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Objective Methods Results Conclusion European Commission Regulation (EU) n°2023/1545 introduced the concept of grouping names in the cosmetics sector in July 2023. These groups bring together allergenic substances with the same level of skin sensitization. Their purpose is to lighten the list of ingredients on cosmetic packaging, by grouping together substances deemed to be similar under the same name. As this classification is based on a single toxic effect − skin sensitization − the present study aims to analyse the relevance of these groupings with regard to other toxic effects of substances in the same group.This study was carried out by consulting an available database, various reports from 5 committees, 2 books and 5 articles in order to complete the toxicological profile of each substance. Then, in order to highlight any discrepancies within the classification, the worst cases were identified. For this purpose, the data for each substance in a group were compared, and in the event of greater criticality for a toxic effect, this was qualified as a worst case. In addition, similar toxic effects between several substances within the same group were also recorded. The aim of this additional research was to validate the definition of the grouping name and the similarities between substances in the same group.From the 17 grouping names, 5 presented worst cases. Two groups had 2 worst cases and the others only one. In total, from the 7 worst cases detected, 3 were due to the toxic effect “skin irritation”. In most cases, the substances in the groupings shared the presence or absence of risk. Only the degree of risk criticality varied.Classification by grouping names appears justified regarding the similarities between substances, particularly in terms of skin sensitization. However, the presence of worst cases qualifies it and highlights the importance of being vigilant when assessing the risk of cosmetic products including these grouping names in their list of ingredients. [ABSTRACT FROM AUTHOR]

Neutron induced reactions on oxygen have been studied with strong interest because of the uncertainties generated on the helium production in fuel and on the neutron multiplication factor in nuclear reactors [1], [2]. Still large discrepancies exist and new measurements are welcome in order to acquire new data aiming at the uncertainty reduction [3]. SCALP (Scintillating ionization Chamber for ALPha particle production in neutron induced reaction) is a new scintillating ionization chamber [4] used as an active target to measure the cross section of (n, alpha) reactions on various gaseous targets such as 19F or 16O, from the reaction threshold up to 15 MeV. It consists of an ionization chamber filled with CF4 (for fluorine measurements) or CF4+CO2(for oxygen measurements) allowing the detection of the energy deposed by the light charged particles emitted in the (n, alpha) reaction. In addition, four Photo- Multiplier Tubes detect the scintillation light produced by the interaction of the particles in the gas active volume. Taking advantage of the fast response of the scintillation, the neutron kinetic energy can be inferred by time-of-flight measurements. SCALP is then well adapted to mono-energetic neutron beams or to white neutron beams that will be delivered at the NFS Facility [5]. Because of its good resolution, SCALP discriminates different channel outputs, enabling to disentangle the different reactions [6]. We will present the performances of the SCALP detector in terms of temporal and energetic features. We will also present tests made at the GENESIS plate-form at the LPSC Grenoble [7].

Recombinant adeno-associated virus (rAAV) vectors appear, more than ever, to be efficient viral vectors for in vivo gene transfer as illustrated by the approvals of 7 drugs across Europe and the United States. Nevertheless, preexisting immunity to AAV capsid in humans remains one of the major limits for a successful clinical translation. Whereas a preexisting humoral response to AAV capsid is well documented, the prevalence of preexisting capsid-specific T cell responses still needs to be studied and characterized. In this study, we investigated the prevalence of AAV-specific circulating T cells toward AAV2, 4, 5, 8, 9, and rh10 in a large cohort of healthy donors using the standard IFNγ ELISpot assay. We observed the highest prevalence of preexisting cellular immunity to AAV9 serotype followed by AAV8, AAV4, AAV2, AAVrh10, and AAV5 independently of the donors' serological status. An in-depth analysis of T cell responses toward the 2 most prevalent serotypes 8 and 9 shows that IFNγ secretion is mainly mediated by CD8 T cells for both serotypes. A polyfunctional analysis reveals different cytokine profiles between AAV8 and AAV9. Surprisingly, no IL-2 secretion was mediated by anti-AAV9 immune cells suggesting that these cells may rather be exhausted or terminally differentiated than cytotoxic T cells. Altogether, these results suggest that preexisting immunity to AAV may vary depending on the serotype and support the necessity of using multiparametric monitoring methods to better characterize anticapsid cellular immunity and foresee its impact in rAAV-mediated clinical trials.

Context: Validated assays to measure autoantigen-specific T-cell frequency and phenotypes are needed for assessing the risk of developing diabetes, monitoring disease progression, evaluating responses to treatment, and personalizing antigen-based therapies., Objective: Toward this end, we performed a technical validation of a tetramer assay for HLA-DRA-DRB1*04:01, a class II allele that is strongly associated with susceptibility to type 1 diabetes (T1D)., Methods: HLA-DRA-DRB1*04:01-restricted T cells specific for immunodominant epitopes from islet cell antigens GAD65, IGRP, preproinsulin, and ZnT8, and a reference influenza epitope, were enumerated and phenotyped in a single staining tube with a tetramer assay. Single and multicenter testing was performed, using a clone-spiked specimen and replicate samples from T1D patients, with a target coefficient of variation (CV) less than 30%. The same assay was applied to an exploratory cross-sectional sample set with 24 T1D patients to evaluate the utility of the assay., Results: Influenza-specific T-cell measurements had mean CVs of 6% for the clone-spiked specimen and 11% for T1D samples in single-center testing, and 20% and 31%, respectively, for multicenter testing. Islet-specific T-cell measurements in these same samples had mean CVs of 14% and 23% for single-center and 23% and 41% for multicenter testing. The cross-sectional study identified relationships between T-cell frequencies and phenotype and disease duration, sex, and autoantibodies. A large fraction of the islet-specific T cells exhibited a naive phenotype., Conclusion: Our results demonstrate that the assay is reproducible and useful to characterize islet-specific T cells and identify correlations between T-cell measures and clinical traits., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

We elucidated the effect of four known T1D-susceptibility associated single nucleotide polymorphism (SNP) markers in three genes (rs12722495 and rs2104286 in IL2RA , rs689 in INS and rs2476601 in PTPN22 ) on CpG site methylation of their proximal promoters in different lymphocyte subsets using pyrosequencing. The study cohort comprised 25 children with newly diagnosed T1D and 25 matched healthy controls. The rs689 SNP was associated with methylation at four CpG sites in INS promoter: -234, -206, -102 and -69. At all four CpG sites, the susceptibility genotype AA was associated with a higher methylation level compared to the other genotypes. We also found an association between rs12722495 and methylation at CpG sites -373 and -356 in IL2RA promoter in B cells, where the risk genotype AA was associated with lower methylation level compared to the AG genotype. The other SNPs analyzed did not demonstrate significant associations with CpG site methylation in the examined genes. Additionally, we compared the methylation between children with T1D and controls, and found statistically significant methylation differences at CpG -135 in INS in CD8+ T cells ( p  = 0.034), where T1D patients had a slightly higher methylation compared to controls (87.3 ± 7.2 vs. 78.8 ± 8.9). At the other CpG sites analyzed, the methylation was similar. Our results not only confirm the association between INS methylation and rs689 discovered in earlier studies but also report this association in sorted immune cells. We also report an association between rs12722495 and IL2RA promoter methylation in B cells. These results suggest that at least part of the genetic effect of rs689 and rs12722495 on T1D pathogenesis may be conveyed by DNA methylation.

Background: In the recent past, wearable devices have been used for gait rehabilitation in patients with Parkinson's disease. The objective of this paper is to analyze the outcome of a wearable hip orthosis whose assistance adapts in real time to the patient's gait kinematics via adaptive oscillators. In particular, this study focuses on a metric characterizing natural gait variability, i.e., the level of long-range autocorrelations (LRA) in series of stride durations., Methods: Eight patients with Parkinson's disease (Hoehn and Yahr stages 1[Formula: see text]2.5) performed overground gait training three times per week for four consecutive weeks, assisted by a wearable hip orthosis. Gait was assessed based on performance metrics such as the hip range of motion, speed, stride length and duration, and the level of LRA in inter-stride time series assessed using the Adaptive Fractal Analysis. These metrics were measured before, directly after, and 1 month after training., Results: After training, patients increased their hip range of motion, their gait speed and stride length, and decreased their stride duration. These improvements were maintained 1 month after training. Regarding long-range autocorrelations, the population's behavior was standardized towards a metric closer to the one of healthy individuals after training, but with no retention after 1 month., Conclusion: This study showed that an overground gait training with adaptive robotic assistance has the potential to improve key gait metrics that are typically affected by Parkinson's disease and that lead to higher prevalence of fall., Trial Registration: ClinicalTrials.gov Identifer NCT04314973. Registered on 11 April 2020., (© 2023. The Author(s).)

Recombinant Adeno-Associated Virus (rAAV) is considered as one of the most successful and widely used viral vectors for in vivo gene therapy. However, host immune responses to the vector and/or the transgene product remain a major hurdle to successful AAV gene transfer. In contrast to antivector adaptive immunity, the initiation of the innate immunity towards rAAV is still poorly understood but is directly dependent on the interaction between the viral vector and innate immune cells. Here, we used a quantitative transcriptomic-based approach to determine the activation of inflammatory and anti-viral pathways after rAAV8-based infection of monocyte-derived dendritic cells (moDCs) obtained from 12 healthy human donors. We have shown that rAAV8 particles are efficiently internalized, but that this uptake does not induce any detectable transcriptomic change in moDCs in contrast to an adenoviral infection, which upregulates anti-viral pathways. These findings suggest an immunologically favorable profile for rAAV8 serotype with regard to in vitro activation of moDC model. Transcriptomic analysis of rAAV-infected innate immune cells is a powerful method to determine the ability of the viral vector to be seen by these sensor cells, which remains of great importance to better understand the immunogenicity of rAAV vectors and to design immune-stealth products.

Gait variability of healthy adults exhibits Long-Range Autocorrelations (LRA), meaning that the stride interval at any time statistically depends on previous gait cycles; and this dependency spans over several hundreds of strides. Previous works have shown that this property is altered in patients with Parkinson's disease, such that their gait pattern corresponds to a more random process. Here, we adapted a model of gait control to interpret the reduction in LRA that characterized patients in a computational framework. Gait regulation was modeled as a Linear-Quadratic-Gaussian control problem where the objective was to maintain a fixed velocity through the coordinated regulation of stride duration and length. This objective offers a degree of redundancy in the way the controller can maintain a given velocity, resulting in the emergence of LRA. In this framework, the model suggested that patients exploited less the task redundancy, likely to compensate for an increased stride-to-stride variability. Furthermore, we used this model to predict the potential benefit of an active orthosis on the gait pattern of patients. The orthosis was embedded in the model as a low-pass filter on the series of stride parameters. We show in simulations that, with a suitable level of assistance, the orthosis could help patients recovering a gait pattern with LRA comparable to that of healthy controls. Assuming that the presence of LRA in a stride series is a marker of healthy gait control, our study provides a rationale for developing gait assistance technology to reduce the fall risk associated with Parkinson's disease.

Background: Allergen-specific type 2 CD4 + T H 2 cells are critically involved in the pathogenesis of IgE-mediated allergic diseases. However, the heterogeneity of the T H 2 response has only recently been appreciated., Objective: We sought to characterize at the single-cell level the ex vivo phenotype, transcriptomic profile, and T-cell receptor (TCR) repertoire of circulating CD4 + T cells specific to the major dog allergens Can f 1, Can f 4, and Can f 5 in subjects with and without dog allergy., Methods: Dog allergen-specific memory CD4 + T cells were detected ex vivo by flow cytometry using a CD154-based enrichment assay and single-cell sorted for targeted gene expression analysis and TCR sequencing., Results: Dog allergen-specific T-cell responses in allergic subjects were dominantly of T H 2 type. T H 2 cells could be phenotypically further divided into 3 subsets, which consisted of T H 2-like (CCR6 - CXCR3 - CRTH2 - ), T H 2 (CCR6 - CXCR3 - CRTH2 + CD161 - ), and T H 2A (CCR6 - CXCR3 - CRTH2 + CD161 + CD27 - ) cells. All these subsets were nonexistent within the allergen-specific T-cell repertoire of healthy subjects. Single-cell transcriptomic profiling confirmed the T H 2-biased signature in allergen-specific T cells from allergic subjects and revealed a T H 1/T H 17 signature in nonallergic subjects. TCR repertoire analyses showed that dog allergen-specific T cells were diverse and allergic subjects demonstrated less clonality compared to nonallergic donors. Finally, TCR and transcriptomic analyses revealed a close relationship between T H 2-like, T H 2, and T H 2A cells, with the last ones representing the most terminally differentiated and highly polarized subtype., Conclusions: Our study demonstrates heterogeneity within allergen-specific T H 2 cells at the single-cell level. The results may be utilized for improving immune monitoring after allergen immunotherapy and for designing targeted immunomodulatory approaches., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Type 1 diabetes is an autoimmune disease typically starting in childhood that culminates in the destruction of insulin-producing beta cells in the pancreas. Although type 1 diabetes is considered to be a primarily T cell-mediated disease, B cells clearly participate in the autoimmune process, as autoantibodies recognizing pancreatic islet antigen commonly appear in circulation before the onset of the disease. T cells providing helper functions to B cells have recently been shown to be involved in the pathogenesis of a wide range of antibody-associated immune disorders. These T cells include CXCR5-positive follicular T helper (Tfh) cells, and a recently described closely related CXCR5-negative subset coined peripheral T helper (Tph) cells. Here, we review the current state of knowledge on different B cell helper T cell subsets, focusing on their potential involvement in the development of type 1 diabetes., (© 2020 The Authors. Scandinavian Journal of Immunology published by John Wiley & Sons Ltd on behalf of The Scandinavian Foundation for Immunology.)

Objective: To assess the prevalence of influenza and respiratory syncytial virus (RSV) in adults hospitalized for a respiratory infection in the winter months and to evaluate the impact of a viral diagnosis on empirical antimicrobial management (antibiotics and antivirals)., Design: Observational cohort study., Setting: Acute-care university hospital., Patients: The study included 963 adult patients hospitalized over a 4-year surveillance period., Methods: Annual surveillance timelines were defined according to epidemiological criteria related to the circulation of RSV and influenza viruses in the general population. Patients were screened following a severe acute respiratory infection (SARI) case definition at the emergency department and were enrolled for molecular assay targeting influenza/RSV viruses after oral informed consent. Epidemiological and clinical data were recorded prospectively, microbiological investigations, antimicrobial management, and outcome data were reviewed retrospectively., Results: An influenza or RSV virus was documented in 316 of 963 patients (33%). Optimization of antimicrobial management (AM) was achieved in 162 of 265 patients (61%) with a positive viral diagnosis and no bacterial infection at admission (AM treatment not initiated, n = 111; discontinued, n = 51). In contrast, only 128 of 462 patients (28%) with negative microbiological investigations did not have AM treatment initiated (n = 116) or had such treatment discontinued (n = 12). Early, targeted antiviral treatment was prescribed in 235 of 253 patients (93%) confirmed with influenza. Epidemiological, clinical, and outcome data were similar in both groups., Conclusion: Epidemiological surveillance associated with influenza/RSV molecular diagnosis in adults hospitalized for severe winter respiratory infections dramatically enhanced antimicrobial management.

Pre-existing immunity to AAV capsid may compromise the safety and efficiency of rAAV-mediated gene transfer in patients. Anti-capsid cytotoxic immune responses have proven to be a challenge to characterize because of the scarcity of circulating AAV-specific CD8 + T lymphocytes which can seldom be detected with conventional flow cytometry or ELISpot assays. Here, we used fluorescent MHC class I tetramers combined with magnetic enrichment to detect and phenotype AAV8-specific CD8 + T cells in human PBMCs without prior amplification. We showed that all healthy individuals tested carried a pool of AAV8-specific CD8 + T cells with a CD45RA + CCR7 - terminally-differentiated effector memory cell (T EMRA ) fraction. Ex vivo frequencies of total AAV-specific CD8 + T cells were not predictive of IFNγ ELISpot responses but interestingly we evidenced a correlation between the proportion of T EMRA cells and IFNγ ELISpot positive responses. T EMRA cells may then play a role in recombinant AAV-mediated cytotoxicity in patients with preexisting immunity. Overall, our results encourage the development of new methods combining increased detection sensitivity of AAV-specific T cells and their poly-functional assessment to better characterize and monitor AAV capsid-specific cellular immune responses in the perspective of rAAV-mediated clinical trials., (Copyright © 2020 Vandamme, Xicluna, Hesnard, Devaux, Jaulin, Guilbaud, Le Duff, Couzinié, Moullier, Saulquin and Adjali.)

Anti-transgene immune responses elicited after intramuscular (i.m.) delivery of recombinant adeno-associated virus (rAAV) have been shown to hamper long-term transgene expression in large-animal models of rAAV-mediated gene transfer. To overcome this hurdle, an alternative mode of delivery of rAAV vectors in nonhuman primate muscles has been described: the locoregional (LR) intravenous route of administration. Using this injection mode, persistent inducible transgene expression for at least 1 year under the control of the tetracycline-inducible Tet-On system was previously reported in cynomolgus monkeys, with no immunity against the rtTA transgene product. The present study shows the long-term follow-up of these animals. It is reported that LR delivery of a rAAV2/1 vector allows long-term inducible expression up to at least 5 years post gene transfer, with no any detectable host immune response against the transactivator rtTA, despite its immunogenicity following i.m. gene transfer. This study shows for the first time a long-term regulation of muscle gene expression using a Tet-On-inducible system in a large-animal model. Moreover, these findings further confirm that the rAAV LR delivery route is efficient and immunologically safe, allowing long-term skeletal muscle gene transfer.

Preventing untoward immune responses against a specific antigen is a major challenge in different clinical settings such as gene therapy, transplantation, or autoimmunity. Following intramuscular delivery of recombinant adeno-associated virus (rAAV)-derived vectors, transgene rejection can be a roadblock to successful clinical translation. Specific immunomodulation strategies potentially leading to sustained transgene expression while minimizing pharmacological immunosuppression are desirable. Tolerogenic dendritic cells (TolDC) are potential candidates but have not yet been evaluated in the context of gene therapy, to our knowledge. Following intramuscular delivery of rAAV-derived vectors expressing an immunogenic protein in the nonhuman primate model, we assessed the immunomodulating potential of autologous bone marrow-derived TolDC generated in the presence of IL10 and pulsed with the transgene product. TolDC administered either intradermally or intravenously were safe and well tolerated. While the intravenous route showed a modest ability to modulate host immunity against the transgene product, intradermally delivery resulted in a robust vaccination of the macaques when associated to intramuscular rAAV-derived vectors-based gene transfer. These findings demonstrate the critical role of TolDC mode of injection in modulating host immunity. This study also provides the first evidence of the potential of TolDC-based immunomodulation in gene therapy.

Viruses represent an important cause of cancer in humans: infections are estimated to account for close to one cancer case out of five.With the ongoing discovery of new infectious agents, this number should be raising in the near future. In 2006, the discovery of a new _-retrovirus in prostate cancer biopsies launched an intense research activity: could this new xenotropic MLV-related virus (XMRV) be the cause of prostate cancer? Five years later, the initial enthusiasm of retrovirologists has dramatically diminished. One by one, arguments favouring the hypothesis of human infection with XMRV are being refuted. The aim of this review article is to present the discovery of XMRV and to analyze recent data arguing against its existence in humans. A synthetic interpretation of XMRV literature will then be suggested.

Cavernous sinus is an important region rich in neurological structures. Its development and its anatomy are very complex and the purpose of our work is to correlate embryology, anatomy and semiology of this region and its content. Interest of medical imaging of cavernous sinus and referred structures is enhanced.