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Model-based approach for two-stage group sequential or adaptive designs in bioequivalence studies using parallel and crossover designs
No full textInternational audienceIn pharmacokinetic (PK) bioequivalence (BE) analysis, the recommended approach is the two one-sided tests (TOSTs) on non-compartmental analysis (NCA) estimates of area under the plasma drug concentration versus time curve and C m a x (NCA-TOST). Sample size estimation for a BE study requires assumptions on between/within subject variability (B/WSV). When little prior information is available, interim analysis using two-stage group sequential (GS) or adaptive designs (ADs) may be beneficial. GS fixes the second stage size, while AD requires sample re-estimation based on first-stage results. Recent research has proposed model-based (MB) TOST, using nonlinear mixed effects models, as an alternative to NCA-TOST. This work extends GS and AD approaches to MB-TOST. We evaluated these approaches on simulated parallel and two-way crossover designs for a one-compartment PK model, considering three variability levels for initial sample size calculation. We compared final sample size, type I error, and power estimates from one-stage, GS, and AD designs using NCA-TOST and MB-TOST. Results showed both NCA-TOST and MB-TOST reasonably controlled type I error while maintaining adequate power in two-stage GS and AD approaches, based on our limited computation power. Two-stage designs reduced sample size compared to traditional designs, especially for highly variable drugs, with many trials stopping at Stage 1 in AD designs. Our findings suggest MB-TOST may serve as a viable alternative to NCA-TOST for BE assessment in two-stage designs, especially when B/WSV impacts BE results
Detection of alpha-HPV types in cutaneous squamous cell carcinoma associated with markers of carcinogenesis: a retrospective study
No full textInternational audienceAbstract Background While the role of oncogenic alpha (α)-HPVs in anogenital and oral mucosal cancers is well-established, their involvement in skin carcinogenesis remains unexplored. Objective To investigate the role of α-HPV in cutaneous squamous cell carcinoma (cSCC). Methods This retrospective study included 129 formalin-fixed, paraffin-embedded cSCC samples. The main outcomes were the proportion of α-HPV positive cSCC and the characterization of viral features, assessed through HPV typing and viral DNA integration analysis. Results The study included 99 cases of invasive cSCCs and 30 Bowen’s disease. HPV DNA was detected in 56.6% of samples. HPV from the α genus were identified in 25 samples, (19.4%), with only a single α-HPV type detected in each positive sample. HPV16 was the main type, detected in 10 samples. Peripheral healthy skin tested negative in 10 out of 11 α-HPV-positive samples. Viral DNA was integrated in host-cell DNA in 8 out of 9 HPV16-positive samples. Conclusions This study highlights a significant prevalence of α-HPV-positive samples among both invasive and in situ cSCC. The virological findings support a carcinogenic role of α-HPV in cSCC.To investigate the role of α-HPV in cutaneous squamous cell carcinoma (cSCC)
Evaluation of the toxic effects of food additives, alone or in mixture, in four human cell models
No full textInternational audienceFood additives are present in more than 50% of food products. Several studies have suggested a link between the consumption of certain food additives and an increased risk of developing cancer. This study aimed to evaluate the genotoxicity of 32 additives and six mixtures identified by the NutriNet-Santé cohort as the most widely consumed. Genotoxicity screening was conducted using the γH2AX (for clastogenic compounds) and pH3 (for aneugenic compounds) biomarkers in four human cell models (colon, liver, kidney, and neurons) representing the target organs of food contaminants. The 32 compounds were categorized into five groups based on their toxicological profiles. Eight additives were cytotoxic, four promoted cell proliferation, two were genotoxic with a clastogenic mode of action, and the remaining 19 were neither cytotoxic nor genotoxic at the concentration tested. Among the six mixtures tested, three were neither cytotoxic nor genotoxic, one was cytotoxic, and two were genotoxic at the highest tested concentrations. The observed genotoxicity of the mixtures could not be attributed to the relative concentrations of the individual additives. These findings suggest the possibility of toxic synergies in mixtures and highlight the challenges of studying the combined effects of multiple substances
The Mythical Mind and the City: Ethnology, Decolonisation and the Birth of Ethnopsychiatry in New Caledonia (1967–1991)
No full textInternational audienceThis article explores New Caledonian ethnopsychiatry’s origins amid the 1960s socio-economic boom, Kanaks migration to Nouméa and decolonisation struggles. During this time, the city of Nouméa became a colonial laboratory for psychiatric knowledge, wherein the impact of urban development on mental illness, a fundamental trope of transcultural psychiatry, could be examined. The article reviews 1967–1991 works by psychiatrists and ethnologists in New Caledonia. It describes how the reappropriation of Kanak culture by colonial psychiatrists reified it and depoliticised Kanak struggles taking place during that same period. Specifically, it discusses how the revisiting of Maurice Leenhardt’s ‘mythical mind’ by twentieth-century psychiatrists, in the backdrop of New Caledonia’s independence movement, supported the view that Kanaks couldn’t assimilate into urban life. The article also highlights Dr Georges Zeldine’s writings, showcasing how his pursuit of humanist psychiatry ironically aligned with far-right opposition to Kanak independence
Tailoring Structure and Mechanical Properties of TiZrHfTa Refractory Alloy Thin Films
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Tailoring composition and microstructure to control mechanical properties and thermal stability of thin film metallic glasses
No full textInternational audienceThin film metallic glasses (TFMGs), with thicknesses below ~500 nm, are materials characterized by a unique mechanical properties involving large yield strength (close to the theoretical limit) and ductility (> 10%) due to the activation of mechanical size effects [1]. However, several scientific questions dealing with their mechanical properties and deformation behavior together with thermal stability are still open, especially focusing on the role of the composition, addressing key questions involving the effect of local order, bond strength and free volume. This is crucial in order to synthetize TFMGs with engineered microstructure (i.e. fully amorphous nanolaminated) with even controlled/boosted mechanical properties and high thermal stability which can be maintained and extended to large thicknesses (> 3 m).Within this context, I will first focus on the effect of composition on mechanical and thermal properties of ZrxCu100-x TFMGs with a large composition range from 24 up to 61 Zr at.% [2]. Different crystallization temperatures have been found with the maximum value of ~380°C for Zr52Cu48, reporting the highest number of mixed Zr-Cu bonds and mixing enthalpy (Hmix). Moreover, the hardness increases with Cu content, from 5.5 up to 7.7 GPa for Cu-rich specimens showing a closer atomic distances and stronger bonds. Additionally, the loading rate dependency analysis revealed that larger pop-in’s appeared at low Cu (at.%) content due to a more disordered atomic structure with less strong atomic bonds enabling the formation of annular shear bands around the indent [2]. In a second part of the talk, I will expand the TFMGs compositional space to ternary alloys in which Al is added to ZrCu (from 0 to 12 at.%), while focusing on the mechanical properties and thermal stability. Synchrotron X-Ray diffraction reveals that the addition of Al reduces the average interatomic distances by 10 pm with the formation of shorter bonds (Al-Zr and Al-Cu), influencing the mechanical response (shear/elastic moduli and hardness) which increases by ~15% for 12 at.% Al. The glass transition (Tg) and crystallization (Tx) temperatures increase by Al addition reaching 450 and 500 °C, respectively, for ZrCuAl12 due to the reduction in atomic mobility inhibiting atomic reconfiguration [3].Finally, I will show how we can exploit the previous knowledge with the fabrication of fully amorphous Zr24Cu76/Zr61Cu39 and ZrCu/ZrCuAl9 nanolaminates with different nanoscale bilayer period (from 200 down to 50 nm) and total thickness of 3 m [4]. The combined effect of local chemistry variation and nanointerface density influences the thermal stability as well as the deformation behavior and the mechanical properties with severe shear displacements and strong compositional intermixing along the shear band-deformed zone. Among the main results, I will show an enhanced thermal stability above the single layer constituents as well as modular mechanical properties with large plastic deformation (> 10%) in compression together with yield strength values >1.5 GPa achieved for the smaller bilayer periods. In conclusion, I will provide guidelines to the design of compositional and microstructural-tailored TFMGs with tuned mechanical properties and thermal stability with potential impact for applications.References:[1] M. Ghidelli et al., Homogeneous flow and size dependent mechanical behaviour in highly ductile Zr65Ni35 metallic glass films, Acta Materialia, 131, 246-259, 2017. [2] A. Brognara, J.P. Best, P. Djemia, D. Faurie, G. Dehm, M. Ghidelli‡, Effect of the composition on mechanical properties and thermal stability of Zr100-xCux thin film metallic glasses, Materials & Design 219, 110752 (2022).[3] C. Poltronieri et al., Thermal stability and mechanical properties of ZrCuAlx thin film metallic glasses: Experiments and first-principles calculations, Acta Materialia, 258, 119226, (2023).[4] C. Poltronieri et al., Effect of chemical composition on mechanical properties and shear band propagation in fully-amorphous ZrCu/ZrCuAl nanolaminates, Submitted to Scripta Materialia (2024)
Context-dependent effects of formic acid on olfactory learning and generalisation in ants
No full textInternational audienceAnimals use learning and memory to recognise cues that predict rewards or punishments, allowing flexible decision-making. When facing new stimuli, they often generalise – responding similarly to different but related cues – enabling adaptive behaviour despite natural variation. Pheromones, chemical signals central to social interactions, are known to affect learning and memory, but their role in generalisation is unknown. This study explores how formic acid, an alarm pheromone in Camponotus aethiops ants, influences odour discrimination and generalisation in an appetitive olfactory discrimination learning task. Using controlled conditioning, we found that formic acid affected learning asymmetrically: it enhanced discrimination when octanal was rewarded and hexanal punished but not when hexanal was rewarded and octanal punished, suggesting a shift in learning priorities. Unexpectedly, formic acid also increased responses to conditioned stimuli and novel odours but only when octanal was the rewarded stimulus. These findings suggest that formic acid modulates associative learning and generalisation in a context-dependent way. Rather than acting solely as an arousal trigger, formic acid appears to reshape cognitive processing by altering stimulus discrimination and odour sensitivity. This highlights a novel role for alarm pheromones in modulating cognition, with broader implications for understanding chemical communication in social insects and beyond
Study of dislocation propagation in (113)-oriented diamond films
No full textInternational audienceDiamond has long been recognized as a very promising material for high-performance electronics due to its exceptional properties. Nevertheless, developing power electronic components, particularly in a vertical geometry, remains a significant challenge insofar that it requires thick and heavily boron-doped films as conducting substrate, ideally as wide as possible. While the (100) orientation is extensively used due to its ease of growth of CVD layers, it is usually not the best choice for n-type doping. (111)-oriented substrates are preferred for the growth of phosphorous-doped layers due to a higher incorporation efficiency and activity but on this orientation, the growth of boron doped thick film is impossible. (113) planes lie in between (100) and (111) planes and are also stable during CVD growth and there has been growing interest in the synthesis of (113)-oriented crystals , especially to favour dopant incorporation, which is still a critical issue in electronics, particularly for phosphorous and indeed, we recently demonstrated that the use of (113)-orientation is an efficient alternative for producing thick conducting substrates with low resistivity and wide functional area.Beyond the possibility of producing conductive diamond substrates, it is also important to control the density of defects and in particular the density of dislocations, which remains one of the limiting factors for the development of vertical power devices. These dislocations can appear either at the growth resuming, but a suitable surface treatment allows limiting their appearance, or can originate from the initial substrate and we talk about threading dislocations. For the latter, growth strategies have been developed by various research groups, often inspired by what has already been developed for GaN. In particular, it has been shown that it is possible to deviate the direction of dislocation propagation either by modifying the shape of the substrate , or by deliberately introducing a high concentration of metal impurities into the diamond before growing the active diamond layer . These techniques have been shown to reduce dislocation densities by more than two orders of magnitude. However, efforts to reduce dislocation density have mainly focused on the (100) orientation, where it is well known that extended defects propagate predominantly in the (100) growth direction.In this work, we focused more specifically on (113)-oriented diamond to study the dislocation propagation in this specific orientation. For this purpose, several samples were produced both on the conventional (100) orientation and tha alternative (113)-orientation, starting from HPHT substrates. These samples consist in two stacked layers: a non-intentionally doped (NID) layers covered by a heavily boron-doped layer. The thickness of each layer was limited to 2 µm so that a TEM lamella could be prepared to observe both the HPHT/NID CVD interface and the NID CVD/p+ doped CVD interface, as presented in Fig.1. The TEM study of these stacked layers revealed for the first time, in addition to the classically observed threading dislocations, the presence of dislocation loops allowing assuming the existence of (110) slip planes, which had never been observed before in CVD diamond. In parallel, H2/O2 etching plasmas were used to reveal etching patterns. We will then discuss their morphologies and orientations, which enabled us to show that on the specific (113) orientation, dislocations do not propagate in the growth direction, contrary to what is observed in orientation (100)