Identification of distinct subgroups of Sj\uf6gren\u27s disease by cluster analysis based on clinical and biological manifestations: data from the cross-sectional Paris-Saclay and the prospective ASSESS cohorts

\ua9 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 licenseBackground: Sj\uf6gren\u27s disease is a heterogenous autoimmune disease with a wide range of symptoms—including dryness, fatigue, and pain—in addition to systemic manifestations and an increased risk of lymphoma. We aimed to identify distinct subgroups of the disease, using cluster analysis based on subjective symptoms and clinical and biological manifestations, and to compare the prognoses of patients in these subgroups. Methods: This study included patients with Sj\uf6gren\u27s disease from two independent cohorts in France: the cross-sectional Paris-Saclay cohort and the prospective Assessment of Systemic Signs and Evolution of Sj\uf6gren\u27s Syndrome (ASSESS) cohort. We first used an unsupervised multiple correspondence analysis to identify clusters within the Paris-Saclay cohort using 26 variables comprising patient-reported symptoms and clinical and biological manifestations. Next, we validated these clusters using patients from the ASSESS cohort. Changes in disease activity (measured by the European Alliance of Associations for Rheumatology [EULAR] Sj\uf6gren\u27s Syndrome Disease Activity Index [ESSDAI]), patient-acceptable symptom state (measured by the EULAR Sj\uf6gren\u27s Syndrome Patient Reported Index [ESSPRI]), and lymphoma incidence during follow-up were compared between clusters. Finally, we compared our clusters with the symptom-based subgroups previously described by Tarn and colleagues. Findings: 534 patients from the Paris-Saclay cohort (502 [94%] women, 32 [6%] men, median age 54 years [IQR 43–64]), recruited between 1999 and 2022, and 395 patients from the ASSESS cohort (370 [94%] women, 25 [6%] men, median age 53 years [43–63]), recruited between 2006 and 2009, were included in this study. In both cohorts, hierarchical cluster analysis revealed three distinct subgroups of patients: those with B-cell active disease and low symptom burden (BALS), those with high systemic disease activity (HSA), and those with low systemic disease activity and high symptom burden (LSAHS). During follow-up in the ASSESS cohort, disease activity and symptom states worsened for patients in the BALS cluster (67 [36%] of 186 patients with ESSPRI score <5 at month 60 vs 92 [49%] of 186 at inclusion; p<0\ub70001). Lymphomas occurred in patients in the BALS cluster (five [3%] of 186 patients; diagnosed a median of 70 months [IQR 42–104] after inclusion) and the HSA cluster (six [4%] of 158 patients; diagnosed 23 months [13–83] after inclusion). All patients from the Paris-Saclay cohort with a history of lymphoma were in the BALS and HSA clusters. This unsupervised clustering classification based on symptoms and clinical and biological manifestations did not correlate with a previous classification based on symptoms only. Interpretation: On the basis of symptoms and clinical and biological manifestations, we identified three distinct subgroups of patients with Sj\uf6gren\u27s disease with different prognoses. Our results suggest that these subgroups represent different heterogeneous pathophysiological disease mechanisms, stages of disease, or both. These findings could be of interest when stratifying patients in future therapeutic trials. Funding: Fondation pour la Recherche M\ue9dicale, French Ministry of Health, French Society of Rheumatology, Innovative Medicines Initiative 2 Joint Undertaking, Medical Research Council UK, and Foundation for Research in Rheumatology

Preparation and Instability of Nanocrystalline Cuprous Nitride

Low-dimensional cuprous nitride (Cu3N) was synthesized by nitridation (ammonolysis) of cuprous oxide (Cu2O) nanocrystals using either ammonia (NH3) or urea (H2NCONH2) as the nitrogen source. The resulting nanocrystalline Cu3N spontaneously decomposes to nanocrystalline CuO in the presence of both water and oxygen from air at room temperature. Ammonia was produced in 60% chemical yield during Cu3N decomposition, as measured using the colorimetric indophenol method. Because Cu3N decomposition requires H2O and produces substoichiometric amounts of NH3\u3e, we conclude that this reaction proceeds through a complex stoichiometry that involves the concomitant release of both N2 and NH3. This is a thermodynamically unfavorable outcome, strongly indicating that H2O (and thus NH3 production) facilitate the kinetics of the reaction by lowering the energy barrier for Cu3N decomposition. The three different Cu2O, Cu3N, and CuO nanocrystalline phases were characterized by a combination of optical absorption, powder X-ray diffraction, transmission electron microscopy, and electronic density of states obtained from electronic structure calculations on the bulk solids. The relative ease of interconversion between these interesting and inexpensive materials bears possible implications for catalytic and optoelectronic applications

Improved Secure Integer Comparison via Homomorphic Encryption

Secure integer comparison has been one of the first problems introduced in cryptography, both for its simplicity to describe and for its applications. The first formulation of the problem was to enable two parties to compare their inputs without revealing the exact value of those inputs, also called the Millionaires\u27 problem. The recent rise of fully homomorphic encryption has given a new formulation to this problem. In this new setting, one party blindly computes an encryption of the boolean $(a<b)$ given only ciphertexts encrypting $a$ and $b$. In this paper, we present new solutions for the problem of secure integer comparison in both of these settings. The underlying idea for both schemes is to avoid decomposing the integers in binary in order to improve the performances. Our fully homomorphic based solution is inspired by Bourse et al, and makes use of the fast bootstrapping techniques recently developpedto obtain scalability for large integers while preserving high efficiency. On the other hand, our solution to the original Millionaires\u27 problem is inspired by the protocol of Carlton et al, based on partially homomorphic encryption. We tweak their protocol in order to minimize the number of interactions required, while preserving the advantage of comparing non-binary integers. Both our techniques provide efficient solutions to the problem of secure integer comparison for large (even a-priori unbounded in our first scenario) integers with minimum interaction

Final results from the PERUSE study of first-line pertuzumab plus trastuzumab plus a taxane for HER2-positive locally recurrent or metastatic breast cancer, with a multivariable approach to guide prognostication

Background: The phase III CLinical Evaluation Of Pertuzumab And TRAstuzumab (CLEOPATRA) trial established the combination of pertuzumab, trastuzumab and docetaxel as standard first-line therapy for human epidermal growth factor receptor 2 (HER2)-positive locally recurrent/metastatic breast cancer (LR/mBC). The multicentre single-arm PERtUzumab global SafEty (PERUSE) study assessed the safety and efficacy of pertuzumab and trastuzumab combined with investigator-selected taxane in this setting. Patients and methods: Eligible patients with inoperable HER2-positive LR/mBC and no prior systemic therapy for LR/mBC (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel with trastuzumab and pertuzumab until disease progression or unacceptable toxicity. The primary endpoint was safety. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Prespecified subgroup analyses included subgroups according to taxane, hormone receptor (HR) status and prior trastuzumab. Exploratory univariable analyses identified potential prognostic factors; those that remained significant in multivariable analysis were used to analyse PFS and OS in subgroups with all, some or none of these factors. Results: Of 1436 treated patients, 588 (41%) initially received paclitaxel and 918 (64%) had HR-positive disease. The most common grade 653 adverse events were neutropenia (10%, mainly with docetaxel) and diarrhoea (8%). At the final analysis (median follow-up: 5.7 years), median PFS was 20.7 [95% confidence interval (CI) 18.9-23.1] months overall and was similar irrespective of HR status or taxane. Median OS was 65.3 (95% CI 60.9-70.9) months overall. OS was similar regardless of taxane backbone but was more favourable in patients with HR-positive than HR-negative LR/mBC. In exploratory analyses, trastuzumab-pretreated patients with visceral disease had the shortest median PFS (13.1 months) and OS (46.3 months). Conclusions: Mature results from PERUSE show a safety and efficacy profile consistent with results from CLEOPATRA and median OS exceeding 5 years. Results suggest that paclitaxel is a valid alternative to docetaxel as backbone chemotherapy. Exploratory analyses suggest risk factors that could guide future trial design

Local and nonlocal continuum modeling of inelastic periodic networks applied to stretching-dominated trusses

We present a nonlocal continuum model and its numerical implementation to describe the macroscale response of periodic discrete networks via second-order homogenization. The scale-bridging technique is applied to the specific example of stretching-dominated elastic and inelastic periodic truss networks. Experiments on small-scale truss structures have highlighted the importance of nodal connections on the effective stiffness and strength. Therefore, we describe the mechanics of trusses by accounting for the stretching of truss members and the deformation of nodes. For the representative 2D examples of lattices having square and triangular architectures and for example bar and nodal constitutive laws, we show that a simple continuum model based on affinely deforming a representative unit cell is sufficient to reproduce the nonlinear elastic behavior of discrete trusses. By contrast, localization that arises, e.g., from inelastic deformation requires a refined model. This is where the presented nonlocal continuum model is capable of accurately capturing details of localized deformation. We illustrate the performance of the model by comparing the results of example finite element simulations using the continuum constitutive model to discrete lattice calculations with elastic–plastic bars. Optimal performance is achieved when the representative unit cell of the continuum model agrees with the actual size of the discrete truss unit cell, which accounts for size effects even in regimes where a separation of scales between finite element size and unit cell size does not strictly apply

Suivi floristique des îles de Mareau-aux-Prés (45). Apparition et évolution de l'abondance des espèces invasives en huit ans (2012-2019)

National audienceDans le cadre du programme de recherche BioMareau (Dynamique de recolonisation de la biodiversité après travaux d'entretien du lit de la Loire), Irstea, LNE et le CBNBP réalisent le suivi floristique des îles de Mareau-aux-Prés (45) sur une superficie de 13 ha au sein de la réserve naturelle nationale de Saint Mesmin. Afin de recenser les espèces rares et émergentes, le relevé est réalisé à l'échelle de l'écocomplexe (mosaïque d'habitats) que constitue chacun des 5 îlots (2 à 3 ha) depuis 2012 à raison de 3 passages annuels (début juillet, août et septembre). Lors de chaque passage, sur chaque îlot, deux opérateurs inventorient toute la flore vasculaire avec un effort de recherche de 1h45', en affectant un code d'abondance allant de 1 (accidentel) à 4 (fréquent) à chaque espèce. Dans cette présentation, les notes d'abondance des 3 passages annuels et des 5 îlots ont été cumulées pour chaque espèce. Ainsi, l'indice d'abondance annuelle de chaque espèce pour les îles de Mareau peut varier entre 0 et 60. Les courbes d'évolution de cet indice entre 2012 et 2019 seront examinées et commentées pour : - les espèces invasives avérées en région Centre-Val de Loire (Desmoulins et al, 2017, version 3.0) - les espèces potentiellement invasives, en liste d'observation ou d'attente (Desmoulins et al, 2017, version 3.0) - les espèces exogènes nouvelles et inhabituelles en Loire moyenne, qui pourraient intégrer la catégorie précédente. Le programme BioMareau se terminant fin 2019, l'intérêt de poursuivre le suivi et de l'étendre à deux autres complexes d'îles plus en amont et en aval sera examiné