"Soap-Bubble" visualization and quantitative analysis of 3D coronary magnetic resonance angiograms.

In order to compare coronary magnetic resonance angiography (MRA) data obtained with different scanning methodologies, adequate visualization and presentation of the coronary MRA data need to be ensured. Furthermore, an objective quantitative comparison between images acquired with different scanning methods is desirable. To address this need, a software tool ("Soap-Bubble") that facilitates visualization and quantitative comparison of 3D volume targeted coronary MRA data was developed. In the present implementation, the user interactively specifies a curved subvolume (enclosed in the 3D coronary MRA data set) that closely encompasses the coronary arterial segments. With a 3D Delaunay triangulation and a parallel projection, this enables the simultaneous display of multiple coronary segments in one 2D representation. For objective quantitative analysis, frequently explored quantitative parameters such as signal-to-noise ratio (SNR); contrast-to-noise ratio (CNR); and vessel length, sharpness, and diameter can be assessed. The present tool supports visualization and objective, quantitative comparisons of coronary MRA data obtained with different scanning methods. The first results obtained in healthy adults and in patients with coronary artery disease are presented.

Comparaison objective de systèmes d'imagerie conventionnelle et numérique en mammographie

L'objectif de ce travail est le développement d'une méthode de caractérisation objective de la qualité d'image s'appliquant à des systèmes de mammographie analogique, utilisant un couple écran-film comme détecteur, et numérique, basé sur une technologie semi-conductrice, ceci en vue de la comparaison de leurs performances. La méthode développée tient compte de la gamme dynamique du détecteur, de la détectabilité de structures de haut contraste, simulant des microcalcifications, et de structures de bas contraste, simulant des opacités (nodules tumoraux). La méthode prend également en considération le processus de visualisation de l'image, ainsi que la réponse de l'observateur. Pour réaliser ceci, un objet-test ayant des propriétés proches de celles d'un sein comprimé, composé de différents matériaux équivalents aux tissus, allant du glandulaire à l'adipeux, et comprenant des zones permettant la simulation de structures de haut et bas contraste, ainsi que la mesure de la résolution et celle du bruit, a été développé et testé. L'intégration du processus de visualisation a été réalisée en utilisant une caméra CCD mesurant directement les paramètres de qualité d'image, à partir de l'image de l'objet-test, dans une grandeur physique commune au système numérique et analogique, à savoir la luminance arrivant sur l'oeil de l'observateur. L'utilisation d'une grandeur synthétique intégrant dans un même temps, le contraste, le bruit et la résolution rend possible une comparaison objective entre les deux systèmes de mammographie. Un modèle mathématique, simulant la réponse d'un observateur et intégrant les paramètres de base de qualité d'image, a été utilisé pour calculer la détectabilité de structures de haut et bas contraste en fonction du type de tissu sur lequel celles-ci se trouvent. Les résultats obtenus montrent qu'à dose égale la détectabilité des structures est significativement plus élevée avec le système de mammographie numérique qu'avec le système analogique. Ceci est principalement lié au fait que le bruit du système numérique est plus faible que celui du système analogique. Les résultats montrent également que la méthodologie, visant à comparer des systèmes d'imagerie numérique et analogique en utilisant un objet-test à large gamme dynamique ainsi qu'une caméra, peut être appliquée à d'autres modalités radiologiques, ainsi qu'à une démarche d'optimisation des conditions de lecture des images.<br/><br/>The goal of this work was to develop a method to objectively compare the performance of a digital and a screen-film mammography system in terms of image quality and patient dose. We propose a method that takes into account the dynamic range of the image detector and the detection of high contrast (for microcalcifications) and low contrast (for masses or tumoral nodules) structures. The method also addresses the problems of image visualization and the observer response. A test object, designed to represent a compressed breast, was constructed from various tissue equivalent materials ranging from purely adipose to purely glandular composition. Different areas within the test object permitted the evaluation of low and high contrast detection, spatial resolution, and image noise. All the images (digital and conventional) were captured using a CCD camera to include the visualization process in the image quality assessment. In this way the luminance reaching the viewer?s eyes can be controlled for both kinds of images. A global quantity describing image contrast, spatial resolution and noise, and expressed in terms of luminance at the camera, can then be used to compare the two technologies objectively. The quantity used was a mathematical model observer that calculates the detectability of high and low contrast structures as a function of the background tissue. Our results show that for a given patient dose, the detection of high and low contrast structures is significantly better for the digital system than for the conventional screen-film system studied. This is mainly because the image noise is lower for the digital system than for the screen-film detector. The method of using a test object with a large dynamic range combined with a camera to compare conventional and digital imaging modalities can be applied to other radiological imaging techniques. In particular it could be used to optimize the process of radiographic film reading.

Points to consider for prioritizing clinical genetic testing services: a European consensus process oriented at accountability for reasonableness.

Given the cost constraints of the European health-care systems, criteria are needed to decide which genetic services to fund from the public budgets, if not all can be covered. To ensure that high-priority services are available equitably within and across the European countries, a shared set of prioritization criteria would be desirable. A decision process following the accountability for reasonableness framework was undertaken, including a multidisciplinary EuroGentest/PPPC-ESHG workshop to develop shared prioritization criteria. Resources are currently too limited to fund all the beneficial genetic testing services available in the next decade. Ethically and economically reflected prioritization criteria are needed. Prioritization should be based on considerations of medical benefit, health need and costs. Medical benefit includes evidence of benefit in terms of clinical benefit, benefit of information for important life decisions, benefit for other people apart from the person tested and the patient-specific likelihood of being affected by the condition tested for. It may be subject to a finite time window. Health need includes the severity of the condition tested for and its progression at the time of testing. Further discussion and better evidence is needed before clearly defined recommendations can be made or a prioritization algorithm proposed. To our knowledge, this is the first time a clinical society has initiated a decision process about health-care prioritization on a European level, following the principles of accountability for reasonableness. We provide points to consider to stimulate this debate across the EU and to serve as a reference for improving patient management.

Use of the dried blood spot sampling process coupled with fast gas chromatography and negative-ion chemical ionization tandem mass spectrometry: application to fluoxetine, norfluoxetine, reboxetine, and paroxetine analysis.

The objective of this work was to combine the advantages of the dried blood spot (DBS) sampling process with the highly sensitive and selective negative-ion chemical ionization tandem mass spectrometry (NICI-MS-MS) to analyze for recent antidepressants including fluoxetine, norfluoxetine, reboxetine, and paroxetine from micro whole blood samples (i.e., 10 microL). Before analysis, DBS samples were punched out, and antidepressants were simultaneously extracted and derivatized in a single step by use of pentafluoropropionic acid anhydride and 0.02% triethylamine in butyl chloride for 30 min at 60 degrees C under ultrasonication. Derivatives were then separated on a gas chromatograph coupled with a triple-quadrupole mass spectrometer operating in negative selected reaction monitoring mode for a total run time of 5 min. To establish the validity of the method, trueness, precision, and selectivity were determined on the basis of the guidelines of the "Société Française des Sciences et des Techniques Pharmaceutiques" (SFSTP). The assay was found to be linear in the concentration ranges 1 to 500 ng mL(-1) for fluoxetine and norfluoxetine and 20 to 500 ng mL(-1) for reboxetine and paroxetine. Despite the small sampling volume, the limit of detection was estimated at 20 pg mL(-1) for all the analytes. The stability of DBS was also evaluated at -20 degrees C, 4 degrees C, 25 degrees C, and 40 degrees C for up to 30 days. Furthermore, the method was successfully applied to a pharmacokinetic investigation performed on a healthy volunteer after oral administration of a single 40-mg dose of fluoxetine. Thus, this validated DBS method combines an extractive-derivative single step with a fast and sensitive GC-NICI-MS-MS technique. Using microliter blood samples, this procedure offers a patient-friendly tool in many biomedical fields such as checking treatment adherence, therapeutic drug monitoring, toxicological analyses, or pharmacokinetic studies.

Modelling the curing process in magneto-sensitive polymers: Rate-dependence and shrinkage

This paper deals with a phenomenologically motivated magneto-viscoelastic coupled finite strain framework for simulating the curing process of polymers under the application of a coupled magneto-mechanical road. Magneto-sensitive polymers are prepared by mixing micron-sized ferromagnetic particles in uncured polymers. Application of a magnetic field during the curing process causes the particles to align and form chain-like structures lending an overall anisotropy to the material. The polymer curing is a viscoelastic complex process where a transformation from fluid. to solid occurs in the course of time. During curing, volume shrinkage also occurs due to the packing of polymer chains by chemical reactions. Such reactions impart a continuous change of magneto-mechanical properties that can be modelled by an appropriate constitutive relation where the temporal evolution of material parameters is considered. To model the shrinkage during curing, a magnetic-induction-dependent approach is proposed which is based on a multiplicative decomposition of the deformation gradient into a mechanical and a magnetic-induction-dependent volume shrinkage part. The proposed model obeys the relevant laws of thermodynamics. Numerical examples, based on a generalised Mooney-Rivlin energy function, are presented to demonstrate the model capacity in the case of a magneto-viscoelastically coupled load.

Development of cardiovascular magnetic resonance imaging techniques for improved characterization of atherosclerotic disease

Atherosclerosis is a chronic cardiovascular disease that involves the thicken¬ing of the artery walls as well as the formation of plaques (lesions) causing the narrowing of the lumens, in vessels such as the aorta, the coronary and the carotid arteries. Magnetic resonance imaging (MRI) is a promising modality for the assessment of atherosclerosis, as it is a non-invasive and patient-friendly procedure that does not use ionizing radiation. MRI offers high soft tissue con¬trast already without the need of intravenous contrast media; while modifica¬tion of the MR pulse sequences allows for further adjustment of the contrast for specific diagnostic needs. As such, MRI can create angiographic images of the vessel lumens to assess stenoses at the late stage of the disease, as well as blood flow-suppressed images for the early investigation of the vessel wall and the characterization of the atherosclerotic plaques. However, despite the great technical progress that occurred over the past two decades, MRI is intrinsically a low sensitive technique and some limitations still exist in terms of accuracy and performance. A major challenge for coronary artery imaging is respiratory motion. State- of-the-art diaphragmatic navigators rely on an indirect measure of motion, per¬form a ID correction, and have long and unpredictable scan time. In response, self-navigation (SM) strategies have recently been introduced that offer 100% scan efficiency and increased ease of use. SN detects respiratory motion di¬rectly from the image data obtained at the level of the heart, and retrospectively corrects the same data before final image reconstruction. Thus, SN holds po-tential for multi-dimensional motion compensation. To this regard, this thesis presents novel SN methods that estimate 2D and 3D motion parameters from aliased sub-images that are obtained from the same raw data composing the final image. Combination of all corrected sub-images produces a final image with reduced motion artifacts for the visualization of the coronaries. The first study (section 2.2, 2D Self-Navigation with Compressed Sensing) consists of a method for 2D translational motion compensation. Here, the use of com- pressed sensing (CS) reconstruction is proposed and investigated to support motion detection by reducing aliasing artifacts. In healthy human subjects, CS demonstrated an improvement in motion detection accuracy with simula¬tions on in vivo data, while improved coronary artery visualization was demon¬strated on in vivo free-breathing acquisitions. However, the motion of the heart induced by respiration has been shown to occur in three dimensions and to be more complex than a simple translation. Therefore, the second study (section 2.3,3D Self-Navigation) consists of a method for 3D affine motion correction rather than 2D only. Here, different techniques were adopted to reduce background signal contribution in respiratory motion tracking, as this can be adversely affected by the static tissue that surrounds the heart. The proposed method demonstrated to improve conspicuity and vi¬sualization of coronary arteries in healthy and cardiovascular disease patient cohorts in comparison to a conventional ID SN method. In the third study (section 2.4, 3D Self-Navigation with Compressed Sensing), the same tracking methods were used to obtain sub-images sorted according to the respiratory position. Then, instead of motion correction, a compressed sensing reconstruction was performed on all sorted sub-image data. This process ex¬ploits the consistency of the sorted data to reduce aliasing artifacts such that the sub-image corresponding to the end-expiratory phase can directly be used to visualize the coronaries. In a healthy volunteer cohort, this strategy improved conspicuity and visualization of the coronary arteries when compared to a con¬ventional ID SN method. For the visualization of the vessel wall and atherosclerotic plaques, the state- of-the-art dual inversion recovery (DIR) technique is able to suppress the signal coming from flowing blood and provide positive wall-lumen contrast. How¬ever, optimal contrast may be difficult to obtain and is subject to RR variability. Furthermore, DIR imaging is time-inefficient and multislice acquisitions may lead to prolonged scanning times. In response and as a fourth study of this thesis (chapter 3, Vessel Wall MRI of the Carotid Arteries), a phase-sensitive DIR method has been implemented and tested in the carotid arteries of a healthy volunteer cohort. By exploiting the phase information of images acquired after DIR, the proposed phase-sensitive method enhances wall-lumen contrast while widens the window of opportunity for image acquisition. As a result, a 3-fold increase in volumetric coverage is obtained at no extra cost in scanning time, while image quality is improved. In conclusion, this thesis presented novel methods to address some of the main challenges for MRI of atherosclerosis: the suppression of motion and flow artifacts for improved visualization of vessel lumens, walls and plaques. Such methods showed to significantly improve image quality in human healthy sub¬jects, as well as scan efficiency and ease-of-use of MRI. Extensive validation is now warranted in patient populations to ascertain their diagnostic perfor¬mance. Eventually, these methods may bring the use of atherosclerosis MRI closer to the clinical practice. Résumé L'athérosclérose est une maladie cardiovasculaire chronique qui implique le épaississement de la paroi des artères, ainsi que la formation de plaques (lé¬sions) provoquant le rétrécissement des lumières, dans des vaisseaux tels que l'aorte, les coronaires et les artères carotides. L'imagerie par résonance magné¬tique (IRM) est une modalité prometteuse pour l'évaluation de l'athérosclérose, car il s'agit d'une procédure non-invasive et conviviale pour les patients, qui n'utilise pas des rayonnements ionisants. L'IRM offre un contraste des tissus mous très élevé sans avoir besoin de médias de contraste intraveineux, tan¬dis que la modification des séquences d'impulsions de RM permet en outre le réglage du contraste pour des besoins diagnostiques spécifiques. À ce titre, l'IRM peut créer des images angiographiques des lumières des vaisseaux pour évaluer les sténoses à la fin du stade de la maladie, ainsi que des images avec suppression du flux sanguin pour une première enquête des parois des vais¬seaux et une caractérisation des plaques d'athérosclérose. Cependant, malgré les grands progrès techniques qui ont eu lieu au cours des deux dernières dé¬cennies, l'IRM est une technique peu sensible et certaines limitations existent encore en termes de précision et de performance. Un des principaux défis pour l'imagerie de l'artère coronaire est le mou¬vement respiratoire. Les navigateurs diaphragmatiques de pointe comptent sur une mesure indirecte de mouvement, effectuent une correction 1D, et ont un temps d'acquisition long et imprévisible. En réponse, les stratégies d'auto- navigation (self-navigation: SN) ont été introduites récemment et offrent 100% d'efficacité d'acquisition et une meilleure facilité d'utilisation. Les SN détectent le mouvement respiratoire directement à partir des données brutes de l'image obtenue au niveau du coeur, et rétrospectivement corrigent ces mêmes données avant la reconstruction finale de l'image. Ainsi, les SN détiennent un poten¬tiel pour une compensation multidimensionnelle du mouvement. A cet égard, cette thèse présente de nouvelles méthodes SN qui estiment les paramètres de mouvement 2D et 3D à partir de sous-images qui sont obtenues à partir des mêmes données brutes qui composent l'image finale. La combinaison de toutes les sous-images corrigées produit une image finale pour la visualisation des coronaires ou les artefacts du mouvement sont réduits. La première étude (section 2.2,2D Self-Navigation with Compressed Sensing) traite d'une méthode pour une compensation 2D de mouvement de translation. Ici, on étudie l'utilisation de la reconstruction d'acquisition comprimée (compressed sensing: CS) pour soutenir la détection de mouvement en réduisant les artefacts de sous-échantillonnage. Chez des sujets humains sains, CS a démontré une amélioration de la précision de la détection de mouvement avec des simula¬tions sur des données in vivo, tandis que la visualisation de l'artère coronaire sur des acquisitions de respiration libre in vivo a aussi été améliorée. Pourtant, le mouvement du coeur induite par la respiration se produit en trois dimensions et il est plus complexe qu'un simple déplacement. Par conséquent, la deuxième étude (section 2.3, 3D Self-Navigation) traite d'une méthode de cor¬rection du mouvement 3D plutôt que 2D uniquement. Ici, différentes tech¬niques ont été adoptées pour réduire la contribution du signal du fond dans le suivi de mouvement respiratoire, qui peut être influencé négativement par le tissu statique qui entoure le coeur. La méthode proposée a démontré une amélioration, par rapport à la procédure classique SN de correction 1D, de la visualisation des artères coronaires dans le groupe de sujets sains et des pa¬tients avec maladies cardio-vasculaires. Dans la troisième étude (section 2.4,3D Self-Navigation with Compressed Sensing), les mêmes méthodes de suivi ont été utilisées pour obtenir des sous-images triées selon la position respiratoire. Au lieu de la correction du mouvement, une reconstruction de CS a été réalisée sur toutes les sous-images triées. Cette procédure exploite la cohérence des données pour réduire les artefacts de sous- échantillonnage de telle sorte que la sous-image correspondant à la phase de fin d'expiration peut directement être utilisée pour visualiser les coronaires. Dans un échantillon de volontaires en bonne santé, cette stratégie a amélioré la netteté et la visualisation des artères coronaires par rapport à une méthode classique SN ID. Pour la visualisation des parois des vaisseaux et de plaques d'athérosclérose, la technique de pointe avec double récupération d'inversion (DIR) est capa¬ble de supprimer le signal provenant du sang et de fournir un contraste posi¬tif entre la paroi et la lumière. Pourtant, il est difficile d'obtenir un contraste optimal car cela est soumis à la variabilité du rythme cardiaque. Par ailleurs, l'imagerie DIR est inefficace du point de vue du temps et les acquisitions "mul- tislice" peuvent conduire à des temps de scan prolongés. En réponse à ce prob¬lème et comme quatrième étude de cette thèse (chapitre 3, Vessel Wall MRI of the Carotid Arteries), une méthode de DIR phase-sensitive a été implémenté et testé

A multistep process of cancer associated fibroblasts determination under CSL-p53 control

Stromal fibroblast senescence has been linked to the aging-associated increase of tumors. However, in epithelial cancer, density and proliferation of cancer associated fibroblasts (CAF) are frequently increased, rather than decreased. We previously showed that genetic deletion or down-modulation of the canonical Notch effector CSL/RBP-JK in dermal fibroblasts is sufficient for CAF activation with consequent development of keratinocyte-derived tumors. We show here that CSL silencing induces senescence of primary fibroblasts from dermis, oral mucosa, breast and lung. CSL functions in these cells as direct repressor of multiple senescence- and CAF-effector genes. It also physically interacts with p53, repressing its activity. CSL is down-modulated in stromal fibroblasts of premalignant skin actinic keratosis lesions and squamous cell carcinomas (SCC), while p53 gene expression and function is down-modulated only in the latter, with paracrine influences of incipient cancer cells as a likely culprit. Concomitant loss of CSL and p53 overcomes fibroblast senescence, enhances CAF effector gene expression and promotes stromal and cancer cell expansion. The findings support a CAF activation/stromal co-evolution model under convergent CSL/p53 control of likely clinical relevance.

A statistical shape model of the human second cervical vertebra.

PURPOSE: Statistical shape and appearance models play an important role in reducing the segmentation processing time of a vertebra and in improving results for 3D model development. Here, we describe the different steps in generating a statistical shape model (SSM) of the second cervical vertebra (C2) and provide the shape model for general use by the scientific community. The main difficulties in its construction are the morphological complexity of the C2 and its variability in the population. METHODS: The input dataset is composed of manually segmented anonymized patient computerized tomography (CT) scans. The alignment of the different datasets is done with the procrustes alignment on surface models, and then, the registration is cast as a model-fitting problem using a Gaussian process. A principal component analysis (PCA)-based model is generated which includes the variability of the C2. RESULTS: The SSM was generated using 92 CT scans. The resulting SSM was evaluated for specificity, compactness and generalization ability. The SSM of the C2 is freely available to the scientific community in Slicer (an open source software for image analysis and scientific visualization) with a module created to visualize the SSM using Statismo, a framework for statistical shape modeling. CONCLUSION: The SSM of the vertebra allows the shape variability of the C2 to be represented. Moreover, the SSM will enable semi-automatic segmentation and 3D model generation of the vertebra, which would greatly benefit surgery planning.

Identification and visualization of multidimensional antigen-specific T-cell populations in polychromatic cytometry data.

An important aspect of immune monitoring for vaccine development, clinical trials, and research is the detection, measurement, and comparison of antigen-specific T-cells from subject samples under different conditions. Antigen-specific T-cells compose a very small fraction of total T-cells. Developments in cytometry technology over the past five years have enabled the measurement of single-cells in a multivariate and high-throughput manner. This growth in both dimensionality and quantity of data continues to pose a challenge for effective identification and visualization of rare cell subsets, such as antigen-specific T-cells. Dimension reduction and feature extraction play pivotal role in both identifying and visualizing cell populations of interest in large, multi-dimensional cytometry datasets. However, the automated identification and visualization of rare, high-dimensional cell subsets remains challenging. Here we demonstrate how a systematic and integrated approach combining targeted feature extraction with dimension reduction can be used to identify and visualize biological differences in rare, antigen-specific cell populations. By using OpenCyto to perform semi-automated gating and features extraction of flow cytometry data, followed by dimensionality reduction with t-SNE we are able to identify polyfunctional subpopulations of antigen-specific T-cells and visualize treatment-specific differences between them.