ability to interpret somatosensory information. Somatosensory information has been shown to critically support movement execution in healthy individuals and stroke survivors. Despite the detrimental effect of somatosensory impairments on performing activities of daily living, somatosensory training—in stark contrast to motor training—does not represent standard care in neurorehabilitation. Reasons for the neglected somatosensory treatment are the lack of high-quality research demonstrating the benefits of somatosensory interventions on stroke recovery, the unavailability of reliable quantitative assessments of sensorimotor deficits, and the labor-intensive nature of somatosensory training that relies on therapists guiding the hands of patients with motor impairments. To address this clinical need, we developed a virtual reality-based robotic texture discrimination task to assess and train touch sensibility. Our system incorporates the possibility to robotically guide the participants' hands during texture exploration (i.e., passive touch) and no-guided free texture exploration (i.e., active touch). We ran a 3-day experiment with thirty-six healthy participants who were asked to discriminate the odd texture among three visually identical textures –haptically rendered with the robotic device– following the method of constant stimuli. All participants trained with the passive and active conditions in randomized order on different days. We investigated the reliability of our system using the Intraclass Correlation Coefficient (ICC). We also evaluated the enhancement of participants' touch sensibility via somatosensory retraining and compared whether this enhancement differed between training with active vs. passive conditions. Our results showed that participants significantly improved their task performance after training. Moreover, we found that training effects were not significantly different between active and passive conditions, yet, passive exploration seemed to increase participants' perceived competence. The reliability of our system ranged from poor (in active condition) to moderate and good (in passive condition), probably due to the dependence of the ICC on the between-subject variability, which in a healthy population is usually small. Together, our virtual reality-based robotic haptic system may be a key asset for evaluating and retraining sensory loss with minimal supervision, especially for brain-injured patients who require guidance to move their hands.

AbstractWhile methods for generative image synthesis and example-based stylization produce impressive results, their black-box style representation intertwines shape, texture, and color aspects, limiting precise stylistic control and editing of artistic images. We introduce a novel method for decomposing the style of an artistic image that enables interactive geometric shape abstraction and texture control. We spatially decompose the input image into geometric shapes and an overlaying parametric texture representation, facilitating independent manipulation of color and texture. The parameters in this texture representation, comprising the image’s high-frequency details, control painterly attributes in a series of differentiable stylization filters. Shape decomposition is achieved using either segmentation or stroke-based neural rendering techniques. We demonstrate that our shape and texture decoupling enables diverse stylistic edits, including adjustments in shape, stroke, and painterly attributes such as contours and surface relief. Moreover, we demonstrate shape and texture style transfer in the parametric space using both reference images and text prompts and accelerate these by training networks for single- and arbitrary-style parameter prediction.

AbstractOcclusion of the major cerebral artery usually results in brain hypoxic-ischemic injury, which evokes neuroinflammation and microglial activation. Activated microglia are considered a source of multiple neurotoxic factors, such as reactive oxygen species (ROS), in the central nervous system (CNS). We herein present a 3D-rendering brain imaging technique in an experimental rodent model of cerebral ischemia based on 2D magnetic images of superparamagnetic iron oxide nanoparticles (SPIONs) using the planar frequency mixing magnetic detection (p-FMMD) technique. A rat model of cerebral ischemia was established by unilateral middle cerebral artery occlusion with reperfusion (MCAO/R) injury. 2,3,5-Triphenyltetrazolium chloride (TTC) staining was performed to demonstrate the irreversibly damaged ischemic brain tissues, and double immunofluorescent labeling of OX6 (activated microglial marker) and ethidium (ROS marker) was conducted to confirm ROS generation in the activated microglia in the infarcted brain region. The ischemic brain sections treated with OX6-conjugated SPIONs were scanned using our p-FMMD system, yielding 2D images on the basis of the nonlinear magnetic characteristics inherent in SPIONs. The p-FMMD signal images representing microglia activation show an infarct ratio of 44.6 ± 7.1% compared to the contralateral counterpart, which is smaller than observed by TTC (60.9 ± 4.9%) or magnetic resonance imaging (MRI, 65.7 ± 2.7%). Furthermore, we developed a 3D-rendering brain imaging process based on the 2D p-FMMD signal images. The 3D reconstructed model showed a decreased ratio of coincidence of the ischemic regions compared with MRI models. In this study, we successfully conducted a feasibility test on whether our p-FMMD technology, a technique for signaling and imaging based on the nonlinearity of SPIONs, can be used to visualize the ischemic brain region in real time by detecting activated microglia in an MCAO/R animal model. Therefore, our method might allow for a different approach to analyze the pathophysiology of ischemic stroke through molecular imaging. Furthermore, we propose that this magnetic particle imaging (MPI) technique that detects the nonlinear magnetization properties of SPIONs could be applied not only to a stroke model but also to various types of pathophysiological studies as a new bioimaging tool.

IntroductionPost-stroke dysphagia is common and associated with significant morbidity and mortality, rendering bedside screening of significant clinical importance. Using voice as a biomarker coupled with deep learning has the potential to improve patient access to screening and mitigate the subjectivity associated with detecting voice change, a component of several validated screening protocols.MethodsIn this single-center study, we developed a proof-of-concept model for automated dysphagia screening and evaluated the performance of this model on training and testing cohorts. Patients were admitted to a comprehensive stroke center, where primary English speakers could follow commands without significant aphasia and participated on a rolling basis. The primary outcome was classification either as a pass or fail equivalent using a dysphagia screening test as a label. Voice data was recorded from patients who spoke a standardized set of vowels, words, and sentences from the National Institute of Health Stroke Scale. Seventy patients were recruited and 68 were included in the analysis, with 40 in training and 28 in testing cohorts, respectively. Speech from patients was segmented into 1,579 audio clips, from which 6,655 Mel-spectrogram images were computed and used as inputs for deep-learning models (DenseNet and ConvNext, separately and together). Clip-level and participant-level swallowing status predictions were obtained through a voting method.ResultsThe models demonstrated clip-level dysphagia screening sensitivity of 71% and specificity of 77% (F1 = 0.73, AUC = 0.80 [95% CI: 0.78–0.82]). At the participant level, the sensitivity and specificity were 89 and 79%, respectively (F1 = 0.81, AUC = 0.91 [95% CI: 0.77–1.05]).DiscussionThis study is the first to demonstrate the feasibility of applying deep learning to classify vocalizations to detect post-stroke dysphagia. Our findings suggest potential for enhancing dysphagia screening in clinical settings. https://github.com/UofTNeurology/masa-opensource

Introduction Stroke code simulations have gained popularity as an educational model for neurology resident and fellow training in the diagnosis and management of hyperacute stroke. Previous simulations have used live patients or standardized patients as surrogates for learners to interact with in the simulated codes. While these provide high fidelity, there can be significant costs associated with the training and deployment of standardized patients, as well as potential for inconsistencies from encounter to encounter. A novel 3D virtual reality based simulator (Dancing Eyes LLC, Skaneateles, NY) aims to reduce the costs of running stroke code simulations while maintaining high fidelity and encounter consistency. It can also have the additional benefit of being utilized at the convenience of the trainee’s schedule, reducing logistical hurdles for scheduling and organizing simulations. Methods Neurology residents (who have previously experienced live simulation stroke codes with standardized patients) will undergo simulation encounters using the 3D virtual reality‐based simulator. We will enroll 20–25 residents at post graduate year levels (PGY) 2–4. Following the simulated encounter, a debriefing session is conducted for learners to review the case, share their experience, and provide additional feedback. A post‐simulation survey will be comnducted that solicits trainee experience with the VR simulator in defined domains such as comfort, ease of use, fidelity, and overall educational experience and value. Results The VR simulator has been designed to be worn over the face and can be adjusted for trainee comfort. The simulator integrates imaging, labs, the ability to use a virtual NIH‐stroke‐scale booklet, and other neurologic examination tools by virtually grabbing them or selecting them from a panel user interface. The simulated VR patient registers the trainee’s voice and shows the speech that was detected. It then attempts to answer the question or perform the issued command based on variables that have been pre‐programmed for the specific encounter/simulation. Trainees are able to perform a full NIH stroke scale assessment on the simulated patient. We aim to report the results of our study in time for the SVIN Annual Meeting/update deadline prior to the meeting. Conclusions Figure 1 shows a trainee using the VR simulator in a simulated stroke code encounter, as well as a rendering of the simulated patient. The VR simulator aims to serve as a high‐fidelity, low‐cost, convenient and consistent training modality for stroke code simulation and enhance trainees ability and comfort with diagnosis and management of hyperacute stroke.

Abstract Stroke significantly impacts the quality of life. However, the long-term cognitive evolution in stroke is poorly predictable at the individual level. There is an urgent need to better predict long-term symptoms based on acute clinical neuroimaging data. Previous works have demonstrated a strong relationship between the location of white matter disconnections and clinical symptoms. However, rendering the entire space of possible disconnection-deficit associations optimally surveyable will allow for a systematic association between brain disconnections and cognitive-behavioural measures at the individual level. Here we present the most comprehensive framework, a composite morphospace of white matter disconnections (disconnectome) to predict neuropsychological scores 1 year after stroke. Linking the latent disconnectome morphospace to neuropsychological outcomes yields biological insights that are available as the first comprehensive atlas of disconnectome-deficit relations across 86 scores—a Neuropsychological White Matter Atlas. Our novel predictive framework, the Disconnectome Symptoms Discoverer, achieved better predictivity performances than six other models, including functional disconnection, lesion topology and volume modelling. Out-of-sample prediction derived from this atlas presented a mean absolute error below 20% and allowed personalize neuropsychological predictions. Prediction on an external cohort achieved an R2 = 0.201 for semantic fluency. In addition, training and testing were replicated on two external cohorts achieving an R2 = 0.18 for visuospatial performance. This framework is available as an interactive web application (http://disconnectomestudio.bcblab.com) to provide the foundations for a new and practical approach to modelling cognition in stroke. We hope our atlas and web application will help to reduce the burden of cognitive deficits on patients, their families and wider society while also helping to tailor future personalized treatment programmes and discover new targets for treatments. We expect our framework’s range of assessments and predictive power to increase even further through future crowdsourcing.

Abstract Funding Acknowledgements Type of funding sources: None. Background/Introduction. Left atrial appendage (LAA) morphology assessed by contrast-enhanced computed tomography (CT) has been associated to the risk of cardioembolic stroke in non-valvular atrial fibrillation. Subsequent studies with the traditional LAA classification system (CS) into 4 morphologies (Chicken wing, Cauliflower, Cactus and Windsock) yielded mixed results in terms of reliability and stroke risk association. Recently, a simple LAA morphology CS (new-LAAcs) based on the LAA bend angle measurement has been suggested. Three-dimensional transesophageal echocardiography (3D TOE) quality imaging has been improved and new volume rendering modalities developed. Purpose. Aim of this study was to evaluate the accuracy and reliability of 2D and new 3D TOE rendering modalities compared to CT in assessing LAA morphology. We used and validated a new simple LAA morphology classification system (new-LAAcs) based on the LAA bend angle in contrast to the traditional CS. Methods. 50 consecutive patients who underwent both cardiac CT and TOE were enrolled. LAA morphology was assessed by three different TEE modalities: (1) 2D TOE inspective evaluation (2D TOE), (2) 3D TOE multiplanar reconstruction (3D TOE MPR) and (3) 3D TOE Philips TrueVue Glass rendering (3D TOE GLASS). We assessed TOE accuracy compared to CT by sensitivity, specificity, accuracy, and Cohen’s kappa. Two trained readers independently adjudicated LAA morphologies in the new-LAAcs and the inter-rater reliability was obtained by percentage agreement and Cohen’s kappa. The reliability of the new- vs. traditional-LAAcs was assessed by CT in terms of reliability rates and influence on LAA morphology prevalence. Results. CT and TOE imaging analyses were feasible in all patients. 2D TOE was fairly accurate in identifying LAA morphology (κ 0.38, p = 0.022) and had only moderate inter-rater (κ 0.46, p = 0.027) and substantial intra-rater (κ 0.62, p = 0.003) reliability rates. 3D TOE showed high validity: 3D TOE MPR had an almost perfect accuracy (κ 0.84, p < 0.001) and substantial (κ 0.77, p < 0.001) inter-rater reliability; 3D TOE GLASS substantial accuracy (κ 0.67, p < 0.001) and almost perfect (κ 0.82, p < 0.001) inter-rater reliability. Intra-rater agreement was almost perfect for both 3D TOE modalities (κ 0.84, p < 0.001). In the comparison among CS the traditional-LAAcs inter-rater reliability was moderate (κ 0.47, p < 0.001) and the intra-rater reliability substantial (κ 0.68, p < 0.001) while the new-LAAcs yielded an almost perfect reliability level (inter-rater κ 0.84, p < 0.001 and intra-rater κ 0.93, p < 0.001). With the traditional-LAAcs, the prevalence of CW LAA was 30 (60%), while with the new-LAAcs the prevalence of low-risk-LAA was 13 (26%), leading to classify 17 (57%) CW morphologies as high-risk-LAA. Conclusions. 3D TOE is an accurate, reliable, and feasible alternative to CT in assessing LAA morphology with the new-LAAcs. The new-LAAcs shows higher reliability rates than the traditional one. Abstract Figure. Abstract Figure.

Abstract Background This study aims to understand the disease burden of Atrial Fibrillation (AF) and how it is treated among older Australian women. Methods Data from the oldest cohort (born 1921-26) of the Australian Longitudinal Study of Women’s Health were linked to state based hospital data to identify AF and to Pharmaceutical Benefit Scheme data for medication details. Yearly prevalence and incidence of AF was calculated, followed by calculation of proportions for different medications received. Results A total of 6671 women were eligible for the analysis. About 1827 women from were identified as having AF between 2000-2015. Despite steady incidence, prevalence of AF increased from 2.7% (95%CI=1.6%-3.8%) when women were aged 74-79 years to 24.8% (95%CI=23.2%-26.4%) in 2015 when women were 89-94 years. About 10% of women with AF did not receive any treatment for AF and another 60% did not receive any prophylaxis for thromboembolism within 3 years of AF onset. More than three quarters of women with AF received a combination of medications. Rate control with Vitamin K Inhibitors and Rate control with Platelet Aggregation Inhibitors were the most common combinations. Conclusions Older women have high prevalence of AF. These women are undertreated for the prevention of the most common and disabling complication of AF, stroke. Key messages Prevalence of AF is increasing and women receive inadequate treatment rendering them at risk of serious complications like stroke. This results in reduced quality of life for patients as well as burdens the health care system.

Nanogels have come out as a great potential drug delivery platform due to its prominently high colloidal stability, high drug loading, core-shell structure, good permeation property and can be responsive to environmental stimuli. Such nanoscopic drug carriers have more excellent abilities over conventional nanomaterials for permeating to brain parenchyma in vitro and in vivo. Nanogel-based system can be nanoengineered to bypass physiological barriers via non-invasive treatment, rendering it a most suitable platform for the management of neurological conditions such as neurodegenerative disorders, brain tumors, epilepsy and ischemic stroke, etc. Therapeutics of central nervous system (CNS) diseases have shown marked limited site-specific delivery of CNS by the poor access of various drugs into the brain, due to the presences of the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB). Hence, the availability of therapeutics delivery strategies is considered as one of the most major challenges facing the treatment of CNS diseases. The primary objective of this review is to elaborate the newer advances of nanogel for CNS drugs delivery, discuss the early preclinical success in the field of nanogel technology and highlight different insights on its potential neurotoxicity.

Abstract Black phosphorus (BP), as a representative metal-free semiconductor, has been extensively explored. It has a higher drug loading capacity in comparison to conventional materials and also possesses excellent biocompatibility and biodegradability. Furthermore, BP nanosheets can enhance the permeability of the blood-brain barrier (BBB) upon near-infrared (NIR) irradiation, owing to their photothermal effect. However, the inherent instability of BP poses a significant limitation, highlighting the importance of surface modification to enhance its stability. Ischemic stroke (IS) is caused by the occlusion of blood vessels, and its treatment is challenging due to the hindrance caused by the BBB. Therefore, there is an urgent need to identify improved methods for bypassing the BBB for more efficient IS treatment. This research devised a novel drug delivery approach based on pterostilbene (Pte) supported by BP nanosheets, modified with polydopamine (PDA) to form BP-Pte@PDA. This system shows robust stability and traverses the BBB using effective photothermal mechanisms. This enables the release of Pte upon pH and NIR stimuli, offering potential therapeutic advantages for treating IS. In a middle cerebral artery occlusion (MCAO) mouse model, the BP-Pte@PDA delivery system significantly reduced infarct size, and brain water content, improved neurological deficits, reduced the TLR4 inflammatory factor expression, and inhibited cell apoptosis. In summary, the drug delivery system fabricated in this study thus demonstrated good stability, therapeutic efficacy, and biocompatibility, rendering it suitable for clinical application.

Abstract Objective: Diseases such as age-related macular degeneration and retinitis pigmentosa cause the degradation of the photoreceptor layer. One approach to restore vision is to electrically stimulate the surviving retinal ganglion cells with a microelectrode array such as epiretinal implants. Epiretinal implants are known to generate visible anisotropic shapes elongated along the axon fascicles of neighboring retinal ganglion cells. Recent work has demonstrated that to obtain isotropic pixel-like shapes, it is possible to map axon fascicles and avoid stimulating them by inactivating electrodes or lowering stimulation current levels. Avoiding axon fascicule stimulation aims to remove brushstroke-like shapes in favor of a more reduced set of pixel-like shapes. Approach: In this study, we propose the use of isotropic and anisotropic shapes to render intelligible images on the retina of a virtual patient in a reinforcement learning environment named rlretina. The environment formalizes the task as using brushstrokes in a stroke-based rendering task. Main Results: We train a deep reinforcement learning agent that learns to assemble isotropic and anisotropic shapes to form an image. We investigate which error-based or perception-based metrics are adequate to reward the agent. The agent is trained in a model-based data generation fashion using the psychophysically validated axon map model to render images as perceived by different virtual patients. We show that the agent can generate more intelligible images compared to the naive method in different virtual patients. Significance: This work shares a new way to address epiretinal stimulation that constitutes a first step towards improving visual acuity in artificially-restored vision using anisotropic phosphenes.

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Research Grants Committee of Hong Kong through the General Research Fund Introduction Patients with atrial fibrillation (AF) often play a passive role in the treatment decision-making process, rendering jeopardized health-related quality of life, suboptimal medication optimization and self-care. Purpose This study aimed to examine the effects of a Nurse-led Multicomponent Behavioral Activation (N-MBA) intervention on HRQoL, knowledge about AF, medication adherence and psychological distress among patients with AF. Methods This parallel two-arm randomized controlled trial recruited community-dwelling patients aged ≥65 years with a confirmed diagnosis of atrial fibrillation, moderate to high risk of stroke but not receiving oral anticoagulation. Participants were randomized in a 1:1 ratio to receive the N-MBA intervention or standard care. The 13-week intervention adopted a novel behavioral activation approach to equip AF patients as an active agent to manage the disease. It consisted of care components to prepare patients for shared decision-making by using a decision aid, an empowerment-based educational module covering relevant AF self-care topics and continuous support through telephone calls. A set of validated instruments was administered at baseline, immediate and 6 months post-intervention. Results A total of 252 participants were randomized to the intervention (n = 127) or control (n = 125) group. Compared with the control group, the intervention group showed greater improvements in HRQoL [β = 10.617, 95% confidence interval (CI) = 1.285 – 20.501, p = 0.023] and AF knowledge (β = 2.129, 95% CI =1.026 – 5.712, p <0.001) at immediate post-intervention. The effects on both outcomes sustained at 6-month follow-up time point. No significant between-group changes in medication adherence, anxiety and depression were detected. Participants in the intervention group were activated to raise their concerns about AF and its treatment with the attending doctors, and they perceived higher compatibility between patient and physician decisions of OAC use upon completion of the intervention. Conclusion The empowerment-based nurse-led intervention is effective at sustaining improvements in HRQoL, AF knowledge and treatment decision making in AF patients with moderate to high stroke risk. It does not increase their psychological distress.

Introduction: Patients with atrial fibrillation (AF) play a passive role in the treatment decision-making process, rendering suboptimal medication optimization and poor self-care. This pilot study aimed to examine the feasibility and preliminary effects of a nurse-led empowerment-based intervention among AF patients. Methods: This study comprised a pilot randomized controlled trial and an exploratory qualitative phase. AF patients who had moderate to high risk of stroke but not receiving oral anticoagulation were recruited. Participants (N = 40) were randomized in 1:1 ratio to receive the intervention or standard care. The 13-week intervention adopted a novel behavioral activation approach to equip AF patients as an active agent to manage the disease. It consisted of care components to prepare patients for shared decision-making by using a decision aid, an empowerment-based educational module covering relevant AF self-care topics and continuous support through telephone calls. Ten participants in the intervention group attended a qualitative interview to explore their engagement experience and perceived feasibility. Results: The intervention was highly feasible and participants gave excellent rating for the satisfaction survey. The overall attendance rate was 82.5%. Compared with the standard care group, the intervention group showed greater improvements in health-related quality of life (HRQoL) [β = -10.617, (95% CI = -20.350 - -0.885), p = 0.033] and AF knowledge [β = 1.950, (95% CI =1.026 - 2.874), p <0.001] at immediate post-intervention. The effects on both outcomes sustained at 6-month follow-up time point. No significant between-group changes in medication adherence, anxiety and depression were detected. Participants in the intervention group were activated to raise their concerns about AF and its treatment with the attending doctors. The qualitative data highlighted the uniqueness of the empowerment process of the intervention in improving their knowledge and self-care behaviors. Conclusions: The empowerment-based nurse-led intervention is highly feasible and acceptable for AF patients. It improved HRQoL, AF knowledge and treatment decision making in AF patients. It did not increase anxiety and depression.

Abstract Background and Aims As there is growing interest in the benefits of exercise training in chronic kidney disease (CKD), it is important to understand the utility of conventional exercise test parameters in quantifying the cardiopulmonary fitness of patients with CKD. Merely extrapolating information from studies of healthy volunteers and heart failure (HF) patients would not suffice. In the present study we evaluated one such parameter, the peak O2-pulse [the rate of peak O2 consumption (VO2max) to peak heart rate (HR)] which is widely used as a surrogate for peak stroke volume (SV) in HF. We tested the hypothesis that peak O2-pulse is a good surrogate marker for peak stroke volume in CKD. Method A cross sectional study of 70 asymptomatic male non-diabetic CKD patients [CKD stages 2-5 (pre dialysis)] without primary cardiac disease. Data from 35 healthy volunteers & 25 HF patients was used for comparison. Specialised cardiopulmonary exercise (CPX) test with CO2 rebreathing technique was utilised to measure peak cardiac output (Qt) and peak SV non-invasively. VO2max was simultaneously measured. Peak O2-pulse was calculated as VO2max/Peak HR. Peripheral O2 extraction [C(a-v)O2] was derived using Fick’s equation, VO2 = Qt x C(a-v)O2. Pearson’s correlation, univariate and multivariate analyses were applied. Results are presented as mean±SD. P<0.05 is considered as significant. Results CKD patients had a mean age of 48.4±12.6 years and a mean eGFR of 33.8±25.5 ml/min. Whereas there was a very strong correlation between peak O2-pulse and peak SV in HF (R2= 0.81), the correlation was less robust in CKD (R2 = 0.49) (Fig 1). On multivariate analysis, in HF, peak SV was the major determinant of O2 pulse (β=1.03). The β for peak C(a-v)O2 was 0.44, both P < 10-3. However, in CKD both peak SV (β =0.76, P<10-3) and peak C(a-v)O2 (β=0.70, P<10-3) were significant determinants of O2-pulse rendering O2-pulse a poor surrogate of SV in CKD. Conclusion Based on the above results we reject the hypothesis that peak O2-pulse is a good surrogate marker of peak SV in CKD. The results highlight the pitfalls in the application of conventional CPX parameters in evaluating cardiopulmonary fitness in CKD. In view of the unique pathophysiology of the uraemic state further CKD-specific studies evaluating the central and peripheral determinants of aerobic exercise capacity are required.

Majority of lower grade glioma (LGG) are located eloquently rendering surgical resection challenging. Aim of our study was to assess rate of permanent deficits and its predisposing risk factors. We retrieved 83 patients harboring an eloquently located LGGs from the prospective LoG-Glio Database. Patients without surgery or incomplete postoperative data were excluded. Sign rank test, explorative correlations by Spearman ρ and multivariable regression for new postoperative deficits were calculated. Eloquent region involved predominantly motor (45%) and language (40%). At first follow up after 3 months permanent neuro-logical deficits (NDs) were noted in 39%. Mild deficits remained in 29% and severe deficits in 10%. Complete tumor removal (CTR) was successfully in 62% of intended cases. Postoperative and 3-month follow up National Institute of Health Stroke Score (NIHSS) showed significantly lower values than preoperatively (p<0.001). 38% cases showed a decreased NIHSS at 3-month, while occurrence was only 14% at 9-12-month follow up. 6/7 patients with mild aphasia recovered after 9-12 months, while motor deficits present at 3-month follow up were persistent in majority of patients. Eastern oncology group functional status (ECOG) significantly decreased by surgery (p < 0.001) in 31% of cases. Between 3-month and 9-12-months follow up no significant improvement was seen. In the multivariable model CTR (p=0.019, OR 31.9), and ECOG>0 (p=0.021, OR 8.5) were independent predictors for permanent postoperative deficit according to NIHSS at 3-month according to multivariable regression model. Patients harboring eloquently located LGG are highly vulnerable for permanent deficits. Almost one third of patients have a permanent reduction of their functional status based on ECOG. Risk of an extended resection has to be balanced with the respective oncological benefit. Especially, patients with impaired pre-operative status are at risk for new permanent deficits. There is a relevant improvement of neurological symptoms in the first year after surgery, especially for patients with slight aphasia.

Neurorehabilitation research suggests that not only high training intensity, but also somatosensory information plays a fundamental role in the recovery of stroke patients. Yet, there is currently a lack of easy-to-use robotic solutions for sensorimotor hand rehabilitation. We addressed this shortcoming by developing a novel clinical-driven robotic hand rehabilitation device, which is capable of fine haptic rendering, and that supports physiological full flexion/extension of the fingers while offering an effortless setup. Our palmar design, based on a parallelogram coupled to a principal revolute joint, introduces the following novelties: (1) While allowing for an effortless installation of the user's hand, it offers large range of motion of the fingers (full extension to 180° flexion). (2) The kinematic design ensures that all fingers are supported through the full range of motion and that the little finger does not lose contact with the finger support in extension. (3) We took into consideration that a handle is usually comfortably grasped such that its longitudinal axis runs obliquely from the metacarpophalangeal joint of the index finger to the base of the hypothenar eminence. (4) The fingertip path was optimized to guarantee physiologically correct finger movements for a large variety of hand sizes. Moreover, the device possesses a high mechanical transparency, which was achieved using a backdrivable cable transmission. The transparency was further improved with the implementation of friction and gravity compensation. In a test with six healthy participants, the root mean square of the human-robot interaction force was found to remain as low as 1.37 N in a dynamic task. With its clinical-driven design and easy-to-use setup, our robotic device for hand sensorimotor rehabilitation has the potential for high clinical acceptance, applicability and effectiveness.

Abstract Background and purpose Cerebral ischemia‒reperfusion injury causes significant harm to human health and is a major contributor to stroke-related deaths worldwide. Current treatments are limited, and new, more effective prevention and treatment strategies that target multiple cell components are urgently needed. Leucine-rich alpha-2 glycoprotein 1 (Lrg1) appears to be associated with the progression of cerebral ischemia‒reperfusion injury, but the exact mechanism of it is unknown. Methods Wild-type (WT) and Lrg1 knockout (Lrg1−/−) mice were used to investigate the role of Lrg1 after cerebral ischemia‒reperfusion injury. The effects of Lrg1 knockout on brain infarct volume, blood‒brain barrier permeability, and neurological score (based on 2,3,5-triphenyl tetrazolium chloride, evans blue dye, hematoxylin, and eosin staining) were assessed. Single-cell RNA sequencing (scRNA-seq), immunofluorescence, and microvascular albumin leakage tests were utilized to investigate alterations in various cell components in brain tissue after Lrg1 knockout. Results Lrg1 expression was increased in various cell types of brain tissue after cerebral ischemia‒reperfusion injury. Lrg1 knockout reduced cerebral edema and infarct size and improved neurological function after cerebral ischemia‒reperfusion injury. Single-cell RNA sequencing analysis of WT and Lrg1−/− mouse brain tissues after cerebral ischemia‒reperfusion injury revealed that Lrg1 knockout enhances blood‒brain barrier (BBB) by upregulating claudin 11, integrin β5, protocadherin 9, and annexin A2. Lrg1 knockout also promoted an anti-inflammatory and tissue-repairing phenotype in microglia and macrophages while reducing neuron and oligodendrocyte cell death. Conclusions Our results has shown that Lrg1 mediates numerous pathological processes involved in cerebral ischemia‒reperfusion injury by altering the functional states of various cell types, thereby rendering it a promising therapeutic target for cerebral ischemia‒reperfusion injury.

BackgroundThe prevalence of obesity has increased significantly in recent decades. Today, it is estimated that more than one-third of the world’s population has overweight or obesity, rendering it one of the most significant global health concerns. This article provides a current estimate of the direct costs associated with managing overweight and obesity, including treatment of related complications, among adolescents (≥15 years) and adults in Switzerland.MethodsPrevalence of overweight and obesity based on the BMI reported in the 2017 Swiss Health Survey was extrapolated to 2021. Systematic literature searches were performed to identify treatment costs and epidemiological data of obesity-related complications and costs were extrapolated to 2021. Costing methodology was based on available source data for individual related complications. Treatment costs for complications attributable to overweight and obesity were estimated by applying their population attributable fraction (PAF).ResultsMore than 3.1 million inhabitants of Switzerland aged ≥15 years met the criteria for overweight or obesity in 2021. The prevalence of overweight increase over the past decades from 30.4% in 1992 to 41.9% in 2017 while prevalence of obesity doubled from 5.4 to 11.3%. Overall, the total attributable costs of overweight and obesity caused by seven assessed obesity-related complications (asthma, coronary heart disease, depression, diabetes mellitus, hypertension, osteoarthritis, and stroke) are estimated at CHF 3657–5208 million with most of the costs (97–98%) caused by the assessed obesity-related complications. Only 2–3% of the total costs were attributable to the combined direct management of overweight and obesity by bariatric surgery (CHF 83 million), pharmacological therapy (CHF 26 million) and dietary counseling (CHF 18 million).ConclusionOverweight and obesity impose a significant cost impact on the Swiss healthcare system, accounting for 4.2–6.1% of total healthcare expenditures in 2021. Notably, direct treatment of overweight and obesity accounts for only 0.08–0.18% of the total healthcare expenditures. The analysis also revealed a significant lack of available health economic evidence, necessitating the use of assumptions and approximations in this estimation. This is noteworthy, as respective data would be available in healthcare systems but are either unpublished or inaccessible.

Article Effect of Glucagon-like Peptide-1 Receptor Agonist on Cardiac Structure and Function in Patients with Heart Failure: A Systematic Review and Meta-analysis Xinyu Zhang 1, and Hongyuan Zhang 2, * 1 Division of Bioscience, University College London, London, UK 2 Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK * Correspondence: hongyuan.zhang-3@postgrad.manchester.ac.uk Received: 23 May 2023 Accepted: 8 August 2023 Abstract: Recent clinical trials have shown that glucagon-like peptide-1 receptor agonists (GLP-1RAs) yield positive effects on composite cardiovascular endpoints, rendering them potentially promising therapeutic agents for heart failure (HF). This study analysed the effect of GLP-1RAs on cardiac structure and function in HF patients. MethodsA comprehensive search was conducted across PubMed, Cochrane Library, Ovid Embase, Ovid Medline, and Web of Science databases, spanning from inception to August 1, 2022, to identify randomised controlled trials (RCTs) comparing alterations in cardiac structure and function in HF patients receiving GLP-1RAs or placebo. Cardiac structures were assessed through left ventricular end-systolic volume (LVESV), left ventricular end-diastolic volume (LVEDV), and left ventricular mass (LVM). Systolic function was evaluated using left ventricular ejection fraction (LVEF), stroke volume (SV), and global longitudinal strain (GLS). Diastolic function was assessed via the early to late diastolic filling velocity ratio (E/A ratio) and the early transmitral filling velocity to early diastolic mitral annular velocity ratio (E/e ratio). The I2 statistic was used to test heterogeneity. Pooled relative risks were calculated using random-effects models. Potential publication bias was assessed using the Cochrane Risk of Bias 2 tool. ResultsA total of 1,417 patients from 16 randomised placebo-controlled trials were enrolled in this meta-analysis. Among all HF patients, GLP-1RAs demonstrated improvement in diastolic function as indicated by E/A (MD = -0.15; 95% CI: -0.21 to -0.09; P < 0.00001; I2 = 43%) and E/e’ (MD = -0.82; 95% CI: -1.53 to -0.11; P = 0.02; I2= 62%). However, GLP-1RAs did not exhibit any improvement in cardiac structure and systolic function parameters for HF patients. ConclusionGLP-1RAs demonstrated potential for improving diastolic function in HF patients, but did not show any impact on systolic function and cardiac structure. Therefore, the application of GLP-1RAs should be based on the specific HF type and accompanying comorbidities.