Connected and shared X-in-the-loop technologies for electric vehicle design

The presented paper introduces a new methodology of experimental testing procedures required by the complex systems of electric vehicles (EV). This methodology is based on real-time connection of test setups and platforms, which may be situated in different geographical locations, belong to various cyber-physical domains, and are united in a global X-in-the-loop (XIL) experimental environment. The proposed concept, called XILforEV, allows exploring interdependencies between various physical processes that can be identified or investigated in the process of EV development. The paper discusses the following relevant topics: global XILforEV architecture; realization of required high-confidence models using dynamic data driven application systems (DDDAS) and multi fidelity models (MFM) approaches; and formulation of case studies to illustrate XILforEV application

Use of beneficial bacteria and their secondary metabolites to control grapevine pathogen diseases

Grapevine is one of the most important economic crops yielding berries, wine products as well as derivates. However, due to the large array of pathogens inducing diseases on this plant, considerable amounts of pesticides—with possible negative impact on the environment and health—have been used and are currently used in viticulture. To avoid negative impacts of such products and to ensure product quality, a substantial fraction of pesticides needs to be replaced in the near future. One solution can be related to the use of beneficial bacteria inhabiting the rhizo- and/or the endosphere of plants. These biocontrol bacteria and their secondary metabolites can reduce directly or indirectly pathogen diseases by affecting pathogen performance by antibiosis, competition for niches and nutrients, interference with pathogen signaling or by stimulation of host plant defenses. Due to the large demand for biocontrol of grapevine diseases, such biopesticides, their modes of actions and putative consequences of their uses need to be described. Moreover, the current knowledge on new strains from the rhizo- and endosphere and their metabolites that can be used on grapevine plants to counteract pathogen attack needs to be discussed. This is in particular with regard to the control of root rot, grey mould, trunk diseases, powdery and downy mildews, pierce’s disease, grapevine yellows as well as crown gall. Future prospects on specific beneficial microbes and their secondary metabolites that can be used as elicitors of plant defenses and/or as biocontrol agents with potential use in a more sustainable viticulture will be further discussed

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase 1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age  6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score  652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc = 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N = 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

Unstable TTTTA/TTTCA expansions in MARCH6 are associated with Familial Adult Myoclonic Epilepsy type 3

Familial Adult Myoclonic Epilepsy (FAME) is a genetically heterogeneous disorder characterized by cortical tremor and seizures. Intronic TTTTA/TTTCA repeat expansions in SAMD12 (FAME1) are the main cause of FAME in Asia. Using genome sequencing and repeat-primed PCR, we identify another site of this repeat expansion, in MARCH6 (FAME3) in four European families. Analysis of single DNA molecules with nanopore sequencing and molecular combing show that expansions range from 3.3 to 14 kb on average. However, we observe considerable variability in expansion length and structure, supporting the existence of multiple expansion configurations in blood cells and fibroblasts of the same individual. Moreover, the largest expansions are associated with micro-rearrangements occurring near the expansion in 20% of cells. This study provides further evidence that FAME is caused by intronic TTTTA/TTTCA expansions in distinct genes and reveals that expansions exhibit an unexpectedly high somatic instability that can ultimately result in genomic rearrangements

Simple scoring system to predict in-hospital mortality after surgery for infective endocarditis

BACKGROUND: Aspecific scoring systems are used to predict the risk of death postsurgery in patients with infective endocarditis (IE). The purpose of the present study was both to analyze the risk factors for in-hospital death, which complicates surgery for IE, and to create a mortality risk score based on the results of this analysis. METHODS AND RESULTS: Outcomes of 361 consecutive patients (mean age, 59.1\ub115.4 years) who had undergone surgery for IE in 8 European centers of cardiac surgery were recorded prospectively, and a risk factor analysis (multivariable logistic regression) for in-hospital death was performed. The discriminatory power of a new predictive scoring system was assessed with the receiver operating characteristic curve analysis. Score validation procedures were carried out. Fifty-six (15.5%) patients died postsurgery. BMI >27 kg/m2 (odds ratio [OR], 1.79; P=0.049), estimated glomerular filtration rate 55 mm Hg (OR, 1.78; P=0.032), and critical state (OR, 2.37; P=0.017) were independent predictors of in-hospital death. A scoring system was devised to predict in-hospital death postsurgery for IE (area under the receiver operating characteristic curve, 0.780; 95% CI, 0.734-0.822). The score performed better than 5 of 6 scoring systems for in-hospital death after cardiac surgery that were considered. CONCLUSIONS: A simple scoring system based on risk factors for in-hospital death was specifically created to predict mortality risk postsurgery in patients with IE

Évaluation des troubles de la perfusion tissulaire dans les états de chocs circulatoires et de l’intérêt thérapeutique du pimobendaneDe la recherche expérimentale aux applications cliniques

Circulatory shock as hypovolemic shock, distributive shock, obstructive shock, cardiogenic shock, sepsis, and septic shock, are syndromes with a complex pathophysiology characterized by the presence of tissue perfusion disorders of multifactorial origin, associated with acute hemodynamic failure. Sepsis and septic shock are the result of deregulation of the body host's response to infection manifested by systemic inflammatory syndrome. This infection can be of extrinsic origin or derive from alterations in the digestive wall. Thus, many conditions can lead to the occurrence of sepsis when this wall is made more permeable to the elements that it contains. Shock concerns a large part of patients hospitalized in intensive care units. They constitute a major public health problem due to their prevalence, the associated mortality rate and the severe complications encountered by some patients during their convalescence. Numerous theoretical and factual arguments underline the preponderant role of disorders of tissue perfusion and of microcirculation in the occurrence of organ failures which constitute the keystone of the pathophysiological mechanisms of shock states. Therefore, today, many research teams are working to develop technologies to measure tissue perfusion disorders and try to develop drugs to fight against these perfusion alterations.In this context, our thesis aimed to explore the advantages and limitations of three techniques for evaluating tissue perfusion: infrared thermography, urethral photoplethysmography and sublingual videomicroscopy. The second objective of this work was to assess the therapeutic value of pimobendan, an inodilator, in the management of these disorders.The studies carried out during this thesis underline that, if the three techniques studied are of undeniable interest, all also have major limitations. It therefore appears highly probable that the optimization of patient care cannot be based on the use of a single tool, but rather on a multimodal approach to the diagnosis and monitoring of tissue hypoperfusions. The preliminary phase of evaluation of the therapeutic benefit of pimobendan was associated with rather encouraging results. These results have not been confirmed in a more complex model of septic shock in pigs.In this work, we tried to show the complexity of the pathophysiological mechanisms involved in shock states and how this complexity impacts research in the field. The future of the management of patients in shock will probably require a better knowledge of the individual pathophysiological variations allowing better identification of the subpopulations of patients most likely to be studied by a particular technology, and the most likely to respond favorably to a particular therapeutic substance.Les états de choc circulatoire ; choc hypovolémique, distributif, obstructif, cardiogénique, sepsis, choc septique, sont des syndromes à la physiopathologie complexe se caractérisant par la présence de troubles de la perfusion tissulaire d’origine multifactorielle, associés à une défaillance hémodynamique aiguë. Le sepsis et le choc septique sont la conséquence d’une dérégulation de la réponse de l’organisme face à une infection se manifestant par un syndrome inflammatoire systémique. Cette infection peut être d’origine extrinsèque ou dériver d’altérations de la paroi digestive. Ainsi, de nombreuses affections peuvent aboutir à la survenue d’un sepsis lorsque cette paroi est rendue plus perméable aux éléments qu’elle contient. Ces états de choc concernent une grande partie des patients hospitalisés en réanimation. Ils constituent un problème de santé publique majeure du fait de leur prévalence, du taux de mortalité qui leur est associé et des complications graves rencontrées par certains patients pendant leur convalescence. De nombreux arguments théoriques et factuels soulignent le rôle prépondérant des troubles de la perfusion tissulaire en général, et de la microcirculation en particulier, dans la survenu de défaillances d’organes qui constituent la clef de voute du tableau physiopathologique des états de choc. C’est pourquoi, aujourd’hui, de nombreuses équipes s’attachent à développer des technologies permettant de mesurer les troubles de la perfusion tissulaire et cherchent à mettre au point des médicaments permettant de lutter contre ces altérations perfusionnelles. Dans ce contexte, notre thèse avait pour objectif d’explorer les avantages et les limites de trois techniques permettant d’évaluer la perfusion tissulaire : la thermographie infrarouge, la photopléthysmographie urétrale et la videomicroscopie sublinguale. Le second objectif de ce travail était d’évaluer l’intérêt thérapeutique du pimobendane, un inodilatateur, dans la prise en charge de ces désordres. Les études réalisées au cours de cette thèse soulignent que, si les trois techniques étudiées présentent un intérêt incontestable, toutes présentent également des limites majeures. Il apparaît donc fort probable que l’optimisation de la prise en charge des patients ne puisse reposer sur l’utilisation d’un seul outil, mais plutôt sur une approche multimodale du diagnostic et du suivi des hypoperfusions tissulaires. La phase préliminaire d’évaluation de l’intérêt thérapeutique du pimobendane était associée à des résultats plutôt encourageants. Ces résultats n’ont pas été confirmés dans un modèle plus complexe de choc septique chez le porc. Dans ce travail, nous avons tenté de montrer la complexité des mécanismes physiopathologiques impliqués dans les états de choc et comment cette complexité impactait la recherche dans le domaine. L’avenir de la prise en charge des patients en choc passera probablement par une meilleure connaissance des variations physiopathologiques individuelles permettant de mieux identifier les sous populations de patients les plus à même d’être étudiées par telle ou telle technologie, et les plus à même de répondre favorablement à telle ou telle substance thérapeutique

Évaluation des troubles de la perfusion tissulaire dans les états de chocs circulatoires et de l’intérêt thérapeutique du pimobendane : de la recherche expérimentale aux applications cliniques

Circulatory shock as hypovolemic shock, distributive shock, obstructive shock, cardiogenic shock, sepsis, and septic shock, are syndromes with a complex pathophysiology characterized by the presence of tissue perfusion disorders of multifactorial origin, associated with acute hemodynamic failure. Sepsis and septic shock are the result of deregulation of the body host's response to infection manifested by systemic inflammatory syndrome. This infection can be of extrinsic origin or derive from alterations in the digestive wall. Thus, many conditions can lead to the occurrence of sepsis when this wall is made more permeable to the elements that it contains. Shock concerns a large part of patients hospitalized in intensive care units. They constitute a major public health problem due to their prevalence, the associated mortality rate and the severe complications encountered by some patients during their convalescence. Numerous theoretical and factual arguments underline the preponderant role of disorders of tissue perfusion and of microcirculation in the occurrence of organ failures which constitute the keystone of the pathophysiological mechanisms of shock states. Therefore, today, many research teams are working to develop technologies to measure tissue perfusion disorders and try to develop drugs to fight against these perfusion alterations. In this context, our thesis aimed to explore the advantages and limitations of three techniques for evaluating tissue perfusion: infrared thermography, urethral photoplethysmography and sublingual videomicroscopy. The second objective of this work was to assess the therapeutic value of pimobendan, an inodilator, in the management of these disorders. The studies carried out during this thesis underline that, if the three techniques studied are of undeniable interest, all also have major limitations. It therefore appears highly probable that the optimization of patient care cannot be based on the use of a single tool, but rather on a multimodal approach to the diagnosis and monitoring of tissue hypoperfusions. The preliminary phase of evaluation of the therapeutic benefit of pimobendan was associated with rather encouraging results. These results have not been confirmed in a more complex model of septic shock in pigs. In this work, we tried to show the complexity of the pathophysiological mechanisms involved in shock states and how this complexity impacts research in the field. The future of the management of patients in shock will probably require a better knowledge of the individual pathophysiological variations allowing better identification of the subpopulations of patients most likely to be studied by a particular technology, and the most likely to respond favorably to a particular therapeutic substance.Les états de choc circulatoire ; choc hypovolémique, distributif, obstructif, cardiogénique, sepsis, choc septique, sont des syndromes à la physiopathologie complexe se caractérisant par la présence de troubles de la perfusion tissulaire d’origine multifactorielle, associés à une défaillance hémodynamique aiguë. Le sepsis et le choc septique sont la conséquence d’une dérégulation de la réponse de l’organisme face à une infection se manifestant par un syndrome inflammatoire systémique. Cette infection peut être d’origine extrinsèque ou dériver d’altérations de la paroi digestive. Ainsi, de nombreuses affections peuvent aboutir à la survenue d’un sepsis lorsque cette paroi est rendue plus perméable aux éléments qu’elle contient. Ces états de choc concernent une grande partie des patients hospitalisés en réanimation. Ils constituent un problème de santé publique majeure du fait de leur prévalence, du taux de mortalité qui leur est associé et des complications graves rencontrées par certains patients pendant leur convalescence. De nombreux arguments théoriques et factuels soulignent le rôle prépondérant des troubles de la perfusion tissulaire en général, et de la microcirculation en particulier, dans la survenu de défaillances d’organes qui constituent la clef de voute du tableau physiopathologique des états de choc. C’est pourquoi, aujourd’hui, de nombreuses équipes s’attachent à développer des technologies permettant de mesurer les troubles de la perfusion tissulaire et cherchent à mettre au point des médicaments permettant de lutter contre ces altérations perfusionnelles. Dans ce contexte, notre thèse avait pour objectif d’explorer les avantages et les limites de trois techniques permettant d’évaluer la perfusion tissulaire : la thermographie infrarouge, la photopléthysmographie urétrale et la videomicroscopie sublinguale. Le second objectif de ce travail était d’évaluer l’intérêt thérapeutique du pimobendane, un inodilatateur, dans la prise en charge de ces désordres. Les études réalisées au cours de cette thèse soulignent que, si les trois techniques étudiées présentent un intérêt incontestable, toutes présentent également des limites majeures. Il apparaît donc fort probable que l’optimisation de la prise en charge des patients ne puisse reposer sur l’utilisation d’un seul outil, mais plutôt sur une approche multimodale du diagnostic et du suivi des hypoperfusions tissulaires. La phase préliminaire d’évaluation de l’intérêt thérapeutique du pimobendane était associée à des résultats plutôt encourageants. Ces résultats n’ont pas été confirmés dans un modèle plus complexe de choc septique chez le porc. Dans ce travail, nous avons tenté de montrer la complexité des mécanismes physiopathologiques impliqués dans les états de choc et comment cette complexité impactait la recherche dans le domaine. L’avenir de la prise en charge des patients en choc passera probablement par une meilleure connaissance des variations physiopathologiques individuelles permettant de mieux identifier les sous populations de patients les plus à même d’être étudiées par telle ou telle technologie, et les plus à même de répondre favorablement à telle ou telle substance thérapeutique

Assessment of tissue perfusion disorders in circulatory shock and of the therapeutic value of pimobendan : from experimental research to clinical applications

Les états de choc circulatoire ; choc hypovolémique, distributif, obstructif, cardiogénique, sepsis, choc septique, sont des syndromes à la physiopathologie complexe se caractérisant par la présence de troubles de la perfusion tissulaire d’origine multifactorielle, associés à une défaillance hémodynamique aiguë. Le sepsis et le choc septique sont la conséquence d’une dérégulation de la réponse de l’organisme face à une infection se manifestant par un syndrome inflammatoire systémique. Cette infection peut être d’origine extrinsèque ou dériver d’altérations de la paroi digestive. Ainsi, de nombreuses affections peuvent aboutir à la survenue d’un sepsis lorsque cette paroi est rendue plus perméable aux éléments qu’elle contient. Ces états de choc concernent une grande partie des patients hospitalisés en réanimation. Ils constituent un problème de santé publique majeure du fait de leur prévalence, du taux de mortalité qui leur est associé et des complications graves rencontrées par certains patients pendant leur convalescence. De nombreux arguments théoriques et factuels soulignent le rôle prépondérant des troubles de la perfusion tissulaire en général, et de la microcirculation en particulier, dans la survenu de défaillances d’organes qui constituent la clef de voute du tableau physiopathologique des états de choc. C’est pourquoi, aujourd’hui, de nombreuses équipes s’attachent à développer des technologies permettant de mesurer les troubles de la perfusion tissulaire et cherchent à mettre au point des médicaments permettant de lutter contre ces altérations perfusionnelles. Dans ce contexte, notre thèse avait pour objectif d’explorer les avantages et les limites de trois techniques permettant d’évaluer la perfusion tissulaire : la thermographie infrarouge, la photopléthysmographie urétrale et la videomicroscopie sublinguale. Le second objectif de ce travail était d’évaluer l’intérêt thérapeutique du pimobendane, un inodilatateur, dans la prise en charge de ces désordres. Les études réalisées au cours de cette thèse soulignent que, si les trois techniques étudiées présentent un intérêt incontestable, toutes présentent également des limites majeures. Il apparaît donc fort probable que l’optimisation de la prise en charge des patients ne puisse reposer sur l’utilisation d’un seul outil, mais plutôt sur une approche multimodale du diagnostic et du suivi des hypoperfusions tissulaires. La phase préliminaire d’évaluation de l’intérêt thérapeutique du pimobendane était associée à des résultats plutôt encourageants. Ces résultats n’ont pas été confirmés dans un modèle plus complexe de choc septique chez le porc. Dans ce travail, nous avons tenté de montrer la complexité des mécanismes physiopathologiques impliqués dans les états de choc et comment cette complexité impactait la recherche dans le domaine. L’avenir de la prise en charge des patients en choc passera probablement par une meilleure connaissance des variations physiopathologiques individuelles permettant de mieux identifier les sous populations de patients les plus à même d’être étudiées par telle ou telle technologie, et les plus à même de répondre favorablement à telle ou telle substance thérapeutique.Circulatory shock as hypovolemic shock, distributive shock, obstructive shock, cardiogenic shock, sepsis, and septic shock, are syndromes with a complex pathophysiology characterized by the presence of tissue perfusion disorders of multifactorial origin, associated with acute hemodynamic failure. Sepsis and septic shock are the result of deregulation of the body host's response to infection manifested by systemic inflammatory syndrome. This infection can be of extrinsic origin or derive from alterations in the digestive wall. Thus, many conditions can lead to the occurrence of sepsis when this wall is made more permeable to the elements that it contains. Shock concerns a large part of patients hospitalized in intensive care units. They constitute a major public health problem due to their prevalence, the associated mortality rate and the severe complications encountered by some patients during their convalescence. Numerous theoretical and factual arguments underline the preponderant role of disorders of tissue perfusion and of microcirculation in the occurrence of organ failures which constitute the keystone of the pathophysiological mechanisms of shock states. Therefore, today, many research teams are working to develop technologies to measure tissue perfusion disorders and try to develop drugs to fight against these perfusion alterations. In this context, our thesis aimed to explore the advantages and limitations of three techniques for evaluating tissue perfusion: infrared thermography, urethral photoplethysmography and sublingual videomicroscopy. The second objective of this work was to assess the therapeutic value of pimobendan, an inodilator, in the management of these disorders. The studies carried out during this thesis underline that, if the three techniques studied are of undeniable interest, all also have major limitations. It therefore appears highly probable that the optimization of patient care cannot be based on the use of a single tool, but rather on a multimodal approach to the diagnosis and monitoring of tissue hypoperfusions. The preliminary phase of evaluation of the therapeutic benefit of pimobendan was associated with rather encouraging results. These results have not been confirmed in a more complex model of septic shock in pigs. In this work, we tried to show the complexity of the pathophysiological mechanisms involved in shock states and how this complexity impacts research in the field. The future of the management of patients in shock will probably require a better knowledge of the individual pathophysiological variations allowing better identification of the subpopulations of patients most likely to be studied by a particular technology, and the most likely to respond favorably to a particular therapeutic substance

Big Data for Biomedical Research and Personalised Medicine: an Epistemological and Ethical Cross-Analysis

Abstract Big data techniques, data-driven science and their technological applications raise many serious ethical questions, notably about privacy protection. In this paper, we highlight an entanglement between epistemology and ethics of big data. Discussing the mobilisation of big data in the fields of biomedical research and health care, we show how an overestimation of big data epistemic power – of their objectivity or rationality understood through the lens of neutrality – can become ethically threatening. Highlighting the irreducible non-neutrality at play in big data tools, we insist upon the ethical importance of a critical epistemological approach in which big data are understood as possibly valuable only when coupled with human intelligence and evaluative rationality.</jats:p