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Recognition memory for details of musical phrases (discrimination between targets and similar lures) improves for up to 15 s following the presentation of a target, during continuous listening to the ongoing piece. This is attributable to binding of stimulus features during that time interval. The ongoing-listening paradigm is an ecologically valid approach for investigating short-term memory, but previous studies made use of relatively mechanical MIDI-produced stimuli. The present study assessed whether expressive performances would modulate the previously reported finding. Given that expressive performances introduced slight differences between initially presented targets and their target-test items, expressive performance could make the task more difficult overall than did the previously used mechanical renderings. However, results revealed an even stronger improvement for the expressive pieces than for the mechanical pieces. The pattern of results was observed for participants varying in their level of musical experience, though the difference between expressive and mechanical conditions was more pronounced for the less-experienced participants. Overall, our study showed that the memory improvement phenomenon extends to more realistic musical material, which includes expressive timing characteristics of live performance.

We report key elements and figures related to the proceedings of the 2020 edition of the XXIVth ISPRS Congress. The COVID-19 pandemic causes global travel challenges and restrictions for the full year 2020. Consequently, the Congress planned in June 2020 in Nice (France) was postponed to July 2021. Papers were already submitted and the review process was almost complete. Thus, it has been decided to achieve the publication of the proceedings of these papers under the label “2020 Edition”. The authors of published papers have the opportunity to present their work during a Virtual Event (31 August – 2 September 2020), while the papers of the 2021 edition will be presented during the (physical) Congress in July 2021.

Our study aims to reconstruct the palaeogeography of the northern part of the Lesser Antilles in order to analyse whether emerged areas might have existed during the Cenozoic, favouring terrestrial faunal dispersals between South America and the Greater Antilles along the present-day Lesser Antilles arc. The stratigraphy and depositional environments of the islands of Anguilla, St Martin, Tintamarre, St Barthélemy, Barbuda and Antigua are reviewed in association with multichannel reflection seismic data acquired offshore since the 80's in the Saba, Anguilla and Antigua Banks and in the Kalinago Basin, including the most recent academic and industrial surveys. Seven seismic megasequences and seven regional unconformities are defined, and calibrated from deep wells on the Saba Bank and various dredges performed during marine cruises since the 70's in the vicinity of the islands. Onshore and offshore correlations allow us to depict an updated and detailed sedimentary organisation of the northern part of the Lesser Antilles from the late Eocene to the late Pleistocene. Paleogeographic reconstructions reveal sequences of uplift and emergence across hundredswide areas during the late Eocene, the late Oligocene, the early middle-Miocene and the latest Miocene-earliest Pliocene, interspersed by drowning episodes. The ∼200 km-long and ∼20 km-wide Kalinago Basin opened as an intra-arc basin during the late Eocene - early Oligocene. These periods of emergence may have favoured the existence of episodic mega-islands and transient terrestrial connections between the Greater Antilles, the Lesser Antilles and the northern part of the Aves Ridge (Saba Bank). During the Pleistocene, archipelagos and mega-islands formed repeatedly during glacial maximum episodes.

Alterations in the voltage-gated sodium channel Nav.1.1 are implicated in various neurological disorders, including epilepsy, Alzheimer’s disease, and autism spectrum disorders. Previous studies suggest that the reduction of Nav1.1 expression leads to a decrease of fast spiking activity in inhibitory neurons. Because interneurons (INs) play a critical role in the temporal organization of neuronal discharge, we hypothesize that Nav1.1 dysfunction will negatively impact neuronal coordination in vivo. Using shRNA interference, we induced a focal Nav1.1 knock-down (KD) in the dorsal region of the right hippocampus of adult rats. Focal, unilateral Nav1.1 KD decreases the performance in a spatial novelty recognition task and the firing rate in INs, but not in pyramidal cells. It reduced theta/gamma coupling of hippocampal oscillations and induced a shift in pyramidal cell theta phase preference. Nav1.1 KD degraded spatial accuracy and temporal coding properties of place cells, such as theta phase precession and compression of ongoing sequences. Aken together, these data demonstrate that a deficit in Nav1.1 alters the temporal coordination of neuronal firing in CA1 and impairs behaviors that rely on the integrity of this network. They highlight the potential contribution of local inhibition in neuronal coordination and its impact on behavior in pathological conditions.

The development history of an oligo-mesophotic, early Miocene, isolated carbonate system (>160 m in thickness), forming the uppermost part of the Oligo-Miocene Yadana buildup (northern Andaman Sea), has been evidenced from the integration of sedimentological core studies from 4 wells (cumulated core length: 343 m), well correlations, seismic interpretation and analysis of the ecological requirements of the main skeletal components. Three types of carbonate factory operated on the top of the platform, depending on water-depth, turbidity and nutrient level: (1) a scleractinian factory developing under mesophotic conditions during periods of high particulate organic matter supplies, (2) an echinodermal factory occupying dysphotic to aphotic area of the platform coevally with the scleractinian factory, (3) a large benthic foraminiferal-coralline algal factories prevailing under oligo-mesophotic and oligo-mesotrophic conditions. The limited lateral changes in facies between wells, together with the seismic expression of the Yadana buildup, suggest deposition on a flat-topped shelf. Carbonate production and accumulation on the Yadana platform was mainly controlled by light penetration, nutrient content and hydrodynamic conditions. Scleractinian-rich facies resulted from transport of coral pieces derived from mesophotic environments (mounds?) and deposited in deeper, low light , mud-rich environments in which lived abundant communities of suspension feeders such as ophiuroids. Changes in monsoonal intensity, terrestrial runoff from the Irrawaddy River, upwelling currents and internal waves activity during the early Miocene are likely responsible for significant variations in water turbidity and nutrient concentration in the Andaman Sea, thus promoting the development of an oligo-mesophotic, incipiently drowned platform.

Goal: This manuscript evaluates atrioventric-ular valve regurgitation (AVVR) in babies born with an already very challenging heart condition, i.e., with single ventricle physiology. Although the second surgery that single ventricle patients undergo is thought to decrease AVVR, there is much controversy in the clinical literature about AVVR treatment. Methods: The effect of AVVR on Stage 1 haemodynamics and resulting acute changes from conversion to Stage 2 circulation in single ventricle patients are analyzed through lumped parameter models. Several degrees of AVVR severity are analyzed, for two types of valve regurgitation: incomplete leaflet closure and valve prolapse. Results: The models show that increasing AVVR in Stage 1 induces the following effects: first, higher stroke volume and associated decrease in ventricular end-systolic volume; second, increase in atrial volumes with V-loop enlargement in pressure-volume curves; third, pulmonary venous hypertension. The Stage 2 surgery results in volume unloading of the ventricle, thereby, driving a decrease in AVVR. However, this effect is offset by an increase in ventricular pressures resulting in a net increase in regurgitation fraction (RF) of approximately 0.1 (for example, in severe AVVR, the preoperative RF increases from $\sim$ 60% to $\sim$ 70% postoperatively). Moreover, despite some improvements to sarcomere function early after Stage 2 surgery, it may deteriorate in cases of severe AVVR. Conclusion: In patients with moderate to severe AVVR, restoration of atrioventricular valve competence prior to, or at the time of, Stage 2 surgery would likely lead to improved haemodynamics and clinical outcome as the models suggest that uncorrected AVVR can worsen across Stage 2 surgery. This was found to be independent of the AVVR degree and mechanisms.

International audience; The clinical application of advanced next-generation sequencing technologies is increasingly uncovering novel classes of mutations that may serve as potential targets for precision medicine therapeutics. Here, we show that a deep intronic splice defect in the COL6A1 gene, originally discovered by applying muscle RNA sequencing in patients with clinical findings of collagen VI-related dystrophy (COL6-RD), inserts an in-frame pseudoexon into COL6A1 mRNA, encodes a mutant collagen a1(VI) protein that exerts a dominant-negative effect on collagen VI matrix assembly, and provides a unique opportunity for splice-correction approaches aimed at restoring normal gene expression. Using splicemodulating antisense oligomers, we efficiently skipped the pseudoexon in patient-derived fibroblast cultures and restored a wild-type matrix. Similarly, we used CRISPR/Cas9 to precisely delete an intronic sequence containing the pseudoexon and efficiently abolish its inclusion while preserving wild-type splicing. Considering that this splice defect is emerging as one of the single most frequent mutations in COL6-RD, the design of specific and effective splice-correction therapies offers a promising path for clinical translation.

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International audience; Today's growing medical image databases call for novel processing tools to structure the bulk of data and extract clinically relevant information. Unsupervised hierarchical clustering may reveal clusters within anatomical shape data of patient populations as required for modern Precision Medicine strategies. Few studies have applied hierarchical clustering techniques to three-dimensional patient shape data and results depend heavily on the chosen clustering distance metrics and linkage functions. In this study, we sought to assess clustering classification performance of various distance/linkage combinations and of different types of input data to obtain clinically meaningful shape clusters. Methods: We present a processing pipeline combining automatic segmentation, statistical shape modelling and agglomerative hierarchical clustering to automatically subdivide a set of 60 aortic arch anatomical models into healthy controls, two groups affected by congenital heart disease, and their respective subgroups as defined by clinical diagnosis. Results were compared with traditional morphometrics and principal component analysis of shape features. Results: Our pipeline achieved automatic division of input shape data according to primary clinical diagnosis with high F-score (0.902±0.042) and Matthews Correlation Coefficient (0.851±0.064) using the Correlation/Weighted distance/linkage combination. Meaningful subgroups within the three patient groups were obtained and benchmark scores for automatic segmentation and classification performance are reported. Conclusion: Clustering results vary depending on the distance/linkage combination used to divide the data. Yet, clinically relevant shape clusters and subgroups could be found with high specificity and low misclassification rates. Significance: Detecting disease-specific clusters within medical image data could improve image-based risk assessment, treatment planning and medical device development in complex disease.

Purpose Spring-assisted cranioplasty is performed to correct the long and narrow head shape of children with sagittal synostosis. Such corrective surgery involves osteotomies and the placement of spring-like distractors, which gradually expand to widen the skull until removal about 4 months later. Due to its dynamic nature, associations between surgical parameters and post-operative 3D head shape features are difficult to comprehend. The current study aimed at applying population-based statistical shape modelling to gain insight into how the choice of surgical parameters such as craniotomy size and spring positioning affects post-surgical head shape. Methods Twenty consecutive patients with sagittal synostosis who underwent spring-assisted cranioplasty at Great Ormond Street Hospital for Children (London, UK) were prospectively recruited. Using a nonparametric statistical modelling technique based on mathematical currents, a 3D head shape template was computed from surface head scans of sagittal patients after spring removal. Partial least squares (PLS) regression was employed to quantify and visualise trends of localised head shape changes associated with the surgical parameters recorded during spring insertion: anterior–posterior and lateral craniotomy dimensions, anterior spring position and distance between anterior and posterior springs. Results Bivariate correlations between surgical parameters and corresponding PLS shape vectors demonstrated that anterior–posterior (Pearson’s \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$r=0.64, p=0.002$$\end{document}r=0.64,p=0.002) and lateral craniotomy dimensions (Spearman’s \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\rho =0.67, p

International audience; Personalised 3D modelling of the heart is of increasing interest in order to better characterise pathologies and predict evolution. The personalisation consists in estimating the parameter values of an electromechanical model in order to reproduce the observed cardiac motion. However, the number of parameters in these models can be high and their estimation may not be unique. This variability can be an obstacle to further analyse the estimated parameters and for their clinical interpretation. In this paper we present a method to perform consistent estimations of electromechanical parameters with prior probabilities on the estimated values, which we apply on a large database of 84 different heartbeats. We show that the use of priors reduces considerably the variance in the estimated parameters, enabling better conditioning of the parameters for further analysis of the cardiac function. This is demonstrated by the application to longitudinal data of paediatric cardiomyopathies, where the estimated parameters provide additional information on the pathology and its evolution.

International audience; Inverse problems in cardiovascular modelling have become increasingly important to assess each patient individually. These problems entail estimation of patient-specific model parameters from uncertain measurements acquired in the clinic. In recent years, the method of data-assimilation, especially the unscented Kalman filter, has gained popularity to address computational efficiency and uncertainty consideration in such problems. This work highlights and presents solutions to several challenges of this method pertinent to models of cardiovascular haemodynamics. These include methods to a) avoid ill-conditioning of covariance matrix; b) handle a variety of measurement types; c) include a variety of prior knowledge in the method; and d) incorporate measurements acquired at different heart-rates, a common situation in the clinic where patient-state differs between various clinical acquisitions. Results are presented for two patient-specific cases of congenital heart disease. To illustrate and validate data-assimilation with measurements at different heart-rates, results are presented on synthetic data-set and on a patient-specific case with heart valve regurgitation. It is shown that the new method significantly improves the agreement between model predictions and measurements. The developed methods can be readily applied to other pathophysiologies and extended to dynamical systems which exhibit different responses under different sets of known parameters or different sets of inputs (such as forcing/excitation frequencies).

International audience; A closed-loop lumped parameter model of blood circulation is considered for single-ventricle shunt physiology. Its parameters are estimated by an inverse problem based on patient-specific haemodynamics measurements. As opposed to a black-box approach, maximizing the number of parameters that are related to physically measurable quantities motivates the present model. Heart chambers are described by a single-fibre mechanics model, and valve function is modelled with smooth opening and closure. A model for valve prolapse leading to valve regurgitation is proposed. The method of data assimilation, in particular the unscented Kalman filter, is used to estimate the model parameters from time-varying clinical measurements. This method takes into account both the uncertainty in prior knowledge related to the parameters and the uncertainty associated with the clinical measurements. Two patient-specific cases – one without regurgitation and one with atrioventricular valve regurgitation – are presented. Pulmonary and systemic circulation parameters are successfully estimated, without assumptions on their relationships. Parameters governing the behaviour of heart chambers and valves are either fixed based on biomechanics, or estimated. Results of the inverse problem are validated qualitatively through clinical measurements or clinical estimates that were not included in the parameter estimation procedure. The model and the estimation method are shown to successfully capture patient-specific clinical observations, even with regurgitation, such as double peaked nature of valvular flows and anomalies in electrocardiogram readings. Lastly, biomechanical implications of the results are discussed.

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International audience; A statistical shape modelling framework to extract 3D shape biomarkers from medical imaging data: assessing arch morphology of repaired coarctation of the aorta Abstract Background: Medical image analysis in clinical practice is commonly carried out on 2D image data, without fully exploiting the detailed 3D anatomical information that is provided by modern non-invasive medical imaging techniques. In this paper, a statistical shape analysis method is presented, which enables the extraction of 3D anatomical shape features from cardiovascular magnetic resonance (CMR) image data, with no need for manual landmarking. The method was applied to repaired aortic coarctation arches that present complex shapes, with the aim of capturing shape features as biomarkers of potential functional relevance. The method is presented from the user-perspective and is evaluated by comparing results with traditional morphometric measurements. Methods: Steps required to set up the statistical shape modelling analyses, from pre-processing of the CMR images to parameter setting and strategies to account for size differences and outliers, are described in detail. The anatomical mean shape of 20 aortic arches post-aortic coarctation repair (CoA) was computed based on surface models reconstructed from CMR data. By analysing transformations that deform the mean shape towards each of the individual patient's anatomy, shape patterns related to differences in body surface area (BSA) and ejection fraction (EF) were extracted. The resulting shape vectors, describing shape features in 3D, were compared with traditionally measured 2D and 3D morphometric parameters. Results: The computed 3D mean shape was close to population mean values of geometric shape descriptors and visually integrated characteristic shape features associated with our population of CoA shapes. After removing size effects due to differences in body surface area (BSA) between patients, distinct 3D shape features of the aortic arch correlated significantly with EF (r = 0.521, p = .022) and were well in agreement with trends as shown by traditional shape descriptors. Conclusions: The suggested method has the potential to discover previously unknown 3D shape biomarkers from medical imaging data. Thus, it could contribute to improving diagnosis and risk stratification in complex cardiac disease.

BACKGROUND: Aortic arch reconstruction after hypoplastic left heart syndrome (HLHS) palliation can vary widely in shape and dimensions between patients. Arch morphology alone may affect cardiac function and outcome. We sought to uncover the relationship of arch three-dimensional shape features with functional and short-term outcome data after total cavopulmonary connection (TCPC).METHODS: Aortic arch shape models of 37 patients with HLHS (age, 2.89 ± 0.99 years) were reconstructed from magnetic resonance data before TCPC completion. A novel, validated statistical shape analysis method was used to compute a three-dimensional anatomic mean shape from the cohort and calculate the deformation vectors of the mean shape toward each patient's specific anatomy. From these deformations, three-dimensional shape features most related to ventricular ejection fraction, indexed end-diastolic volume, and superior cavopulmonary pressure were extracted by partial least-square regression analysis. Shape patterns relating to intensive care unit and hospital lengths of stay after TCPC were assessed.RESULTS: Distinct deformation patterns, which result in an acutely mismatched aortic root and ascending aorta, and a gothic-like transverse arch, correlated with increased indexed end-diastolic volume and higher superior cavopulmonary pressure but not with ejection fraction. Specific arch morphology with pronounced transverse arch and descending aorta mismatch also correlated with longer intensive care unit and hospital lengths of stay after TCPC completion.CONCLUSIONS: Independent of hemodynamically important arch obstruction, altered aortic morphology in HLHS patients appears to have important associations with higher superior cavopulmonary pressure and with short-term outcomes after TCPC completion as highlighted by statistical shape analysis, which could act as adjunct to risk assessment in HLHS.

International audience; Primary microcephaly is a neurodevelopmental disorder that is caused by a reduction in brain size as a result of defects in the proliferation of neural progenitor cells during development. Mutations in genes encoding proteins that localize to the mitotic spindle and centrosomes have been implicated in the pathogenicity of primary microcephaly. In contrast, the contractile ring and midbody required for cytokinesis, the final stage of mitosis, have not previously been implicated by human genetics in the molecular mechanisms of this phenotype. Citron kinase (CIT) is a multi-domain protein that localizes to the cleavage furrow and midbody of mitotic cells, where it is required for the completion of cytokinesis. Rodent models of Cit deficiency highlighted the role of this gene in neurogenesis and microcephaly over a decade ago. Here, we identify recessively inherited pathogenic variants in CIT as the genetic basis of severe microcephaly and neonatal death. We present postmortem data showing that CIT is critical to building a normally sized human brain. Consistent with cytokinesis defects attributed to CIT, multinucleated neurons were observed throughout the cerebral cortex and cerebellum of an affected proband, expanding our understanding of mechanisms attributed to primary microcephaly.

Highlights • This paper presents a voxelwise atlas rating approach for computer-aided diagnosis. • The method relies on multiple atlas databases, but does not require annotated images. • The method reports an accuracy of 97.3%, which is higher than other state-of-the-art methods., Graphical abstract, Atlas-based analysis methods rely on the morphological similarity between the atlas and target images, and on the availability of labelled images. Problems can arise when the deformations introduced by pathologies affect the similarity between the atlas and a patient’s image. The aim of this work is to exploit the morphological dissimilarities between atlas databases and pathological images to diagnose the underlying clinical condition, while avoiding the dependence on labelled images. We propose a voxelwise atlas rating approach (VoxAR) relying on multiple atlas databases, each representing a particular condition. Using a local image similarity measure to assess the morphological similarity between the atlas and target images, a rating map displaying for each voxel the condition of the atlases most similar to the target is defined. The final diagnosis is established by assigning the condition of the database the most represented in the rating map. We applied the method to diagnose three different conditions associated with dextro-transposition of the great arteries, a congenital heart disease. The proposed approach outperforms other state-of-the-art methods using annotated images, with an accuracy of 97.3% when evaluated on a set of 60 whole heart MR images containing healthy and pathological subjects using cross validation.

International audience; Objective. We quantitatively investigate the biocompatibility of chemical vapour deposited (CVD) nanocrystalline diamond (NCD) after the inclusion of boron, with and without nanostructuring. The nanostructuring method involves a novel approach of growing NCD over carbon nanotubes (CNTs) that act as a 3D scaffold. This nanostructuring of BNCD leads to a material with increased capacitance, and this along with wide electrochemical window makes BNCD an ideal material for neural interface applications, and thus it is essential that their biocompatibility is investigated. Approach. Biocompatibility was assessed by observing the interaction of human neural stem cells (hNSCs) with a variety of NCD substrates including undoped ones, and NCD doped with boron, which are both planar, and nanostructured. hNSCs were chosen due to their sensitivity, and various methods including cell population and confluency were used to quantify biocompatibility. Main results. Boron inclusion into NCD film was shown to have no observable effect on hNSC attachment, proliferation and viability. Furthermore, the biocompatibility of nanostructured boron-doped NCD is increased upon nanostructuring, potentially due to the increased surface area. Significance. Diamond is an attractive material for supporting the attachment and development of cells as it can show exceptional biocompatibility. When boron is used as a dopant within diamond it becomes a p-type semiconductor, and at high concentrations the diamond becomes quasi-metallic, offering the prospect of a direct electrical device-cell interfacing system.

Auteur collectif : MOCHA Investigators: Edward Bove MD and Adam Dorfman MD (University of Michigan, USA); Andrew Taylor MD, AlessandroGiardini MD, Sachin Khambadkone MD, Marc de Leval MD, Silvia Schievano PhD, and T-Y Hsia MD (Institute of Child Health, UK); G. Hamilton Baker MD and Anthony Hlavacek (Medical University of South Carolina, USA); Francesco Migliavacca PhD, Giancarlo Pennati PhD, and Gabriele Dubini PhD (Politecnico di Milano, Italy); Richard Figliola PhD and John McGregor PhD (Clemson University, USA); Alison Marsden PhD (University of California, San Diego,USA); Irene Vignon-Clementel (National Institute of Research inInformatics and Automation, France).; International audience; Simulation divergence due to backflow is a common, but not fully addressed, problem in three-dimensional simulations of blood flow in the large vessels. Because backflow is a naturally occurring physiologic phenomenon, careful treatment is necessary to realistically model backflow without artificially altering the local flow dynamics. In this study, we quantitatively compare three available methods for treatment of outlets to prevent backflow divergence in finite element Navier-Stokes solvers. The methods examined are (1) adding a stabilization term to the boundary nodes formulation, (2) constraining the velocity to be normal to the outlet, and (3) using Lagrange multipliers to constrain the velocity profile at all or some of the outlets. A modification to the stabilization method is also discussed. Three model problems, a short and long cylinder with an expansion, a right-angle bend, and a patient-specific aorta model, are used to evaluate and quantitatively compare these methods. Detailed comparisons are made to evaluate robustness, stability characteristics, impact on local and global flow physics, computational cost, implementation effort, and ease-of-use. The results show that the stabilization method offers a promising alternative to previous methods, with reduced effect on both local and global hemodynamics, improved stability, little-to-no increase in computational cost, and elimination of the need for tunable parameters.

The EuroBioBank (EBB) network (www.eurobiobank.org) is the first operating network of biobanks in Europe to provide human DNA, cell and tissue samples as a service to the scientific community conducting research on rare diseases (RDs). The EBB was established in 2001 to facilitate access to RD biospecimens and associated data; it obtained funding from the European Commission in 2002 (5th framework programme) and started operation in 2003. The set-up phase, during the EC funding period 2003-2006, established the basis for running the network; the following consolidation phase has seen the growth of the network through the joining of new partners, better network cohesion, improved coordination of activities, and the development of a quality-control system. During this phase the network participated in the EC-funded TREAT-NMD programme and was involved in planning of the European Biobanking and Biomolecular Resources Research Infrastructure. Recently, EBB became a partner of RD-Connect, an FP7 EU programme aimed at linking RD biobanks, registries, and bioinformatics data. Within RD-Connect, EBB contributes expertise, promotes high professional standards, and best practices in RD biobanking, is implementing integration with RD patient registries and 'omics' data, thus challenging the fragmentation of international cooperation on the field. EBB thanks EURORDIS for administrative support, Fondazione Telethon for administrative and financial support, the EC for providing funds (grants: FP5 EuroBioBank, contract N. 02769; FP6 TREAT-NMD, contract N. 036825; and FP7 RD-Connect, grant agreement N. 305444), and AFM for the vision of the network and for encouraging the network to get together. EBB gratefully acknowledges patients and collaborating clinicians/researchers for contributing samples and data to the network, and biobank staffs for running the EBB biobanks. The MRC support to the biobank in London and Newcastle is also gratefully acknowledged. Sí

Item does not contain fulltext The objective of this work was to develop and validate a set of clinical criteria for the classification of patients affected by periodic fevers. Patients with inherited periodic fevers (familial Mediterranean fever (FMF); mevalonate kinase deficiency (MKD); tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS); cryopyrin-associated periodic syndromes (CAPS)) enrolled in the Eurofever Registry up until March 2013 were evaluated. Patients with periodic fever, aphthosis, pharyngitis and adenitis (PFAPA) syndrome were used as negative controls. For each genetic disease, patients were considered to be 'gold standard' on the basis of the presence of a confirmatory genetic analysis. Clinical criteria were formulated on the basis of univariate and multivariate analysis in an initial group of patients (training set) and validated in an independent set of patients (validation set). A total of 1215 consecutive patients with periodic fevers were identified, and 518 gold standard patients (291 FMF, 74 MKD, 86 TRAPS, 67 CAPS) and 199 patients with PFAPA as disease controls were evaluated. The univariate and multivariate analyses identified a number of clinical variables that correlated independently with each disease, and four provisional classification scores were created. Cut-off values of the classification scores were chosen using receiver operating characteristic curve analysis as those giving the highest sensitivity and specificity. The classification scores were then tested in an independent set of patients (validation set) with an area under the curve of 0.98 for FMF, 0.95 for TRAPS, 0.96 for MKD, and 0.99 for CAPS. In conclusion, evidence-based provisional clinical criteria with high sensitivity and specificity for the clinical classification of patients with inherited periodic fevers have been developed.

Single ventricle heart defects involve pathologies in which the heart has only one functional pumping chamber. In these conditions, treatment consists of three staged procedures. At stage 1 pulmonary flow is provided through an artificial shunt from the systemic circulation. Representative hemodynamics models able to explore different virtual surgical options can be built based on pre-operative imaging and patient data. In this context, the specification of boundary conditions is necessary to compute pressure and flow in the entire domain. However, these boundary conditions are rarely the measured variables. Moreover, to take into account the rest of the circulation outside of the three-dimensional modeled domain, a number of reduced order models exist. A simplified method is presented to iteratively, but automatically, tune reduced model parameters from hemodynamic data clinically measured before stage 2 surgery. Patient-specific local hemodynamics around the distal systemic-to-pulmonary shunt anastomosis and the connected pulmonary arteries are also analyzed. Multi-scale models of pre-stage 2 single ventricle patients are developed, including a 3D model of shunt-pulmonary connection and a number of pulmonary arteries. For each pulmonary outlet a total downstream resistance is identified, consistent with measured flow split and pressures. Target pressures such as minimum, maximum or average over one or both lungs are considered, depending on the clinical measurement. When possible, both steady and pulsatile identifications are performed. The methodology is demonstrated with six patient-specific models: the clinical target data are well-matched, except for one case where clinical data were subsequently found inconsistent. Inhomogeneous pressure, swirling blood flow patterns and very high wall shear stress 3D maps highlight similarities and differences among patients. Steady and pulsatile tuning results are similar. This work demonstrates (1) how to use routine clinical data to define boundary conditions for patient-specific 3D models in pre-stage 2 single ventricle circulations and (2) how simulations can help to check the coherence of clinical data, or provide insights to clinicians that are otherwise difficult to measure, such as in the presence of kinks. Finally, the choice of steady vs. pulsatile tuning, limitations and possible extensions of this work are discussed.

International audience

International audience; We draw attention to a number of important considerations in the arguments about screening and outcome of intervention in children with autism and other developmental disorders. Autism screening in itself never provides a final clinical diagnosis, but may well identify developmental deviations indicative of autism-or of other developmental disorders-that should lead to referral for further clinical assessment. Decisions regarding population or clinic screening cannot be allowed to be based on the fact that prospective longitudinal RCT designs over decades could never be performed in complex developmental disorders. We propose an alternative approach. Early screening for autism and other developmental disorders is likely to be of high societal importance and should be promoted and rigorously evaluated.

International audience; The native aorta in new-borns with hypoplastic left heart syndrome (HLHS) is often small or malformed. It requires surgical reconstruction and enlargement to enable systemic blood flow from the single right ventricle. However, morbidity and mortality remain high after surgery. The shape and size of the reconstruction are important factors affecting the hemodynamics in the aortic arch as well as potentially impacting on ventricular performance by inducing changes in afterload. To facilitate the diagnosis of abnormal or high-risk cases, an average reference model of theaortic arch is necessary. Such a representative mean shape of the patient population (the “atlas”) helps to quantify shape variations in 3D and allows statistical correlation of shape features to clinical outcomes.This retrospective study is based on a patient population of n=35 children with HLHS who underwent surgical arch reconstruction and subsequent cardiovascular magnetic resonance (CMR) examination. Three-dimensional surface models of the surgically enlarged aortic arches, excluding the brachiocephalic arteries, were reconstructed from the CMR whole-heart sequence serving as input data for the atlas calculation, Fig. 1. The atlas was calculated using a diffeomorphic surface registration algorithm based on a forward model, in which the surfaces are represented non-parametrically by currents [1]. Principal Component Analysis (PCA) was applied to the resulting shape vectors to determine dominant shape features in our population. The deviation of each patient’s aorta from the atlas was calculated as a dimensionless number in the space of currents.Fig. 1 shows the input surface meshes and the resulting atlas. Ten principal deformation modes from PCA accounted for 90% of the shape variation. Remarkably, 4 out of 5 patients with poor clinical outcome (defined as either death or cardiac transplantation) showed deviations from the atlas above the median value, Fig. 1. We present the first 3D shape atlas of the reconstructed aortic arch in patients with palliated HLHS. Our data suggest that clinical outcomes can be associated with shape features. The calculated PCA modes allow investigating this correlation more in detail. Results from such analyses can improve risk assessment and consequently affect surgical decision making in the completion of aortic arch reconstructions.

International audience; In patients with congenital heart disease and a single ventricle (SV), ventricular support of the circulation is inadequate, and staged palliative surgery (usually 3 stages) is needed for treatment. In the various palliative surgical stages individual differences in the circulation are important and patient-specific surgical planning is ideal. In this study, an integrated approach between clinicians and engineers has been developed, based on patient-specific multi-scale models, and is here applied to predict stage 2 surgical outcomes. This approach involves four distinct steps: (1) collection of pre-operative clinical data from a patient presenting for SV palliation, (2) construction of the pre-operative model, (3) creation of feasible virtual surgical options which couple a three-dimensional model of the surgical anatomy with a lumped parameter model (LPM) of the remainder of the circulation and (4) performance of post-operative simulations to aid clinical decision making. The pre-operative model is described, agreeing well with clinical flow tracings and mean pressures. Two surgical options (bi-directional Glenn and hemi-Fontan operations) are virtually performed and coupled to the pre-operative LPM, with the hemodynamics of both options reported. Results are validated against postoperative clinical data. Ultimately, this work represents the first patient-specific predictive modeling of stage 2 palliation using virtual surgery and closed-loop multi- scale modeling.

International audience; The three-dimensional Navier-Stokes simulation of blood flow and pressure in large vessels requires inlet or outlet boundary conditions that incorporate reduced models of the rest of the circulation (typically 1D or 0D models). Reverse flow may occur in part of or on entire coupling boundaries due to physiological conditions or complex geometry. This warrants careful coupling conditions, so that the scheme is stable, without artificially altering the local flow dynamics. The first idea that comes in mind consists in enforcing the pressure at this coupling boundary to be uniform, that is, the pressure coming from the reduced model. However, such a condition does not appear as the standard boundary condition in most formulations. In fact, in the latter, the traction appears as the natural boundary condition and its normal component is thus enforced to be the uniform reduced model pressure. This energetically generates a convective boundary term that can be destabilizing in the presence of reverse flow. Actually, other Navier-Stokes formulations rather involve the total pressure, which has been shown to lead to an energetically stable coupling between 3D and reduced models of blood flow. Some of these authors have been expecting instabilities when the dynamic pressure is not included in the boundary condition but did not see them numerically. In our experience and the experience of others, numerical instabilities do actually arise, in the presence of reverse flow. A dissipative stabilization has been proposed to counteract the destabilizing effect of the convective boundary term in such a case. In all these methods, the reduced model pressure is imposed as a uniform boundary condition for the Navier-Stokes equations. But in complex flow, such as with reverse flow, there is a priori no reason that the normal traction or the total pressure are uniform on a coupling boundary. In this work, we propose to handle the outflow boundary conditions by coupling the 3D Navier-Stokes equations with another 3D compartment. This artificial compartment involves modified Navier-Stokes equations that mimick a three-element Windkessel model (as an example of reduced model). The advantages of such approach are that the coupling 1) does not enforce the traction at the interface to be uniform, and 2) is energetically close to the usual 3D Navier-Stokes - Windkessel one, without the potentially destabilizing convective boundary term. Numerical tests will be presented to compare these methods in patient- specific geometries of various pathophysiological complexities.

International audience; Background: Computational fluid dynamics has been increasingly used in congenital heart surgery to simulate pathophysiological blood flow, investigate surgical options, or design medical devices. Several commercial and research computational or numerical codes have been developed. They present different approaches to numerically solve the blood flow equations, raising the question whether these numerical codes are equally reliable to achieve accurate simulation results. Accordingly, we sought to examine the influence of numerical code selection in several complex congenital cardiac operations. Material and methods: The main steps of blood flow simulations are detailed (geometrical mesh, boundary conditions, and solver numerical methods) for congenital cardiac operations of increasing complexity. The first case tests different numerical solutions against an analytical, or exact, solution. In the second case, the three-dimensional domain is a patient-specific superior cavopulmonary anastomosis. As an analytical solution does not exist in such a complex geometry, different numerical solutions are compared. Finally, a realistic case of a systemic-to-pulmonary shunt is presented with both geometrically and physiologically challenging conditions. For all, solutions from a commercially available code and an open-source research code are compared. Results: In the first case, as the mesh or solver numerical method is refined, the simulation results for both codes converged to the analytical solution. In the second example, velocity differences between the two codes are greater when the resolution of the mesh were lower and less refined. The third case with realistic anatomy reveals that the pulsatile complex flow is very similar for both codes. Conclusions: The precise setup of the numerical cases has more influence on the results than the choice of numerical codes. The need for detailed construction of the numerical model that requires high computational cost depends on the precision needed to answer the biomedical question at hand and should be assessed for each problem on a combination of clinically relevant patient-specific geometry and physiological conditions.

International audience; Computer fluid dynamics is now a common tool to explore hemodynamics in patient- specific simulations, either to better understand a specific physiopathology, explore several physiological states or to create a representative hemodynamics model preoperatively to explore several virtual surgical options. In this context, the specification of boundary conditions is key because pressure and flow within the modeled domain are driven by the interplay between geometry (form) and hemodynamics boundary conditions (function). However, these boundary conditions are rarely the measured variables. We thus show how one can go from patient-specific clinical data (MRI and catheterization) to simulation input parameters, including modeling assumptions and the impact of both on simulation results. To take into account the rest of the circulation outside of the three-dimensional modeled domain, a number of reduced order models exist. We explain how Windkessel models and more involved lumped parameter models can be calibrated, and discuss their predictive aspects. The specification of boundary conditions in patient-specific simulations can also create numerical challenges for which recent developments are explained. Applications include preoperative modeling and virtual surgical options in the Fontan palliation of single ventricle congenital heart disease, under rest and exercise.

MOCHA Investigators: Andrew Taylor, MD, Alessandro Giardini, MD, Sachin Khambadkone, MD, Silvia Schievano, PhD, Marc de Leval, MD, and T.-Y. Hsia, MD (Institute of Child Health, London, United Kingdom); Edward Bove, MD, and Adam Dorfman, MD (University of Michigan, Ann Arbor, MI); G. Hamilton Baker, MD, and Anthony Hlavacek (Medical University of South Carolina, Charleston, SC); Francesco Migliavacca, PhD, Giancarlo Pennati, PhD, and Gabriele Dubini, PhD (Politecnico di Milano, Milan, Italy); Alison Marsden, PhD (University of California, San Diego, CA); Jeffrey Feinstein, MD (Stanford University, Stanford, CA) Irene Vignon-Clementel (National Institute of Research in Informatics and Automation, Paris, France); Richard Figliola, PhD, and John McGregor, PhD (Clemson University, Clemson, SC).; International audience; Single ventricle malformations are complex congenital heart defects which require a three-stage surgical treatment, starting from the very first days of life, to separate the systemic and pulmonary circulations, and restore the serial circuit occurring in normal patients. The final surgery results in a total cavopulmonary connection (TCPC), where both the superior and the inferior vena cava are connected to the right pulmonary artery. Several clinical and computational studies have been done to optimize the geometry of the TCPC, with the aim of minimizing energy losses and improving surgical outcomes. To date, only few modeling studies have taken into account respiration and exercise as important factors to quantify the performance of a Fontan geometry. The objective of this work is to test the dependence of fluid dynamic variables and energy efficiency on respiration in patient-specific models of Fontan circulation, when subjected to exercise tests.|A closed-loop multiscale approach was used, including a simple respiration model that modulates the extravascular pressures in the thoracic and abdominal cavities, to generate physiologic time-varying flow conditions. A lumped parameter network (LPN) representing the whole circulation was coupled to a patient-specific 3D finite volume model of the preoperative bidirectional cavo-pulmonary anastomosis (BCPA) with detailed pulmonary anatomy. Subsequently, three virtual TCPC alternatives were coupled to the LPN and investigated in terms of both local and global hemodynamics. In particular, a T-junction of the venae cavae to the pulmonary arteries, a design with an offset between the venae cavae and a Y-graft design were compared under exercise conditions.|Results showed that the BCPA model is able to realistically capture oscillations due to both cardiac and respiratory effects, when compared to the venous Doppler velocity tracings acquired preoperatively on the patient.|The differences in hemodynamics between the three investigated TCPC options were minimal and similar to those obtained without inclusion of respiratory effects. Hence, the three surgical options result to be equivalent according to the analyzed parameters. Moreover, although the simulation of the Fontan circulation with a respiratory model requires a longer computational time, the developed framework allows for a more physiologic method to incorporate respiratory effects that was not possible using other methods.

International audience; Learning embryology remains difficult, since it requires understanding of many complex phenomena. The temporal evolution of developmental events has classically been illustrated using cartoons, which create difficulty in linking spatial and temporal aspects, such correlation being the keystone of descriptive embryology. We synthesized the bibliographic data from recent studies of atrial septal development. On the basis of this synthesis, consensus on the stages of atrial septation as seen in the human heart has been reached by a group of experts in cardiac embryology and pediatric cardiology. This has permitted the preparation of three-dimensional (3D) computer graphic objects for the anatomical components involved in the different stages of normal human atrial septation. We have provided a virtual guide to the process of normal atrial septation, the animation providing an appreciation of the temporal and morphologic events necessary to separate the systemic and pulmonary venous returns. We have shown that our animations of normal human atrial septation increase significantly the teaching of the complex developmental processes involved, and provide a new dynamic for the process of learning. Anat Sci Ed 2:69-77, 2009. (c) 2009 American Association of Anatomists.

International audience; We show that microinjecting cyclic GMP (cGMP) into unfertilized sea urchin eggs activates them by stimulating a rise in the intracellular free calcium ion concentration ([Ca21]i). The increase in [Ca21]i is similar in both magnitude and duration to the transient that activates the egg at fertilization. It is due to mobilization of calcium from intracellular stores but is not prevented by the inositol trisphosphate (InsP3) antagonist heparin. Furthermore, cGMP does not stimulate the eggs Na+/H+ antiport when the [Ca21]i transient is blocked by the calcium chelator bis-(O-aminophenoxy)-N,N,NN'-tetraacetic acid (BAPTA), suggesting that cGMP does not activate eggs by interacting with the their phosphoinositide signaling pathway. However, the [Ca21]i increase and activation are prevented in eggs in which the InsP3sensitive calcium stores have been emptied by the prior microinjection of the InsP3 analogue inositol 1,4,5-trisphosphorothioate. These data indicate that cGMP activates eggs by stimulating the release of calcium from an InsP3-sensitive calcium store via a novel, though unidentified, route independent of the InsP3 receptor.