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Regioselective C-alkylation in a series of functionalized 1,2,3-triazoles: An unexpected preference over O-alkylation
No full textInternational audienceA series of novel 1,2,3-triazole derivatives were synthesized via Cu(I)-catalyzed click chemistry, introducing structural diversity at positions 1 and 4 of the triazole ring, to explore their reactivity toward alkylation. Attempts to perform O-alkylation on hydroxymethyl-substituted triazoles unexpectedly led to unreported regioselective C-alkylation at the methylene adjacent to the triazole ring. The C-alkylation was optimized using DBU and choline acetate in acetonitrile and subsequently examined across a range of alkyl and benzyl bromides to establish its scope and generality. The resulting racemic C-alkylated products were fully characterized, including confirmation of the regioselectivity by X-ray crystallography, and their enantiomers were separated by supercritical fluid chromatography. This work reveals a novel and synthetically valuable C-alkylation pathway for 1,2,3-triazoles, offering new opportunities for the development of structurally diverse and potentially bioactive triazole derivatives
Lipid-based coating of supersaturated amorphous solid dispersions: could it represent an approach to improving their physical stability or oral bioavailability?
No full textInternational audienceAmorphous solid dispersions (ASDs) are widely recognized as an effective formulation strategy to enhance the in vivo performance of poorly water-soluble drugs; however, their broader application is often limited by insufficient long-term physical stability especially if the drug load is higher than the saturation concentration of the drug in the polymer under standard storage temperature conditions. In this study, the objective was to investigate the functional role of a lipid coating in modulating physical stability and in vitro release and bioaccessibility of a supersaturated praziquantel amorphous solid dispersions (ASD-PZQ). ASD-PZQ systems composed of praziquantel and a vinylpyrrolidone–vinyl acetate copolymer was coated using two lipid-based formulations predominantly composed of either beeswax or tristearin. These lipid systems differ in chemical composition, physicochemical characteristics, and biopharmaceutical behavior, particularly with respect to lipid digestibility. Selected additives (surfactants) were incorporated to tailor manufacturability, stability, and coating functionality. As amorphous systems are particularly sensitive to moisture-induced recrystallisation, the coated ASDs were deliberately directly exposed to harsh storage conditions, namely excessive humidity (60% RH) and their physical stability was monitored over a six-month period. To better capture the complexity of gastrointestinal processes, the bioperformance of the lipid coating was assessed using an in vitro multicompartmental digestion model. From a stability standpoint, the lipid coating reduced moisture-induced plasticization during storage. In terms of biopharmaceutical performance, ASD-PZQ coated with beeswax-based formulations exhibited enhanced bioaccessibility compared with uncoated ASD-PZQ, whereas tristearin-based coatings resulted in a prolonged drug release profile. Overall, this work demonstrates that a lipid coating on supersaturated amorphous solid dispersions would mitigate key stability challenges associated with ASD development but also enables the introduction of new functional attributes. These findings position lipid-coated ASDs as advanced, multifunctional drug delivery systems for poorly water-soluble compounds and reinforce their relevance as high-value platforms in pharmaceutical research
MASLD, MASH, and the CKM Spectrum: A Roadmap for Multi-Organ Clinical Trial Design
No full textInternational audienceCardiovascular, kidney, and metabolic (CKM) diseases and liver disease are not merely linked by shared risk factors but also frequently coexist as comorbidities with overlapping pathophysiology. Metabolic dysfunction-associated steatotic liver disease (MASLD) is highly prevalent in individuals with CKM disorders, and vice versa. The concomitant presence of these conditions amplifies the risk of both CKM and liver-related outcomes, raising the question of whether the CKM model should formally incorporate liver dysfunction. In this review, we detail the epidemiological and pathophysiological evidence that supports this expanded framework, highlighting the shared mechanisms of systemic inflammation, lipotoxicity, and fibrotic remodeling that unify these conditions. We then critically appraise the current landscape of selected heart failure, chronic kidney disease, and MASLD/metabolic dysfunction-associated steatohepatitis (MASH) trials, demonstrating how focus on single disease states with the exclusion of or insufficient data on the others has created knowledge gaps. Building on this, we provide a pragmatic outline for designing integrated multi-organ trials. We outline strategies for enriching trial populations, discuss the evidence and challenges for establishing non-invasive tests as surrogate endpoints to replace liver biopsy, and provide a framework for leveraging advanced biomarker and imaging sub-studies in CKM and MASLD/MASH trials. Finally, we advocate for a transition from isolated studies to patient-centered basket and platform trials that use master protocols to develop holistic therapies for these interconnected diseases.</div
Burden of rodent-borne viruses in rodents and zoonotic risk in humans in Cambodia
No full textInternational audienceRodent-borne viruses, including orthohantaviruses, mammarenaviruses, and rat hepatitis virus (HEV-C), pose significant health threats to humans, causing severe diseases such as hemorrhagic fevers, respiratory illness, and hepatitis. In Cambodia, data on these viruses remain limited, and their burdens on human health are unknown. This study investigated the presence of these viruses in rodents and assessed potential human exposure across diverse environmental and socio-economic contexts in Cambodia. The study was conducted in urban, semi-urban, and rural areas of Cambodia during the rainy season of 2020 and dry season of 2022. Rodents were screened for viruses using RT-PCR. Human serum samples from the same sites were tested for IgG antibodies using ELISA. Factors associated with virus spillover into humans were analyzed. Among 750 rodents, 9.7% carried at least one virus: 5.2% mammarenavirus, 3.3% orthohantavirus, and 1.9% HEV-C. Infection rates were highest in urban (14.5%), followed by semi-urban (11.9%) and rural (2.1%) interfaces. Mammarenavirus was more prevalent in the rainy season, while orthohantavirus and HEV-C remained consistent across seasons. In humans, seroprevalence was 12.7% for mammarenavirus, 10.0% for orthohantavirus, and 24.2% for HEV. Higher mammarenavirus seroprevalence was associated with urban residency. Orthohantavirus seroprevalence was associated with urban residency, acute hepatitis history, and flood-prone living areas. HEV seroprevalence increased with urban residency, increasing age, and medical condition history. Our findings highlighted the need for rodent control, improved market infrastructure, enhanced waste management, and public awareness of hygiene practices and zoonotic risks, especially in urban high-risk areas. IMPORTANCE Rodents can carry viruses that may spread to humans, sometimes causing serious diseases. However, little was known about the presence of these viruses in Cambodia or their potential impact on human health. This study investigated rodent populations across urban, semi-urban, and rural areas and tested both rodents and humans for three key viruses: arenavirus, hantavirus, and hepatitis E virus. The findings confirm the presence of these viruses in rodents and indicate human exposure, particularly in urban areas. Factors such as urban residency and living in flood-prone areas were associated with an increased risk of exposure. These results emphasize the need for improved rodent control, waste management, and public awareness of zoonotic disease risks. A better understanding of virus transmission dynamics will help guide health officials in developing effective strategies to prevent infections and protect communities
Clinical Phenotypes of Critically Ill Patients with COVID-19 Infected with Omicron: A Nationwide Prospective Cohort Study
No full textInternational audienceINTRODUCTION: The clinical presentation of critically ill patients with coronavirus disease 2019 (COVID-19) has evolved significantly with the emergence of the Omicron variant. Current intensive care unit (ICU) admissions involve patients with diverse comorbidities and immune statuses, highlighting the need to redefine homogeneous phenotypic subgroups within this population. This study aimed to characterize distinct clinical phenotypes among critically ill patients with COVID-19 and acute respiratory failure. METHODS: This multicenter prospective substudy of the SEVARVIR cohort included adult patients from 39 French ICUs between December 2021 and October 2024 with acute respiratory failure and infected with the Omicron variant. Clustering analysis was conducted using Kohonen’s self-organizing maps (SOMs) and validated with ClinTrajan, two unsupervised clustering methods, to identify homogeneous patient phenotypes. RESULTS: During the study period, 777 patients with Omicron infection were included, and 7 distinct clinical clusters were identified. Clusters 1 and 2 included patients with metabolic and cardiovascular comorbidities. Cluster 3 featured younger, mildly ill patients with isolated chronic respiratory failure, while cluster 4 comprised older male patients with isolated respiratory failure. Cluster 5 included patients with isolated hematologic malignancies, cluster 6 patients with multiorgan failure, and cluster 7 organ transplant recipients, with high severity scores and impaired renal function. ICU management varied substantially across clusters. Patients in clusters 5 and 7 had the highest requirements for organ support, with frequent use of invasive mechanical ventilation, vasopressors (cluster 6), and renal replacement therapy (cluster 7). Dexamethasone and tocilizumab were most commonly prescribed in cluster 4 (91.3% and 30.2%, respectively). Mortality at day 28 varied significantly across clusters, ranging from 13.1% in cluster 3 to 41.1% in cluster 6. CONCLUSIONS: This clustering analysis highlights, for the first time, the clinical heterogeneity of critically ill patients infected with Omicron, identifying seven distinct clusters with varying clinical presentations, management strategies and outcomes. These findings underscore the relevance of a phenotype-driven approach to support personalized treatment strategies and guide future clinical trials. TRIAL REGISTRATION: Clinicaltrials.gov, NCT05162508. A Graphical Abstract is available for this article
Converting Liminal Uncertainty into Collective Agency: A Futures Literacy Lab in Maré, Rio de Janeiro
No full textFutures literacy is more than a pedagogical tool for enhancing people’s perceptions of the various anticipatory systems and processes. When embedded in a process to promote social recommitment and social transformation, it converts liminal uncertainty into collective agency. This study shows the case of Conjunto de favelas da Maré (Rio de Janeiro) – through Redes da Maré (NGO) – where communities exposed to a state of permanent crisis struggle to move from recognizing challenges to taking action. We ask how a Futures Literacy Laboratory (FLL) can be designed and evidenced so that community imaginaries travel beyond workshops into agendas, roles, and institutional footholds. Using participatory action research, we co-led a UNESCO-type FLL in Maré (Nov 2023–Jul 2024) with ~30 residents and staff; data included workshop artefacts, transcripts, field notes, and participant reflections. The contribution is interpretive and methodological: a gated six-stage cycle specifies checkpoints and roles, showing how shared imaginaries act as coordination devices that yield ranked agendas and endogenous governance capacity. The resulting Maré Framework unwinds a portable chain: Uncertainty → Displacement → Cognitive Openness → Futures Exploration → Social Recommitment; and replaces vague “vulnerability”, making it empirically traceable. Policy implications include embedding community-ranked agendas in participatory budgeting and brokering cross-scalar alliances. This intervention also functioned as a structured research device. It demonstrates that a participatory futures laboratory can simultaneously generate community imagination and empirical insight into the social conditions of anticipation
Chronic cadmium exposure promotes TRPM7-dependent acquisition of a myofibroblast-like phenotype in pancreatic stellate cells
No full textInternational audienceCadmium (Cd) is a metallic pollutant which has been classified as a possible pancreatic carcinogen. Cd uses similar ion channels than divalent cations to accumulate into the cells. These include the Transient Receptor Potential Cation Channel Subfamily M Member 7 (TRPM7) which has been also shown as a biomarker of pancreatic cancer. Pancreatic carcinogenesis is associated with the establishment of a fibrous stroma induced by pancreatic stellate cell (PSC) activation. Although several stress factors have been identified as activators of PSCs, the impact of pollutants, particularly Cd, is still unknown. Here, we chronically exposed human PSCs to Cd and we observed that Cd-exposed cells acquired a myofibroblast-like phenotype. Moreover, TRPM7 expression and activity were upregulated following Cd exposure. Both TRPM7 inhibition by silencing or NS8593 treatment prevented the Cd-induced PSC cell migration indicating that TRPM7 regulated PSC activation. We used a model of indirect co-culture to study the impact of PSC on MIA PaCa-2 cancer cell migration. Interestingly, we showed that Cd-exposed PSCs stimulated MIA PaCa-2 cancer cell migration to a greater extent than non-exposed PSCs. TRPM7 inhibition in PSCs abolished the migration of cancer cells. Finally, in a mouse model with the KRASG12D mutation inducing spontaneous pancreatic intraepithelial neoplasia, Cd exposure aggravates collagen deposition in fibrotic areas showing high α-SMA and TRPM7 expressions. In summary, our study showed that Cd exposure upregulates TRPM7 leading to PSC activation and aggravation of precancerous pancreatic fibrosis in viv
Compassionate Use of Olorofim for Invasive Mold Infections: A Nationwide Observational Study in France
No full textInternational audienceBackground: The increasing incidence of resistant invasive mold infections (IMIs) has highlighted the need for novel antifungal agents. Olorofim, a first-in-class orotomide, has shown promising efficacy in a recent phase II study, but clinical data remain limited.Methods: We conducted a retrospective multicenter cohort study in France, including all patients who received olorofim under compassionate use for proven or probable non-Mucorales IMIs. Eligible patients had IMIs refractory to or intolerance to standard antifungals or no effective treatment options. Efficacy was defined as mycological and clinical control of infection; safety was also assessed.Results: Between January 2020 and December 2023, 17 patients (median age, 39 years) received olorofim. Underlying conditions included primary immunodeficiency (n = 4) and lung transplantation (n = 5). Sites of infection included the lung (88.2%) and the central nervous system (23.5%), with 5 cases of disseminated disease. In total, 23 strains were identified, mostly Aspergillus fumigatus (34.8%) and Microascus spp (13%). The median duration of prior antifungal therapy was 9.1 months. Olorofim was used primarily for refractory IMIs (70.6%) and in combination with other antifungals in 82.4% of cases. Olorofim minimum inhibitory concentrations were ≤0.5 mg/L in the 8 available isolates. Among 15 evaluable patients, 5 (33.3%) achieved clinical and mycological success, 7 (46.7%) had partial responses, and 3 (20%) experienced treatment failure. The 3-month mortality rate was 29.4% (5 of 17). No severe adverse events were reported.Conclusions: Olorofim exhibited potential efficacy and good tolerability in patients with refractory IMIs. Further data from ongoing clinical trials are needed to confirm these findings
Socioeconomic and nutritional determinants outweigh gut microbiota influence on neurodevelopment in young children from Antananarivo, Madagascar
No full textInternational audienceIn 2024, stunted child growth affected 150 million children under the age of five years, underscoring its critical impact on global health. Stunting has also been associated with neurodevelopmental delays. This study explores the relationship between stunting, the fecal microbiota, and neurodevelopment in 2–5-year-old children from the Afribiota cross-sectional study in Madagascar. Children were assessed using the Ages and Stages Questionnaire (ASQ-3), covering five developmental domains (communication, personal-social, problem-solving, fine and gross motor). Fecal samples were analyzed via 16S rRNA gene amplicon sequencing. Classical bi- and multivariate analysis was combined with Structural Equation Modelling to evaluate direct and indirect associations between different clinical factors, the microbiota and neurodevelopment. Our study shows that stunting and low socioeconomic status are consistently linked to poorer neurodevelopmental outcomes, while low branched-chain amino acids and hemoglobin levels are associated with stunting. Furthermore, a higher microbial diversity within individuals (α-diversity—specifically the Shannon index-) was directly linked to improved neurodevelopment scores in one of the tested models, while gut microbiota variation between individuals (β-diversity) was not associated with neurodevelopment. These findings support the hypothesis of neurodevelopment being primarily influenced by nutritional and social factors, with a more limited role for microbiota diversity
Update on the molecular and cellular biology of hepatitis E virus and therapeutic opportunities
No full textInternational audienceHepatitis E virus (HEV) is an emerging zoonotic pathogen and the leading cause of acute viral hepatitis worldwide. Nevertheless, HEV remains largely underestimated and poorly controlled. HEV infects a broad range of host species, transmits through diverse routes and can cause chronic infections in immunocompromised individuals and severe hepatitis in pregnant women. Currently, there is no HEV-specific antiviral treatment available and the only licensed vaccine is restricted to a few countries. Taken together, this highlights its significance as a global health treat and underscores the urgent need for new preventive and therapeutic strategies. This review provides a comprehensive overview of HEV molecular and cellular biology with a focus on antiviral opportunities. First, we summarize the epidemiology and clinical spectrum of HEV infection, as well as the current prevention, vaccination and treatment strategies. Next, we review the molecular mechanisms underlying HEV entry, replication, and assembly/egress, detailing host and viral factors that represent promising antiviral targets. We present the available in vitro and in vivo experimental models that are essential for studying the HEV life cycle and evaluating therapeutic candidates.Particular attention is given to recent discoveries in HEV entry pathways, the organization and functions of the ORF1 replicase complex, and host-virus interactions. Importantly, we provide an up-to-date overview of host-targeting antivirals (HTAs) and direct-acting antivirals (DAAs) against HEV that have been identified so far. This review emphasizes how fundamental virology informs drug discovery and paves the way toward the development of effective antivirals against this underestimated pathogen of increasing global concern