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Available data have shown an association between direct oral anticoagulant (DOAC) plasma concentration and clinical, particularly bleeding, events. Factors that may influence DOAC plasma concentration are therefore the focus of particular attention. Population pharmacokinetic (PopPK) analyses can help in identifying such factors while providing predictive models. The main aim of the present study was to identify all the PopPK models to date for the four most frequently used DOACs (dabigatran, apixaban, rivaroxaban, and edoxaban). The secondary aim was to use these models to simulate different DOAC plasma concentration-time profiles in relevant clinical scenarios. The results of our model-based simulations confirm the clinical relevance of the known major factors influencing DOAC exposure and support the current approved dose adaptation, at least for atrial fibrillation. They also highlight how the accumulation of covariates, not currently considered for dose adaptation due to their seemingly minor influence on DOAC exposure, lead to supratherapeutic blood concentrations and could thus enhance the risk of major bleeding. The present results therefore question DOAC dose adaptation in the presence of these covariates, such as drug-drug interaction or genotypes, alongside the known existing covariates. As the overall effect of accumulation of several covariates could be difficult to apprehend for the clinicians, PopPK modeling could represent an interesting approach for informed precision dosing and to improve personalized prescription of DOACs.

Precision dosing strategies require accounting for between-patient variability in pharmacokinetics together with subsequent pharmacodynamic differences. Liquid biopsy is a valuable new approach to diagnose disease prior to the appearance of clinical signs and symptoms, potentially circumventing invasive tissue biopsies. However, the possibility of quantitative grading of biomarkers, as opposed to simply confirming their presence or absence, is relatively new. In this study, we aimed to verify expression measurements of cytochrome P450 (CYP) enzymes and the transporter P-glycoprotein (P-gp) in liquid biopsy against genotype and activity phenotype (assessed by the Geneva cocktail approach) in 30 acutely ill patients with cardiovascular disease in a hospital setting. After accounting for exosomal shedding, expression in liquid biopsy correlated with activity phenotype for CYP1A2, CYP2B6, CYP2C9, CYP3A, and P-gp (r = 0.44–0.70, P ≤ 0.05). Although genotype offered a degree of stratification, large variability (coefficient of variation (CV)) in activity (up to 157%) and expression in liquid biopsy (up to 117%) was observed within each genotype, indicating a mismatch between genotype and phenotype. Further, exosome screening revealed expression of 497 targets relevant to drug metabolism and disposition (159 enzymes and 336 transporters), as well as 20 molecular drug targets. Although there were no functional data available to correlate against these large-scale measurements, assessment of disease perturbation from healthy baseline was possible. Verification of liquid biopsy against activity phenotype is important to further individualize modeling approaches that aspire to achieve precision dosing from the start of drug treatment without the need for multiple rounds of dose optimization.

Even though direct oral anticoagulants (DOAC) are at risk for drug-drug interactions, they are barely mentioned in the dose adjustment guidelines and contradictory information is found in the summary of product characteristics of individual DOACs. This represents a significant issue for general and internal medicine clinicians, as it is well established that patients with atrial fibrillation receive numerous co-medications, and that polymedication increases the bleeding risk. Our multidisciplinary team (composed of clinical pharmacologists and pharmacists, internal medicine and hemostasis physicians) proposes here practical recommendations for pharmacokinetic drug-drug interactions with DOAC, based on the best available clinical and pharmacological evidence that can be easily implemented at the bedside. These recommendations aim pragmatically to more clearly define the situations that require the clinician's attention and provide suggestions for appropriate action in presence of drug-drug interactions with DOAC.

The Actual and the Rational: Hegel and Objective Spirit, by Jean-François Kervégan. Translated by Daniela Ginsburg and Martin Shuster. Chicago: University of Chicago Press, 2018. xxiii + 384 pp.Avicenna and the Aristotelian Left, by Ernst Bloch. Translated by Loren Goldman and Peter Thompson. New York: Columbia University Press, 2019. xxvi +109 pp.Critique of Forms of Life, by Rahel Jaeggi. Translated by Ciaran Cronin. Cambridge, MA: Belknap Press of Harvard University Press, 2018. xx + 395 pp.

Coronavirus disease 2019 (COVID‐19), caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection, is a severe acute respiratory syndrome with an underlying inflammatory state. We have previously demonstrated that acute inflammation modulates cytochromes P450 (CYPs) activity in an isoform‐specific manner. We therefore hypothesized that COVID‐19 might also impact CYP activity, and thus aimed to evaluate the impact of acute inflammation in the context of SARS‐CoV‐2 infection on the six main human CYPs activity. This prospective observational study was conducted in 28 patients hospitalized at the Geneva University Hospitals (Switzerland) with a diagnosis of moderate to severe COVID‐19. They received the Geneva phenotyping cocktail orally during the first 72 hours of hospitalization and after 3 months. Capillary blood samples were collected 2 hours after cocktail administration to assess the metabolic ratios (MRs) of CYP1A2, 2B6, 2C9, 2C19, 2D6, and 3A. C‐reactive protein (CRP), interleukin 6 (IL‐6), and tumor necrosis factor‐α (TNF‐α) levels were also measured in blood. CYP1A2, CYP2C19, and CYP3A MRs decreased by 52.6% (P = 0.0001), 74.7% (P = 0.0006), and 22.8% (P = 0.045), respectively, in patients with COVID‐19. CYP2B6 and CYP2C9 MRs increased by 101.1% (P = 0.009) and 55.8% (P = 0.0006), respectively. CYP2D6 MR variation did not reach statistical significance (P = 0.072). As expected, COVID‐19 was a good acute inflammation model as mean serum levels of CRP, IL‐6, and TNF‐α were significantly (P

We sought in this case-control retrospective study to compare posaconazole and isavuconazole (PCZ and IVC, respectively) plasma trough concentration ( C trough ) levels in high-risk allogeneic hematopoietic cell transplant (HCT) recipients who received letermovir (LET) or not. PCZ/IVC C trough levels were not found to be significantly different between cases and controls, as they were 1.31 mg/liter (median) (interquartile range [IQR], 0.90) versus 1.36 mg/liter (IQR, 1.16) ( P = 0.31) and 3.20 mg/liter (IQR, 2.40) versus 2.35 mg/liter (IQR, 1.50) ( P = 0.17), respectively.

Th is article off ers a history of pluralism as a term in scholarly discourse. It presents the existing research on the question and off ers a contribution on the basis of an inclusive approach that is not limited to one discipline (philosophy or political science) or to one linguistic area. In particular, it references the rich German debate and the important French intellectual developments. Moreover, it considers not only the proponents but also the adversaries of pluralism. Th ere are two recurring elements in the debates on political pluralism. One is the existence, even among the critics of pluralism, of a recognition of plurality at some level. Th e other is the advocacy, even by authors who strongly emphasize confl ict and dissent, of some necessary unity.

This article explores the reception of Emile Durkheim in Germany at the beginning of the twentieth century. In recent years, the classical assumption according to which sociology is neatly organised in distinct national traditions has been challenged. This article further contributes to this challenge by analysing the case of two prominent German-speaking legal scholars, Hans Kelsen and Carl Schmitt. Despite major differences in their political and scientific outlook, both argued against the encroachments of the social sciences into the field of legal studies. This article shows how Kelsen mounted a polemic against Durkheim, on the basis of a first-hand knowledge of his writings. Kelsen believed that Durkheim committed several errors. In particular, he interpreted Durkheim’s famous sentence according to which ‘social facts must be treated as things’ as a clear sign of a materialistic, deterministic and positivistic attitude which neglects the power of ideas and norms. Schmitt targeted sociology by way of a criticism not of Durkheim but of Léon Duguit, who had been inspired by Durkheim and pleaded for a collaboration between legal scholars and social scientists. According to Schmitt, a sociological approach to law amounts to a dangerous denial of the centrality of the state in politics.

Oral anticoagulants and antiplatelet drugs are commonly prescribed to lower the risk of cardiovascular diseases, such as venous and arterial thrombosis, which represent the leading causes of mortality worldwide. A significant percentage of patients taking antithrombotics will nevertheless experience bleeding or recurrent ischemic events, and this represents a major public health issue. Cardiovascular medicine is now questioning the one-size-fits-all policy, and more personalized approaches are increasingly being considered. However, the available tools are currently limited and they are only moderately able to predict clinical events or have a significant impact on clinical outcomes. Predicting concentrations of antithrombotics in blood could be an effective means of personalization as they have been associated with bleeding and recurrent ischemia. Target concentration interventions could take advantage of physiologically based pharmacokinetic (PBPK) and population-based pharmacokinetic (POPPK) models, which are increasingly used in clinical settings and have attracted the interest of governmental regulatory agencies, to propose dosages adapted to specific population characteristics. These models have the benefit of combining parameters from different sources, such as experimental in vitro data and patients' demographic, genetic, and physiological in vivo data, to characterize the dose-concentration relationships of compounds of interest. As such, they can be used to predict individual drug exposure. In the near future, these models could therefore be a valuable means of predicting personalized antithrombotic blood concentrations and, hopefully, of preventing clinical non-response or bleeding in a given patient. Existing approaches for personalization of antithrombotic prescriptions will be reviewed using practical examples for P2Y

Der franzosische Soziologie Emile Durkheim (1858–1917) sah die Essenz religioser Phanomene im Sakralen. Sakral/heilig kann jede gesellschaftliche Erscheinung sein, die die Gruppe im Vergleich zum alltaglichen, d. h. profanen Leben als radikal getrennt und gleichzeitig als uberlegen betrachtet. Durkheim lieferte auch eine Theorie des Ursprungs religioser Phanomene. Ihm zufolge sind die sakralen Dinge das Symbol des Sozialen, sodass die Religion als eine Form von Selbstverehrung der Gesellschaft interpretiert werden kann. Verehrt werde die Gesellschaft, weil sie aus der Perspektive des Individuums eine wohltuende Kraft sei, die dem Individuum alles gibt (u. a. Schutz, Wohlbefinden, Sprachfahigkeit, Kenntnisse, Identitat und Werte). Zur Deutung des Religiosen entwickelte des Weiteren Durkheim einen anti-intellektualistischen Ansatz, der die wichtige Rolle von religiosen Ritualen und die Zentralitat von Momenten der kollektiver Erregung betonte. Durkheims Anliegen war es, die essentielle Nahe zwischen dem Religiosen und dem Sozialen, sei es in vormodernen oder in modernen Kontexten, hervorzuheben.

Antithrombotic drugs are regularly prescribed for the treatment and prevention of venous or arterial thromboembolic events. The co-prescription of an anticoagulant and antiplatelet drug is frequent in daily practice even if evidence of benefit associated with such an association is limited, while the increased bleeding risk is well established. The aim of this article is to review the situations where antiplatelet drugs are indicated in patients already treated with long-term anticoagulants. The perspective of adapting and personalizing antithrombotic therapy according to each patient's characteristics is also discussed.Les médicaments antithrombotiques sont régulièrement prescrits pour le traitement et la prévention d’événements thromboemboliques veineux ou artériels. La coprescription d’un anticoagulant et d’un antiplaquettaire se retrouve fréquemment en pratique quotidienne, même si les preuves d’un bénéfice associé à un tel traitement sont limitées, alors que l’augmentation du risque hémorragique est bien établie. Cet article a donc pour but de revoir les situations dans lesquelles un ou plusieurs antiplaquettaires sont indiqués chez des patients anticoagulés au long cours. La perspective de l’adaptation et de la personnalisation du traitement antithrombotique en fonction des caractéristiques des patients est également abordée.

SummaryThe factors causing the transition from recreational drug consumption to addiction remain largely unknown. It has not been tested whether dopamine (DA) is sufficient to trigger this process. Here we use optogenetic self-stimulation of DA neurons of the ventral tegmental area (VTA) to selectively mimic the defining commonality of addictive drugs. All mice readily acquired self-stimulation. After weeks of abstinence, cue-induced relapse was observed in parallel with a potentiation of excitatory afferents onto D1 receptor-expressing neurons of the nucleus accumbens (NAc). When the mice had to endure a mild electric foot shock to obtain a stimulation, some stopped while others persevered. The resistance to punishment was associated with enhanced neural activity in the orbitofrontal cortex (OFC) while chemogenetic inhibition of the OFC reduced compulsivity. Together, these results show that stimulating VTA DA neurons induces behavioral and cellular hallmarks of addiction, indicating sufficiency for the induction and progression of the disease.Video Abstract

Introduction « Il faut plus de concurrence » : s’il fallait retenir un slogan incantatoire des politiques economiques et sociales actuelles, ce serait celui-la. L’introduction ou le renforcement de la concurrence resoudrait les problemes des ecoles et des universites, ceux des chemins de fer et des compagnies aeriennes, ceux des fournisseurs d’electricite et des agences pour l’emploi, ou encore ceux des systemes de sante et des retraites. C’est pourquoi toutes les energies et toutes les resso...

Der Artikel stellt Emile Durkheims Erklarungsansatze zur Entwicklung von Moral und Religion in der Moderne vor. Obwohl er eine allmahliche Schwachung der traditionellen Religionen voraussah, war Durkheim uberzeugt, dass selbst moderne Gesellschaften einen Sinn fur das Sakrale beibehalten wurden. Er ging davon aus, dass eine funktionierende Moral in ihrem Kern einen sakralen Gegenstand besitzen muss. In der heutigen Zeit, mit ihrer zunehmenden Trennung von Religion und Moral, ist der sakrale Gegenstand der Moral die menschliche Person. Der Artikel prasentiert und diskutiert Durkheims Erklarungsansatze zur Entstehung des modernen Ideals der Person. Es lassen sich zwei Erklarungen dieses Prozesses in Durkheims Werk auffinden. In den Vorlesungen zur Physik der Sitten und des Rechts beschreibt Durkheim das moderne Ideal der Person vorwiegend als ein Produkt des Staates. In spateren Texten, insbesondere in den Elementaren Formen des religiosen Lebens, betonte Durkheim zunehmend die Rolle der Gesellschaft selbst: Er versuchte u. a. mithilfe von Beispielen aus der Zeit der Franzosischen Revolution zu zeigen, wie gesellschaftliche Ideale in Momenten der kollektiven Erregung entstehen.

The main results of the 2011 excavations campaign on the site of Guran in south Istria are presented in this article. These concern the fortified early medieval settlement the origin of which is dated to the Carolingian period and which is abandoned in the late Middle Ages, and the church of St Cecilia situated some few hundred meters to the north of the settlement. The results of the excavations of St Cecilia were particularly rich, revealing at least six phases prior to the existing church. Main objectives of this international project are the analysis of the origin and the architectural development of the church erected on the site of a roman villa, as well as that of the settlement, combined with the study of the territorial and ecclesiastic organisation of this part of Istria during the late Antiquity and the early Middle Ages.

The prevalence of AF is increasing and represents a major public health issue. Current guidelines recommend screening with an ECG in all patients65 years with an irregular pulse. However, single time point screening has a low yield, particularly for silent AF. Silent or infra clinical AF nevertheless carries a thromboembolic risk clinically similar to declared AF The development of continuous heart monitoring devices now enables earlier detection and management of AF. Data demonstrating efficacy of oral anticoagulant in silent AF is lacking, therefore it appears too early to recommend changes to current screening procedures.

The main results of the 2012 excavations campaign on the site of Guran in south Istria are presented. These concern the fortified early medieval settlement the origin of which is dated to the Carolingian period and which was abandoned in the late Middle Ages, and the church of St Cecilia situated some few hundred meters to the north of the settlement. The presented results of the excavations and the restoration of St Cecilia shed some light on the dating of at least two of six phases prior to the existing church. Main objectives of this international project are the analysis of the origin and the architectural development of the church erected on the site of a roman villa, as well as that of the settlement, combined with the study of territorial and ecclesiastic organisation of this part of Istria during late Antiquity and the early Middle Ages.

Der Aufsatz geht Durkheims Versuchen nach, die Gesellschaft als ein Ding, als eine Entitat mit eigener Logik und Stabilitat zu fassen und als originares wissenschaftliches Objekt der Soziologie zu begrunden. Der Dingcharakter der Gesellschaft wirft unmittelbar die Frage nach ihrer Verortung auf. Im Werk Durkheims finden sich unterschiedliche Positionen zu dieser Frage, die schlieslich in der Formel kulminieren, die Gesellschaft sei „in uns, aber ohne uns“: Das Soziale besteht durch und durch aus Vorstellungen, jedoch sind dies Vorstellungen einer besonderen Art, da sie nicht das Ergebnis individuellen Denkens sind und auf dieses einen Zwang ausuben. Wie lasst sich die Verortung der Gesellschaft im mentalen Leben der Individuen verstehen? Der Aufsatz geht den Antworten Durkheims auf dieses Problem nach, indem er die Verwendung des Begriffes des gesellschaftlichen „Substrats“ nachzeichnet, der in seinem gesamten Werk wiederkehrt. Mit diesem Begriff versucht Durkheim, eine Antwort auf die Frage nach der Verortung der Gesellschaft in der materiellen Welt und im Bewusstsein der Individuen zu geben.

Zusammenfassung. In den letzten Jahren hat die Kantonsarchaologie in Genf im Bereich der christlichen Archaologie auf recht begrenztem Territorium eine beachtliche Zahl von Grabungen durchgefuhrt. Die Untersuchungen betrafen sowohl die grosen Gotteshauser im Zentrum der Stadt als auch die bescheideneren Kirchen im Umland. Der vorliegende Artikel behandelt den zweiten, die Christianisierung der landlichen Gebiete betreffenden Aspekt.

Addiction is a behavioral disease of which core components can be modeled in rodents. Much evidence implicates drug evoked synaptic plasticity in cocaine evoked locomotor sensitization cue induced cocaine seeking and incubation of cocaine craving. However the type of plasticity evoked by different modalities of cocaine administration (e.g. contingent versus non contingent) and its role in reshaping circuit function remains largely elusive. Here we exposed mice to various regimens of cocaine and recorded excitatory transmission onto identified medium sized spiny neurons (MSN expressing fluorescent proteins under the control of either D1R or D2R dopamine receptor promotor) in the nucleus accumbens (NAc) at time points when behavioural adaptations are observed. In D1 MSN we found the presence of GluA2 lacking a amino 3 hydroxy 5 methyl 4 isoxazolepropionic acid receptors (AMPARs) after single or chronic non contingent exposure to cocaine as well as after cocaine self administration. We also report an increase in the AMPA/NMDA ratio (A/N) in D1 MSN which was observed only after repeated passive injections associated with locomotor sensitization as well as in a condition of self administration (SA) leading to seeking behaviour. Remarkably insertion of GluA2 lacking AMPARs was also detected in D2 MSN after self administration of a high dose of cocaine but not regular dose (1.5 vs. 0.75 mg/kg) which was the only condition where incubation of cocaine craving was observed in this study. Moreover synapses containing GluA2 lacking AMPARs belonged to amygdala inputs in D2 MSN and to medial prefrontal cortex (mPFC) inputs in D1 MSN. Taken together this study allows for a refinement of a circuit model of addiction based on specific synaptic changes induced by cocaine.

This article describes the history of the concept of ‘the social’ as a substantivated adjective. Despite the growing use of the terms ‘society’ and ‘social’ in the eighteenth and nineteenth century, it is only at the beginning of the twentieth century that ‘the social’ started being used as an independent concept. In its simplest and most general meaning, ‘the social’ is the ensemble of phenomena involving a relation between human beings, and thus distinct from the individual and the natural. Emile Durkheim and Marcel Mauss used the expression in this sense. In the 1950s, Hannah Arendt gave a more limited meaning to the expression: she spoke of ‘the rise of the social’ to describe and criticize the development of modern industrialized societies; in these societies, economic activities (the production and consumption of goods) have become the primary concern of individuals, and the distribution of benefits the central activity of governments, resulting in a loss of political freedom. In the last decades of the twentieth century, the importance of the concept of ‘the social’ has steadily grown, thereby becoming one of the fundamental notions of the social sciences, central to many social theorists. ‘The social’ has thereby acquired a meaning of its own, independent of ‘society’: a more abstract term applicable to the macrolevel, as well as to the microlevel and with less connotations of homogeneity and boundedness, it is even often described, instead of ‘society,’ as the proper object of the social sciences and social philosophy.

In intellectual history and in political science, among other disciplines, the notion of ‘national tradition’ often plays an important role. This article presents and discusses some recent descriptions of the French political tradition, proposing a distinction between those who identify ‘one dominant tradition’ and those who favour an approach in terms of multiple, equally influential, yet by and large incommensurable traditions. Taking the intellectual life of the French Third Republic as an example, the article shows how political traditions are transformed by historical events as well as how, far from being fixed and stable entities, they often stand in a relation to each other which allows for processes of emulation or conscious borrowing. In conclusion, the article suggests that the problem with ‘national traditions’ has less to do with the quantitative difficulty of correctly counting their number than with the very notion of tradition itself.

I. Introduction La réflexion sur la culture et les identités culturelles revêt aujourd’hui une importance accrue : devant la multiplication des conflits décrits comme ‘identitaires’ au Sud et en Europe on assiste au développement de toute une littérature, en sciences sociales notamment, qui cherche à revaloriser la notion de culture. Dans ce cadre on cherche à montrer que les sujets sociaux agissent bien plus en fonction de référents propres à leur communauté d’origine qu’en fonction de l’int...

Quelle a été, hors de France, la réception de l’œuvre d’Émile Durkheim au cours des cent dernières années ? Dans la présente tentative de fournir une réponse à cette question, il ne sera bien sûr pas question d’offrir un tour d’horizon complet, mais simplement d’identifier quelques lignes de force. À côté d’indications sommaires retraçant les grandes étapes de la réception d’É. Durkheim dans trois contextes intellectuels bien distincts (Grande‑Bretagne, États‑Unis, monde germanophone), je me ...

International audience; Nucleus accumbens neurons serve to integrate information from cortical and limbic regions to direct behaviour. Addictive drugs are proposed to hijack this system, enabling drug-associated cues to trigger relapse to drug seeking. However, the connections affected and proof of causality remain to be established. Here we use a mouse model of delayed cue-associated cocaine seeking with ex vivo electrophysiology in optogenetically delineated circuits. We find that seeking correlates with rectifying AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor transmission and a reduced AMPA/NMDA (N-methyl-D-aspartate) ratio at medial prefrontal cortex (mPFC) to nucleus accumbens shell D1-receptor medium-sized spiny neurons (D1R-MSNs). In contrast, the AMPA/NMDA ratio increases at ventral hippocampus to D1R-MSNs. Optogenetic reversal of cocaine-evoked plasticity at both inputs abolishes seeking, whereas selective reversal at mPFC or ventral hippocampus synapses impairs response discrimination or reduces response vigour during seeking, respectively. Taken together, we describe how information integration in the nucleus accumbens is commandeered by cocaine at discrete synapses to allow relapse. Our approach holds promise for identifying synaptic causalities in other behavioural disorders.