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Mechanisms of blood-brain barrier penetration: A molecular dynamics study on R9 and MPG peptide translocation
No full textInternational audienceOne of the major obstacles in treating diseases that affect the central nervous system is delivering drugs across the blood-brain-barrier (BBB). Cell-penetrating peptides (CPPs) can be used as delivery vectors, but their translocation mechanism is still poorly understood, in part due to the simplistic membrane models applied to their interpretation. Here we investigate the translocation mechanism of two CPPs, R9 and MPG, using molecular dynamics and enhanced sampling techniques on a realistic membrane model of human brain microvascular endothelial cells. The results suggest that R9 induces greater membrane disruption compared to MPG, yet that both face a significant free energy barrier to translocation. In both peptides the first interactions were initiated by the N-terminus and prominently involved arginine residues even for MPG. The crucial role of the plasticity of both partners (BBB bending, partial CPP unfolding) on the translocation energetics was also explored by sampling ad hoc collective variables, revealing the important role of long polyunsaturated acyl chain lipids. Together, these findings provide mechanistic insight into CPP-mediated transport and offer guidelines for rational design
Première mésencéphalotomie par thermothérapie laser interstitielle guidée par IRM (MRgLITT) pour douleurs cancéreuses réfractaires
No full textInternational audienceIntroductionLa mésencéphalotomie stéréotaxique cible les voies spinothalamiques pour traiter les douleurs réfractaires. Nous rapportons le premier cas de mésencéphalotomie par MRgLITT assistée par robot pour douleur maligne intraitable.ObservationUn homme de 47 ans atteint de mélanome métastatique présentait des douleurs sévères réfractaires (EVA > 7) liées à des lésions sous-cutanées inflammatoires de l’hémicorps droit, malgré corticoïdes, opioïdes, kétamine et anesthésiques topiques. Une mésencéphalotomie par MRgLITT assistée par robot ROSA a été proposée dans ce contexte palliatif.La planification utilisait une IRM haute résolution (3D-T1, SWAN, tenseur de diffusion) et un scanner en coupes fines. Les coordonnées cibles localisaient le faisceau spinothalamique avant son entrée thalamique (1 mm en avant de la tangente à l’aqueduc, 5 mm postérieur à CP, 5 mm sous CA-CP, 8 mm latéral).Sous anesthésie locale, un cadre stéréotaxique a été fixé. Le robot a guidé une microélectrode pour macrostimulation de contrôle (50 Hz, 2,5 V). Ensuite, une sonde laser a été positionnée. L’ablation thermique sous controle IRM en temps réel a permit de créé une lésion sphérique de 5 mm de diamètre (Fig. 1).En postopératoire, l’EVA a diminué à moins de 3, sans déficit neurologique. Les opioïdes ont été réduits. Le patient est malheureusement décédé un mois plus tard des suites de la maladie cancéreuse.DiscussionLa MRgLITT offre un guidage IRM temps réel et une précision lésionnelle supérieure aux techniques neurochirurgicales historiques. Les alternatives (cordotomie, myélotomie, stimulation cérébrale profonde) étaient inadaptées à la topographie douloureuse ou présentaient des risques spécifiques. Cette technique mini-invasive représente une option prometteuse pour les douleurs réfractaires en contexte palliatif.ConclusionLa mésencéphalotomie par MRgLITT constitue une option mini-invasive prometteuse pour les douleurs cancéreuses réfractaires, permettant une amélioration significative de la qualité de vie en soins palliatifs
Conference report for 'Cultures of Democracy: Commonwealth leadership, grassroots activism and people empowerment in times of crisis'
No full textThis two-day conference was organised to coincide with two major anniversaries of the Commonwealth of Nations, as highlighted by Kingsley Abbott in his opening remarks.First, the creation of the Commonwealth Secretariat 60 years ago, which went on to establish a Commonwealth-wide team of diplomats and administrators to oversee programmes and policies and to provide informed insights; and secondly, the Millbrook Action Programme on the Harare Declaration, which set up the Commonwealth Ministerial Action Group (CMAG) 30 years ago to promote democracy, human rights and the rule of law as well as sanction states found to be in violation of these tenets. But with the advance of far-right and populist regimes in recent years, there have been increasingly blatant displays of transactional diplomacy and attacks (both actual and contemplated) on international regimes of sovereignty, human rights and the rule of law. While this is not unprecedented, attacks on democratic governance have in recent months benefited from rising disregard for fact-checking, particularly in the age of social media and artificial intelligence. This has highlighted the importance of responsible and accountable reporting, as well as the safeguarding of sites of knowledge production across the world, as a key priority for states, people, and international organisations whose commitment to democracy is primordial.In this context, the panellists and the audience coming together for this conference, in-person and online, considered a series of vital questions for the Commonwealth as an organisation of states and peoples, looking both at the relevance of programmes and dialogue within the Commonwealth and at the relevance of the Commonwealth itself (state and non-state) on the wide international stage. How wellequipped is the Commonwealth to face the multiplicity of challenges posed to a rulesbased international system? What leadership, or support, can its experience, expertise, institutions and networks provide, to preserve and promote the rule of law, in both domestic contexts and on the international stage?</div
CARDIOVASCULAR EFFECTS OF LANDIOLOL IN INTENSIVE CARE PATIENTS: A RETROSPECTIVE SAFETY ANALYSIS
No full textInternational audienc
Hyperpolypharmacy in patients with chronic kidney disease and its impact on clinical outcomes
No full textInternational audienceHyperpolypharmacy (≥ 10 daily medications) is frequent in patients with chronic kidney disease (CKD), but its impact remains poorly characterized. This study, based on 3,011 non-dialyzed, non-transplant CKD outpatients from the CKD-REIN cohort (eGFR < 60 mL/min/1.73 m2) aimed to describe drug burden and assess associations between hyperpolypharmacy and adverse outcomes. Drug prescription, kidney function, adverse drug reactions (ADRs), hospitalizations, kidney replacement therapy and deaths before KRT were prospectively recorded over five years. Median age was 69 years and mean eGFR was 34 mL/min/1.73 m2. At baseline, 80% of the cohort had polypharmacy (≥ 5 daily medications), and 33% had hyperpolypharmacy. These rates remained stable over time. Diabetes, dyslipidemia, and a history of cardiovascular and respiratory diseases were the main contributors to hyperpolypharmacy status. Hyperpolypharmacy was associated with greater likelihoods of an ADR (hazard ratio (HR) [95% confidence interval (CI)] 1.21 [1.04-1.40]), hospitalization (HR [95%CI] 1.34 [1.18-1.51]) and death before KRT (HR [95%CI] 1.46 [1.17-1.82]). Among patients with eGFR ≥ 30 mL/min/1.73m2, hyperpolypharmacy also raised the risk of KRT initiation (HR [95%CI] 1.46 [1.00-2.13]), but not in those with eGFR < 30 (HR [95%CI] 0.94 [0.78-1.14]). These results identify hyperpolypharmacy as a significant concern in CKD and underscore the importance of regular medication reviews to reduce adverse outcomes
A rapid immunochromatographic assay for the detection of BK Polyomavirus in urine samples from hematopoietic stem cell transplant recipients
No full textInternational audienceHemorrhagic cystitis (HC) following hematopoietic stem cell transplantation (HSCT) is a significant event that can lengthen hospital stays and the need for care. The causes of HC can be multiple, but BK Polyomavirus (BKPyV) is the main protagonist in frequency. Currently, the clinical tool widely used to detect the presence of the virus in urine is PCR-based viral genome testing. We have developed a new rapid test for the antigenic detection of BKPyV in urine. The aim of this diagnostic study was to retrospectively evaluate the performance of this new assay as compared to BKPyV PCR on urine from HSCT patients with suspected HC. 49 samples from 49 different patients were evaluated, 20 of whom presented with HC. Of these 20 samples, 19 (95%) were positive by the rapid antigen test. Of the 37 BKPyV PCR-positive samples, 31 were above 7log10 copies/mL, including the 20 patients with HC. Thus, the overall performance of the rapid test for HC is greatly improved compared with PCR, with specificity rising from 62.1% to 86.2% and positive predictive value from 64.5% to 82.6%. In conclusion, this new tool could be implemented as a point-of-care test to rapidly confirm or rule out a suspicion of BKPyV-HC after HSCT
Development of a Prognostic Model for Poststroke Dementia Using Multiple International Cohorts
No full textInternational audienceBackground and objectives: Dementia risk prediction models developed for the general population perform poorly in stroke cohorts. Existing stroke-specific models are few and limited by short prediction horizons or reliance on neuroimaging. The aim of this study was to develop a clinically practical model for predicting 5-year dementia risk after stroke using commonly available variables and individual participant data from the Stroke and Cognition Consortium (STROKOG).Methods: Data were pooled from 12 studies across 10 countries. Dementia was diagnosed mainly by expert panel consensus and algorithmic classification. Fine-Gray subdistribution hazard models estimated dementia probability, accounting for death as a competing event. Candidate predictors included routinely collected baseline clinical and stroke-related variables, selected through backward stepwise elimination. Model performance was evaluated using discrimination (C-index) and calibration for prediction up to 5 years after stroke. Internal-external cross-validation (IECV) assessed generalizability across studies, regions, and study periods.Results: A total of 2,663 participants (mean age 67.0 years [SD 11.1]; 40% female) were followed for a median of 2.0 years (IQR 1.0-5.0), during which 655 developed dementia (8.7 per 100 person-years). The final model included age, sex, education, history of previous stroke, diabetes, stroke severity, 2 interactions (age × sex; age × stroke severity), and study-level variables including national current health expenditure. An Excel-based risk calculator is available in the Supplement (eAppendix 1). The model demonstrated strong discrimination (C-index: 0.81; 95% CI 0.75-0.87) and excellent calibration in the full data set used for development. In IECV, discrimination was acceptable across individual studies (pooled C-index: 0.70 [0.67-0.73]) and higher in recent (post-2010; 0.79 [0.76-0.82]) and European (0.74 [0.71-0.78]) cohorts. Risks were slightly overestimated in Asian cohorts. Case numbers were too small for reliable assessment in other regions.Discussion: We developed and internally-externally validated a 5-year dementia risk model for stroke survivors using routinely available clinical variables. The model showed strong performance in the full development data set and generalized well to recent and European cohorts, although external validation in diverse populations is needed. This tool can help identify high-risk individuals for targeted cognitive monitoring and follow-up. By informing clinical decision making and resource planning, it offers a practical means to improve long-term outcomes
A Hybrid Genetic Algorithm for Sustainable Multi-Site Logistics: Integrating Production, Inventory, and Distribution Planning with Proactive CO<sub>2</sub> Emission Forecasting
No full textInternational audienceThis paper introduces a novel, integrated optimization framework for sustainable multi-site logistics planning, which simultaneously addresses production, inventory, and distribution decisions. The proposed hybrid methodology combines a Genetic Algorithm (GA) with Linear Programming (LP) to minimize total logistics costs while proactively integrating environmental impact assessment. The model determines optimal production schedules across multiple facilities, manages inventory levels, and solves the Vehicle Routing Problem (VRP) for distribution. A key innovation is the incorporation of a CO2 emission forecasting module directly into the optimization loop, allowing the algorithm to anticipate and mitigate the environmental consequences of logistics decisions during the planning phase, rather than performing a post-hoc evaluation. The framework was implemented in Python 3.13.4, utilizing the PuLP library for LP components and custom-developed GA routines. Its performance was validated through a numerical case study and a series of sensitivity analyses, which investigated the effects of fluctuating demand and key cost parameters. The results demonstrate that the inclusion of emission forecasting enables the identification of solutions that achieve a superior balance between economic and environmental objectives, leading to significant reductions in both total costs and predicted CO2 emissions. This work provides practitioners with a scalable and practical decision-support tool for designing more sustainable and resilient multi-echelon supply chains
Temperature overrides nutritional cues for optimal oviposition decision in a polyphagous invasive insect
No full textInternational audiencePolyphagous insects rely on multiple cues to choose oviposition sites, including substrate temperature and nutritional quality that often do not coincide. We examined how females of the invasive fly Drosophila suzukii make oviposition decisions when temperature and nutrition mismatch, and whether infection with the symbiotic bacterium Wolbachia influences these choices. We first quantified female performance (egg number, offspring development time, survival, and mass) on four fruit purees at three ambient temperatures. We then assessed oviposition preferences when either substrate temperature or fruit quality varied independently. Finally, we conducted multi-choice experiments combining thermal and nutritional cues to test which most strongly drives oviposition. Both temperature and fruit quality affected offspring performance. While females were not always choosing the most favorable fruit, they consistently prioritized thermally optimal sites, even when these were nutritionally suboptimal. This behaviour gave partial support to the preference-performance hypothesis, which mainly held for temperature –the factor with the strongest effect on offspring development and survival in no-choice tests. Wolbachia infection enhanced offspring survival and reduced development time. It also altered oviposition patterns, leading to a more even distribution of eggs across fruit, though females maintained their preference for thermally favourable sites. Our findings suggest that the invasive success of D. suzukii could partly result from its capacity to select oviposition sites that maximise offspring performance under variable conditions. More broadly, they highlight the need to study behavioural decisions under conflicting environmental constraints to understand how behavioural flexibility contributes to individual fitness and population persistence in changing environments. French Abstract Les insectes polyphages s'appuient sur de nombreux signaux pour choisir leurs sites de ponte, notamment la température du substrat et sa qualité nutritionnelle, qui ne coïncident pas toujours. Cette étude analyse le choix de ponte des femelles de la mouche invasive Drosophila suzukii lorsque ces signaux sont contradictoires, ainsi que l'effet de l'infection par la bactérie symbiotique Wolbachia. L’étude s'est déroulée en quatre étapes : (i) la mesure des performances des descendants (nombre d’œufs, temps de développement, survie, masse de la progéniture) sur quatre purées de fruits à trois températures ambiantes ; l’évaluation des préférences de ponte lorsque (ii) la qualité du fruit ou (iii) la température du substrat variaient indépendamment ; et (iv) des tests à choix multiples pour déterminer le signal influençant le plus le choix de ponte. La température et la qualité du fruit impactent toutes deux la performance de la descendance. Bien que les femelles ne choisissent pas toujours le fruit le plus favorable, elles privilégient systématiquement les sites les plus chauds, thermiquement optimaux, même lorsqu'ils sont nutritionnellement sous-optimaux. Ce comportement soutient l'hypothèse préférence–performance, la température étant le principal facteur déterminant pour le développement et la survie. L'infection par Wolbachia augmente la survie et réduit le temps de développement, tout en modifiant les choix de ponte avec une répartition plus homogène entre les fruits, sans altérer la préférence pour les sites chauds. Ces résultats suggèrent que le succès invasif de D. suzukii pourrait découler de sa capacité à sélectionner des sites de ponte maximisant la performance de la descendance en conditions environnementales variables. Ils soulignent également l'importance d’étudier les décisions comportementales face à des contraintes antagonistes pour comprendre la contribution de la flexibilité comportementale à la valeur sélective des individus et à la persistance des populations
Rethinking Central Bank Money: The Endogeneity of CBDCs and post-Keynesian Theory
No full textInternational audienceThis paper examines how Central Bank Digital Currencies (CBDCs) interact with post-Keynesian theories of endogenous money, focusing on two main issuance scenarios: conversion from existing bank deposits and discretionary issuance by the central bank. By mobilising the debate between horizontalists, structuralists and institutionalists, our analysis shows that issuing CBDCs against deposits is fully compatible with endogenous money theory. Discretionary issuance, where money would be created without prior demand for it and with no relation to banks’ financing operations, raises critical questions and challenges traditional post-Keynesian views, as it introduces an exogenous component into the money supply. However, drawing on recent theoretical advances, particularly the distinction between instrument-level and system-level endogeneity, we argue that CBDCs may transform monetary regimes without necessarily undermining the endogeneity of money at the system level. Although CBDCs do not inherently undermine the endogeneity of money, their macroeconomic impact and political acceptability depend on their design and the broader institutional context. In particular, discretionary issuance opens new possibilities for monetary policy, akin to a digital form of helicopter money, but raises important concerns regarding central bank independence, financial stability, and democratic legitimacy