LE PONT-DE-CLAIX, France, Sept. 18, 2024 /PRNewswire/ -- BD (Becton, Dickinson and Company) (NYSE: BDX) a leading global medical technology company announced the commercial release of the BD Neopak™ XtraFlow™ Glass Prefillable Syringe and the latest capacity expansion of the BD Neopak™ Glass Prefillable Syringe platform to serve the growing market for biologic therapies The BD Neopak™ Glass Prefillable Syringe platform is designed to address key development needs for biologic drugs and our customers have received approval to utilize this platform for more than 24 indications cardiovascular disease and various rare diseases BD has expanded usability of this platform with the commercial release of the BD Neopak™ XtraFlow™ Glass Prefillable Syringe This solution features an 8-millimeter needle length and thinner wall cannula to optimize subcutaneous delivery of higher viscosity drug profiles by reducing the injection force and time required for a fixed solution viscosity1,2* This improvement allows pharmaceutical developers to break design barriers enhancing flow and usability beyond today's limits versus a standard half-inch needle3* "BD is seeing significant growth in the biologics segment driven by novel drug formulations across indications such as metabolic disorders and oncology," said Patrick Jeukenne "With over 30 drugs approved across 12 markets and many more in development with the BD Neopak™ Glass Prefillable Syringe platform As a global leader in prefillable drug-delivery systems BD aims to evolve as rapidly as the global biologics pipeline to enable supply and delivery of these drugs for patients worldwide." our manufacturing site in Le Pont-de-Claix France has successfully integrated a high-volume manufacturing line for the BD Neopak™ Glass Prefillable Syringe platform increasing the production capacity of a single line by sevenfold4 This achievement marks a significant milestone for BD enabling unprecedented large-scale production of advanced BD glass syringes The launch of our BD Neopak™ XtraFlow™ Glass Prefillable Syringe allows developers to take advantage of a single platform approach while dismantling existing design barriers such as drug viscosity The successful addition of the high-volume line at the Pont-de-Claix site allows BD to be more resilient to supply constraints and further demonstrates our commitment to continuously evolve to meet the needs of our pharmaceutical partners and patients worldwide These expansions add to BD's leadership in offering a broad range of injection solutions to enable delivery of treatments such as GLP-1s and other next generation treatments for chronic disease This press release contains certain forward-looking statements regarding the BD Neopak™ Glass Prefillable Syringe platform Forward-looking statements involve risks and uncertainties that could cause actual results to differ materially from those expressed or implied in such statements challenges inherent in product development including the development of new technologies or products by other companies or other factors listed in BD's 2023 Annual Report on Form 10-K and other filings with the SEC BD expressly disclaims any undertaking to update any forward-looking statements set forth herein to reflect events or circumstances after the date hereof except as required by applicable laws or regulations Media:                                                  Fallon McLoughlin                  Public Relations         201.258.0361                                  201.847.6927        [email protected]               [email protected]     Injection time and ejection force calculation [internal study] BD NeopakTM XtraFlowTM 2.25 mL prototype evaluation [internal study] 3. Pager et al. (2020), "User experience for manual injection of 2 mL viscous solutions is enhanced by a new prefillable syringe with staked 8 mm ultra-thin wall needle", Expert Opinion on Drug Delivery, https://doi.org/10.1080/17425247.2020.1796630 *When compared to 12.7 mm special thin wall needle today announced 510(k) clearance from the U.S has launched a new advanced hemodynamic monitoring.. Health Care & Hospitals Medical Pharmaceuticals Medical Equipment New Products & Services Do not sell or share my personal information: announced a strategic collaboration with Ypsomed to advance self-injection solutions for high-viscosity biologic drugs Ypsomed and BD have pre-assessed and streamlined integration of the BD Neopak™ XtraFlow™ Glass Prefillable Syringe with Ypsomed’s YpsoMate® 2.25 autoinjector platform addressing current limitations by enabling the delivery of higher viscosity (>15cP) biologic drugs in an autoinjector format The BD Neopak™ XtraFlow™ Glass Prefillable Syringe is BD’s latest portfolio addition and thinner wall cannula to optimize subcutaneous delivery of higher viscosity drug profiles enhancing flow and usability beyond today’s limits versus a standard half-inch needle1,2* This solution is a part of the BD Neopak™ Glass Prefillable Syringe Platform which is designed to address key development needs for biologic drugs Ypsomed is expanding its YpsoMate® 2.25 two-step autoinjector platform to accommodate the new syringe format This includes adapting parts of the autoinjector for the shorter needle and performing extensive technical testing to ensure reliability The YpsoMate autoinjector device is handled in two steps: simply remove the cap and push on skin designed so that people with impaired grip or vision can administer their medication easily and safely Supporting our pharmaceutical partners to de-risk and accelerate combination product development “We are excited to welcome the first pharmaceutical customers to experience the benefits of the BD Neopak™ XtraFlow™ Glass Prefillable Syringe with the YpsoMate® 2.25 autoinjector,” said Ulrike Bauer Chief Business Officer of Ypsomed Delivery Systems “This collaboration underscores our commitment to enhancing patient care through innovative drug delivery solutions.” “Cross-supplier collaborations are vital in today’s pharmaceutical ecosystem,” said Patrick Jeukenne worldwide president of BD Pharmaceutical Systems “These partnerships can help drive innovation and ensure that systems work by design and over lifecycles allowing our pharmaceutical partners to get life-saving therapies to patients faster.”      BD and Ypsomed are key leaders in drug delivery enabling the administration of chronic condition therapeutics such as GLP-1s Combining BD’s robust syringe platform technology with Ypsomed’s leading autoinjector platform this collaboration leverages shared expertise to deliver reliable device systems “User experience for manual injection of 2 mL viscous solutions is enhanced by a new prefillable syringe with staked 8 mm ultra-thin wall needle” https://doi.org/10.1080/17425247.2020.1796630 YpsoMate is a registered trademark of Ypsomed AG BD and the BD Logo are trademarks of Becton All other trademarks are the property of their respective owners All Blog Posts › has announced the commercial release of the BD Neopak XtraFlow Glass Prefillable Syringe and the latest capacity expansion of the BD Neopak Glass Prefillable Syringe platform to serve the growing market for biologic therapies The BD Neopak Glass Prefillable Syringe platform is designed to address key development needs for biologic drugs and customers have received approval to utilise this platform for more than 24 indications BD has expanded usability of this platform with the commercial release of the BD Neopak XtraFlow Glass Prefillable Syringe This solution features an 8-millimeter needle length and thinner wall cannula to optimize subcutaneous delivery of higher viscosity drug profiles by reducing the injection force and time required for a fixed solution viscosity enhancing flow and usability beyond today's limits versus a standard half-inch needle BD's manufacturing site in Le Pont-de-Claix, France has successfully integrated a high-volume manufacturing line for the BD Neopak Glass Prefillable Syringe platform increasing the production capacity of a single line by sevenfold MM Activ Singapore Pte Ltd 1 North Bridge Road,#08-08 High Street Centre communications@biospectrumasia.com +65 90150305 Copyright 2025 MM Activ Singapore Pte Ltd Built on the Grands Moulins de Villancourt heritage site in France the contemporary Centre de sciences Cosmocité aims to be the cultural cornerstone of Ville de Pont-de-Claix’s urban renewal Architects Jean-Yves Guibourdenche and Jean-François Julien have unveiled their design for the new Centre de sciences Cosmocité, which has opened in Pont-de-Claix, a commune in the Isère department in southeastern France In line with the museum concept developed by scenographer CREO and in close collaboration with cultural centre La Casemate and the wider scientific community the building aims to preserve the memory of the Grands Moulins de Villancourt site an important part of  the municipalities of Echirolles and Pont-de-Claix in the 19th and 20th centuries Taking up the exact layout of the demolished building the architects created two distinct volumes – one rectangular white volume and a sweeping black curve – link the region’s industrial past with the contemporary scientific focus of the new institution The glossy white section of the building houses the passageways and related spaces, while the centre’s opaque black volume houses spaces dedicated to the dissemination of scientific content: the planetarium immersion room and permanent exhibition hall Finding inspiration in the universe’s great mysteries and humankind’s place in the cosmos and mysterious quality invites onlookers to reflect the vertical and horizontal corridors are bathed in natural light and offer views of the surrounding landscape the circular planetarium is inclined at 10° including 4 for people with reduced mobility and provides a 360° view of a semi-spherical screen The architectural team called on the Montreal-based digital studio CREO to create the Cosmocité scenography To meet the numerous requirements of this ambitious project CREO put together a multidisciplinary design team who worked in close collaboration with the project’s Grenoble-based scientific committee as well as with Centre de Culture Scientifique Cosmocité’s highly interactive exhibition is designed to answer fundamental questions such as: Is the Earth unique from the birth of stars to the causes of earthquakes Get a curated collection of design and architecture news in your inbox by signing up to our ICON Weekly newsletter Please enable JS and disable any ad blocker Volume 9 - 2018 | https://doi.org/10.3389/fimmu.2018.03034 CD9 was recently identified as a marker of murine IL-10-competent regulatory B cells Functional impairments or defects in CD9+ IL-10-secreting regulatory B cells are associated with enhanced asthma-like inflammation and airway hyperresponsiveness all asthma-related features can be abrogated by CD9+ B cell adoptive transfer and molecular mechanisms of the regulatory properties of CD9+ B cells in human and mouse The profile of CD9+ B cells was analyzed using blood from severe asthmatic patients and normal and asthmatic mice by flow cytometry The regulatory effects of mouse CD9+ B cells on effector T cell death and mitochondrial depolarization were determined using yellow dye MAPK phosphorylation was analyzed by western blotting Patients with severe asthma and asthmatic mice both harbored less CD19+CD9+ B cells although these cells displayed no defect in their capacity to induce T cell apoptosis Molecular mechanisms of regulation of CD9+ B cells characterized in mouse showed that they induced effector T cell cycle arrest in sub G0/G1 leading to apoptosis in an IL-10-dependent manner This process occurred through MAPK phosphorylation and activation of both the intrinsic and extrinsic pathways This study characterizes the molecular mechanisms underlying the regulation of CD9+ B cells to induce effector T cell apoptosis in mice and humans via IL-10 secretion Defects in CD9+ B cells in blood from patients with severe asthma reveal new insights into the lack of regulation of inflammation in these patients and CD9 thus appears to be a reliable marker for defining both mouse and human Bregs that mouse and human CD9+ B cells elicit regulatory properties through IL-10 secretion and transitional CD24hiCD38hiB cells expressing CD9 are decreased in the blood of severe asthmatic patients We report that CD9+ B cells induce effector T cell apoptosis via the secretion of IL-10 T cell proliferation is blocked at the sub G0/G1 cell cycle phase leading to activation of the intrinsic and extrinsic apoptotic pathways via a MAPK-dependent mechanism These data reveal new insights on the lack of regulation of inflammation in severe asthmatic patients and help pave the way to the discovery of potential novel therapies Peripheral blood mononuclear cells (PBMCs) were isolated by Ficoll-Paque (GE Healthcare France) gradient centrifugation and frozen Immunophenotyping of PBMCs from 9 severe asthmatic patients was performed using flow cytometry PBMCs from 10 HV were analyzed as controls PBMCs were rapidly thawed by placing cryovials at 37°C washed and stained according to standard protocols using the following mAbs: CD19-BUV395 These markers were used to distinguish CD19+ B lymphocytes CD19+CD27− naïve cells CD19+CD24−CD38+ plasma cells dead cells were excluded using the Zombie NIR™ Fixable Viability kit (BioLegend Human anti–IL-10 (BD Biosciences) was used to inhibit the IL-10 pathway Samples were assessed on a BD LSRFORTESSA X-20 (BD Biosciences and the data were analyzed using FlowJo v10 software (FlowJo LLC Six week-old wild-type BALB/c mice were purchased from Charles River Laboratories (Ecully, France). Allergic inflammation was induced using a total House Dust Mite (HDM) extract (Dermatophagoïdes farinae) provided by Stallergenes (Antony, France), as previously described (31) This study was performed in accordance with the recommendations of the Regional Ethical Committee for Animal Experiments of Pays de la Loire (ceea.2012.77) under accreditation number 3455 The protocol was approved by the Regional Ethical Committee for Animal Experiments of Pays de la Loire Six week-old wild-type BALB/c mice were purchased from Charles River Laboratories (Ecully Splenic cells were isolated and stained with the following antibodies for cell sorting by flow cytometry: CD19-APC-H7 (1D3) These markers were used to distinguish CD19+CD9− non-regulatory B cells CD19+CD9+ Breg cells and CD3+CD4+CD25− effector T cells Cells were sorted on a BD FACSARIA III (BD Biosciences Mouse cells (1 million/mL) were cultured for 48 h in RPMI-1640 medium with 10% fetal calf serum and 2 mM glutamine CD19+CD9− non-regulatory B cells or CD19+CD9+ Breg cells were activated with 2 μg/mL anti-CD40 (HM40-3) (BD Biosciences France) for 48 h and 10 μg/mL LPS for 5 h CD3+CD4+CD25− effector T cells were activated with 100 U/mL interleukin-2 (IL-2) for 48 h Effector T cells were then co-cultured for 48 h with non-regulatory or Breg cells at a ratio of 1:1 and at a concentration of 1 million/ml on plates coated with anti-CD3 (145-2C11) (BD Biosciences the same protocol was used except that B cells were activated with 50 ng/mL recombinant human soluble CD40L (R&D Systems Europe France) plus 2.5 mg/mL CpG oligodeoxynucleotide 2006 (InvivoGen and T cells were activated with 50 U/mL recombinant IL-2 (SARL Pharmaxie the cells were treated with 50 nM Z-VAD (R&D Systems Europe To inhibit IL-10 and the transforming growth factor-beta (TGF-β) and Fas pathways the cells were treated during co-culture with 10 μg/mL anti–IL-10 (BD Biosciences 10 μg/mL anti–TGF-β1 (Abcam or 20 μg/mL anti-Fas ligand (R&D Systems Europe the cells were treated during co-culture with 0.2 μg/μL KMC8 monoclonal antibody (BD Biosciences the cells were treated with 10 ng/mL recombinant IL-10 (R&D Systems Europe To determine the percentage of dead CD3+CD4+CD25− effector T cells the cells were stained using a LIVE/DEAD Fixable Yellow Dead Cell Stain Kit according to the manufacturer's recommendation (Invitrogen B cells were removed from the analysis using a gating strategy based on CD19-APC-H7 (1D3) staining T cell cycle stages were assessed using propidium iodide (PI) staining (Beckman Coulter France) and the percentage of apoptotic T cells by Annexin V-FITC staining (BD Biosciences Samples were run on a BD LSRFORTESSA X-20 (BD Biosciences The analysis of CD3+CD4+CD25− effector T cells protein expression was performed by western blotting after negative selection with MACS columns (Miltenyi Biotec The following primary antibodies were used: anti-Bid Mitochondrial membrane potential was measured using the potential-sensitive fluorescent probe tetraethylbenzimidazolylcarbocyanine iodide (JC-1) (Life Technologies Cells were incubated in Hank's Balanced Salt Solution (Gibco Life Technologies France) with JC-1 at 5 mg/mL for 30 min at 37°C CD19-APC-H7 (1D3) antibody staining allowed the removal of B cells from the analysis cells were stained with the following Phosflow antibodies: anti-phospho-p38-PeCy-7 and anti-phospho-JNK-PE (BD Biosciences France); anti-phospho-ERK1/2-PE (eBioscience France); and CD19-APC-H7 (1D3) antibody to remove B cells from the analysis Comparisons of experimental values between the two groups were analyzed using the Mann–Whitney U-test The non-parametric Kruskal–Wallis test with Dunn's posttest were used for comparisons between more than two groups All statistical analyses were performed using GraphPad Prism v7 (La Jolla showing that CD19+CD24hiCD38hi transitional cells were included in the CD9+ B cell subset B lymphocyte subpopulations in the blood of severe asthmatic patients (A) Gating strategy used after immunostaining to determine all B cell subsets and CD9+ B cells in 10 healthy volunteers (HV) and 9 severe asthmatic patients (SA) (*p < 0.05 (C) Expression of the mean fluorescence intensity of CD9 in transitional and non-transitional B cell subsets (***p < 0.001) Asthmatic mice had significantly fewer CD19+CD9+ B cells in the spleen and lung than control mice (4.5% ± 0.3 and 3.1% ± 0.2 vs 7.8% ± 0.7 and 6.8% ± 1 in the spleen and lung of asthmatic and control mice These data validate the mouse as a relevant model for asthma in humans we report that patients with severe asthma and asthmatic mice both harbor a defect in number of CD19+CD9+ B cells Percentage and regulatory properties of CD9+ B cells in asthmatic mice (A) Induction protocol in asthma mice: House dust mite model (B) Percentage of CD9+ B cells among CD19+ cells in the spleen and lung of control and asthmatic mice (n = 4 (C) Gating strategy used to remove B cells from the analysis by CD4 FITC staining splenic CD3+CD4+CD25− effector T cells from asthmatic and naive Balb-c mice were co-cultured for 48 h with CD19+CD9+ or CD19+CD9− B cells or alone as controls Cells were stained with yellow dye to measure T cell death induced by CD9+ or CD9− B cells Percentage of Annexin V-positive T cell staining (n = 6 (E) Percentage of T cell death induction by CD19+CD9+ or CD19+CD9− B cells (ns CD19+CD9− B cells from asthmatic mice or controls did not induce CD3+CD4+CD25− effector T cell death (0.8% ± 5.9 vs 0.4% ± 2.6 in control and asthmatic mice These data show that although asthmatic mice have reduced number of CD19+CD9+ B cells these cells display no defects in their capacity to induce T cell apoptosis Although CD9 has been identified as a marker of B cells that are secreting IL-10 their full regulatory mechanisms remain unknown Because there was no difference in function between CD19+CD9+ from naïve and asthmatic mouse we further investigated the regulatory properties of these cells to decipher the molecular pathway leading to T cell death in naïve mice No difference was observed when T cells were co-cultured with or without CD19+CD9− B cells CD3+CD4+CD25− effector T cell S-phase progression did not appear to be significantly altered under any of the conditions showing that B cells had no effect on T cell proliferation per se these data show that CD19+CD9+ B cells induce CD3+CD4+CD25− effector T cell cycle arrest in sub G0/G1 Effects of CD9+/− B cells on T cell proliferation and death splenic CD3+CD4+CD25− effector T cells from Balb-c mice were co-cultured for 48 h with CD19+CD9+ or CD19+CD9− B cells at a 1:1 ratio or alone as controls Cells were stained with CD4 FITC antibody to remove B cells from the analysis (A) Cells were stained with propidium iodide to measure T cell cycle stages Representative staining of the different cell cycle stages (B) Percentage of T cells in the different cell cycle stages (n = 6) Treatment with an anti-CD9 agonist had no effect on the T cell death induced by CD19+CD9+ B cells showing that this effect was not mediated by CD9 (50.3% ± 4.6; ns compared with T cells co-cultured with CD19+CD9+ B cells) a specific inhibitor of apoptotic cell death blocked the T cell apoptosis induced by CD19+CD9+ B cells (18.8% ± 5.6; p < 0.01) these data show that CD19+CD9+ B cells induce CD3+CD4+CD25− effector T cell cycle arrest in sub G0/G1 Effects of CD9+/− B cells on T cell apoptosis splenic CD3+CD4+CD25− effector T cells from Balb-c mice were co-cultured for 48 h with CD19+CD9+ or CD19+CD9− B cells or alone as controls the cells were also treated with 2 μg/μL KMC8 anti-CD9 antibody 10 μg/mL anti–TGF-β1 Cells were also co-cultured in trans-wells The cells were stained with CD4 antibody to remove B cells from the analysis and with Annexin V to measure T cell apoptosis (A) Representative results of Annexin V staining (B,C) Percentage of Annexin V-positive T cells in each co-culture condition (n = 6 CD3+CD4+CD25− effector T cells from 9 healthy volunteers were co-cultured for 48 h with CD19+CD9+ or CD19+CD9− B cells or alone as controls Cells were also treated with 20 μg/mL anti–IL-10 and stained with CD4 antibody to remove B cells from the analysis and stained with Annexin V to measure T cell apoptosis Percentage of Annexin V-positive T cells in the different co-culture conditions (n = 9; *p < 0.05) To determine whether direct B cell-T cell contact was necessary for CD19+CD9+ B cells to induce T cell apoptosis, CD3+CD4+CD25− effector T cells were co-cultured with CD19+CD9+ B cells in classical or trans-well plate assays (Figure 4C) CD19+CD9+ B cells induced T cell death in both situations (44% ± 4.1 vs the T cell death induced by CD19+CD9+ B cells was not affected when the co-culture was performed in the presence of anti-TGF-β (40% ± 2 vs 33.8% ± 3.6 with or without anti-TGF-β ns) nor anti-Fas ligand (45% ± 5.1 ns compared with T cells co-cultured with CD19+CD9+ B cells) anti-IL-10 prevented T cell death and fully restored T cell viability (17.2% ± 1.9 vs 17.6% ± 4.1 for T cells alone and T cells co-cultured with CD19+CD9+ B cells/anti-IL-10 CD3+CD4+CD25− effector T cells treated with IL-10 underwent apoptosis (35% ± 3.4 p < 0.05 compared with T cells alone) confirming its involvement in T cell apoptosis induced by CD19+CD9+ B cells these data show that T cell-B cell contact is not necessary for T cell apoptosis induction by CD19+CD9+ B cells and that apoptosis induction is dependent on IL-10 induced apoptosis of T cells (2.8% ± 0.8 for T cells alone 14.3% ± 1.7 for T cells co-cultured with CD19+CD9− B cells and 21.4% ± 2.7 for T cells co-cultured with CD19+CD9+ B cells; T cells alone vs T cells co-cultured with CD19+CD9+ B cells Treatment with anti-IL-10 reduced apoptosis induced by human T cells (15.7% ± 1.1; T cells alone vs T cells co-cultured with CD19+CD9+ B cells/anti-IL-10 human CD19+CD9+ B cells induce CD3+CD4+CD25− effector T cell apoptosis via IL-10 these data show that CD19+CD9+ B cells induce CD3+CD4+CD25− effector T cell apoptosis via both extrinsic and intrinsic pathways through MAPK activation Effects of CD9+ B cells on MAPK phosphorylation Bid and caspase cleavage and mitochondrial depolarization splenic CD3+CD4+CD25− effector T cells from Balb-c mice were co-cultured for 48 h with CD19+CD9+ CD19+CD9− B cells or alone as controls (A) B cells were removed from the analysis by CD4 staining and ERK1/2 in CD3+CD4+CD25− effector T cells was assessed by flow cytometry (B) CD3+CD4+CD25− effector T cells were negatively selected using MACS columns and the ratios of cleaved/pro-caspases were calculated (C) CD3+CD4+CD25− effector T cells were negatively selected by MACS columns Bid cleavage was assessed by western blotting (D) Mitochondrial depolarization was assessed by JC-1 staining Representative results of JC-1 staining and percentage of monomeric JC-1 cells in all culture conditions (n = 5 The ability of Bregs to normalize lung function and airway inflammation and the notable alterations of this Breg pool in asthmatic mice clearly point to these cells as an interesting target in allergic diseases We demonstrated that these cells regulate effector T cell proliferation but the mechanisms responsible for such an effect remain unknown we demonstrated that CD9+ B cells harbored strong suppressive properties These cells induced the death of effector T cells via the intrinsic and extrinsic pathways of apoptosis in an IL-10-dependent manner and through the MAPK cascade in humans and reported that severe asthmatic patients have reduced number of CD9+ B cells with regulatory properties these data not only clearly support CD9 as a potential biomarker of Bregs but also suggest a possible role in asthma physiopathology differing from the classical role of B cells as IgE producers no mechanism of action has yet been reported for CD9+ B cells These cells did not induce cleavage of caspase 12 which is characteristic of endoplasmic reticulum stress as treatment with necrostatin-1 did not abrogate T cell death (data not shown) we report that the number of CD9+ B cells was reduced in the blood of severe asthmatic patients as demonstrated in asthmatic mice lacking CD9+ B cells but displaying no functional defect these cells were able to induce effector T cell apoptosis in the same manner as CD9+ B cells from wild type mice our data are the first to characterize the molecular mechanisms of the regulation of CD9+ B cells to induce effector T cell apoptosis in mice and humans The lack of CD9+ Breg cells in severe asthmatic patients suggests Bregs as a potential target for future therapeutic strategies A better understanding of the immunological mechanisms underlying allergic diseases is essential for the development of new preventive and therapeutic Breg interventions and AM: analysis and interpretation of data All authors critical revision for important intellectual content All authors approved the final version of the manuscript prior to submission This work was supported by a grant from l'Institut de Recherche en Santé Respiratoire-Pays de la Loire This work was achieved in the context of the BASAL project financed by Région Pays de la Loire and the IHU-Cesti project the DHU Oncogreffe and the LabEX IGO thanks to French government financial support managed by the National Research Agency via the Investment into the Future program (ANR-10-IBHU-005 and ANR-11- LABX-0016-01) The IHU-Cesti project is also supported by Nantes Métropole and Région Pays de la Loire The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest We thank the participating patients and their families and cooperation were essential for the collection of the data used in this study We also thank the main EXPRESA investigators: Pr We also thank the pulmonology team of CIC-Thorax (Megguy Bernard and Annick Joly) for the EXPRESA follow-up Haro from the Cytocell Cytometry Facility in Nantes (SFR Bonamy) and the Unité Thérapeutique Expérimentale in Nantes for the animal experimentation facility The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2018.03034/full#supplementary-material Cytokine-producing B cells as regulators of pathogenic and protective immune responses Costimulatory molecules and T-cell-B-cell interactions Lymphocytes as antigen-presenting cell-based genetic vaccines Effector and regulatory B cells: modulators of CD4+ T cell immunity Role of regulatory B cells in immune tolerance to allergens and beyond B cells regulate autoimmunity by provision of IL-10 Mechanisms of regulatory B cell function in autoimmune and inflammatory diseases beyond IL-10 Selective targeting of B cells with agonistic anti-CD40 is an efficacious strategy for the generation of induced regulatory T2-like B cells and for the suppression of lupus in MRL/lpr mice Regulatory B cells prevent and reverse allergic airway inflammation via FoxP3-positive T regulatory cells in a murine model Prevention of arthritis by interleukin 10-producing B cells Immunologic human renal allograft injury associates with an altered IL-10/TNF-α expression ratio in regulatory B cells Regulatory B cells: an exciting target for future therapeutics in transplantation tolerant kidney transplant patients produce B cells with regulatory properties Transitional B lymphocytes are associated with protection from kidney allograft rejection: a prospective study Regulatory B cells are enriched within the IgM memory and transitional subsets in healthy donors but are deficient in chronic GVHD Transplantation tolerance: don't forget about the B cells The expanding family of regulatory B cells Schistosomes induce regulatory features in human and mouse CD1d(hi) B cells: inhibition of allergic inflammation by IL-10 and regulatory T cells 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questions CrossRef Full Text Multi-ethnic reference values for spirometry for the 3-95-yr age range: the global lung function 2012 equations PubMed Abstract | CrossRef Full Text International ERS/ATS guidelines on definition Prime role of IL-17A in neutrophilia and airway smooth muscle contraction in a house dust mite-induced allergic asthma model Various modes of cell death induced by DNA damage Measuring the DNA content of cells in apoptosis and at different cell-cycle stages by propidium iodide staining and flow cytometry Involvement of stress activated protein kinases (JNK and p38) in 1,25 dihydroxyvitamin D3-induced breast cell death Mitogen-activated protein kinases in apoptosis regulation Addressing unmet needs in understanding asthma mechanisms: from the European asthma research and innovation partnership (EARIP) work package (WP)2 collaborators Mechanisms of allergen-specific immunotherapy: multiple suppressor factors at work in immune tolerance to allergens (2010) 126:1081–91; quiz 1092–3 Deficiency of regulatory B cells increases allergic airway inflammation Tetraspanins CD9 and CD81 are molecular partners of trimeric Fc€RI on human antigen-presenting cells Binding of pregnancy-specific glycoprotein 17 to CD9 on macrophages induces secretion of IL-10 Antibody cross-linking of human CD9 and the high-affinity immunoglobulin E receptor stimulates secretion from transfected rat basophilic leukaemia cells PubMed Abstract | CrossRef Full Text | Google Scholar Molecular cell biology of apoptosis and necroptosis in cancer Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy Combination of lenalidomide with vitamin D3 induces apoptosis in mantle cell lymphoma via demethylation of BIK Stat3-dependent induction of p19INK4D by IL-10 contributes to inhibition of macrophage proliferation Heme oxygenase-1 mediates the anti-inflammatory effect of interleukin-10 in mice Control of mitochondrial apoptosis by the Bcl-2 family Mitochondria and cell death: outer membrane permeabilization and beyond Interleukin-10 induces apoptosis in developing mast cells and macrophages Regulatory B-cell induction by helminths: implications for allergic disease B10 cells induced by Schistosoma japonicum soluble egg antigens modulated regulatory T cells and cytokine production of T cells trigger the development of regulatory B cells Pathogen-derived immunomodulatory molecules: future immunotherapeutics Amelioration of allergic airway inflammation in mice by regulatory IL-35 through dampening inflammatory dendritic cells Unique B cell differentiation profile in tolerant kidney transplant patients expanding diversity and common goal ofregulatory T and B cells Magnan A and Brouard S (2018) CD9+ Regulatory B Cells Induce T Cell Apoptosis via IL-10 and Are Reduced in Severe Asthmatic Patients Received: 28 August 2018; Accepted: 07 December 2018; Published: 21 December 2018 Copyright © 2018 Brosseau, Durand, Colas, Durand, Foureau, Cheminant, Bouchaud, Castan, Klein, Magnan and Brouard. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) distribution or reproduction in other forums is permitted provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited in accordance with accepted academic practice distribution or reproduction is permitted which does not comply with these terms *Correspondence: Sophie Brouard, c29waGllLmJyb3VhcmRAdW5pdi1uYW50ZXMuZnI= †These authors have contributed equally to this work Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher 94% of researchers rate our articles as excellent or goodLearn more about the work of our research integrity team to safeguard the quality of each article we publish Drug Delivery Business November 16, 2021 By BD (NYSE:BDX) announced today that it broke ground on its $200 million pre-filled drug delivery device manufacturing plant in Spain Franklin Lakes, New Jersey-based BD announced in May that it would build the $201.5 million (€165 million) high-tech manufacturing facility in Zaragoza, Spain with expectations of creating up to 600 jobs at the facility by 2030 which will initially register a size of 86,000 square feet (8,000 square meters) with BD beginning the recruitment process to fill key positions supporting the design and set-up of the plant “These roles will be on the front lines of building a sustainable, state-of-the-art and fully digital site incorporating the latest in intelligent and autonomous solutions,” Thibault Naegelen, Program Director for BD’s Zaragoza facility, said in the release “We look forward to building a team in Zaragoza that helps BD meet its mission of advancing the world of health by supplying our European customers with devices that enhance drug delivery.” In December 2020, BD announced its intent to invest $1.2 billion over four years to expand and upgrade multiple drug-delivery facilities The company said it would open the new facility and build upon its six existing sites in Columbus The Zaragoza team will produce drug delivery devices mainly for biopharmaceutical companies supporting the European market with drugs in pre-fillable syringes including vaccines and other biologic drugs BD said the new facility will add much-needed capacity to support major vaccination campaigns going forward including the ongoing effort to vaccinate the world against COVID-19 The company is set to hire operators and production staff to oversee production lines closer to the opening date for the plant in 2023 BD intends to ensure that the site meets high sustainability and eco-efficiency standards and anticipates that the facility will employ up to 600 people with an area of 323,000 square feet (30,000 square meters) by 2030 “Pre-fillable drug systems are a known factor in helping health care providers effectively reliably and consistently administer drug therapies,” BD Pharmaceutical Systems Worldwide President Eric Borin said more than 70% of the top 100 biopharmaceutical companies rely on BD pre-fillable syringes This groundbreaking marks an important milestone in our ability to extend manufacturing capacity for our customers as they continue to grow their vaccine and biologic drug pipelines.” Sean Whooley is an associate editor who mainly produces work for MassDevice, Medical Design & Outsourcing and Drug Delivery Business News. He received a bachelor's degree in multiplatform journalism from the University of Maryland, College Park. You can connect with him on LinkedIn or email him at swhooley@wtwhmedia.com Copyright © 2025 · WTWH Media LLC and its licensors The material on this site may not be reproduced except with the prior written permission of WTWH Media Privacy Policy | RSS The architectural consortium comprised of ARCANE Architectes (France) and Cardin Julien (Canada) is delighted to unveil the new Centre de sciences Cosmocité built on the Grands Moulins de Villancourt heritage site in Pont-de-Claix conceived by architects Jean-Yves Guibourdenche and Jean-François Julien is in line with the museum concept developed by scenographer CREO in close collaboration with La Casemate and the scientific community Cosmocité aims to preserve the industrial memory of the Grands Moulins de Villancourt site which was an important part of the industrial and human heritage of the urban agglomeration and the municipalities of Echirolles and Pont-de-Claix in the 19th and 20th centuries With its location at the municipality's northern entrance Cosmocité is the cultural cornerstone of Ville de Pont-de-Claix's urban renewal The commissionTaking up the exact placement layout of the demolished building the architects created an assemblage of volumes that link the region's industrial past with the contemporary scientific focus of the new institution embodied by the black volume glossy white volume houses the passageways and related spaces while the matte and opaque black volume houses all  spaces dedicated to the dissemination of scientific content: the planetarium Recalling the universe's great mysteries and humankind's place in the cosmos and mysterious quality invites onlookers to fathom its scale The volumetric design reflects the building's function and contributes to the site's global message: science that's welcoming and open to all The programCosmocité houses:- An 80-seat planetarium The role of a planetarium is to teach and popularize astronomy and space science for both school and family audiences.- A permanent tour based on two themes: “EARTH” and “COSMOS” with interactive floor and wall screens- A 14-metre-high Foucault pendulum- A variable activity space: children/youth audience area and a modular room- Additional facilities: reception and logistics- A roof terrace overlooking the Grenoble basin and its surrounding mountains- The facility is designed to welcome around 57,000 visitors per year The planetariumCircular and inclined at 10° the space can be accessed via a vision adaptation waiting area and an acoustic airlock providing a 360° view of a semi-spherical screen It is lined with a circular technical gallery and a data centre The permanent exhibitionThe architectural team called on the Montreal-based digital studio CREO to create the Cosmocité scenography who worked in close collaboration with the project's Grenoble-based scientific committee Cosmocité's highly interactive exhibition is designed to answer fundamental questions such as: Is the Earth unique it covers everything from the birth of stars to the causes of earthquakes a 14-metre-high Foucault pendulum spans the building to demonstrate the Earth's rotation A bioclimatic designThe building has been designed to balance the space of the west-facing garden with that of the eastern forecourt The hall and staircase are glazed to capture free energy from the sun and to encourage the public to use the staircase to climb to the upper floors this solar energy is controlled by screen-printed glass to prevent overheating the building opens onto the garden and the Vercors landscape while the cantilevered planetarium hall shelters it from the summer sun Interior characteristicsThe acoustic comfort has been carefully studied to avoid any sound transfer between spaces Summer thermal comfort is ensured by:- A heat inert cement structure;- Efficient solar protection: 50% screen-printed glass on the east facade and external solar shading;- Openings for natural ventilation;- Air quality is ensured by a double-flow system Energy optimizationEnergy efficiency is primarily about reducing the building's thermal requirements which is made possible via a compact construction and a high-performance envelope The building's main structure is in reinforced concrete which is insulated from the outside to eliminate thermal bridges and the associated risk of condensation and to benefit from an inertia conducive to summer comfort The building envelope's performance has been designed to be well below the French regulatory threshold in terms of energy requirements Heating is provided by way of a district heating system an urban stone forecourt accommodates the varying flow of visitors drawn to this site and its activities a garden and its outdoor amphithéâtre form a buffer zone between the parking lots and the Centre de sciences a conserved hundred-year-old cedar tree serves as a reminder of the city's continuing renewal Direction/cultural and scientific programming: La Casemate Scientific curator: UGA / CNRS / OSUG Construction cost: 6 732 000 € HT Architecture ARCANE Architectes and Cardin Julien Engineering Mechanical-electrical engineering: CET Bâtiment & Energie [AK1] [ÉP2]  Structural and economy: BETREC I.G Scenography CREO François Tourny (engineer) Specialists Immersive room and Planetarium: RSA Cosmos / Theoriz Environmental quality: Etamine Road works and various networks: MTM Infra Acoustics: Echologos ARCANE Architectes is a resolutely generalist firm with the ability to respond to operations on all scales in both the private and public sectors Based in Grenoble since its founding in 1986 its strength resides in its talented and creative team which supports its clients at every stage of the building process Backed by a wealth of experience in both new construction and restoration the firm is renowned for its rigorous approach to deadlines Each project is conceived as a unique adventure driven by creativity and innovation and always carried out in a sustainable and resource-efficient manner Among ARCANE's finest achievements are the Palais des Sports et des Congrès in Megève (France the Centre de sciences Cosmocité in Le-Pont-Claix (France and the Arboréa multiple-unit dwelling program in Pringy (France) for which it was awarded the Grand Prix Régional des Pyramides d'Argent 2022 About Cardin JulienFounded in Montreal in 1992 Cardin Julien is an architecture firm that conceives and produces major projects in the public and private sectors The firm specializes in the design of public and cultural buildings serving the community Guided by the principles of sustainable development the group proposes distinctive designs that are in harmony with their surroundings the firm aims to leave an impression on both minds and hearts Following its success in several architectural competitions Cardin Julien has carried out several major cultural projects such as the Rio Tinto Alcan Planetarium in Montreal (with Aedifica) the Planétarium du Jardin des sciences at Université de Strasbourg (with frenak+jullien and m+ mathieu holdrinet) and Centre de sciences Cosmocité in Grenoble (with ARCANE Architectes).Cardin Julien's mission is to co-create to reveal the full potential of your ideas and to build places for better living.Media contacts France Amandine Kowalskiamandine.kowalski@arcane-archi.frTel: + (33) 4 76 03 27 27 Canada and Worldwide Etienne Proulxeproulx@cardinjulien.comTel: +1 514 272-6798 BD EffivaxTM Glass Prefillable Syringe Features Enhanced Technology that Builds on Company's Decades of Expertise in the Prefillable Syringe Market and Supports Customers' Manufacturing Needs FRANKLIN LAKES, N.J., Sept. 13, 2022 /PRNewswire/ -- BD (Becton, Dickinson and Company) (NYSE: BDX) today introduced a next-generation glass prefillable syringe (PFS) that sets a new standard in performance for vaccine PFS with new and tightened specifications for processability The new BD EffivaxTM Glass Prefillable Syringe has been designed in collaboration with leading pharmaceutical companies to meet the complex and evolving needs of vaccine manufacturing "As biopharmaceutical companies continue to rapidly grow their vaccine pipelines demand for PFS is accelerating across the globe – given their proven ability to facilitate faster administration support dose sparing and reduce vaccine waste." said Eric Borin Worldwide President of BD Pharmaceutical Systems "The launch of BD EffivaxTM Glass Prefillable Syringe strategically supports this growth and will create needed efficiencies in end-to-end production." Approximately 70 percent of the top 100 biopharmaceutical companies rely on BD for supply of PFS.2  BD EffivaxTM Glass Prefillable Syringe will further help customers meet the stringent demands of today's vaccine manufacturing through design enhancements focused on fill/finish and container reliability BD EffivaxTM is designed to reduce the risk of line stoppage3 and improve the total cost of ownership,4 manufacturing capacity and supply availability including mRNA and those used for COVID-19 the company remains committed to maintaining robust capacity for PFS to help reduce the time and labor required for vaccine preparation with traditional vial formats About PFSPrefillable syringes (PFS) are an important option in the packaging and delivery of injectable drug products PFS help enable the administration of a drug in two ways a PFS is a drug delivery system designed to administer the appropriate amount of the drug to the patient both safely and reliably PFS packaging helps assure that there are no adverse effects on the quality purity or potency of the drug over its full shelf life Public Relations           201.847.5743          [email protected] [email protected]  Customer Quality Specification BD Hypak(tm) for Vaccine SC000110 BD Medical – Pharmaceutical Systems Le Pont de Claix 2 IQVIA-based analysis and BD internal Systems (SAP) today announced results for its fiscal 2025 second.. today announced that it will present at the Bank of.. Volume 13 - 2022 | https://doi.org/10.3389/fimmu.2022.786859 This article is part of the Research TopicThe Biological and Clinical Aspects of HLA-G, Volume IIView all 16 articles Preservation of a functional keratinocyte stem cell pool is essential to ensure the long-term maintenance of epidermis integrity through continuous physiological renewal and regeneration in case of injury Protecting stem cells from inflammation and immune reactions is thus a critical issue that needs to be explored we show that the immature CD49fhigh precursor cell fraction from interfollicular epidermis keratinocytes is able to inhibit CD4+ T-cell proliferation both the stem cell-enriched CD49fhigh/EGFRlow subpopulation and the less immature CD49fhigh/EGFRhigh progenitors ensure this effect we show that HLA-G and PD-L1 immune checkpoints are overexpressed in CD49fhigh precursors as compared to CD49flow differentiated keratinocytes This potency may limit immune reactions against immature precursors including stem cells and protect them from exacerbated inflammation Further exploring this correlation between immuno-modulation and immaturity may open perspectives in allogenic cell therapies Stem cells are essential for the maintenance and renewal of tissues, thus survival of this cellular pool is critical (1) we explored the question whether the degree of keratinocyte ‘stemness’ in the interfollicular epidermis is associated with a particular immune status through expression of immune checkpoints Understanding the immune properties of these adult stem cells will provide information on the mechanisms protecting these cells from immune reactions and contributing to the maintenance of skin tissue in a stress environment The present work aimed at investigating whether keratinocyte stem and progenitor cells from the human interfollicular epidermis develop specific immunosuppressive properties by modifying the expression of HLA-G1 and PD-L1 immune checkpoints enzymatic treatment with a solution containing (v/v) 3/4 grade II dispase 2.4 U mL−1 (Roche Molecular Biochemicals Germany) and 1/4 trypsin 0.25% (Gibco) was conducted for 24 h at 4°C We used two categories of cells in this study: cells directly extracted from the tissue and not amplified (tissue keratinocytes) amplified and used between passage 1 and 3 in culture (amplified keratinocytes) Amplified adult epidermal keratinocytes were obtained as follows: bulk cultures were generated in a serum-containing medium, in the presence of a feeder layer of human dermal fibroblasts growth-arrested by 60 Gy γ irradiation (23) All cultures were performed in plastic flasks coated with type-I collagen (BioCoat The composition of the serum-containing medium consisted of DMEM and Ham’s F12 media (Gibco 10 ng/mL epidermal growth factor (EGF) (Chemicon and 100 U/mL penicillin/streptomycin (Gibco keratinocytes were seeded at 1000 cells/cm2 and sub-cultured weekly Feeder cells were seeded at 5000 cells/cm2 For analysis of cell-surface immune marker expression keratinocytes were processed as single-cell suspensions and stained for 1 h at room temperature with monoclonal antibodies The staining monoclonal antibodies used were: phycoerythrin (PE) conjugated rat anti-human CD49f (ITA6) (clone GoH3 Alexa Fluor 405 conjugated rat anti-human EGFR (clone ICR10 PE-cy7-conjugated mouse anti-human PD-L1 (clone MIH1 Alexa 700-conjugated mouse anti-human HLA-G (clone 87G FITC conjugated mouse anti-human TGFB (clone 1D11 PE conjugated mouse anti-human IL-10 (clone B-S10 Non-reactive antibodies of similar species and isotype TGFB and IL-10 expression profiles were analyzed using an Astrios cell-sorter (Beckman Coulter Data were analyzed using FlowJo software (BD Biosciences Adult epidermal keratinocytes were sorted according to CD49f and EGFR expression using phycoerythrin (PE)-conjugated rat anti-human CD49f (ITA6) monoclonal antibody (clone GoH3 France) and Alexa Fluor 405 conjugated rat anti-human EGFR monoclonal antibody (clone ICR10 Appropriate isotype controls were systematically used Cells were sorted using a FACS Aria 3 sorter (BD Biosciences Keratinocytes were plated in 96 well plates (TPP Switzerland) at a concentration of 3000 cells/cm2 cells were stained for 1 hour at room temperature using the following monoclonal antibodies: phycoerythrin (PE)-conjugated rat anti-human CD49f (ITA6) (clone GoH3 APC-conjugated mouse anti-human PD-L1 (clone MIH1 Alexa700-conjugated mouse anti-human HLA-G (clone 87G Nuclei staining was performed using Hoescht (Thermofisher MHC1 and HLA-G expression profiles were analyzed using AnalysisCellInsight CX7 High-Content Screening (HCS) Platform (Thermofisher Keratinocytes were seeded at various ratios in 96-well culture plates (collagen-1 96-well France) and incubated for 4 h at 37°C in 5% CO2 in 100 μL RPMI medium (Sigma PBMCs were incubated for 20 min with a proliferation dye (eBioscience Cell Proliferation Dye eFluor 450 then stimulated or not by anti-CD2:anti-CD3:anti-CD28-coated beads (T-Cell Activation/Expansion Kit and seeded at 100,000 cells per well with or without keratinocytes PBMC proliferation was quantified by reduction in cell dye intensity after 7 days The ability of keratinocytes to modulate CD4+ T-cell proliferation was analyzed by comparing CD4+ T-cell dye intensity decrease in the presence versus absence of keratinocytes cells were stained for 20 minutes at room temperature using Viobright FITC conjugated mouse anti-human CD4 (clone REA623 Significant differences were assessed via 2-tailed Mann–Whitney U-test or t-test Differences were considered significant for p < 0.05; * = p < 0.05 *** = p < 0.001 and **** = p < 0.0001 We noticed that no effect was observed in the condition with differentiated keratinocytes contrarily to conditions with immature keratinocytes although responder cells and beads were the same in every condition This result rules out steric hindrance as a mechanism for responder cell proliferation inhibition Tissue keratinocyte precursors were therefore more effective than differentiated keratinocytes in suppressing CD4+ T-cell proliferation Figure 1 Keratinocyte precursors limit CD4+ T cell proliferation (A) Representative flow cytometry profiles of keratinocytes directly extracted from the tissue and sorted according to their immaturity level visualized thanks to CD49f and EGFR stainings 10,000 or 100,000 tissue keratinocytes (adult stem cells progenitors or differentiated cells) from one representative donor were incubated with 100,000 PBMC for 7 days PBMCs were pre-marked with a proliferation dye PBMC proliferation was quantified by dye decrease at day 7 (B) Representative flow cytometry profiles at day 7 (C) CD4+ T-cell proliferation inhibition according to the keratinocyte number and immaturity level (mean ± SEM (D) Representative flow cytometry profiles of amplified keratinocytes sorted according to their CD49f level sorted according to their CD49f expression after amplification for 7 days were incubated with 100,000 PBMC during 7 days (E) Representative flow cytometry profiles at day 7 F CD4+ T-cell proliferation inhibition according to the keratinocyte CD49f expression (mean ± SEM Exact p-values were determined according to the t-test * = p < 0.05 Keratinocyte precursors therefore retained their ability to reduce CD4+ T-cell proliferation after in vitro amplification Figure 2 Keratinocyte precursors overexpress the immune checkpoints HLA-G1 and PD-L1 Cells from one representative donor were cultivated for 7 14 or 20 days in a culture medium with serum and a layer of feeder cells Analysis by high content single-cell image analysis C) Representative profiles of HLA-G1 and PD-L1 expression according to CD49f expression on keratinocytes amplified for 7 days D) High content single-cell image analysis of HLA-G1 and PD-L1 levels (Average intensity of fluorescence) (mean ± SEM G) Representative flow cytometry profiles of HLA-G1 and PD-L1 expression on keratinocytes amplified for 7 days H) Analysis by flow cytometry of HLA-G1 and PD-L1 expression (mean ± SEM n=6) according to CD49f level on keratinocytes amplified for 7/14/20 days Exact p-values were determined according to the Mann-Whitney U-test ** = p < 0.01 and **** = p < 0.0001 Keratinocytes obtained from donor skin samples could be separated into stem cells with an CD49fhigh EGFRlow phenotype, progenitors with an CD49fhigh EGFRhigh phenotype, or differentiated keratinocytes with an CD49flow phenotype (2, 3) We show here that these populations exhibited distinct immune profiles whether tissue extracted or amplified in cell culture exert immunomodulatory properties by inhibiting CD4+ T-cell in vitro proliferation Investigating the expression of immune checkpoints on keratinocyte precursors in hair follicles could therefore provide a better understanding of their immune privilege and autoimmune-associated pathologies overexpression of PD-L1 and HLA-G by keratinocyte precursors should be considered in understanding the function of skin tumor initiator cells the generation of allogeneic skin grafts presents a double stake the maintenance of epidermal stem cells with high regenerative potential The raw data supporting the conclusions of this article will be made available by the authors The studies involving human participants were reviewed and approved by ethical research committee IDF-3 The patients/participants provided their written informed consent to participate in this study All authors contributed to the article and approved the submitted version This research received no external funding All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher and Christelle Doliger from the flow cytometry platform of Saint-Louis Hospital Authors also thank Alexandre Lellouch (HEGP The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2022.786859/full#supplementary-material Supplementary Figure 1 | Expression of immunomodulatory cytokines by keratinocyte precursors (B) Expression of TGFB by keratinocytes according to their immaturity level (mean ± SEM Exact p-values were determined according to the Mann-Whitney U-test Plasticity of Epithelial Stem Cells in Tissue Regeneration PubMed Abstract | CrossRef Full Text | Google Scholar Identification and Isolation of Candidate Human Keratinocyte Stem Cells Based on Cell Surface Phenotype Proc Natl Acad Sci USA (1998) 95:3902–7 Long-Term Expansion of Human Functional Epidermal Precursor Cells: Promotion of Extensive Amplification by Low TGF-Beta1 Concentrations KLF4 Inhibition Promotes the Expansion of Keratinocyte Precursors From Adult Human Skin and of Embryonic-Stem-Cell-Derived Keratinocytes HNRNPK Maintains Epidermal Progenitor Function Through Transcription of Proliferation Genes and Degrading Differentiation Promoting mRNAs Generation of hiPSC Line TCIERi001-A From Normal Human Epidermal Keratinocytes Glucocorticoid Receptor and Klf4 Co-Regulate Anti-Inflammatory Genes in Keratinocytes Mol Cell Endocrinol (2015) 412:281–9 Stem Cells Repurpose Proliferation to Contain a Breach in Their Niche Barrier Human Keratinocytes Inhibit CD4+ T-Cell Proliferation Through TGFB1 Secretion and Surface Expression of HLA-G1 and PD-L1 Immune Checkpoints Quiescent Tissue Stem Cells Evade Immune Surveillance Keratinocyte-Associated B7-H1 Directly Regulates Cutaneous Effector CD8 + T Cell Responses 2 Expressions Are Decreased in the Psoriatic Epidermis Control of Peripheral T-Cell Tolerance and Autoimmunity via the CTLA-4 and PD-1 Pathways doi: 10.1111/j.1600-065X.2008.00662.x PD-1 and Its Ligands in Tolerance and Immunity doi: 10.1146/annurev.immunol.26.021607.090331 Direct Evidence to Support the Role of HLA-G in Protecting the Fetus From Maternal Uterine Natural Killer Cytolysis Proc Natl Acad Sci USA (1997) 94:11520–5 Implication of HLA-G Molecule in Heart-Graft Acceptance CrossRef Full Text | Google Scholar CD3+CD4low and CD3+CD8low Are Induced by HLA-G: Novel Human Peripheral Blood Suppressor T-Cell Subsets Involved in Transplant Acceptance Human Leukocyte Antigen-G (HLA-G) Expression in Biliary Epithelial Cells Is Associated With Allograft Acceptance in Liver-Kidney Transplantation Role of HLA-G as a Predictive Marker of Low Risk of Chronic Rejection in Lung Transplant Recipients: A Clinical Prospective Study Cytometry-Based Analysis of HLA-G Functions According to ILT2 Expression CD8+PD-1-ILT2+ T Cells Are an Intratumoral Cytotoxic Population Selectively Inhibited by the Immune Checkpoint HLA-G Cancer Immunol Res (2019) 7(10):1619–32 Exploration of the Functional Hierarchy of the Basal Layer of Human Epidermis at the Single-Cell Level Using 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February 2022 Copyright © 2022 Mestrallet, Carosella, Martin, Rouas-Freiss, Fortunel and LeMaoult. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) *Correspondence: Joel LeMaoult, Sm9lbC5MZU1hb3VsdEBjZWEuZnI=; Nicolas O. Fortunel, Tmljb2xhcy5Gb3J0dW5lbEBjZWEuZnI= †These authors have contributed equally to this work September 18, 2024 By The Neopak XtraFlow glass prefillable syringe. [Image courtesy of BD]BD (NYSE:BDX) announced today that it launched its Neopak XtraFlow glass prefillable syringe and expanded the capacity for the platform The company said the launch and expansion aim to serve the growing market for biologic therapies Neopak glass prefillable syringes address key development needs for biologic drugs The syringes have approval for use with more than 24 indications BD said it expanded the platform’s usability with the latest commercial release as the Neopak XtraFlow features an 8mm needle length and thinner wall cannula to optimize the subcutaneous delivery of higher viscosity drug profiles It achieves this by reducing the injection force and time required for a fixed solution viscosity The company says this improvement enables pharmaceutical developers to break design barriers It enhances flow and usability beyond today’s limits compared to a standard half-inch needle BD also integrated a high-volume manufacturing line at its Le Pont-de-Claix The integration increases the production capacity of a single line of Neopax syringes by sevenfold for large-scale production The company says the addition of this line allows for more resilience with supply constraints “BD is seeing significant growth in the biologics segment driven by novel drug formulations across indications such as metabolic disorders and oncology,” said Patrick Jeukenne “With over 30 drugs approved across 12 markets and many more in development with the BD Neopak glass prefillable syringe platform BD aims to evolve as rapidly as the global biologics pipeline to enable supply and delivery of these drugs for patients worldwide.” December 2, 2020 By Becton Dickinson (NYSE:BDX) announced today that it plans to invest $1.2 billion to expand and upgrade multiple drug-delivery facilities N.J.-based BD plans to invest the $1.2 billion over a four-year period to expand and upgrade manufacturing capacity and technology for pre-fillable syringes (PFS) and advanced drug-delivery systems (ADDS) across its six global manufacturing locations while adding another manufacturing facility in Europe Becton Dickinson’s six manufacturing facilities for its pharmaceutical systems include locations in Columbus The company anticipates that the Europe facility will be operational by the end of 2023 manufacturing technology enhancements and business continuity improvements BD has commitments for over 800 million needles and syringes to deliver future COVID-19 vaccines in the U.S. Canada and elsewhere — a $100 million to $150 million opportunity “BD invented the ready-to-fill pre-fillable syringe technology and today’s announcement demonstrates our continued commitment to better serve our customers,” BD Pharmaceutical Systems worldwide president Eric Borin said in the release BD has added 350 million units of manufacturing capacity for glass barrel pre-fillable syringes and this new commitment will invest in additional upgrades at all of our Pharmaceutical Systems manufacturing facilities and across multiple product categories this investment positions BD to have the needed surge capacity for increased pre-fillable syringe demand during times of pandemic response or periods of significant growth of new injectable drugs and vaccines This significant investment in one of BD’s fastest-growing business units will further advance our leadership position and enable continued strong growth in the years ahead.” This cookie policy is intended to inform visitors how and why cookies are used by Becton The entity responsible for the use of these cookies is: Additionally, we invite you to read our Privacy Notice in which we explain our commitment to protecting your Personal Data which can be stored on your computer upon your visit to websites They can perform different functions but typically keep a record of websites visited Your internet browser downloads a cookie on the first visit to a website The next time you visit the website with the same user device 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For more information on the practical implications of changing cookie settings, you can consult this external page: https://www.allaboutcookies.org/ web browsers are automatically configured to accept cookies you can configure your browser in a way that it informs you of each cookie sent or to avoid them being stored on your hard drive please consult the following external pages: we cannot guarantee the full experience of our website This means that refusal could render the website less user-friendly or it is running at reduced speed Where the website is managed by another BD company please note that it may be governed by different laws and policies and may feature products and services that are not available locally Please contact your local BD representative if you have any questions or should you require further support May 18, 2021 By BD (NYSE:BDX) announced today that it will build a more than $200 million drug delivery device manufacturing facility in Spain The approximately $201.5 million (€165 million) high-tech manufacturing facility in Zaragoza is expected to create up to 600 jobs by 2030 In December, BD announced its plan to invest $1.2 billion over four years to expand and upgrade multiple drug-delivery facilities The company said it intended to open the new facility and build upon its six existing sites in Columbus The company said the new site continues its operations in Spain a country where BD has three production plants that produce 10 billion medical devices annually Its facility in Fraga represents a key production site for manufacturing COVID-19 vaccine injection devices “This new plant will also add needed capacity to support major vaccination campaigns such as the one currently taking place in response to the COVID-19 pandemic.” BD plans to start construction on the Zaragoza plant late this year with the site starting with a workforce of 150 people in an area of 86,000 square feet it will employ up to 600 people at the facility which will be expanded to 323,000 square feet by then The company said the new facility will meet high sustainability and eco-efficiency standards while operating as a fully digital site The facility is subject to the completion of an administration process “After the December 2020 announcement of BD’s intention to build a new plant in Europe a detailed site location search process resulted in Zaragoza Aragon being selected because of the optimal conditions offered by the region the synergies that could be produced with BD’s Fraga facility and the results and excellent performance of the plants that currently exist in Spain,” BD general director in Spain & Portugal Lourdes López said The Danish cyclist had even looked like an early contender for the final mountain stage, a 152.8km ride from Le Pont-de-Claix to La Bastille in south-eastern France with a steep climb to the finish. Read moreBut despite an attack with one kilometre to go, the Jumbo-Visma rider was no match for Giulio Ciccone of Trek-Segafredo. Ciccone bounced back from missing the Giro d’Italia owing to Covid-19 and dedicated his victory to his fiancee “My condition wasn’t 100% so I started here with the Tour de France in my head but saw this week my condition getting better and better So I’m really happy to close this week with a victory,” Ciccone said Vingegaard will celebrate overall victory after beating Adam Yates who finished 2min 23sec behind after nearly 30 hours of racing “It’s a very big thing for me to win this race So of course I’m very happy to win,” said Vingegaard who recently extended his contract with Jumbo-Visma until 2027 Vingegaard cracks a smile while standing atop the podium Photograph: Anne-Christine Poujoulat/AFP/Getty Images“I think I can be very satisfied with the whole week I’m in a good shape and the whole team rode fantastically Free weekly newsletterThe best of our sports journalism from the past seven days and a heads-up on the weekend’s action I’m surprised with the gaps in the overall standings Now I’ll relax a few days and then I’ll do the last bit of preparation for the Tour de France December 2, 2022 By BD (NYSE:BDX) announced recently that it inaugurated a new $38.6 million manufacturing facility in Tijuana Government officials from Mexico and the state of Baja California joined in the opening of the medication management plant BD plans for the facility to produce devices and technologies that improve medication safety within healthcare settings The company expects to add 500 new jobs there over the next two years BD plans to create 75 jobs responsible for manufacturing automated dispensing cabinets that dispense medication to patients the company intends to export these devices to North America “Our new facility in Tijuana is BD’s 12th manufacturing plant in Mexico and is a testament to our commitment to Mexico and the strong relationship we’ve built in communities across the country over the past 65 years,” said Julio Duclos “The 17,000 BD employees in Mexico are focused on producing high-quality medical devices that are used by health care providers and patients around the world We look forward to continuing to grow in Mexico.” BD plans to build upon its six existing sites in Columbus Ben O'Connor (AG2R Citroën Team) was next best in the overall standings Wout van Aert won the points classification and Jumbo-Visma claimed the best team classification and two stages while Tobias Halland (Uno-X) showed his promise by winning the best young riders' classification The Critérium du Dauphiné has been a traditional form-check for the Tour de France since its inception in 1947 It was created by the newspaper Le Dauphiné Libéré much like the Tour started out as an idea to boost circulation for l'Auto The race was originally known as the Critérium du Dauphiné Libéré but after the newspaper ended as title sponsor and the Tour de France organisers ASO took over Although the Dauphiné is considered a test for the Tour only 10 riders have won both races in the same year 2016) while Bernard Hinault did the double in 1979 and 1981 The most victories in the Dauphiné by a single rider stands at three: Luis Ocana (1970 - Investment includes new manufacturing facility in Europe today announced plans to invest approximately $1.2 billion over a 4-year period to expand and upgrade manufacturing capacity and technology for pre-fillable syringes (PFS) and advanced drug delivery systems (ADDS) across its six global manufacturing locations and add a new manufacturing facility in Europe The new manufacturing facility in Europe is expected to be operational by the end of 2023 The investment will also fund capacity expansion manufacturing technology enhancements and business continuity improvements across its existing network all designed to maximize supply and reduce risks for pharmaceutical companies that rely on ready-to-fill syringes for their injectable drugs — including complex biologics vaccines and small molecules.     "BD invented the ready-to-fill pre-fillable syringe technology and today's announcement demonstrates our continued commitment to better serve our customers," said Eric Borin This significant investment in one of BD's fastest growing business units will further advance our leadership position and enable continued strong growth in the years ahead." The six current manufacturing facilities for BD Pharmaceutical Systems that will see a portion of this investment include facilities in Columbus Kristen M. Stewart, CFABD Investor Relations201.847.5378[email protected] Logo: https://mma.prnewswire.com/media/1346788/BD_Logo.jpg Ciccone hangs on from the breakaway on ultra-steep final climb above Grenoble Victor Campenaerts (Lotto Dstny) in the Polka Dot Mountain Jersey David De La Cruz (Astana Qazaqstan) and Clément Champoussin (Arkea Samsic) in the stage 8 breakaway(Image credit: Getty Images)Jonas Vingegaard (Jumbo Visma) in the Yellow leader jersey descends safely on stage 8 (Image credit: Getty Images)Omar Fraile (INEOS Grenadiers) at the front of the breakaway on stage 8 (Image credit: Getty Images)LR Giulio Ciccone (Trek Segafredo) first place Jonas Vingegaard (Jumbo-Visma) and third place Ben OConnor (AG2R Citroen) on the podium(Image credit: Getty Images)Christophe Laporte (Jumbo-Visma) wins the overall best sprinter of the Criterium du Dauphine cycling(Image credit: Getty Images)Jonas Vingegaard (Jumbo-Visma) sealed the overall title at the Critérium du Dauphiné as Giulio Ciccone (Trek-Segafredo) won the final stage above Grenoble.  Ciccone attacked from the breakaway on the penultimate climb of Col de Porte before soloing down into Grenoble and then fending off Vingegaard on the ultra-steep final climb up to the Bastille Fortress that overlooks the city.  Vingegaard himself responded to efforts from Adam Yates (UAE Team Emirates) on the final two climbs before easing clear in the final kilometre in another disarming display of dominance As he rode away from an already-small GC group it looked like he might catch Ciccone to seal his overall title with a third stage win.  But Ciccone held firm on the double-digit gradients losing his sunglasses that are usually tossed to the crowd whenever he wins but still celebrating in style as he bounced back from having to miss the Giro d'Italia through COVID-19 my condition wasn't 100% so started here with the Tour de France in the head but saw this week my condition getting better and better so I'm really happy to close this week with a victory," Ciccone said.  I looked behind and saw I was still in front with some gap Ciccone made it into a strong breakaway after a chaotic start to a 152.8km final stage that featured six climbs and then a trio of major ascents ahead of the descent into Grenoble and the kick up the Bastille was the danger man in the original nine-man move while Vingegaard placed a teammate there in Tiesj Benoot along with Ciccone and Clément Champoussin (Arkéa-Samsic) who were left as the front-runners as the break exploded on the hors-catégorie Col du Granier (9.6km at 8.6%) They rode together over the Col du Coucheron (7.7km at 6.2%) with a slim advantage over the Jumbo-led bunch before Ciccone let rip and went solo on the Col de Porte (7.4km at 6.8%) He extended his lead to almost minute on the 15km descent but and then refused to fade on the final 1800-metre climb that averaged an eye-watering 14.2% Vingegaard couldn't quite make up enough ground to deny the Italian but he still handed his GC rivals another sound beating UAE Team Emirates shredded the bunch on the Col de Porte and Vingegaard marked an opening attack from Yates there before Rafal Majka returned on the descent to bust the 15-man GC group open again on the final climb Vingegaard took control and eased clear with a seated acceleration He closed to within 30 seconds but had to settle for second place on the day with Yates crossing the line in third place 10 seconds later to seal second overall Ben O'Connor (AG2R Citroën Team) finished fourth to fend off Jai Hindley (Bora-Hansgrohe) and clinch the final spot on the podium Vingegaard claimed the third WorldTour stage race crown of his career - after the Tour de France and Itzulia Basque Country - with the biggest winning margin at the Dauphiné in 20 years "It s very very big for me to win this race so I'm very happy to win," said Vingegaard "Yeah in some kind of way I'm surprised [by the winning margin] Now I relax for a few days then start preparing the last bit for the Tour de France I still have a little bit of work to do but not a lot." The stage started out in breathless fashion uphill almost from the flag and with no shortage of interest in the breakaway The day's break did form on the the Côte de Pinet (6.3km at 6.1%) but it went through various changes and iterations before the top of the climb.  Ciccone himself jumped across to it from the peloton as big-name GC riders like Richard Carapaz (EF Education-EasyPost) and David Gaudu (Groupama-FDJ) started moving.  They were reabsorbed but Ciccone went again alongside polka-dot jersey wearer Victor Campenaerts (Lotto Dstny) and they were joined by six other riders near the top: Alaphilippe Campenaerts took the maximum five points at the top of the Pinet to extend his lead in the mountains classification With the gap at just 30 seconds on the subsequent rolling plateau more riders looked to bridge across and three were successful: Benoot Nelson Oliveira (Movistar) and Matteo Trentin (UAE) The nine-man group extended their lead to 1:15 over the Col des Mouilles (3.9km at 7%) after 45km - with Campenaerts once again taking maximum points - and then moved out to 2:30 on the subsequent stretch through the valley After the intermediate sprint in Pontcharra with 65km to go - also won by Campenaerts - it was time for the real climbing and Porte to scale before the Grenoble finale The Granier saw an almost-immediate selection in the breakaway and - after a bit of yo-yo-ing - Champoussin soon the last man standing Ineos Grenadiers took it up and started to reduce the gap but then decided to send Jonathan Castroviejo on the attack sitting back to allow Jumbo-Visma to pace as the Spaniard set about trying to bridge to the break.  The bunch crested the Granier 1:15 down on the leaders but that grew as the break upped the pace on the Cucheron where Castroviejo made an enormous effort to go from dangling ahead of the peloton to joining the break inside the final kilometre of the climb Benoot wasn't contributing but still helped himself to the mountain points atop the Granier and Cucheron.  Onto the Col de Porte and the moves had to be made early taking over from Jumbo-Visma's Dylan van Baarle to force a tempo that immediately raised the stakes Riders like the Ineos duo of Dani Martinez and Egan Bernal were dropped and soon only 15 riders remained Ciccone knew he couldn't hang around and launched a vicious acceleration to which only Alaphilippe could respond Yates tried an attack near the summit but was marked by Vingegaard and eventually the other members of that GC selection scrambled back Louis Meintjes (Intermarché-Circus-Wanty) Pedrero attacked and took a slim lead onto the descent while Majka came back with Castroviejo and Carlos Rodriguez (Ineos Grenadiers) But things exploded once again on the steep final ramps in the final 1800 metres.  Majka took it up for Yates and they passed Pedrero as only Vingegaard Vingegaard made his move and was away with a minimum of fuss.  and the finale turned into a pursuit of Ciccone for the stage win had enough power in the legs and rode impressively through the final couple of horrifically steep bends to claim his third win of the season Results powered by FirstCycling Save A young Denise Maso stands on the balcony of an apartment in Le Pont-de-Claix (Courtesy of Marion Renault)On her first night home from the hospital “Qu’est-ce que j’ai fait?”: “What did I do?” is 82 and in the late stages of Alzheimer’s disease which means she can no longer form new memories Late last summer—it’s impossible to say when Pain became the fall’s only remnant evidence to understand why she’d stopped eating or getting out of bed In anticipation of her second discharge from the hospital When I arrived at the apartment where she lived alone I was entirely unprepared for how intensely the Alzheimer’s could amplify her suffering My grandmother’s throat rattled with every breath she kicked her legs and flailed her arms when I tried to get her out of bed to eat She developed a cough so intense that it sounded and sometimes did turn into vomiting as her body tried to convulse the pain away resulting in a panic that made her even more vulnerable to its punishment “To have pain is to have certainty,” the essayist Elaine Scarry wrote in her 1985 book “To hear about pain is to have doubt.” Helping someone cope with pain requires glimpsing the invisible interior of another person’s body—and then accepting that imagined suffering as real and true When a patient’s cognitive condition prevents reliable self-assessment our ability to see a person’s pain and treat what we see is even further limited the riddle of their suffering becomes nearly unsolvable can undermine the entire process of conveying pain A person with Alzheimer’s might express discomfort by wandering but the same behaviors might express loneliness or sadness—or they might be symptoms of the disease itself Asked to choose which emotional expression on a chart matches their current state point to the face they think they should feel told me about a patient who complained of frequent headaches Only later did she realize that “headache” was the woman’s metaphor for not being able to remember “It just adds to the complexity of taking care of people with Alzheimer’s disease,” Brangman said “That person may not be able to communicate what’s wrong with them.” Instead of figuring out how to ease the suffering caregivers are stuck simply trying to understand its source “It’s a population that’s just silently suffering,” Todd Monroe a registered nurse and neuroscientist at Ohio State University In addition to the five senses, nineteenth-century German academics believed in Gemeingefühl: a slate of perceivable bodily states “in the most diffuse and general sense”—fluctuating temperatures “and perhaps throw light on what parts of the brain were involved in producing such feelings.” Read: Beating Alzheimer’s with brain waves Melzack’s invention, the McGill Pain Questionnaire asked patients to describe their pain using words that fell into three categories: the sensory The sensory category identifies pain’s physicality through qualities such as temperature or sting—and each of these sensations can be unlike any of the others.) affective category capture pain’s emotional impact—whether it exhausts or sickens and most narrow evaluative category assesses the overall episode: Was it annoying language can provide “an external image of interior events,” as the essayist Scarry put it Questionnaires like the MPQ also elevated pain from a handful of physical symptoms to an experience nested in emotion and there’s the suffering of pain,” says Nancy Berlinger Alzheimer’s irreversibly robs a person of the cognition required to make this conception of pain medically useful a person loses the ability to create new memories or convey the world around and inside them Over the past quarter century, about 30 different tools or methods have been developed to specifically assess pain in people with dementia. Unfortunately, general practitioners who take care of these patients are often not even aware of their existence. (A 2018 survey of 157 GPs in Ireland found while 98 percent of respondents agreed that dementia makes pain difficult to assess only 10 percent were aware of any dementia-specific pain-assessment tools.) And evidence for their effectiveness often comes from studies with small sample sizes and other sources of biases Among the dozens of options, there is no general agreement on which instrument or technique should be recommended for patients with dementia “There’s not one single tool that’s determined to be the best,” Monroe is the uncertainty about how Alzheimer’s disease affects a person’s various pain-perception networks It’s clear that the disease impacts their ability to assign meaning to pain That has led to some cruel assumptions about people with Alzheimer’s some caretakers—professional and otherwise—decided it wasn’t worth the hassle of treatment if the patient couldn’t perceive physical sensations or would soon forget any unpleasant episodes I would hear that Alzheimer’s patients don’t feel pain or they don’t feel it as much,” Monroe says The body processes pain through several interconnected neural networks that help a person feel, describe, understand, and respond to pain. Preliminary research in neuroscience suggests that the major brain regions involved in pain perception and processing still function there’s no absence of brain activity in the areas related to pain “If somebody thinks dementia has just messed the brain up so much they don’t feel pain five years of active recruitment led by a dedicated recruitment specialist and a full-time research assistant resulted in the successful testing of fewer than two participants The result is that most of the existing clinical research has been conducted on participants who are younger and more mobile than the overall dementia population (women and Black and Latino people are the most likely to develop dementia) Any treatments based on these studies might not work as well in patients not represented in the trials—which is to say “I don’t think we have enough answers,” Brangman told me Evelyne and Jocelyne.Without reliable research to guide them caregivers are left to rely on their patients’ visible symptoms of untreated discomfort—exclamations like “Ow” or “Ouch,” and movements like massaging But even for people closest to the patient Brangman has seen patients become agitated not because of pain or anger but because of low blood sugar or high blood pressure They might stop sleeping because they’re uncomfortable or cold or stop eating because they’re lonely told me her mother often complained of chest pain and trouble breathing in the last five years of her life Doctors told McDaniel it was only allergies though allergy medicine did nothing to alleviate any discomfort Some suggested that her mother wasn’t feeling the pain she was describing One doctor wrote it off as a cry for attention McDaniel’s mother had been suffering from breast cancer She died less than six months after the cancer diagnosis “We didn’t put two and two together until it was much too late,” McDaniel said “I still feel guilty to this day for not listening to her instead of the doctors.” Read: Is the leading theory about Alzheimer’s wrong? “You have to look for other signals that they’re uncomfortable And it’s not one set thing,” Brangman said “It takes a lot of intuitive work and careful examination.” Given the tightening squeeze on geriatric care in the U.S. it’s not always possible for practitioners to form these kinds of close sustained relationships with their patients and even fewer of them are trained to deal with the complexities of dementia As the number of people with Alzheimer’s more than doubles by 2050 In the absence of a robust professional workforce, family members, friends, or other unpaid caregivers provide a large majority—about 83 percent—of elderly care. Among them, more than 16 million provide an estimated $244 billion worth of care for those with Alzheimer’s or other forms of dementia but they must nevertheless try to translate subtle facial expressions or unusual habits to doctors and nurses when they suspect that a person with dementia is suffering from untreated pain Many of the experts I spoke with had relatives or friends who had suffered from these diseases Monroe’s grandmother battled breast cancer and Alzheimer’s at the end of her life they felt a powerlessness they’ve tried to dismantle through research or medical care Alison Anderson, a nurse practitioner and dementia researcher at Vanderbilt University, watched her mother struggle through early dementia as she began studying the disease. In 2017, Anderson examined existing research and found study after study suggesting that the basics of care—touch and the presence of another human being—can help relieve pain in dementia patients my grandmother now resides in the Alzheimer’s wing of a nursing home I found that our moments of communion kept her physical agony at bay We rooted through boxes of old photographs together and I distracted her with stories about how I had filled my suitcase with sesame bagels for her all I could do for her was lie down in bed beside her as she whimpered "BD's new plant in Zaragoza will produce drug delivery devices primarily for pharmaceutical companies that supply the European market with drugs in pre-fillable syringes such as vaccines and other biologic drugs," said Eric Borin "This new plant will also add needed capacity to support major vaccination campaigns such as the one currently taking place in response to the Covid-19 pandemic.” The plant will initially have a workforce of 150 people and cover an area of 8,000 m2 BD expects to employ up to 600 staff with the plant extended to cover 30,000 m2 BP said it chose Zaragoza after a “detailed location search process” because of the region’s optimal conditions on offer the synergies available with the firm’s Fraga facility as well as the “results and excellent performance” of its other plants in Spain Two more Spanish plants are located in San Agustin de Guadalix and Almaraz the three existing plants in Spain produce 10 billion medical devices each year and employ 1,500 people BD added that the Fraga plant is a key site for manufacturing Covid-19 vaccination injection devices Last December, BD announced a $1.2 billion investment program spread over four years to expand and upgrade its manufacturing capacity and technology for pre-fillable syringes and advanced drug delivery systems will see projects implemented across six locations worldwide as well as the addition of the new Spanish plant The six facilities are located in Le Pont-de-Claix ProteiNext is an annual symposium that offers a platform for sharing insights on protein analysis and strategic direction in an exclusive CHEManager International interview Jonas Vingegaard wins Criterium du Dauphine ahead of Tour de France title defenceReutersJonas Vingegaard (26) warmed up for the defence of his Tour de France crown by winning the 75th Criterium du Dauphine on Sunday underlining his credentials as one of the favourites for cycling's biggest race which starts on July 1st.The Danish cyclist had even looked an early contender for the final mountain stage too a 152.8-kilometre ride from Le Pont-de-Claix to La Bastille with a steep climb to the finish But despite an attack with one kilometre to go, the Jumbo-Visma rider was no match for Giulio Ciccone (28) of Trek-Segafredo who bounced back from missing the Giro d'Italia due to COVID-19 and dedicated his victory to his fiancée whom he marries next week "My condition wasn't 100% so I started here with the Tour de France in my head but saw this week my condition getting better and better So I'm really happy to close this week with a victory," Ciccone said Nevertheless, Vingegaard will celebrate overall victory after beating Briton Adam Yates (30), who finished two minutes and 23 seconds behind after nearly 30 hours of racing, while Australia's Ben O'Connor (27) was third "It's a very big thing for me to win this race So of course I'm very happy to win," said Vingegaard "I think I can be very satisfied with the whole week I'm in a good shape and the whole team rode fantastically I'm surprised with the gaps in the overall standings Now I'll relax a few days and then I'll do the last bit of preparation for the Tour de France The Tour de France runs from July 1st to July 23rd Check out the full results from the Dauphine with Flashscore. Profile of 2023 Criterium du Dauphine stage 1 Profile of stage 2 of the 2023 Critérium du Dauphiné Profile of stage 3 for the 2023 Critérium du Dauphiné Profile of stage 4 of the 2023 Critérium du Dauphiné Profile of stage 5 for the 2023 Critérium du Dauphiné Profile of stage 6 of the 2023 Critérium du Dauphiné Profile of stage 8 of the 2023 Critérium du Dauphiné Eight stages for the pre-Tour de France form test in June The 2023 Critérium du Dauphiné presents riders with a slow build from the rolling terrain of the Puy-de-Dôme department at Chambon-sur-Lac to the highest finish in the race's history on the Col de la Croix-de-Fer over eight stages 2023: Stage 1 - Chambon-sur-Lac to Chambon-sur-Lac The opening stage takes place around Chambon-sur-Lac a commune that sits in the shadow of the sprawling Parc naturel régional des Volcans d'Auvergne - an area of 80 dormant volcanoes - one of which The peloton will have to wait to tackle any major climbs as they skirt the Super-Besse ski station and tackle instead five category 4 climbs in the foothills the stage finishes with three loops of a circuit that includes the Côte du Rocher de l'Aigle the last ascent crested with around 10km to go before a descent to the finish and uphill kick to the line Stage 2 of the 2023 Criterium du Dauphine takes place on June 5 with a 167.3km route out of Brassac-les-Mines in Puy-de-Dôme and into Haute-Loire with a finishing circuit in La Chaise-Dieu.  It's a lumpy route with four categorized climbs but is front-loaded with two category 3 ascents the Col de la Toutée  (2.2 km at 6%) and Col des Fourches (2.7 km at 6.5%) The two finish laps include the category 4 Côte des Guêtes (1 km at 8%) with another climb inside 10km to go The sprinters will have their day if all goes to plan on stage 3 with the Critérium du Dauphiné leaving the Massif Central and heading toward flatter ground outside Lyon Riders must tackle the category 2 Côte de Bellevue-la-Montagne (4.9 km at 5.8%) just 36km into the stage it should be smooth sailing on this longest stage of the race.  The category 4 Côte de Neulise  (7.5 km at 3%) inside 20km to go will hardly get in the way of the sprinters and will probably only spell the end of the day's early breakaway The battle for the overall victory in the 2023 Critérium du Dauphiné begins in earnest with the 31.1km individual time trial on stage 4 The route is a bit tougher than the similar test in 2022 which Filippo Ganna (Ineos Grenadiers) won by two seconds over Wout van Aert (Jumbo-Visma).  The distance is enough for some contenders to put a minute or more into the pure climbers and last year the similar stage in La Bâtie d’Urfé was where Primož Roglič (Jumbo-Visma) set the stage for his overall victory The Critérium du Dauphiné gets more complicated on stage 5 as the peloton heads into the Jura department and the climbs get harder and steeper first two hours will help riders recover from the time trial but they'll need to find their climbing legs by the final 40 kilometres the Côte de Château-Chalon (4.4 km at 4.5%) at km 97.7 and Côte d’Ivory (2.3km at 5.9%) at km 154.6 They'll top the beastly Côte de Thésy (3.6km at 8.8%) inside 15km to go so it will undoubtedly be a climber who wins this stage The build of intensity ramps up another notch on stage 6 of the Dauphiné The stage from Nantua to Crest-Voland heads into the Alps with one category 2 climb coming in the first half of the day One category 2 and two category 3 ascents cap off the stage inside the last 20km The Côte de Droisy (5.4km at 7%) comes 100km before the Col des Aravis (7.8km at 5.7%) so the fight to get into the breakaway will come either before or on the Droisy but the descent following it will allow some riders to chase back on The Côte de Notre-Dame-de-Bellecombe (3.2km at 6.1%) comes directly before the final climb to the finish the Côte de Crest-Voland (2.3km at 6.6%) without much descending to break it up Profile of stage 7 of the 2023 Critérium du Dauphiné(Image credit: ASO)Profile of the Col de la Madeleine(Image credit: ASO)Profile of the Col du Mollard(Image credit: ASO)Profile of the final climb the Col de la Croix de Fer(Image credit: ASO)The queen stage of the 2023 Critérium du Dauphiné comes on the penultimate stage with the highest finish in the event's history (by three metres) coming on the Col de la Croix de Fer At just 147.7km in length and the first of two hors categorie climbs coming at the midpoint there could be attacks from the overall contenders early in the stage The riders hit the Col de la Madeleine (25.1km at 6.2%) at kilometre 75.5 then have a long descent and chase through the valley to the Col du Mollard (18.5km at 5.8%) at km 127.9.  it's less than 20km to the summit of the Col de la Croix de Fer with little in the way of descents for recovery The final climb is 13.1km and averages 6.2% but that belies the punishing sections of double-digit grades including the final kilometre Riders crested the Croix de Fer in 2022 but it was a mid-stage climb It's been featured 21 times in the Tour de France and five other times in the Dauphiné but this is the first time the climb has been used as a stage finish the final stage of the Critérium du Dauphiné is no cakewalk This 152.8km stage has six categorised climbs including the final kick to the Bastille of Grenoble with two category 2 climbs - the Côte de Pinet (6.3km at 6.1%) and Col des Mouilles (3.9km at 7%) in the first 50km and four climbs in the last 50km The hors categorie Col du Granier (9.6km at 8.6%) category 2 Col du Cucheron (7.7km at 6.2%) and Col de Porte (7.4km at 6.8%) will batter the riders before they face the killer climb to the Fort de la Bastille It's 1,800 metres long but a ridiculous 14.2% average and a section of 22% grades A punishing finale that will certainly produce a worthy winner she coordinates coverage for North American events and global news As former elite-level road racer who dabbled in cyclo-cross and track Laura has a passion for all three disciplines When not working she likes to go camping and explore lesser traveled roads UCI governance and performing data analysis The Team Sky rider, who went on to win the Tour after his Dauphiné wins in 2013 and 2015 ended the final stage 12 seconds ahead of the Frenchman Romain Bardet The final 151km seventh stage from Le-Pont-de-Claix to Superdévoluy was won by another Briton Steve Cummings (Dimension Data) “Coming into this week I hoped I’d be fighting for the podium,” Froome told Eurosport It is great timing to have a win under the belt it does help build the morale a bit and build the team around me “There’s still some work to do before July I’ve not raced much this year in order to be at my best during the third week of the Tour.” the battle for general classification unfolded behind him on the ascent of the Col du Noyer Tinkoff’s Alberto Contador attacked twice and forced Froome to react with Bardet (AG2R-La Mondiale) and Richie Porte (BMC) paying close attention including the first nine in the overall rankings Dan Martin (Etixx-Quick Step) claimed second – 3min 58sec behind Cummings – ahead of Bardet who took second overall in the race ahead of Martin as Porte was displaced from the podium places In the overall standings Froome finished in 29hr 59min 31sec to give him the win over Bardet with Martin a further seven seconds back two seconds in front of Porte in the final rankings Metrics details Immunogenicity of recombinant human acid-alpha glucosidase (rhGAA) in enzyme replacement therapy (ERT) is a safety and efficacy concern in the management of late-onset Pompe disease (LOPD) long-term effects of ERT on humoral and cellular responses to rhGAA are still poorly understood To better understand the impact of immunogenicity of rhGAA on the efficacy of ERT clinical data and blood samples from LOPD patients undergoing ERT for >4 years (n = 28) or untreated (n = 10) were collected and analyzed anti-rhGAA antibodies peaked within the first 1000 days of ERT while long-term exposure to rhGAA resulted in clearance of antibodies with residual production of non-neutralizing IgG Analysis of  T cell responses to rhGAA showed detectable T cell reactivity only after in vitro restimulation Upregulation of several cytokines and chemokines was detectable in both treated and untreated LOPD subjects while IL2 secretion was detectable only in subjects who received ERT These results indicate that long-term ERT in LOPD patients results in a decrease in antibody titers and residual production of non-inhibitory IgGs Immune responses to GAA following long-term ERT do not seem to affect efficacy of ERT and are consistent with an immunomodulatory effect possibly mediated by regulatory T cells Here we characterized the immune responses to rhGAA in a large cohort of LOPD subjects either receiving long-term ERT or untreated In this study we demonstrate that rhGAA infusion results in the early production of high-titer antibodies in a subset of subjects however antibodies appear to drop over time with continuation of ERT IgG subclass characterization shows production of non-inhibitory antibodies with no evident effect on enzyme activity or uptake while rhGAA-specific T cell activation profile is consistent with immune modulation Long-term ERT in LOPD patients results in a decrease of anti-rhGAA antibodies Anti-rhGAA IgG1 and IgG4 are the most prevalent subclasses of antibodies developed in response to long-term ERT (A–F) Anti-rhGAA antibodies measured with a capture assay specific for IgG1 Estimated antibody concentrations are reported for each subject Average and standard deviation are indicated for each of the study cohorts: LOPD subjects receiving ERT (Treated Unpaired two-tailed t-test was used to compare results across the study cohorts (**P < 0.01) T cell reactivity to rhGAA is detectable after restimulation of PBMCs with the antigen (A) Comparison of IFNγ ELISpot count in PBMCs isolated from LOPD subjects receiving ERT before and after DC-mediated restimulation Cells were either directly plated in the ELISpot assay (−) or restimulated in vitro with 10 μg/ml of rhGAA prior to the assay (+) Results are expressed in spot forming units (SFU) per 106 cells Results are reported as average of triplicate testing +/− standard deviation Images of the test wells in the IFNγ ELISpot assay are shown below the histogram plot (B) Combined results for all subjects screened with the IFNγ ELISpot assay after PBMC restimulation PBMCs from LOPD subjects receiving ERT (Treated Results are expressed as ratio between SFU/106 cells in rhGAA-restimulated cells vs (C–F) PBMCs from LOPD subjects receiving ERT (n = 3) were restimulated with 10 μg/ml of rhGAA for 48h and then stained intracellularly for IFNγ Results are reported as percentage of CD4+ T cells secreting a given cytokine Cytokine profiling of supernatant from PBMCs restimulated with rhGAA Supernatants from cells restimulated with rhGAA were collected after 48 hours of restimulation in vitro and assayed for cytokine and chemokine production (A) Levels of IL2 measured in conditioned media in LOPD subjects receiving ERT (Treated Error bars represent the standard deviation of the mean Mann-Whitney test was used to compare data across the study groups (B–L) Cytokine and chemokine concentration in media measured with the Luminex array technology; shown are individual values measured in LOPD subjects receiving ERT (Treated Error bars represent the average of a cohort +/− standard deviation (M) Pearson correlation matrix comparing measurements of cytokine and chemokine production in responses to rhGAA in treated (n = 28) and untreated (n = 10) LOPD subjects Numbers in the table represent the correlation coefficient between two variables with the relative p value (t-test) (N) Depletion of CD25+ in PBMCs from treated LOPD subjects The untouched CD25neg PBMC fraction was co-cultured with autologous DCs pulsed with rhGAA antigen or unpulsed DCs as negative control Results of the IFNγ ELISpot assay are shown as average of spot forming units (SFU) per 106 cells plated in the assay +/− standard deviation of triplicate testing (O) Sorted untouched CD19+CD24negCD38neg PBMC fraction from treated LOPD subjects co-cultured with autologous DCs pulsed with rhGAA antigen (or negative control) followed by IFNγ ELISpot Results of are shown as average SFU/106 cells +/− standard deviation of triplicate testing (*P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001 not supporting the involvement of CD19+CD24hiCD38hi B cells in the observed hyporesponsiveness to rhGAA Serum cytokine and chemokine profiling of LOPD subjects before and after ERT (A–E) Luminex cytokine and chemokine measurements before (PRE) and immediately after (POST) rhGAA administration (over the course of four hours) in LOPD subjects (n = 10) Shown are cytokines for which a significant change in serum levels was measured at the end of ERT Paired t-test was used to compare data analysis PRE vs POST infusion (*P < 0.05; **P < 0.01) Clinical outcome measures and statistical analysis of results (A) % forced vital capacity (FVC) measurements expressed as % predicted in healthy individuals over a period of 4 years in 21 treated LOPD subjects; the red line represents the average evolution of the measurement The estimated slope is −1.16% per year; the estimated intercept is 58.9%; p value is given by linear mixed models (see Methods) The following equations were used to calculate the % FVC: [FVC predicted for males = 0.060 * height − 0,0214 * age – 4.65]; [FVC predicted for females = 0.0491 * height − 0.0216 * age – 3.59]; [FVC (%) = FVC observed/FVC predicted * 100] (B) Six-minute walk test (6MWT) measured over a period of 4 years in 19 subjects the red line represents the average evolution of the measurement The estimated slope is −2.06% per year; the estimated intercept is 59.6%; p value is given by linear mixed models (see Methods) (***P < 0.001) The following equations were used to calculate the % 6MWT: [6MWT predicted for males = −309–5.02 * age − 1.76 * weight + 7.57 * height]; [6MWT predicted for females = 667–5.78 * age − 2.29 * weight + 2.11 * height]; [6MWT (%) = 6MWT observed/6MWT predicted * 100] (C) Spearman correlation of measurements of immune responses to rhGAA with clinical outcome measures recorded at the time of blood collection The numbers in the table represent the correlation coefficient between two variables with the relative p value (t-test) (NS In our analysis, no correlation was found between the evolution of FVC and 6MWT and the measurements of immune responses to rhGAA after long-term ERT (Fig. 6C) consistent with the fact that no neutralizing antibody response was detected after long-term ERT no relationship between clinical endpoints of disease progression and immune responses to rhGAA is found the mechanisms driving the immunogenicity of rhGAA in ERT for Pompe disease are largely unknown residual expression of the endogenous GAA in these subjects may also result in an increased immunogenicity of rhGAA as we showed that infusion of rhGAA in LOPD patients triggered immediate systemic secretion of several cytokines and chemokines it is not surprising that the measurements of immune responses after long-term exposure to ERT do not correlate with the longitudinal analysis of 6MWT and FVC This is likely to be the results of multiple factors including (1) all subjects after long-term ERT had low residual levels of anti-rhGAA antibodies which were not neutralizing (2) the fact that the immune responses measured were more consistent with a state of unresponsiveness to rhGAA and (3) the fact that the immune assays were performed far in time from the peak of antibody responses to rhGAA thus not warranting the use of immunomodulatory strategies to eradicate anti-GAA antibodies LOPD subjects included in this study were part of the French registry of adult Pompe disease patients Approvals from the competent health authorities and the local Ethical Committee of the Pitie-Salpetriere Hospital were obtained prior to the initiation of the study (CNIL N/Ref MMS/CWR/AR155497; CCTIRS N: 14.520; CCP approval 25/06/2014) Informed consent was given by each participant prior to inclusion in the study All the experiments were carried out in accordance with the relevant guidelines for clinical investigation in France and Europe Study inclusion criteria were diagnosis of PD defined as deficiency of GAA enzyme activity measured in blood or skin fibroblasts PD diagnosis was confirmed by GAA gene sequencing Exclusion criteria were age older than 80 years ongoing or recent (less than 3 months) immunosuppressive treatment Blood samples were collected via venipuncture in heparin tubes and used to isolate serum and PBMCs De-identified HD blood samples (n = 43) were collected through the French blood bank (Etablissement Française du Sang De-identified PD patient fibroblasts lacking GAA activity were obtained from the Coriell Institute repository (Camden Antibody titers over time in treated subjects were determined as previously described10 To study the IgG subclasses specific to GAA 96-well Nunc Polysorp Immunoplate microplates (Dutscher France) were coated with rhGAA to a final concentration of 1 μg/ml A standard curve made of purified human IgG (Gamunex serum samples were added at dilutions of 1:10 and 1:20 in duplicate and incubated overnight at 4 °C Monoclonal anti-human Ig biotin-conjugated antibodies specific for each subclass (all from Sigma-Aldrich Binding of the secondary antibodies was detected with alkaline phosphatase-conjugated streptavidin (Sigma-Aldrich The enzymatic reaction was developed with p-nitrophenyl phosphate (Sigma-Aldrich France) substrate and color development was read at 405 nm using a microplate reader (MRX Relevation Anti-rhGAA antibody concentration was determined against the Ig subclass-specific standard curve using 4-parameters regression PBMCs were restimulated in vitro according to a protocol designed to enhance detection of antigen-specific T cell responses26 PBMCs from the three cohorts studied were stimulated with rhGAA to a final concentration of 10 μg/ml Cells recovered after the short-term restimulation protocols were used to perform antigen-specific T cell assays CD25+ T cell depletion was performed prior to restimulation of PBMC with antigen using magnetic beads conjugated with anti-CD25 antibodies (Miltenyi Biotec Flow cytometry was used to assess the efficacy of depletion PBMC depleted of CD19+CD24hiCD38hi B cells were obtained by staining cells with anti-CD19 France) following by sorting on a FACSAria (BD Biosciences) The IFNγ ELISpot assay was performed as previously described64 rhGAA was used at a concentration of 10 μg/ml and a mix of 0.05 μg/ml of phorbol 12-myristate 13-acetate (PMA France) and 1 μg/ml of ionomycin (Sigma-Aldrich All antigens and controls were tested in triplicate Intracellular cytokine staining (ICS) was performed by incubating PBMCs from treated LOPD with rhGAA protein (10 μg/ml) France) were added to the cultures at a concentration of 1 μg/ml and 2 μM A mix of PMA (0.05 μg/ml) and ionomycin (1 μg/ml) was used as positive control in the ICS assay cells were harvested and a mix of fluorescently-labeled antibodies specific for the surface markers CD4 (PerCP-Cy5.5 An amine-reactive aqua dye (Life Technologies Cells were then fixed and permeabilized with Cytofix/Cytoperm (BD Biosciences Le Pont de Claix France) and intracellular staining was performed using antibodies against IL2 (PE-Cy7 Cells were acquired on a BD LSRFortessa flow cytometer (BD Biosciences Data analysis was performed using Flowjo software version 10 (Tree star Supernatants from PBMC restimulation in vitro and serum samples from LOPD subjects were used for the detection of cytokines and chemokines using a multiplexed bead immunoassay based on the Luminex technology and TNFα) were measured with the Bio-Plex Pro human cytokine 17-plex immunoassay (BioRad France) following the manufacturer’s instructions A Bioplex 200 system (BioRad) was used to analyze the samples All data are shown as mean value +/− standard deviation Data analysis was performed as indicated in figure legends using GraphPad Prism version 6 (GraphPad Software Inc. P values lower than 0.05 were considered significant Hierarchical clustering of the levels of cytokines and chemokines in HD and PD patients was performed with the StatistiXL software (Digital River UK) using the Pearson correlation coefficient In both correlation matrices the correlation coefficient r was transformed to t using the formula t = r × [√(n − 2)/√(1 − r2)] for statistical testing and the p value adjusted for multiple comparisons using the false discovery rate method Long-term exposure to Myozyme results in a decrease of anti-drug antibodies in late-onset Pompe disease patients Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations In The Metabolic and Molecular Basis of Inherited Disease (ed A The genotype-phenotype correlation in Pompe disease Cross-reactive immunologic material status affects treatment outcomes in Pompe disease infants Recombinant human acid alpha-glucosidase (rhGAA) in adult patients with severe respiratory failure due to Pompe disease Recombinant human acid [alpha]-glucosidase: major clinical benefits in infantile-onset Pompe disease doi: 10.1212/01.wnl.0000251268.41188.04 (2007) The emerging phenotype of long-term survivors with infantile Pompe disease Open-label extension study following the Late-Onset Treatment Study (LOTS) of alglucosidase alfa A randomized study of alglucosidase alfa in late-onset Pompe’s disease Survival and long-term outcomes in late-onset Pompe disease following alglucosidase alfa treatment: a systematic review and meta-analysis Elimination of antibodies to recombinant enzyme in Pompe’s disease Persistence of high sustained antibodies to enzyme replacement therapy despite extensive immunomodulatory therapy in an infant with Pompe disease: need for agents to target antibody-secreting plasma cells Clinical outcomes after long-term treatment with alglucosidase alfa in infants and children with advanced Pompe disease High antibody titer in an adult with Pompe disease affects treatment with alglucosidase alfa modified approach to desensitize infants and young children with Pompe disease and significant reactions to alglucosidase alfa infusions Enzyme therapy for Fabry disease: neutralizing antibodies toward agalsidase alpha and beta doi: 10.1111/j.1523-1755.2004.00924.x (2004) Mutation analysis of the acid beta-glucosidase gene in a patient with type 3 Gaucher disease and neutralizing antibody to alglucerase Enzyme replacement therapy induces T-cell responses in late-onset Pompe disease Immune responses and hypercoagulation in ERT for Pompe disease are mutation and rhGAA dose dependent Mapping the T helper cell response to acid alpha-glucosidase in Pompe mice Immunomodulatory gene therapy prevents antibody formation and lethal hypersensitivity reactions in murine pompe disease Distinct characteristics of antibody responses against factor VIII in healthy individuals and in different cohorts of hemophilia A patients IgG4 production is confined to human IL-10-producing regulatory B cells that suppress antigen-specific immune responses IgG4 and IgA by T regulatory cells and toll-like receptors doi: 10.1111/j.1398-9995.2008.01774.x (2008) acDCs enhance human antigen-specific T-cell responses Cytokine production by CD4+ T cells specific for coagulation factor VIII in healthy subjects and haemophilia A patients Functional and molecular comparison of anergic and regulatory T lymphocytes Cytokines in immune-mediated inflammatory myopathies: cellular sources multiple actions and therapeutic implications Transcriptional response to GAA deficiency (Pompe disease) in infantile-onset patients CD4 T cell hypo-responsiveness induced by schistosome larvae is not dependent upon eosinophils but may involve connective tissue mast cells CD19(+)CD24(hi)CD38(hi) B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic Lupus Erythematosus patients Immune response to enzyme replacement therapies in lysosomal storage diseases and the role of immune tolerance induction The effect of antidrug antibodies on the sustainable efficacy of biologic therapies in rheumatoid arthritis: practical consequences Correlation between factor VIII genotype and inhibitor development in hemophilia A A risk-based bioanalytical strategy for the assessment of antibody immune responses against biological drugs Anti-adalimumab antibodies in rheumatoid arthritis patients are associated with interleukin-10 gene polymorphisms Anti-dystrophin T cell responses in Duchenne muscular dystrophy: prevalence and a glucocorticoid treatment effect Dystrophin immunity in Duchenne’s muscular dystrophy Pompe disease diagnosis and management guideline doi: 10.109701.gim.0000218152.87434.f3 (2006) The impact of antibodies in late-onset Pompe disease: a case series and literature review Dangerous liaisons: how the immune system deals with factor VIII Impaired autophagy affects acid alpha-glucosidase processing and enzyme replacement therapy efficacy in late-onset glycogen storage disease type II McArdle disease: another systemic low-inflammation disorder Pro-inflammatory cytokines and the pathogenesis of Gaucher’s disease: increased release of interleukin-6 and interleukin-10 Successful immune tolerance induction to enzyme replacement therapy in CRIM-negative infantile Pompe disease Bortezomib in the rapid reduction of high sustained antibody titers in disorders treated with therapeutic protein: lessons learned from Pompe disease A longitudinal evaluation of anti-FVIII antibodies demonstrated IgG4 subclass is mainly correlated with high-titre inhibitor in haemophilia A patients Rapid acquisition of immunologic tolerance to factor VIII and disappearance of anti-factor VIII IgG4 after prophylactic therapy in a hemophilia A patient with high-titer factor VIII inhibitor Mechanisms of immune tolerance to allergens: role of IL-10 and Tregs Chronic cat allergen exposure induces a TH2 cell-dependent IgG4 response related to low sensitization IgG4 inhibits peanut-induced basophil and mast cell activation in peanut-tolerant children sensitized to peanut major allergens Prolonged immunization results in an IgG4-restricted response High incidence of anti-FVIII antibodies against non-coagulant epitopes in haemophilia A patients: a possible role for the half-life of transfused FVIII Immune tolerance improves the efficacy of enzyme replacement therapy in canine mucopolysaccharidosis I Immune tolerance after long-term enzyme-replacement therapy among patients who have mucopolysaccharidosis I Enhanced efficacy from gene therapy in Pompe disease using coreceptor blockade Induction of immune tolerance in haemophilia A inhibitor patients by the ‘Bonn Protocol’: predictive parameter for therapy duration and outcome The strength of persistent antigenic stimulation modulates adaptive tolerance in peripheral CD4+ T cells Durable and sustained immune tolerance to ERT in Pompe disease with entrenched immune responses Desensitization of an adult patient with Pompe disease and a history of anaphylaxis to alglucosidase alfa Effect of enzyme replacement therapy in late onset Pompe disease: open pilot study of 48 weeks follow-up A method for rapid prenatal diagnosis of glycogenosis II (Pompe’s disease) AAV-1-mediated gene transfer to skeletal muscle in humans results in dose-dependent activation of capsid-specific T cells Download references David Scott for critical review of the manuscript Supported by a grant from the Vaincre les Maladies Lysosomales (VML) association the French Muscular Dystrophy Association (AFM) This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No Olivier Benveniste & Federico Mingozzi Pasqualina Colella & Federico Mingozzi Department of Internal Medicine and Clinical Immunology Kuberaka Mariampillai & Olivier Benveniste Neuromuscular Physiology and Evaluation Lab Centre de référence de pathologie musculaire Paris-Ouest Centre de compétence de pathologie neuromusculaire Centre de référence de pathologie neuromusculaire Paris-Est Service ENMG et Pathologies Neuromusculaires Service de médecine physique et de réadaptation Centre de compétence des maladies neuromusculaires Centre de référence des maladies neuromusculaires rares Rhône-Alpes Centre Hospitalo-Universitaire de Montpellier Centre de référence des maladies neuromusculaires CHU de Bordeaux-GH Sud - hôpital Haut-Levesque CHU de Lyon-GH Est hôpital Femme-Mère-Enfant Service de Neurologie D et centre de réference des maladies rares neuromusculaires Centre de référence des maladies neuromusculaires Nantes-Angers Centre de référence des maladies neuromusculaires Nantes/Angers Service de réanimation et unité de ventilation à domicile Service de soins de suite et de réadaptation neurologie Centre de référence maladies neuromusculaires de la région Rhône-Alpes Centre de compétences maladies neuromusculaires Centre de réference des maladies Neuromusculaires et SLA Centre de référence des maladies neuromusculaires et de la SLA groupe hospitalier La Rochelle – Ré – Aunis Hôpital d’Instruction des Armées Clermont Tonnerre and the French Pompe registry contributed to the collection of human samples and relative clinical history: G.B. Pascal Laforet has received grants and honoraria from Genzyme Company and honoraria from BioMarin and Amicus Therapeutics and all the other authors declare no competing financial interests Download citation Anyone you share the following link with will be able to read this content: a shareable link is not currently available for this article Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology Tuesday World Subscribers only Israel prepares large-scale Gaza offensive to achieve lasting occupation World Subscribers only Romania enters government crisis amid election World Subscribers only In Zurich the leaf blower war or the anti-'woke' backlash World Subscribers only Germany's Friedrich Merz is embracing pragmatism World Subscribers only Founder of Sant'Egidio community fears next pope could undo Francis's legacy Opinion Subscribers only 'Russian gas and Europe is an old story that ended badly Economy Subscribers only Europe's steel industry flattened by crisis World Subscribers only How European countries plan to fund defense efforts France Subscribers only Macron announces citizens' convention on school schedules France Subscribers only 21 charged over French prison attacks as investigation narrows in on drug traffickers France Subscribers only French mosque stabber was driven by 'morbid fascination,' prosecutor says France Subscribers only At the trial of Kim Kardashian's robbers Videos World expos: From Paris 1855 to Osaka 2025 Videos How the Trump administration is attacking scientific research in the US Videos Tesla cars set on fire in Las Vegas as calls to boycott Musk's company grow worldwide Videos Can France's nuclear deterrent protect Europe Opinion Subscribers only 'The American dream is dying' Editorial European call to aid foreign researchers is too modest Opinion Subscribers only John Bolton: 'The term chaos is commonly used to describe the top of the Defense Department' Magazine Subscribers only Tracking down the pianos taken from French Jews during the Nazi Occupation Magazine Subscribers only Eve Rodsky the American helping couples balance the mental load Magazine Subscribers only Desecration or more glory Joan Didion's private diaries are revealed Magazine Subscribers only For Jewish cartoonist Joann Sfar 2025."> Pixels Subscribers only Golden Owl solution is revealed but leaves players of 31-year hunt disappointed Pixels Subscribers only Secrets of decades-long Golden Owl treasure hunt to be revealed Lifestyle Inside Chanel's French leather workshops Culture Subscribers only The marvelous bronzes of Angkor on display at the Musée Guimet in Paris Layoffs are rising across sectors including automotive Politicians and trade unions are discussing how to stem further job losses Employees of the Vencorex chemical plant during a demonstration after the company went bankrupt in September JEFF PACHOUD / AFP Should we be working on developing a European industrial strategy Or should we instead hold companies that have received public funding accountable as suggested by trade union leaders Sophie Binet (CGT) and Marylise Léon (CFDT) should the government block the approval of certain redundancy plans as advocated by left-wing MP François Ruffin which is preparing to cut 2,389 jobs; and the receivership of chemical manufacturer Vencorex political leaders and trade unionists are wondering how to stop further losses on the social front In the three years after the Covid-19 pandemic companies – supported by state-guaranteed loans various aid programs during lockdowns and a relatively stable economy – hired extensively and laid off few employees the horizon is darkening and difficulties are piling up "There will probably be announcements of site closures in the coming weeks and months," Ferracci said on France Inter radio on Saturday referring to the possible destruction of "thousands of jobs." 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You have 69.38% of this article left to read Lecture du Monde en cours sur un autre appareil Vous pouvez lire Le Monde sur un seul appareil à la fois Ce message s’affichera sur l’autre appareil Parce qu’une autre personne (ou vous) est en train de lire Le Monde avec ce compte sur un autre appareil Vous ne pouvez lire Le Monde que sur un seul appareil à la fois (ordinateur En cliquant sur « Continuer à lire ici » et en vous assurant que vous êtes la seule personne à consulter Le Monde avec ce compte Que se passera-t-il si vous continuez à lire ici Ce dernier restera connecté avec ce compte Vous pouvez vous connecter avec votre compte sur autant d’appareils que vous le souhaitez mais en les utilisant à des moments différents Nous vous conseillons de modifier votre mot de passe Votre abonnement n’autorise pas la lecture de cet article merci de contacter notre service commercial You can read this article in 12 minutesAgnieszka Kulikowska - Wielgus French traffic bans apply to trucks and vehicle combinations with a DMC above 7.5 tonnes with the exception of special vehicles and agricultural vehicles This guide explains when the bans are in force in 2021 The truck bans start at 10pm on Saturdays and the evening before public holidays and last until 10pm on a Sunday or a public holiday The calendar of holidays in France for 2021 is as follows: the following additional restrictions will apply in France: – Prohibitions in winter : from 7 am to 6 pm on the ‘Auvergne-Rhône-Alpes’ roads listed below 20th as well as February 7th and March 6th 2021 – A40 from Pont d’Ain (intersection A40 / A42) to Passy-le-Fayet (intersection A40 / RD1205) – RD1084 from Pont d’Ain (intersection RD1084 / RD1075) to Bellegarde – A43 from the A46 south / A43 junction to the A43 / A432 junction towards Lyon-Chambery – A43 from the intersection A43 / A432 to Frejus Tunnel – A430 from Pont Royal (intersection A43 / A430) to Gilly-sur-Isere (intersection A430 / RN90) – RD1090 from Pont-Royal to Gilly-sur-Isere (intersection A430 / RN90) – RN90 from Gilly-sur-Isere (intersection A430 / RN90) to Bourg-Saint-Maurice – RD306 (Rhône) and RD1006 (Isère and Savoie) from Saint-Bonnet-de-Mure to Freney – A48 from Coiranne (intersection A48 / A43) to Saint Egrève (intersection A48 / A480) – A480 from Saint Egrève (intersection A48 / A480) to Pont-de-Claix (intersection A480 / RN85) – RN85 from Pont-de-Claix (intersection A480 / RN85) to Vizille (intersection RN85 / RD1091) – RD1091 from Vizille (intersection RN85 / RD1091) to Briançon – A41 north from Saint Julien-en-Genevois (junction A40 / A41 north) to Cruseilles (junction A410 / A41 north) – RD1201 from Saint Julien-en-Genevois to Annecy – A410 from Scientrier (intersection A410 / A40) to Cruseilles (intersection A410 / A41 north) -A41 north of Cruseilles (junction A410 / A41 north) to the junction with A43 Chambery – A41 south between Grenoble and A43 (Francin) on Montmelian northbound – RD1090 between Montmelian (73) and Pontcharra (38) – Summer bans: from 7 to 19 for the whole of the French road network on Saturdays: 24 and 31 July and 7 14 and 21 August 2021 r. In the Saturday traffic will be allowed from hours additional traffic bans will apply as every year They apply to specific roads in a specific direction and are valid on the following dates: – on the eve of a public holiday from 4pm to midnight – Saturdays from 10am to 6pm and from 10pm to midnight – Sundays and public holidays around the clock – Saturdays and the eve of public holidays from 10pm to midnight – Mondays and the day after a public holiday from 6pm to 10pm The bans in Île-de-France include the following motorway sections: A6b from the Paris beltway to the intersection with the A6 and A10 motorways (commune of Wissous) – A106 from the intersection with A6b to Orly airport – A6 from the intersection with A6a and A6b to the intersection with RN 104-Est / East (commune of Lisses) – A10 from the intersection with A6a and A6b to RN20 (commune of Champlan) – A12 from the junction with the A13 (Rocquencourt triangle) to the RN10 (Montigny-le-Bretonneux commune) – A13 from the Paris ring road to the Poissy-Orgeval junction (Orgeval commune) truck traffic is permanently banned on some roads in France – national road N59 between Lunéville and Sélestat – a ban applies on all vehicles in transit with a GVW exceeding 3.5 tonnes – national road N66 – prohibitions in place for vehicles over 3.5 tons between Remiremont and Cernay; ban for vehicles over 19 tonnes between 6am-10pm with a loading or unloading point in Lorraine (Lorraine) or Alsace (Alsace) national road N227 (3 – 4 km) – prohibition for vehicles in transit over 3.5 tonnes leaving the A1 motorway and heading north – A557 motorway – prohibitions for vehicles over 3.5 tons – A55 motorway (4 km) – prohibitions for vehicles over 3.5 tons in Marseille between the Vieux Port intersection and the Cap Pinède intersection – connection of the A50 (Toulon est / Toulon east) and A57 (Toulon est / Toulon west) motorways – Toulon tunnel – no heavy goods vehicles over 19 tonnes going to Marseille – A8 motorway – a 24-hour ban on the carriage of ethylene oxide by road on the section between the toll station in Antibes and Italy. For this type of transport the sea route Lavera – Tavazzano is recommended – national road N7 – traffic ban for vehicles over 6 tons on the transit route through the Orange agglomeration between the intersection with the RD976 and the intersection with the RD950; a ban on vehicles with a GVW of over 16 tons on the transit route through the Mondragon agglomeration – national road N85 – no vehicles over 26 tons (not equipped with speed limiters) on the border of the departments of Isère and Hautes Alpes and the city of Gap – national road N580 – traffic ban for vehicles over 25 tons in Avignon – national road N94 – vehicles over 26 tons (not equipped with speed limiters) between the southern Embruns roundabout and the border with Italy are prohibited – A7 and A6 motorways (25 km) between Ternay and Anse – vehicles with a DMC above 7.5 t are prohibited – national road N205 (Mont-Blanc Tunnel) – no vehicles carrying hazardous materials vehicles with a height exceeding 4.7 m and cars meeting Euro 0 emission standards – A43 motorway Fréjus tunnel – no vehicles carrying class 1 hazardous materials vehicles with a height exceeding 4.3 m and cars meeting Euro 0 emission standards – A47 motorway – traffic ban on the section connecting A47 (westbound) and A7 towards Lyon city center (Ternay intersection) – national road N7 – traffic ban for vehicles with a GVW over 6 tonnes – national road N7 in Tain l’Hermitage – no vehicles over 3.5 tons southbound between Vienne and the Roussillon toll station – national road N85 Laffrey – traffic ban for vehicles with a GVW above 7.5 t – Lyon North Bypass – vehicles with a height exceeding 3.5 m and trucks over 19 tons and vehicles carrying hazardous materials are prohibited – Fourvière Tunnel – vehicles with a height exceeding 4.3 m and for trucks transporting hazardous materials are prohibited Photo credit: François GOGLINS / Wikimedia Commons Pölös Zsófia Journalist Trans.info | 6.05.2025 Fragrance on the Fly: Why Pocket Perfumes Are Perfect for Airplane TravelSponsored Article 6.05.2025 Dickinson and Company (BD) has announced plans to invest approximately $1.2 billion over a 4-year period to expand and upgrade manufacturing capacity and technology for pre-fillable syringes (PFS) and advanced drug delivery systems (ADDS) across its six global manufacturing locations and add a new manufacturing facility in Europe all designed to maximise supply and reduce risks for pharmaceutical companies that rely on ready-to-fill syringes for their injectable drugs — including complex biologics “BD invented the ready-to-fill pre-fillable syringe technology and today’s announcement demonstrates our continued commitment to better serve our customers,” said Eric Borin This significant investment in one of BD’s fastest growing business units will further advance our leadership position and enable continued strong growth in the years ahead.” You can read this article in 5 minutesAgnieszka Kulikowska - Wielgus The French authorities have published dates for additional winter and summer truck traffic restrictions Photo credits @ Wikimedia Commons (illustrative purposes only) the French Ministry of the Interior issued a decree supplementing the general system of traffic restrictions for heavy goods vehicles with a gross vehicle weight (GVW) of over 7.5 tonnes The decree introduces additional winter traffic bans on the road network in the “Auvergne-Rhône-Alpes” region These restrictions will be in effect on Saturdays Bellegarde and Saint-Julien-en-Genevois – Annecy – Albertville truck traffic is restricted across the entire road network of mainland France on Saturdays and fans can expect another blockbuster Championship filled with sensational rugby team tries and moments of individual brilliance In anticipation of the start of Rugby’s Greatest Championship Planet Rugby has a closer look at key players from each team The Italian superstar was where he would later go on to represent the French Pro D2 club Grenoble over 50 times in a three-year stint Courtesy of his Italian father, Capuozzo came through the Italy U20 ranks and Italy ‘A’ before making his international debut in last season’s Six Nations scoring a brace against Scotland in his first Test Toulouse snapped up the speedster who would kick on from a positive debut and finish 2022 as World Rugby’s Breakthrough Player of the Year Capuozzo is regarded as one of rugby’s greatest prospects as he is expected to take his game even further despite his relative inexperience at the highest level The outside back’s X-factor and running ability are what separate him from others There is this sense of anticipation every time Capuozzo touches the ball as a moment of magic could happen at any moment which he instinctively uses to unlock defensive lines to either go on his own or play a teammate in Undoubtedly anything venomous coming from Italy in this year’s Six Nations likely has Capuozzo’s fingerprints on it Whilst no great weaknesses have dramatically shown their head the most obvious one is lack of physicality Capuozzo does not offer much on the physical front rugby has seen the likes of Cheslin Kolbe thrive at any level although it is inevitable that in certain situations he will come off second best in the collision Capuozzo’s Test career began around this time last year when he burst onto the scene with a brace against Scotland it would not be his greatest moment in the championship which came in the last round against Wales There were only a couple of minutes left on the clock with Italy in striking distance but never looked like winning until the ball got cleared to the Italian phenom Capuozzo received possession in his own half skirted around the defensive line and found space in the right-hand flank He proceeded to slalom past a defender before tipping it off to teammate Edoardo Padovani who scored with seconds left History for Italy as they claimed their first win in Cardiff the rugby world knew the name Ange Capuozzo 🇮🇹 Ange Capuozzo, take a bow ❤️pic.twitter.com/vweWr0TCju — Planet Rugby (@PlanetRugby) March 19, 2022 The young star is arguably the brightest prospect on the globe He is potent with ball in hand and knows his way to the try-line no doubt head coach Kieran Crowley will want his players to get the ball to Capuozzo in the right spaces as much as possible It is a massive championship for the outside back as the rugby world will watch to see if he can kick on and become one of the greatest Italian players in years to come READ MORE: Six Nations: Wales hand Leigh Halfpenny first start in 19 months for Ireland opener Toulouse’s Champions Cup title defence entertainingly ended at the semi-final stage as Bordeaux produced a steeled hometown performance to fully merit their progress to the decider Following a 38-15 victory for Toulouse against Sale Sharks in their Champions Cup round of 16 clash here's James While's five takeaways from the game Following a 38-15 victory over Sale Sharks in the Champions Cup round of 16 clash at the Stadium Toulouse Toulouse have reportedly come to a decision on how they will cover for Antoine Dupont