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Variability and uncertainty of data from genotoxicity Test Guidelines: What we know and why it matters
No full textInternational audienceThis review comprehensively examines the variability and uncertainty associated with test guideline (TG)-conform genotoxicity data and explores the respective implications for the integration of non-animal-methods (NAMs) into regulatory frameworks. Historical amendments to OECD TGs are mapped to reveal the method’s evolution that improves the scientific quality of the data but also explains data heterogeneity within available databases. An analysis of the major genotoxicity databases ECVAM, ISSMIC, and OASIS demonstrates substantial variability in genotoxicity calls. Using the EFSA genotoxicity database, which currently harbours the best-curated (meta-) data, we estimate that 22–77% of compounds exhibit similarity of replicate results below 85%, depending on the assay. The potentially most important variables statistically explaining variability and sensitivity were analysed. The practical limitations to identify them with high reliability and to define their optimum needs to be accepted as a qualitative baseline uncertainty. These findings underscore the necessity of contextualizing NAM performance evaluations within the intrinsic variability and uncertainty of animal and in vitro reference data. We propose that this variability is explicitly considered in the development and validation of NAM-based Integrated Approaches for Testing and Assessment (IATAs). This review provides a critical foundation for regulators and scientists aiming to enhance the acceptance and utility of NAMs in genotoxicity assessment
Targeted Photodynamic Therapy for Pancreatic Cancer: Recent Innovations from Fundamentals to <i>In Vivo</i> and Clinical Applications (2020-2025)
No full textInternational audiencePhotodynamic Therapy (PDT) is a clinically-approved medical modality to treat different types of localised conditions such as cancer, infections or skin conditions. Pancreatic cancer (PC) is a deadly cancer displaying a dramatic overall prognosis that has barely improved in decades as the majority of PC patients are diagnosed at a locally advanced or metastatic stage and cannot benefit of surgical resection which is the only curative treatment, the overall 5-year survival rate remains extremely low. Thus, finding new therapies for non-metastatic PC to improve local control as a bridge to surgical resection and improve survival outcomes remains a huge challenge. In this context, PDT could be an interesting option. This review will focus on the use of PDT with targeted photosensitisers or nanoparticles to treat PC in recent studies (2020-2025) from in vitro to in vivo experiments and clinical applications
Influence of Time Interval Between the Two Stages of Delayed Coloanal Anastomosis on the Risk of Anastomotic Leakage: Multicenter Study from the GRECCAR Group
No full textInternational audienceBACKGROUND: The optimal time interval between the two surgical stages of a delayed coloanal anastomosis has never been investigated. OBJECTIVE: Assess the influence of time interval on anastomotic leakage occurrence DESIGN: Retrospective cohort study. SETTINGS: Multicentric study (30 colorectal centers). PATIENTS: All patients who underwent delayed coloanal anastomosis (2010-2021). MAIN OUTCOME MEASURES: anastomotic leakage in relation to the time interval between the two surgical stages. RESULTS: A total of 506 patients (female: 42%, median age: 62.1 years) underwent delayed colo-anal anastomosis, 63% immediately after a low anterior resection (primary delayed coloanal anastomosis) and 37% after failure of primary pelvic surgery as a salvage procedure (salvage delayed coloanal anastomosis). The main reasons for salvage delayed coloanal anastomosis were chronic pelvic sepsis (42%) and rectovaginal fistula (38%). The mean time interval between two stages was 8.6 ± 3.8 days, ranging from 1 to 22 days. In the entire cohort, the incidence of anastomotic leakage was 18% (89/506, 95 CI [14%, 21%]) and time interval did not affect the occurrence of anastomotic leakage ( p = 0.529). In sub-group analysis, anastomotic leakage risk was not associated with time interval among primary delayed coloanal anastomosis patients ( p = 0.579) whereas it was for salvage delayed coloanal anastomosis patients ( p = 0.013). In salvage delayed coloanal anastomosis patients, multivariate analysis showed that a longer time interval (adjusted OR=0.89, 95 CI [0.81-0.98], p = 0.035) and surgery in centers performing ≥4 delayed coloanal anastomosis per year (adjusted OR = 0.07, 95 CI [0.01-0.36], p = 0.011) were significantly linked to a lower risk of anastomotic leakage. Each additional day between the two salvage delayed coloanal anastomosis procedures was estimated to reduce the risk of anastomotic leakage by 11%. LIMITATIONS: The retrospective design. CONCLUSIONS: In the context of primary delayed coloanal anastomosis, increasing the time interval between the two stages of delayed coloanal anastomosis does not influence the risk of anastomotic leakage. For salvage delayed coloanal anastomosis, extending the time interval significantly reduces the risk of anastomotic leakage.Multicentric study (30 colorectal centers)
MolGAN-QRL: a hybrid framework for molecule generation using quantum-enhanced reinforcement learning
No full textInternational audienceDiscovering novel drug candidates remains a considerable challenge in pharmaceutical research. Generative AI models such as Generative Adversarial Networks (GANs) have shown considerable promise in de novo molecular generation. They demonstrated high potential in drug discovery applications, yet they often face challenges such as limited chemical coverage and mode collapse. In the present study, we developed MolGAN-QRL, a hybrid quantum-classical framework that introduced quantum-enhanced reinforcement learning within the MolGAN architecture to address these limitations. The proposed framework leveraged a hybrid reward mechanism to further optimize chemical validity, uniqueness, and drug-likeliness of the generated molecules. Experimental results demonstrated that MolGAN-QRL consistently achieved enhanced generative performances compared to classical MolGAN, with up to a 16-fold increase in the count of unique and valid generated compounds under certain conditions. These gains reflected the effectiveness of quantum-guided exploration and highlighted the known trade-off between uniqueness and validity in generative chemistry. Overall, our findings underlined the value of quantum-enhanced reward modeling in mitigating mode collapse and advancing molecular generation, and support the potential of hybrid quantum-classical methods to advance generative chemistry for drug discovery applications
Characterization of broad host range bacteriophages vKpIN31 and vKpIN32 against hospital-acquired Klebsiella pneumoniae in Dakar, Senegal
No full textInternational audienceKlebsiella pneumoniae, a common gut colonizer, has become a major opportunistic pathogen, especially with the rise of multidrug-resistant (MDR) strains. This study aimed to characterize two lytic bacteriophages against MDR K. pneumoniae strains isolated from hospital associated infections in Senegal. Among 28 MDR K. pneumoniae strains tested, phage vKpIN31 effectively lyse 15 strains encompassing 12 distinct K locus types. While phage vKpIN32 lysed 12 strains with 9 different K locus types, demonstrating broad host range activity. The isolated phages exhibited thermal and pH stability. One-step growth analysis revealed a latent period of 25 and 20 minutes and burst sizes of 281 and 246 PFU/cell for vKpIN31 and vKpIN32 respectively. The in vitro lytic activity of phages vKpIN31 and vKpIN32 at different multiplicity of infection (1, 10⁻¹, and 10⁻³) revealed variable lysis efficacy against three K. pneumoniae strains (KP6, KP7, and KP17), with the highest effectiveness observed at an MOI of 10⁻³ for both phages. Also, combination of both phages as cocktail led to improved efficacy against the targeted strains Also, both phages significantly reduced biofilm levels, from 18.6% to 67.9% for 24-hour mature biofilms and from 18.1% to 58.7% for 48-hour mature biofilms. Genomic analysis identified both phages as linear dsDNA viruses belonging to the Caudoviricetes class, and Sugarlandvirus sugarland species. No genes associated with a temperate life cycle, integrases, transposable elements, antibiotic resistance, or bacterial virulence were detected in their genomes. These findings highlight vKpIN31 and vKpIN32 as promising candidates for phage therapy. Additionally, their potential extends to serving as sources for antibacterial and antibiofilm agents, signifying their clinical relevance and therapeutic potential
Green gold of the Pacific: unlocking compounds from terrestrial flora for antitumor and immunomodulatory drug discovery
No full textInternational audienceCovering up to 2025Natural products (NPs) from the terrestrial biodiversity play a key role in oncology drug discovery. While historically identified through bioactivity-guided fractionation, recent advances in high-content screening (HCS) assays, metabolomics, and in silico modeling have significantly enhanced the potential and attractiveness of flora-derived NPs for the development of anticancer therapeutics. This includes immunomodulatory molecules that are able to target the tumor microenvironment to promote immune-mediated clearance of the tumor, thereby improving patient response. This review highlights the untapped potential of molecules extracted from the South Pacific's terrestrial flora in the search for novel antitumor and immunomodulatory compounds. The unique biodiversity of Oceania, including Australia, New Zealand, and Pacific Island Countries and Territories (PICTs) across Micronesia, Melanesia and Polynesia, offers a promising yet largely unexplored reservoir for discovering plant-derived molecules with antitumor and immunomodulatory activities. Herein, we examine the recent pharmacological advances in this field and highlight the need for sustainable and collaborative research. Leveraging cutting-edge technologies could help overcome the challenge of NP-based drug discovery on these geographically isolated islands, unlocking the region's vast potential for plant-derived cancer therapeutics
Effet de l'augmentation de la température sur le virus de la dengue chez le vecteur Aedes aegypti en Nouvelle-Calédonie
No full textInternational audienceDengue virus (DENV) is a major public health concern in tropical and subtropical regions, including the Pacific. Temperature is recognised as a major driver of transmission under climate change. Understanding how higher temperatures may alter DENV transmission is essential to anticipate future dengue risk. Therefore, we assessed the effect of temperature on DENV-1 in Aedes aegypti from New Caledonia. Mosquitoes were orally infected and maintained for 14 days at 26.6 °C (average temperatures during recent outbreaks) or 31.1 °C (SSP5-8.5 scenario projected temperatures). Mosquito bodies, heads, and saliva were analysed separately to determine infection, dissemination, and transmission rates as well as transmission efficiencies. Infectious virus was detected by using a fluorescent focus assay, and viral titres were quantified via TCID50 assays. No significant differences were observed in infection, dissemination, and transmission rates or transmission efficiencies between the two temperatures. However, DENV titres in mosquito bodies and heads were significantly higher at 31.1 °C than 26.6 °C. Our results indicate that elevated temperature increases viral loads within the insect but not the proportion of infectious mosquitoes, highlighting the importance of considering temperature as a key parameter in assessing dengue risk under climate change. Further studies are needed to investigate the effects of temperature on virus–mosquito interactions.Le virus de la dengue (DENV) est un problème majeur de santé publique dans les régions tropicales et subtropicales, y compris dans le Pacifique. La température est reconnue comme un facteur majeur de transmission dans le contexte du changement climatique. Il est essentiel de comprendre comment la hausse des températures peut modifier la transmission du DENV afin d'anticiper les risques futurs liés à la dengue. Nous avons donc évalué l'effet de la température sur le DENV-1 chez les moustiques Aedes aegypti de Nouvelle-Calédonie. Les moustiques ont été infectés par voie orale et maintenus pendant 14 jours à une température de 26,6 °C (température moyenne lors des récentes épidémies) ou de 31,1 °C (température prévue selon le scénario SSP5-8,5). Le corps, la tête et la salive des moustiques ont été analysés séparément afin de déterminer les taux d'infection, de dissémination et de transmission, ainsi que l'efficacité de la transmission. Le virus infectieux a été détecté à l'aide d'un test de focalisation fluorescente, et les titres viraux ont été quantifiés à l'aide de tests TCID50. Aucune différence significative n'a été observée entre les deux températures en termes de taux d'infection, de dissémination et de transmission ou d'efficacité de transmission. Cependant, les titres DENV dans le corps et la tête des moustiques étaient significativement plus élevés à 31,1 °C qu'à 26,6 °C. Nos résultats indiquent qu'une température élevée augmente la charge virale chez l'insecte, mais pas la proportion de moustiques infectieux, soulignant l'importance de considérer la température comme un paramètre clé dans l'évaluation du risque de dengue dans le contexte du changement climatique. D'autres études sont nécessaires pour étudier les effets de la température sur les interactions entre le virus et les moustiques
Modulating complex brain states using MVPA-based neurofeedback: A systematic review
No full textInternational audienceMulti-voxel pattern analysis (MVPA)-based fMRI neurofeedback is a promising tool for modulating brain states and influencing cognition and behaviour, yet its effectiveness remains unclear. This systematic review investigates its efficacy across emotion regulation, fear conditioning, associative and perceptual learning, attention, craving, semantic neurofeedback and motor rehabilitation, incorporating a meta-analytic synthesis of neural effects. A systematic search of PubMed, Web of Science, IEEE, and DPBL databases identified 29 studies. Published studies exhibit considerable variability in protocol designs and methodological aspects related to the implementation of MVPA-based neurofeedback. Overall, the global meta-analysis revealed a moderate, statistically significant effect of MVPA-based neurofeedback on neural outcomes, with subgroup analysis indicating a similar moderate effect in emotion regulation. Most studies support neural modulation following neurofeedback training across multiple domains, though behavioural outcomes are less consistent. Fear reduction, attention and perceptual learning studies demonstrated both neural and behavioural changes, while associative learning and craving reduction studies showed evidence of neural regulation but unclear behavioural outcomes. Studies on motor rehabilitation and semantic neurofeedback demonstrated neural modulation but lacked behavioural assessments. Emotion regulation studies consistently supported neural modulation, however, only a few studies reported behavioural improvements. While these findings highlight the potential of neurofeedback, they also emphasise the need for standardized methodologies and clearer theoretical frameworks. Clarifying terminology used to define different approaches and addressing MVPA-specific methodological considerations – such as preprocessing, motion correction, and classifier selection - will be critical for refining neurofeedback protocols and unlocking the full potential of MVPA-based neurofeedback for both clinical and research applications
Pregnant and breastfeeding women's intention to follow medical advice before antibiotic use: A comparative pilot analysis using the theory of planned behavior in Mahajanga, Madagascar
No full textSource Agritrop Cirad (https://agritrop.cirad.fr/616276/) * Autres projets (id;sigle;titre): 72068719CA00001;RISE;(MDG) Recherche, Innovation, Surveillance et Evaluation//International audienceBackground Antibiotic misuse among pregnant and breastfeeding women is a critical public health challenge in low-resource settings. Individual attitudes, social expectations, and structural barriers shape women's intentions to follow medical advice. Thus, this study investigates how attitudes, subjective norms, and perceived behavioral control shape pregnant and breastfeeding women's intentions to seek medical advice prior to antibiotic use. Methods Using the theory of planned behavior (TPB), this mixed-methods study collected data from 115 women in the urban and rural districts of Mahajanga, Madagascar. Qualitative analysis explored statements and informational practices, whereas linear regressions, partial least squares regressions (PLS-R), and binary logistic regression (BLR) identified determinants of intention. Results Overall, 79.1% of women expressed a willingness to consult healthcare providers, although this was often undermined by unclear prescriptions, family influence, and limited access to care. In urban areas, subjective norms (SN) were the strongest predictor of intention, reflecting the role of social expectations. In rural areas, perceived behavioral control (PBC) was most influential, underscoring the importance of access and self-efficacy. Logistic regression confirmed these patterns: favorable attitude (ATB) (p = 0.005) and high PBC (p = 0.029) significantly increased intention in rural areas. Obtaining antibiotics from official sources was associated with a significantly lower intention in rural areas (p = 0.037). Conclusion Strengthening women's intention to follow medical advice requires addressing knowledge gaps, improving communication, and reducing structural barriers. Interventions should be focused on access and empowerment in rural areas and education and social norms in urban areas. In both urban and rural areas, the engagement of community health workers is a trusted mediator. These findings highlight the need for interventions that integrate both behavioral and structural approaches to ensure rational antibiotic use in terms of maternal and child health
Prise en charge clinique et thérapeutique des hépatopathies stéatosiques associées à une dysfonction métabolique (MASLD)
No full textInternational audienceMetabolic dysfunction–associated steatotic liver disease (MASLD) is currently the leading cause of chronic liver disease worldwide. It arises from complex interactions between genetic susceptibility, excessive caloric intake, sedentary lifestyle, and insulin resistance, predominantly affecting individuals with obesity or type 2 diabetes. Approximately 20% of patients with MASLD progress to metabolic dysfunction–associated steatohepatitis (MASH), which may further evolve to fibrosis, cirrhosis, and hepatocellular carcinoma. Management prima¬rily relies on lifestyle interventions aimed at weight loss, including adherence to a Mediterranean diet, increased physical activity, and reduction of sedentary behavior, with bariatric surgery indicated in severe obesity. Recent therapeu¬tic advances include resmetirom, a thyroid hormone receptor β agonist and the first approved pharmacological treatment for MASH, as well as GLP-1 receptor agonists, co-agonists, pan-PPAR agonists, and FGF21 analogues, all demonstrating promising effects on MASH resolution and fibrosis improve¬ment. Non-invasive biological scores may play a central role in evaluating disease severity and therapeutic response, positioning clinical laboratories at the core of patient management.Les hépatopathies stéatosiques associées à une dysfonction métabolique (MASLD pour metabolic dysfunction-associated steatotic liver disease) constituent aujourd’hui la principale cause de maladie hépatique. Elles résultent d’interactions entre facteurs génétiques, excès alimentaire, sédentarité et insulino-résistance, et touchent surtout les personnes obèses ou diabétiques. Environ 20 % des pala sédentarité. La chirurgie bariatrique est indiquée pour les obésités sévères. De nouvelles options thérapeutiques émergent, notamment le resmétirom agoniste du récepteur thyroïdien β, premier traitement approuvé pour la MASH, les agonistes du GLP-1 (sémaglutide), les co-agonistes (tirzépatide), les agonistes pan-PPAR (lanifibranor) et les analogues du FGF21 (éfruxifermine, pégozafermine). Toutes ces molécules ont montré des résultats encourageants sur la résolution de la MASH et l’amélioration de la fibrose. L’évaluation de ces traitements pourra faire appel aux scores biologiques non invasifs, plaçant le laboratoire de biologie médicale au coeur du suivi thérapeutique