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Pain Reduction in Linzagolix-Treated Patients With Uterine Fibroids: A Secondary Mediation Analysis of the PRIMROSE 1 and 2 Phase 3 Trials.
No full textAmong women with uterine fibroids (UFs), we assess the extent to which the linzagolix effect on pain alleviation is explained by its effect on reducing heavy menstrual bleeding (HMB) and fibroid volume (FV). Post hoc analysis on the pooled data from two randomised double-blind placebo-controlled phase 3 trials. 94 sites in the US (PRIMROSE 1 trial) and 95 sites in Europe/US (PRIMROSE 2 trial). Women aged ≥ 18 years with ultrasound-confirmed UFs and HMB (n = 1012). Participants were randomised to linzagolix (100 mg and 200 mg, with and without hormonal add-back therapy) versus placebo. A post hoc mediation analysis was conducted on the pooled PRIMROSE 1 and PRIMROSE 2 data. The effect of linzagolix versus placebo on pain reduction was divided into three components (effect explained by HMB reduction associated with linzagolix, FV reduction associated with linzagolix, and remaining [not yet explained] treatment effect), with proportions of each component reported. The mediation analysis outcome was clinically significant pain reduction, defined as a change of ≥ 2 pain categories from baseline to Week 24 using the Numeric Rating Scale (pain categories: no pain (0), and mild (1-3), moderate (4-6), severe pain (7-10)). In the mediation analysis, 28%-51% (depending on treatment arm) of linzagolix effect on pain reduction was explained by its effect on HMB reduction, while 2%-8% was explained by its effect on FV reduction. The residual proportion ranged between 44% and 67%, depending on treatment arm, and was statistically significant only in the linzagolix 200 mg without add-back therapy arm (p = 0.002). This analysis showed that reductions in pain were significantly mediated by reductions in HMB (all doses) and FV (200 mg alone) in linzagolix-treated women with UFs. Further research is needed to identify additional mediating factors. ClinicalTrials.gov: NCT03070899 and NCT03070951
Structure and pH Dependence of Membranolytic Mechanisms by Truncated Oxidized Phospholipids.
No full textMembrane lipid oxidation is a universal process that occurs in situations of oxidative stress and is encountered in numerous physiological and pathological situations. Oxidized truncated phospholipids make up a large part of the oxidation products and alter the membrane properties in a way that can lead to cell death. However, the underlying mechanisms are not well understood nor is it clear whether environmental factors, such as pH, can modulate these effects. Using model membranes, we investigate how individual lipid aldehydes and carboxylic acids with truncated acyl chains alter the membrane structure. Our data shows that lipid aldehydes and carboxylic acids have different permeabilization efficiencies towards molecules of varying charge and size and that ΔC9 truncated lipids are usually more efficient in permeabilizing membranes than ΔC5. In terms of physical mechanisms, the ΔC9 truncated lipid carboxylic acid induces permeabilization and membrane curvature in a pH-dependent fashion. This is explained by ionization-dependent exposure of the carboxyl group to the water-bilayer interface, which increases the intrinsic molecular curvature of the oxidized lipid. Conversely, ΔC9 truncated lipid aldehydes and nonionized carboxyls do not induce curved structures but are more efficient in increasing permeability toward larger molecules. We further show that truncated lipids can escape the bilayer and accumulate at interfaces, implying that they might act on neighboring cells. This study indicates that oxidized phospholipids with truncated acyl chains disrupt membrane structure, depending on their specific molecular structure and the pH of the environment, opening a possible route for the design of lipid nanoparticles with pH-dependent drug release
The gut microbiome and cancer: from tumorigenesis to therapy.
No full textThe gut microbiome has a crucial role in cancer development and therapy through its interactions with the immune system and tumour microenvironment. Although evidence links gut microbiota composition to cancer progression, its precise role in modulating treatment responses remains unclear. In this Review, we summarize current knowledge on the gut microbiome's involvement in cancer, covering its role in tumour initiation and progression, interactions with chemotherapy, radiotherapy and targeted therapies, and its influence on cancer immunotherapy. We discuss the impact of microbial metabolites on immune responses, the relationship between specific bacterial species and treatment outcomes, and potential microbiota-based therapeutic strategies, including dietary interventions, probiotics and faecal microbiota transplantation. Understanding these complex microbiota-immune interactions is critical for optimizing cancer therapies. Future research should focus on defining microbial signatures associated with treatment success and developing targeted microbiome modulation strategies to enhance patient outcomes
Dose-Dependent Regional Synchronicity Changes Using Weighted Phase Lag Index: Towards Optimizing Vagus Nerve Stimulation Titration Process
No full textAbstract— Vagus Nerve Stimulation (VNS) is an effective therapy for drug-resistant epilepsy (DRE), but its efficacy varies across individuals. This study uses the weighted Phase Lag Index (wPLI) across multiple frequency bands to examine the dose-dependent regional brain synchronization effect at an individual level. EEG data from four DRE patients (two responders and two non-responders) were analyzed under controlled VNS intensities. Results show that non-responders exhibit an increased synchrony at higher intensity levels, particularly in the beta band and the broadband. Findings highlight individualized neural responses to VNS, underscoring the possibility for personalized stimulation strategies to optimize therapy. Clinical Relevance— Refining the VNS titration process through dose-dependent brain connectivity analysis could accelerate optimization, improving therapeutic outcomes and personalization for drug-resistant epilepsy patients
Constitutionnalisation de la protection et du bien-être des animaux : révision symbolique ou effet papillon ?
No full textSi le chien est le meilleur ami de l’homme, les juristes approchaient jusqu’à il y a peu cette amitié avec une déconcertante froideur. Les animaux sont des choses, au même titre qu’une table ou une chaise. Le droit belge et international a toutefois tenté de corriger cette approche lugubre en veillant à davantage protéger les animaux et leur bien-être. L’insertion récente du bien-être animal dans la Constitution belge mérite que l’on s’y attarde. Dans les lignes qui suivent, nous évaluons s’il faut y voir un simple symbole ou un bouleversement significatif de notre ordre juridique
Pascal and salvation: reflections on the contours of a possible Pascalian philosophy
No full textThis article sets out in what sense a philosophy of salvation can be discerned in Blaise Pascal's notes, known as Pensées. The aim is to characterize a twofold movement of thought accomplished by Pascal, consisting both in inserting salvation into the horizon of human concerns, and in demonstrating the operativity of the Christian religion in matters of salvation. We are thus led to consider the ways in which the theme of salvation emerges, from the study of the human condition in the light of the three classical questions of metaphysics, through death and the image of the castaway, to the immortality of the soul. Finally, the thread of salvation allows us to sketch the outlines of a philosophy with its own characteristics, giving Pascal a marked place in the history of modern philosophy
How to institutionalize permanent citizens’ assemblies?
No full textHow to institutionalize permanent citizens’ assemblies? A response based on two cases
Rituals in Grief: Why Meaning Matters More than Numbers
No full textThe COVID-19 pandemic severely restricted social interactions and ritual practices, deeply affecting mourning rituals. This longitudinal study investigates how prevented and performed rituals influence grief reactions evolution among bereaved individuals in the province of Quebec (Canada). Data were gathered via online surveys conducted five times (every six months) from March 2021 to May 2023. With 529 participants at baseline, we assessed their experiences with pre- and postmortem rituals, satisfaction levels, and grief reactions using the Traumatic Grief Inventory Self Report (TGI-SR). At the start, 32% of participants with a loss occurring ≥ 6 months showed probable Prolonged Grief Disorder (PGD), which decreased to 13.9% by the second data collection. Participants had an average of 2.9 out of eight traditional rituals prevented by the pandemic. Those with probable PGD reported significantly lower satisfaction with performed rituals compared to those with fewer grief reactions. Mixed models analysis indicated that the number of prevented rituals did not predict TGI-SR scores, but satisfaction with performed rituals significantly predicted grief trajectories. Higher satisfaction was associated with lower grief reactions over time. These results suggest that meaningful ritual experiences can help reduce grief intensity even when the number of rituals is limited. The study demonstrates the adaptability of bereaved individuals during the pandemic and emphasizes that the quality, rather than the quantity, of rituals is crucial in the grieving process. This underscores the need to support the facilitation of meaningful rituals to aid those grieving
Le PIAF a vingt ans. Retours sur deux décennies d’archivistique francophone
No full textEn 2025, le Portail international archivistique francophone (PIAF) célèbre ses vingt ans. Pensé à la fin des années 1990 et mis en ligne en 2005, il constitue un espace virtuel de formation, d’information et d’échange dédié à l’archivistique et aux archivistes. Conçu comme une réponse concrète aux besoins d’une communauté professionnelle plurielle, mais réunie par la langue française, ce portail n’a cessé depuis d’évoluer, de s’enrichir et de s’adapter jusqu’à devenir une référence incontournable. Financé depuis l’origine par l’Association internationale des archives francophones, le PIAF entend offrir, gratuitement, une formation complète en archivistique en français. Il est aussi un espace de veille et de mutualisation des savoirs ainsi qu’un lieu d’échange entre archivistes issus de la francophonie et au-delà