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Translational approach to study pathophysiological mechanisms and find out prognostic factors of immune checkpoint inhibitors-induced myocarditis
No full textInternational audienceIntroductionImmune checkpoint inhibitors (ICIs) are widely used in cancer therapy but can trigger severe immune-related adverse events, including myocarditis (ICI-M), a potentially life-threatening condition. While early detection of ICI-M has recently reduced mortality, its underlying pathophysiology remains poorly understood. Emerging clinical and preclinical studies suggest a pivotal role for T cells in disease onset, yet the precise mechanisms driving myocardial inflammation remain to be elucidated.ObjectiveDeveloping a translational approach to characterize the pathophysiological mechanisms and to identify prognostic factors of ICI-M to improve patient management.MethodWe prospectively collect clinical, biological, and cardiac imaging data from patients before and during treatment with ICIs. Peripheral blood mononuclear cells (PBMCs) and induced pluripotent stem cell (hiPSC)-derived cardiac cells from the same selected patients serve as models to explore cellular and molecular mechanisms. A preclinical mouse model is used to analyze in vivo cardiac function and to complement molecular and cellular analyses. PBMCs are collected before ICIs, during ICI-M management, and three months post-treatment in non-ICI-M patients. We generate hiPSC-derived endothelial cells and cardiomyocytes from 3 representative ICI-M and non-ICI-M patients. CD4+/CD8+ T cells are isolated for RNA sequencing and functional analyses, and co-cultured with hiPSC-derived cardiac cells to establish an in vitro cardiotoxicity model.ResultsWe identified specific protein signatures in CD8+ T cells from ICI-M patients, notably increased interferon-gamma (IFN-γ) production. Activation of the NLRP3 inflammasome, in response to IFN-γ treatment, was observed in hiPSC-derived endothelial cells and cardiomyocytes from patients. Our results reveal that endothelial cells are highly sensitive to inflammatory cytokines linked to ICI-M, showing a stronger response than cardiomyocytes, with distinct regulatory patterns depending on the cell type or patient group. As observed in humans, our preclinical model shows that few animals develop myocarditis, with only a subset exhibiting conduction abnormalities, myocardial lymphocytic infiltration, and upregulation of PD-L1 and GBP5 proteins, mirroring human observations.ConclusionThis study integrates clinical, human cellular, and animal data, bridging the gap between fundamental research and patient care and reinforcing the relevance and validity of our results. By creating a continuum between clinical and fundamental research, this integrative and translational approach has led to significant breakthroughs in our understanding of ICI-M. It also aims to improve both the safety and efficacy of ICIs while paving the way for personalized management of ICI-M patients
New Insights into Lower Bound for Lie Groups and their Applications
No full textInternational audienceThis article presents a comprehensive review of recent advances in intrinsic Cramér-Rao bounds (ICRBs) for Lie groups (LGs), which play a pivotal role in addressing estimation problems involving parameters and/or observations constrained by geometric structures. The review encompasses both deterministic and Bayesian frameworks, with a detailed examination of their formulation, derivation, and theoretical foundations. Furthermore, we underscore significant theoretical contributions and extend the discussion to practical estimation challenges, offering insights into their applicability. Emphasis is placed on methodologies for validating these bounds, providing a robust framework for performance evaluation across a variety of estimation problems in engineering and applied sciences
Euclid preparation. Establishing the quality of the 2D reconstruction of the filaments of the cosmic web with DisPerSE using Euclid photometric redshifts
No full textInternational audienceCosmic filaments are prominent structures of the matter distribution of the Universe. Modern detection algorithms are an efficient way to identify filaments in large-scale observational surveys of galaxies. Many of these methods were originally designed to work with simulations and/or well-sampled spectroscopic surveys. When spectroscopic redshifts are not available, the filaments of the cosmic web can be detected in projection using photometric redshifts in slices along the Line of Sight, which enable the exploration of larger cosmic volumes. However, this comes at the expense of a lower redshift precision. It is therefore crucial to assess the differences between filaments extracted from exact redshifts and from photometric redshifts for a specific survey. We apply this analysis to capture the uncertainties and biases of filament extractions introduced by using the photometric sample of the Euclid Wide Survey. The question that we address in this work is how can we compare two filament samples derived with redshifts of different precisions in the Euclid Wide Survey context. We apply the cosmic web detection algorithm DisPerSE, in the redshift range , to the GAlaxy Evolution and Assembly (GAEA) simulated galaxy sample which reproduces several characteristics of the Euclid Wide Survey. We develop a method to compare skeletons derived from photometric redshifts to those derived from true galaxy positions. This method expands the commonly used measure of distance between filaments to include geometrical (angles between filaments) and astrophysical considerations (galaxy mass gradients and connectivity-mass relations). We assess whether this approach strengthens our ability to correctly identify filaments in very large surveys such as the Euclid Wide Survey. [abridged
When Pattern-by-Pattern Works: Theoretical and Empirical Insights for Logistic Models with Missing Values
No full textPredicting a response with partially missing inputs remains a challenging task even in parametric models, since parameter estimation in itself is not sufficient to predict on partially observed inputs. Several works study prediction in linear models. In this paper, we focus on logistic models, which present their own difficulties. From a theoretical perspective, we prove that a Pattern-by-Pattern strategy (PbP), which learns one logistic model per missingness pattern, accurately approximates Bayes probabilities in various missing data scenarios (MCAR, MAR and MNAR). Empirically, we thoroughly compare various methods (constant and iterative imputations, complete case analysis, PbP, and an EM algorithm) across classification, probability estimation, calibration, and parameter inference. Our analysis provides a comprehensive view on the logistic regression with missing values. It reveals that mean imputation can be used as baseline for low sample sizes, and improved performance is obtained via nonlinear multiple iterative imputation techniques with the labels (MICE.RF.Y). For large sample sizes, PbP is the best method for Gaussian mixtures, and we recommend MICE.RF.Y in presence of nonlinear features.</div
Refined genotype–phenotype correlations in neurofibromatosis type 1 patients with NF1 point variants
No full textInternational audienceBackground: Neurofibromatosis type 1 (NF1) is one of the most frequent genetic disorders. NF1 is caused by dominant loss-of-function pathogenic variants (PVs) of the tumour-suppressor gene NF1, which encodes neurofibromin, a negative regulator of rat sarcoma proteins. NF1 is an autosomal dominant disorder with complete penetrance, but a highly variable expression. Identification of genotype-phenotype correlations is challenging because of the wide clinical variability, the progressive nature of the disorder and the extreme diversity of the mutation spectrum. Only a few NF1 point variants have been associated with a specific phenotype in NF1 patients.Methods: We investigated a large, well-phenotyped NF1 cohort.Results: We report analyses of genotype-phenotype correlations in 112 NF1 patients with specific NF1 point variants: p.Arg1809 missense variants were associated with a mild form of NF1 (n=24), while a more severe phenotype was associated with codons 844-848 (n=27), p.Arg1276 (n=25) and p.Lys1423 (n=35) missense variants. We describe a new correlation for p.Arg1204 missense variants (n=11), with no neurofibroma observed in patients. Functional studies will be critical for drawing conclusions on the potential hypomorphic or dominant-negative effects of these variants.Conclusion: The current data confirms several genotype-phenotype correlations in NF1, which may be relevant to the management and surveillance of NF1 patients with specific NF1 PVs
Target trial emulation to replicate randomised clinical trials using registry data in multiple sclerosis
No full textInternational audienceBackground: Target trial emulation (TTE) offers a formal framework for causal inference using observational data, but its validity must be evaluated in each research domain by replicating randomised clinical trials (RCTs). We aimed to replicate eight RCTs evaluating the efficacy of disease-modifying therapies (DMTs) in multiple sclerosis (MS) using French registry data.Methods: This multicentre, retrospective, observational study was conducted using data extracted in December 2023 from the Observatoire Français de la Sclérose en Plaques (OFSEP) database. For each emulated trial, patients were included when they initiated one of the DMT evaluated in the corresponding RCT and met its inclusion criteria. Clinical outcomes were the annualised relapse rate and 3-month confirmed Expanded Disability Status Scale progression. Radiological outcomes were new/enlarged T2-lesions and new gadolinium-enhanced T1-lesions on a brain MRI. A targeted maximum likelihood estimator was used to estimate the treatment effect adjusted for confounding factors between groups and corrected for censoring and missing outcome assessment.Results: 14 111 patients were included in eight emulated trials: ASSESS (fingolimod vs glatiramer acetate), BEYOND (interferon beta vs glatiramer acetate), CONFIRM (dimethyl fumarate (DMF) vs glatiramer acetate), OPERA (ocrelizumab vs interferon beta), REGARD (interferon beta vs glatiramer acetate), RIFUND-MS (rituximab vs DMF), TENERE (teriflunomide vs interferon beta) and TRANSFORMS (fingolimod vs interferon beta). Treatment effects estimated in emulated trials were concordant with RCT findings in seven of eight trials for relapse rate, and in all six trials assessing disability progression. Radiological outcomes were more challenging to replicate; concordance was achieved in three of five trials for new T2-lesions, and one of four trials for new gadolinium-enhanced T1-lesions.Conclusion: The combined use of a TTE methodology and high-quality registry data is a valid tool to evaluate treatment effectiveness in MS
Awake surgery with direct electrical stimulation mapping and real-time cognitive monitoring for functionally guided tumor resection: how we do it
No full textInternational audienceBackground: Awake surgery is the reference for diffuse low-grade glioma resection, allowing maximal tumor removal while preserving neurocognitive functions. It is also applicable to other brain tumors. However, key technical elements must be followed to ensure optimal conditions for intraoperative cognitive testing and reliable functional mapping.Method: We describe the asleep-awake-asleep technique with real-time cognitive monitoring and provide practical guidance for safe and effective implementation.Conclusion: Success relies on rigorous intraoperative standards to optimize functional mapping. Beyond oncological outcomes, this surgical philosophy preserves quality of life by respecting individual brain organization, reflecting a shift toward personalized functional neurooncology
Otto Neurath, précurseur de l’économie écologique ? L’étrange actualité de la pensée d’Otto Neurath
No full textInternational audienceThe work of the Austrian socialist economist Otto Neurath has, after a century-long eclipse,recently experienced a resurgence of interest, particularly in the eyes of those who seek today todraw on the history of ideas for theoretical tools to help envision a just ecological transition.Neurath has thus been identified as one of the precursors of ecological economics and of theconcept of ecological planning. However, very few studies have critically examined thisidentification, which remains debatable, if only because the issues Neurath’s work addressed largelydiffer on some aspects from today’s socio-ecological challenges. Furthermore, the central element ofNeurath’s work underpinning this identification -namely, “calculation in kind”- has not yet been thesubject of a systematic and comprehensive analysis. This article aims to address both of these gapsand, as a result, to clarify the conditions under which Neurath’s ideas might fruitfully be mobilized toconfront our current socio-ecological issues.La pensée de l’économiste socialiste autrichien Otto Neurath connait depuis quelquestemps, après une éclipse d’un siècle, un regain d’intérêt, notamment aux yeux de noscontemporains qui souhaitent puiser dans l’histoire des idées des outils théoriques pour penser unetransition écologique juste. Neurath a ainsi été identifié comme l’un des précurseurs de l’économieécologique et du concept de planification écologique. Cependant, il existe très peu de travaux quimettent à l’épreuve cette identification, laquelle demeure en l’état discutable, ne serait-ce queparce que les enjeux auxquels la pensée de Neurath répond sont très différents sur certains aspectsde nos enjeux socio-écologiques contemporains. De plus, l’élément central de la pensée de Neurathsur lequel se fonde cette identification, à savoir le « calcul en nature », n’a pas encore fait l’objetd’une analyse qui se veut systématique et exhaustive. L’article vise à combler ces deux lacunes, etpar conséquent, à préciser, à nos yeux, les conditions heureuses d’une mobilisation de la pensée deNeurath pour faire face à nos enjeux socio-écologiques contemporains
Otto Neurath: the First Socialist Planning Model in Western Europe
No full textInternational audienceOtto Neurath (1882-1945) stands out in the history of planning as the first Western European intellectual to outline a general plan for a socialist economy. As such, he was the initiator of the socialist calculation debate, which fueled a trend of planning thinkers up to contemporary works. This contribution aims at delineating Neurath’s model as well as displaying the historical context which gives meaning to Neurath’s project, all the more so as Neurath himself was an actor of the 1919-20 German Revolution by designing plans for Saxony and Bavaria. However, the literature on Neurath on the subject has limited itself to general considerations on Neurath’s regime. This chapter aims at delving as much as possible into the details of the working of such a regime. It will focus on the most advanced version of the new planning-friendly socialist regime he calls for, which can be found in his early 1920s works, while giving insights about the variations of this model
Dynamic quantum spin Hall effect for light
No full textInternational audienceQuantum Hall effects are prominent phenomena in condensed matter physics that consist in a precisely quantized electrical transport along sample edges [1]. Optical analogs of these effects have been proposed and realized experimentally [2]. We demonstrate that electromagnetic waves not only allow for mimicking these condensed-matter physics phenomena but also add a new dimension to their study. In particular, dynamical aspects of transport phenomena in quantum Hall effects can be studied in optical and microwave experiments whereas these aspects are hardly accessible for electrical transport experiments in solid-state setups. Our experiments use microwaves propagating in carefully designed two-dimensional photonic crystals to demonstrate topologically protected transport of the optical orbital momentum along an interface between two topologically distinct crystals or along crystal edges [3]. This is analogous to the quantum spin Hall effects (QSHE) with the optical orbital momentum playing the role of electron spin (intrinsic angular momentum). Signals carrying orbital angular momenta of opposite signs propagate in opposite directions. Together with the sensitivity of the band structure to the properties of the photonic crystal boundary (an interface with another photonic crystal or with the free space), this allows for controlling the direction of signal propagation by choosing the position of the source and tuning its frequency. The emitted pulse propagates at a speed that is two orders of magnitude slower than the speed of light in the free space and goes around obstacles without backscattering. The last property is due to the topological protection resulting from the topologically nontrivial band structure of our photonic crystals. Although our experiments are performed in the microwave frequency range, they can be readily scaled to optical wavelengths. This opens new opportunities for studying questions of fundamental importance as well as for routing optical signals in photonic applications.This work was funded by the Agence Nationale de la Recherche (Grant No. ANR-20-CE30-0003 LOLITOP).[1] S. Oh, Science 340, 153 (2013)[2] T. Ozawa et al., Rev. Mod. Phys. 91, 015006 (2019)[3] L.A. Razo López, P. Wulles, G. J. Aubry, S.E. Skipetrov, F. Mortessagne, arXiv:2502.2091