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Atypical hemolytic uremic syndrome (aHUS) is a rare thrombotic microangiopathic disorder that may be familial or sporadic. Complement factor H (CFH), factor I, and membrane cofactor protein (MCP; CD46), 3 regulators of the alternative pathway of the complement system activation, have been implicated in this pathological state. To date, 29 different mutations of CD46 have been reported, with incomplete penetrance and better clinical outcome compared with CFH mutations. Of those mutations, only 6 were found to be homozygous (accounting for 8 patients), and 5 resulted in a lack of or dramatically decreased cell-surface CD46 expression. We report here the seventh patient with a null mutation associated with recurrent aHUS. This mutation, a guanine to cytosine substitution in the first nucleotide of intron 2, disrupts a splice donor site. Interestingly, the patient's disease-free sister showed the same homozygous mutation. Extensive analysis of other complement regulatory protein- and polymorphism-associated risk factors did not uncover a difference between the patient and his sister. In conclusion, we describe for the first time a disease-free individual with complete CD46 deficiency, confirming the extremely variable penetrance and genetic complexity of aHUS. Copyright © 2008 National Kidney Foundation, Inc. [ABSTRACT FROM AUTHOR]

La sclérodermie systémique (ScS) est une maladie auto-immune rare caractérisée par des interactions étroites entre vaculopathie, perturbation du système immunitaire et fibrose. Les macrophages périvasculaires, sous l'influence des cellules endothéliales sclérodermiques sont susceptibles de modifier l'homéostasie tissulaire et l'équilibre des facteurs pro vs anti-inflammatoires/résolutifs via leur fonction d'efferocytose, modifiant ainsi le phénotype et la fonction des cellules environnantes notamment les cellules endothéliales et les fibroblastes. L'objectif est ici d'étudier l'effet des surnageants des macrophages post-efferocytose sur le phénotype des fibroblastes. Les fibroblastes ont été isolés et purifiés à partir de biopsies de peau de sujets sains. Les macrophages ont été préalablement générés en exposant des monocytes de donneurs sains à des surnageants conditionnés de cellules endothéliales dermiques de sujets sains (MφSNCE(HD)) ou de patients sclérodermiques (MφSNCE(ScS)), activées ou non par l'IL-1β (MφSNCE(HD)-IL-1β et MφSNCE(ScS)-IL-1β). Ces macrophages ont ensuite été incubés en présence de cellules Jurkat rendues apoptotiques pour induire l'efferocytose. Leurs surnageants ont été incubés avec les fibroblastes puis cultivées, pendant 48 h. Le profil d'expression des fibroblastes a été étudié en analysant les gènes COL1A1, FN1, α-SMA et TAGLN (pro-fibrotique) MMP-1 et TIMP-1 (pro-remodelant) et CCL2 (pro-inflammatoire) par RTqPCR. Les surnageants de macrophages générés en présence de surnageant conditionné de cellules endothéliales (MφSNCE) a induit peu de changements dans l'expression des gènes des fibroblastes, à l'exception de la fibronectine et de la transgéline, dont l'expression a été induite, mais indépendamment de la source des cellules endothéliales (HD ou ScS). En condition endothéliale activée par l'IL-1β (MφSNCE-IL-1β), les macrophages ont favorisé un phénotype fibroblastique pro-remodelant et inflammatoire, mais seuls les surnageants post-efferocytose ont induit une régulation à la hausse significative du ratio MMP-1/TIMP-1, ainsi qu'une régulation à la baisse de l'α-SMA et de la fibronectine, avec un effet plus prononcé dans les conditions sclérodermiques (ScS). Ces données suggèrent que l'IL-1β, qui est augmentée dans la peau des patients sclérodermiques, pourrait altérer la capacité d'efferocytose des macrophages périvasculaires, conduisant à une perturbation de l'homéostasie des tissus environnements. [ABSTRACT FROM AUTHOR]

Crystalline silica (the most abundant form of silicon dioxide) is a natural element that is ubiquitous in the Earth's crust. Chronic personal or professional exposure has been implicated in various pathologies, including silicosis and autoimmune diseases since the early 20th century. More recently, a specific pathogenic role for crystalline silica has been identified through its impact on lung epithelial cells as well as immune cells present at this organism barrier. This review summarizes the current in vitro and in vivo knowledge regarding the physiopathology of crystalline silica at the lung-environment interface, discusses its effects on innate and adaptive immune cells and epithelial cells, and reviews current therapeutic perspectives explored in mouse models to alleviate its impact, especially on autoimmune phenotypes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: Systemic sclerosis (SSc) is a rare autoimmune disease currently classified into two subgroups based on skin extension. The aim of this study was to determine in a large cohort whether the determination of autoantibody (AAb) profile among a full antinuclear AAbs panel including nine specificities had a higher impact than skin phenotype on stratifying the risk of organ involvement and mortality in SSc., Methods: Data for patients with SSc followed in seven French university hospitals were retrospectively analysed in terms of skin phenotype, AAbs (anti-topoisomerase I (ATA), anticentromere (ACA), anti-RNA polymerase III (anti-RNAPIII), anti-U1RNP, anti-U3RNP, anti-Pm/Scl, anti-Ku, anti-Th/To, anti-NOR90), organ involvement and mortality. Multivariate analyses were performed to identify independent factors associated with organ involvement and mortality., Results: We included 1605 patients with SSc (367 with diffuse cutaneous SSc). On multivariate analysis, ATAs were associated with interstitial lung disease and mortality (OR=3.27 (95% CI 2.42 to 4.42); HR=1.9 (95% CI 1.01 to 3.58)), anti-RNAPIII with scleroderma renal crisis and mortality (OR=7.05 (95% CI 2.98 to 16.72); HR=2.35 (95% CI 1.12 to 4.93)), anti-U1RNP with arthritis (OR=3.79 (95% CI 2.16 to 6.67)), anti-Pm/Scl and anti-Ku with myositis (OR=7.09 (95% CI 3.87 to 12.98) and 7.99 (95% CI 2.41 to 26.46)). The skin phenotype was not associated with survival or organ involvement on multivariate analysis without stepwise selection., Conclusion: This study unravels, by contrast with skin phenotype, a strong association between AAbs specificities, organ involvement and outcome in SSc and suggests that patients' classification based on only skin extension is not sufficient for defining prognosis and phenotype., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Chronic histiocytic intervillositis of unknown origin (CHI) is a rare placental disorder associated with adverse pregnancy outcomes, frequent recurrence, and a lack of effective preventive strategies. Recent insights indicate a potential link between CHI-associated inflammatory lesions and the inflammasome pathway, suggesting innovative therapeutic avenues. Here we show a potential role of the inflammasome pathway in CHI through comprehensive transcriptomic analysis of grade 2 or 3 histopathologic CHI samples, paired with placental controls. Additionally, we present case studies of three individuals with recurrent CHI, who have undergone treatment with anakinra and colchicine throughout pregnancy, resulting in improved perinatal outcomes. Notably, all cases are characterized by the birth of healthy, full-term infants, with reduced or absent intervillositis recurrence. Placental assessment unveils heightened activation of the NLRP3-PYCARD inflammasome pathway and IL-1β processing in CHI samples, with downregulation observed in treated pregnancy samples, devoid of intervillositis. Collectively, these findings suggest a potential therapeutic role for targeting the inflammasome pathway in preventing recurrent CHI in pregnant individuals., (© 2024. The Author(s).)

Introduction: Systemic sclerosis (SSc) is a serious life-threatening tissue disease. A significant aspect of its mortality arises from comorbid conditions. Our study aimed at mapping out the prevalence of these comorbidities and their relation to mortality, thus creating a 'comorbidome'., Methods: In our retrospective, single-centre observational study, we recorded each patient's data, including demographic informations, vital stats and SSc-related organ involvement, along with the presence or absence of 14 predefined comorbidities. We also documented the dates of their initial and most recent visits. To construct survival curves, we used the Kaplan-Meier method, followed by a Cox regression model for multivariate analysis., Results: Our study involved 400 participants, 74 of whom unfortunately passed away. It is important to note that three specific comorbidities showed significant correlation to mortality: neoplasia, cardiovascular diseases and polypharmacy, as well as two SSc-specific organ involvements (lung and cardiac)., Conclusion: Our research led to the successful creation of the SSc comorbidome. Comorbidities are a major concern for patients suffering from SSc, particularly cardiovascular diseases and neoplasms. Our study highlights the effects of polypharmacy. The resultant comorbidome offers a comprehensive and analytical perspective on this complex issue and underscores the inter-relatedness of the data. Our study, however, was limited by a small sample size. Therefore, to confirm our findings, validation on a larger scale is necessary. This could potentially contribute to the creation of a future mortality scoring tool., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

We induced systemic sclerosis (SSc)-like disease in both wild-type and Dnase1l3-deficient mice using two distinct approaches involving bleomycin and hypochlorous acid injections. Our observations revealed that the deficiency in DNASE1L3 did not affect tissue fibrosis or inflammation caused by these treatments. Despite the association of single nucleotide polymorphisms in humans with SSc pathogenesis, our study demonstrates that DNASE1L3 is dispensable in two inducible murine models of SSc-like pathogenesis., (© 2024 The Authors. European Journal of Immunology published by Wiley‐VCH GmbH.)

Background: Myocarditis is commonly diagnosed in the intensive care cardiology unit (ICCU). No current recommendation nor guideline aids exist for aetiological assessments., Methods: From September 2021 to October 2023, 84 patients with acute myocarditis underwent thorough and systematic serum and blood cell panel evaluations to determine the most common causes of myocarditis., Results: Of the 84 patients (median age 34 years, range 22-41 years, 79% male), 16 presented with complicated myocarditis. The systematic aetiological assessment revealed that 36% of patients were positive for lupus anticoagulant, 12% for antinuclear antibodies, 8% for anti-heart antibodies, and 12% for anti-striated muscle antibodies. Viral serology did not yield any significant results. After the aetiological assessment, one patient was diagnosed with an autoimmune inflammatory disorder (Still's disease). T-cell subset analyses indicated that myocarditis severity tended to increase with the T-cell lymphopenia status., Conclusions: A comprehensive, systematic aetiological assessment was of limited value in terms of predicting the clinical or therapeutic outcomes in myocarditis patients presenting to the ICCU.

Objectives: To estimate the association between SSc clinical phenotypes and quantitative occupational exposure to crystalline silica, chlorinated solvents, trichloroethylene, and pesticides using job-exposure matrices., Methods: In the VISS-EXPOSITION transversal study, data on declarative occupational exposure to crystalline silica, solvents, and pesticides were retrieved. In parallel, the Lifetime Occupational History was evaluated using a questionnaire and cursus laboris for SSc patients followed at Bordeaux University Hospital (France). Using job-exposure matrices, we assessed patients' occupational exposure in relation to relevant clinical phenotypic forms of the disease., Results: Toxic exposure to crystalline silica and pesticides is underestimated by patients. Non-biased job-exposure matrices retrieved more exposed patients than the declarative assessment (10.1% of patients by job-exposure matrices versus 6.3% by declaration for crystalline silica and 25.9% versus 12.2% for pesticides). Patients overestimate their solvent exposure (7.9% for chlorinated solvents and 4.8% for trichlorethylene assessed by job-exposure matrices and 24.4% declarative exposure to solvents at large). Clinical form evaluation revealed a nonsignificant trend toward an increased risk of crystalline silica occupational exposure in the pulmonary fibrotic group of SSc patients (OR 3.12 CI 95% [0.80-12.15]). We also observed a nonsignificant trend toward elevated OR (OR 2.89 CI 95% [0.93-8.95]) for chlorinated solvent occupational exposure and the vascular phenotype of SSc. Of note, pesticide occupational exposure evaluation represents one of the largest to date in SSc patients., Conclusion: This study emphasizes that many exposed SSc patients are unaware of their occupational exposure. Job-exposure matrices allow better exposure screening for SSc secondary prevention and occupational exposure compensation., Clinical Trial Registration: clinicaltrials.gov, https://www.clinicaltrials.gov, NCT03543956., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Group movement leadership is associated with higher risks for those in the front. Leaders are the first to explore new areas and may be exposed to predation. Individual differences in risk-taking behavior may be related to hormonal differences. In challenging circumstances, such as risk-taking leadership that may pose a cost to the leader, cortisol is secreted both to increase the likelihood of survival by restoring homeostasis, and to mediate cooperative behavior. Testosterone too has a well-established role in risk-taking behavior, and the dual-hormone hypothesis posits that the interaction of testosterone and cortisol can predict social behavior. Based on the dual-hormone hypothesis, we investigated here whether the interaction between testosterone and cortisol can predict risk-taking leadership behavior in wild rock hyraxes (Procavia capensis). We used proximity loggers, observations, and playback trials to characterize hyrax leaders in three different leadership contexts that varied in their risk levels. In support of the dual-hormone hypothesis, we found that cortisol and testosterone interactions predict leadership that involves risk. Across different circumstances that involved low or high levels of risk, testosterone was positively related to leadership, but only in individuals (both males and females) with low levels of cortisol. We also found an interaction between these hormone levels and age at the low-risk scenarios. We suggest that the close social interactions and affiliative behavior among hyrax females within small egalitarian groups may make female leadership less risky, and therefore less stressful, and allow female leaders to influence group activities., (© 2023. Springer Nature Limited.)

Bronchi of chronic obstructive pulmonary disease (COPD) are the site of extensive cell infiltration, allowing persistent contact between resident cells and immune cells. Tissue fibrocytes interaction with CD8 + T cells and its consequences were investigated using a combination of in situ , in vitro experiments and mathematical modeling. We show that fibrocytes and CD8 + T cells are found in the vicinity of distal airways and that potential interactions are more frequent in tissues from COPD patients compared to those of control subjects. Increased proximity and clusterization between CD8 + T cells and fibrocytes are associated with altered lung function. Tissular CD8 + T cells from COPD patients promote fibrocyte chemotaxis via the CXCL8-CXCR1/2 axis. Live imaging shows that CD8 + T cells establish short-term interactions with fibrocytes, that trigger CD8 + T cell proliferation in a CD54- and CD86-dependent manner, pro-inflammatory cytokines production, CD8 + T cell cytotoxic activity against bronchial epithelial cells and fibrocyte immunomodulatory properties. We defined a computational model describing these intercellular interactions and calibrated the parameters based on our experimental measurements. We show the model's ability to reproduce histological ex vivo characteristics, and observe an important contribution of fibrocyte-mediated CD8 + T cell proliferation in COPD development. Using the model to test therapeutic scenarios, we predict a recovery time of several years, and the failure of targeting chemotaxis or interacting processes. Altogether, our study reveals that local interactions between fibrocytes and CD8 + T cells could jeopardize the balance between protective immunity and chronic inflammation in the bronchi of COPD patients., Competing Interests: EE, EM, JS, PH, PE, TT, JD, AL, AS, HB, MT, RH, RM, FL, PV, CC No competing interests declared, MZ MZ reports personal fees from AstraZeneca, Boehringer Ingelheim, Novartis, Chiesi, GlaxoSmithKline and non-financial support Lilly outside the submitted work, PG POG has a patent (EP 3050574: Use of plerixafor for treating and/or preventing acute exacerbations of chronic obstructive pulmonary disease) granted. POG reports grants, personal fees and non-financial support from AstraZeneca, personal fees and non-financial support from Chiesi, personal fees and non-financial support from GlaxoSmithKline, personal fees and non-financial support from Novartis, personal fees and non-financial support from Sanofi, outside the submitted work, PB PB has a patent (EP N3050574: Use of plerixafor for treating and/or preventing acute exacerbations of chronic obstructive pulmonary disease) granted. PB reports grants from AstraZeneca, Glaxo-Smith-Kline, Novartis, Chiesi, which support COBRA during the conduct of the study; grants and personal fees from AstraZeneca, BoehringerIngelheim, Novartis, personal fees and non-financial support from Chiesi, Sanofi, Menarini, outside the submitted work, ID ID has a patent (EP 3050574: Use of plerixafor for treating and/or preventing acute exacerbations of chronic obstructive pulmonary disease) granted, (© 2023, Eyraud et al.)

Topical administration of active substances may be promoted by optimizing not only the vehicle formulation but also the application protocol. The formulation aspects are widely studied in the literature while a few works are dedicated to the development of application methods. In this context, we studied an application protocol usable as a part of skincare routine by investigating the effect of massage on the skin penetration of retinol. Retinol is a lipophilic molecule widely used as an anti-ageing firming agent in cosmetic formulations. Massage was applied to pig skin explants mounted to Franz diffusion cells after or before the deposit of the retinol-loaded formulation. Thetype of skin massage (roll or rotary type) and its duration were varied.The massage protocol had a significant influence on retinol skin penetration. Due to its highly lipophilic character, retinol accumulated into the stratum corneum but, depending on the massage protocol, a significant retinol concentration was obtained after 4 h in epidermis and dermis layers. Results showed that the roll-type massage was significantly more efficient than the rotary process that exhibited little effect on retinol cutaneous penetration. Such results could be interesting for the development of massage devices in association with cosmetic formulations., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

For addressing health issues and ecological concerns, the cosmetic and pharmaceutical industries are facing the challenge of designing emulsions without the use of surfactants. Emulsions stabilized by colloidal particles, known as Pickering emulsions, are promising in this matter. In this article, three different types of particles (neutral, anionic and cationic) are used alone or in binary mixtures as stabilizers of Pickering emulsions. The influence of the particles' charge on the emulsions' properties and the synergies between the different types of particles are studied. It is demonstrated that the kinetics of adsorption of the particles at the water/oil interface control the coverage and their organization at the droplet surface, rather than their interactions after adsorption. Binary mixtures of differently charged particles are a powerful way to control the droplet coverage and the particle loading in the emulsions. In particular, the combination of anionic and cationic particles led to smaller droplets and higher particle coverage of emulsion droplets.

Background: To produce viral vaccines, avian cell lines are interesting alternatives to replace the egg-derived processes for viruses that do not grow well on mammalian cells. The avian suspension cell line DuckCelt ® -T17 was previously studied and investigated to produce a live attenuated metapneumovirus (hMPV)/respiratory syncytial virus (RSV) and influenza virus vaccines. However, a better understanding of its culture process is necessary for an efficient production of viral particles in bioreactors., Results: The growth and metabolic requirements of the avian cell line DuckCelt ® -T17 were investigated to improve its cultivation parameters. Several nutrient supplementation strategies were studied in shake flasks highlighting the interest of (i) replacing L-glutamine by glutamax as main nutrient or (ii) adding these two nutrients in the serum-free growth medium in a fed-batch strategy. The scale-up in a 3 L bioreactor was successful for these types of strategies confirming their efficiencies in improving the cells' growth and viability. Moreover, a perfusion feasibility test allowed to achieve up to ~ 3 times the maximum number of viable cells obtained with the batch or fed-batch strategies. Finally, a strong oxygen supply - 50% dO 2 - had a deleterious effect on DuckCelt ® -T17 viability, certainly because of the greater hydrodynamic stress imposed., Conclusions: The culture process using glutamax supplementation with a batch or a fed-batch strategy was successfully scaled-up to 3 L bioreactor. In addition, perfusion appeared as a very promising culture process for subsequent continuous virus harvesting., (© 2023. The Author(s).)

Perivascular space (PVS) burden is an emerging, poorly understood, magnetic resonance imaging marker of cerebral small vessel disease, a leading cause of stroke and dementia. Genome-wide association studies in up to 40,095 participants (18 population-based cohorts, 66.3 ± 8.6 yr, 96.9% European ancestry) revealed 24 genome-wide significant PVS risk loci, mainly in the white matter. These were associated with white matter PVS already in young adults (N = 1,748; 22.1 ± 2.3 yr) and were enriched in early-onset leukodystrophy genes and genes expressed in fetal brain endothelial cells, suggesting early-life mechanisms. In total, 53% of white matter PVS risk loci showed nominally significant associations (27% after multiple-testing correction) in a Japanese population-based cohort (N = 2,862; 68.3 ± 5.3 yr). Mendelian randomization supported causal associations of high blood pressure with basal ganglia and hippocampal PVS, and of basal ganglia PVS and hippocampal PVS with stroke, accounting for blood pressure. Our findings provide insight into the biology of PVS and cerebral small vessel disease, pointing to pathways involving extracellular matrix, membrane transport and developmental processes, and the potential for genetically informed prioritization of drug targets., (© 2023. The Author(s).)

[This corrects the article DOI: 10.1371/journal.pbio.1001090.]., (Copyright: © 2023 Tauzin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry 1,2 . Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis 3 , and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach 4 , we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry 5 . Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries., (© 2022. The Author(s).)

Objective: To characterize the role of interleukin-1β (IL-1β) and microvascular endothelial cells (MVECs) in the generation of alternatively activated macrophages in the skin, and to explore their role in the development of skin fibrosis in patients with systemic sclerosis (SSc; scleroderma)., Methods: Conditioned medium prepared with MVECs purified from the skin of healthy donors and the skin of SSc patients was used to generate monocyte-derived macrophages. Flow cytometry, multiplex protein assessment, real-time quantitative polymerase chain reaction, and tissue immunofluorescence were used to characterize MVEC-induced polarization of alternatively activated macrophages. Coculture experiments were conducted to assess the role of MVEC-induced alternatively activated macrophages in fibroblast activation. Alternatively activated macrophages were characterized in the skin of healthy donors and SSc patients using multiparametric immunofluorescence and multiplex immunostaining for gene expression. Based on our in vitro data, we defined a supervised macrophage gene signature score to assess correlation between the macrophage score and clinical features in patients with SSc, using the Spearman's test., Results: IL-1β-activated MVECs from SSc patients induced monocytes to differentiate into DC-SIGN+ alternatively activated macrophages producing high levels of CCL18, CCL2, and CXCL8 but low levels of IL-10. DC-SIGN+ alternatively activated macrophages showed significant enhancing effects in promoting the production of proinflammatory fibroblasts and were found to be enriched in perivascular regions of the skin of SSc patients who had a high fibrosis severity score. A novel skin transcriptomic macrophage signature, defined from our in vitro findings, correlated with the extent of skin fibrosis (Spearman's r = 0.6, P = 0.0018) and was associated with early disease manifestations and lung involvement in patients with SSc., Conclusion: Our findings shed new light on the vicious circle implicating unabated IL-1β secretion, MVEC activation, and the generation of DC-SIGN+ alternatively activated macrophages in the development of skin fibrosis in patients with SSc., (© 2021 American College of Rheumatology.)

In many mammalian species, both sexes may take leadership role, but different traits may play a role in determining variation within species. Here we examine the effect of sex on leadership. We present three complementary datasets derived from a well-studied population of wild rock hyrax ( Procavia capensis ). The findings demonstrated that male and female rock hyraxes take on different leadership positions, depending on the context. When risk is moderate, more likely to lead are younger resident males, which experience high cortisol and lower testosterone levels. However, during acute predation scenarios, more likely to lead are males with lower centrality status. We suggest that hyrax males exhibit risky behaviors that may reflect their need for self-advertisement. In contrast, leadership among group females is more equally distributed. Females have little to gain from risky actions due to the lack of competition among them, but nonetheless take leadership positions., Competing Interests: The authors declare no competing interest., (© 2022 The Author(s).)

Objective: We aimed to evaluate in two large SSc French cohorts the prevalence and associated factors with the autoantibodies linked to erosive arthritis., Methods: 448 SSc patients were recruited from May 2015 to January 2019. Standardized clinical and laboratory variables were collected in accordance with the EUSTAR database. ELISAs for IgM rheumatoid factor (RF), IgG anti-citrullinated proteins (ACPA) and IgG anti-carbamylated proteins antibodies (anti-CarP) were all determined in a central laboratory. The prevalence and clinical associations of the different antibodies were investigated., Results: RF positivity was observed in 113 patients (25%) compared to 39 (9%) for ACPA and 63 (14%) for anti-CarP antibodies. Through multivariate regression analysis, both RF and ACPA positivity resulted to be associated with RA overlap disease (OR 5.7, 95% CI 2.3-13.8 and OR 44.1, 95% CI 15.4-126.3, respectively). Additionally, ACPA was found to be significantly related to synovitis/ tenosynovitis (OR 1.7, 95% CI 1.0-2.6). RF positivity was associated to a "vascular subset" (i.e. any major vascular complication) (OR 2.1, 95% CI 1.3-3.4). Moreover, anti-CarP antibodies were associated with a fibrotic subset and with digital ulcers (OR 2.0, 95% CI 1.1-3.6 and OR 1.9, 95% CI 1.1-3.4)., Conclusion: We corroborated that ACPA could be useful in identifying patients with a more prominent joint disease and RA overlap disease. Of the most interest we found that anti-CarP antibodies could be a relevant biomarker related to fibrotic skin and lung disease., Competing Interests: Declarations of Competing Interest None., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Cerebral small vessel disease (cSVD) is a leading cause of ischaemic and haemorrhagic stroke and a major contributor to dementia. Covert cSVD, which is detectable with brain MRI but does not manifest as clinical stroke, is highly prevalent in the general population, particularly with increasing age. Advances in technologies and collaborative work have led to substantial progress in the identification of common genetic variants that are associated with cSVD-related stroke (ischaemic and haemorrhagic) and MRI-defined covert cSVD. In this Review, we provide an overview of collaborative studies - mostly genome-wide association studies (GWAS) - that have identified >50 independent genetic loci associated with the risk of cSVD. We describe how these associations have provided novel insights into the biological mechanisms involved in cSVD, revealed patterns of shared genetic variation across cSVD traits, and shed new light on the continuum between rare, monogenic and common, multifactorial cSVD. We consider how GWAS summary statistics have been leveraged for Mendelian randomization studies to explore causal pathways in cSVD and provide genetic evidence for drug effects, and how the combination of findings from GWAS with gene expression resources and drug target databases has enabled identification of putative causal genes and provided proof-of-concept for drug repositioning potential. We also discuss opportunities for polygenic risk prediction, multi-ancestry approaches and integration with other omics data., (© 2022. Springer Nature Limited.)

Background: Early diagnosis of thrombotic thrombocytopenic purpura (TTP) versus hemolytic and uremic syndrome (HUS) is critical for the prompt initiation of specific therapies., Objective: To evaluate the diagnostic performance of the proteinuria/creatininuria ratio (PU/CU) for TTP versus HUS., Patients/methods: In a retrospective study, in association with the "French Score" (FS) (platelets < 30 G/L and serum creatinine level < 200 µmol/L), we assessed PU/CU for the diagnosis of TTP in patients above the age of 15 with thrombotic microangiopathy (TMA). Patients with a history of kidney disease or with on-going cancer, allograft or pregnancy were excluded from the analysis., Results: Between February 2011 and April 2019, we identified 124 TMA. Fifty-six TMA patients for whom PU/CU were available, including 35 TTP and 21 HUS cases, were considered. Using receiver-operating characteristic curves (ROC), those with a threshold of 1.5 g/g for the PU/CU had a 77% sensitivity (95% CI (63, 94)) and a 90% specificity (95% CI (71, 100)) for TTP diagnosis compared with those having an 80% sensitivity (95% CI (66, 92)) and a 90% specificity (95% CI (76, 100) with a FS of 2. In comparison, a composite score, defined as a FS of 2 or a PU/CU ≤ 1.5 g/g, improved sensitivity to 99.6% (95% CI (93, 100)) for TTP diagnosis and enabled us to reclassify seven false-negative TTP patients., Conclusions: The addition of urinary PU/CU upon admission of patients with TMA is a fast and readily available test that can aid in the differential diagnosis of TTP versus HUS alongside traditional scoring.

Objective: Innate lymphoid cells-2 (ILC2) were shown to be involved in the development of lung or hepatic fibrosis. We sought to explore the functional and phenotypic heterogeneity of ILC2 in skin fibrosis within systemic sclerosis (SSc)., Methods: Blood samples and skin biopsies from healthy donor or patients with SSc were analysed by immunostaining techniques. The fibrotic role of sorted ILC2 was studied in vitro on dermal fibroblast and further explored by transcriptomic approach. Finally, the efficacy of a new treatment against fibrosis was assessed with a mouse model of SSc., Results: We found that ILC2 numbers were increased in the skin of patients with SSc and correlated with the extent of skin fibrosis. In SSc skin, KLRG1 - ILC2 (natural ILC2) were dominating over KLRG1 + ILC2 (inflammatory ILC2). The cytokine transforming growth factor-β (TGFβ), whose activity is increased in SSc, favoured the expansion of KLRG1 - ILC2 simultaneously decreasing their production of interleukin 10 (IL10), which regulates negatively collagen production by dermal fibroblasts. TGFβ-stimulated ILC2 also increased myofibroblast differentiation. Thus, human KLRG1 - ILC2 had an enhanced profibrotic activity. In a mouse model of SSc, therapeutic intervention-combining pirfenidone with the administration of IL10 was required to reduce the numbers of skin infiltrating ILC2, enhancing their expression of KLRG1 and strongly alleviating skin fibrosis., Conclusion: Our results demonstrate a novel role for natural ILC2 and highlight their inter-relationships with TGFβ and IL10 in the development of skin fibrosis, thereby opening up new therapeutic approaches in SSc., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Non-ideal behaviour of mixed ions is disclosed in skin absorption experiments of mixed halide anions in excised pig skin. Comparison of skin absorption of pure and mixed ions shows enhanced penetration of chaotropic ions from mixed solutions. An experimental design and statistical analysis using a Scheffé {3,2} simplex-lattice allows investigating the full ternary diagram of anion mixtures of fluoride, bromide and iodide. Synergism in mixed absorption is observed for chaotropic bromide and iodide anions. A refined analysis highlighting specific interactions is made by considering the ratio of the absorbed amount to the ion activity instead of the directly measured absorbed amount. Statistical analysis discards non-significant effects and discloses specific interactions. Such interactions between bromide and iodide cause an absorption enhancement of their partner by a factor of 2-3 with respect to the case of ideal mixing. It is proposed that enhanced absorption from mixed solution involves the formation of neutral complex species of mixed bromide and iodide with endogenous magnesium or calcium inside stratum corneum., (Copyright © 2021. Published by Elsevier B.V.)

Objective: Pickering emulsions are increasingly used in the pharmaceutical and cosmetic fields, especially for topical applications, since these systems require solid particles as emulsifiers instead of surfactants which are known to cause skin irritation. The solid inorganic nanoparticles (TiO 2 and ZnO) used as UV filters in sunscreen formulations may also stabilize emulsion droplets, so that the utility of surfactants may be questioned. Surfactant-free sunscreen emulsions solely stabilized by such nanoparticles (NPs) have been studied., Methods: The ability of these NPs to stabilize o/w emulsions containing a 'model' oil phase, the C 12 -C 15 alkylbenzoate, has been assessed. ZnO and hydrophilic silica-coated TiO 2 NPs widely used in sunscreen products were used together with their mixtures. The emulsification efficiency, the control of droplet size and the stability of o/w Pickering emulsions solely stabilized by NPs were investigated. A ZnO/TiO 2 NPs mixture characterized by a theoretical SPF of 45 was finally used as unique emulsifiers to develop a surfactant-free sunscreen emulsion., Results: Stable Pickering emulsions containing 10 up to 60 wt% of C 12 -C 15 alkyl benzoate were formulated with 2 wt% ZnO in the aqueous phase. The droplet size was controlled by the solid NPs content with respect to oil and the emulsification process. Hydrophilic TiO 2 NPs did not allow the stabilization of emulsions. The substitution of TiO 2 for ZnO up to 60-70 wt% in a 20/80 o/w emulsion was successfully performed. Finally, a ZnO/TiO 2 NP mixture was tested as unique emulsifier system for the formulation of a sunscreen cream. Despite a lower viscosity, the obtained Pickering emulsion was stable and exhibited a photoprotective effect similar to the corresponding surfactant-based sunscreen cream with an in vitro SPF of about 45., Conclusion: Surfactant-free Pickering emulsions can be stabilized by the UV-filter nanoparticles for the manufacture of sunscreen products., (© 2021 Society of Cosmetic Scientists and the Société Française de Cosmétologie.)

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by a loss of tolerance toward self-nucleic acids, autoantibody production, interferon expression and signaling, and a defect in the regulatory T (T reg ) cell compartment. In this work, we identified that platelets from patients with active SLE preferentially interacted with T reg cells via the P-selectin/P-selectin glycoprotein ligand-1 (PSGL-1) axis. Selectin interaction with PSGL-1 blocked the regulatory and suppressive properties of T reg cells and particularly follicular T reg cells by triggering Syk phosphorylation and an increase in intracytosolic calcium. Mechanistically, P-selectin engagement on T reg cells induced a down-regulation of the transforming growth factor-β axis, altering the phenotype of T reg cells and limiting their immunosuppressive responses. In patients with SLE, we found an up-regulation of P- and E-selectin both on microparticles and in their soluble forms that correlated with disease activity. Last, blocking P-selectin in a mouse model of SLE improved cardinal features of the disease, such as anti-dsDNA antibody concentrations and kidney pathology. Overall, our results identify a P-selectin-dependent pathway that is active in patients with SLE and validate it as a potential therapeutic avenue., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Background and Objectives: Young adults represent an increasingly large proportion of healthy volunteers in brain imaging research, but descriptions of incidental findings (IFs) in this age group are scarce. We aimed to assess the prevalence and severity of IFs on brain MRIs of healthy young research participants aged 18-35 years, and to describe the protocol implemented to handle them. Methods: The study population comprised 1,867 participants aged 22.1 ± 2.3 years (72% women) from MRi-Share, the cross-sectional brain MRI substudy of the i-Share student cohort. IFs were flagged during the MRI quality control. We estimated the proportion of participants with IFs [any, requiring medical referral, potentially serious (PSIFs) as defined in the UK biobank]: overall, by type and severity of the final diagnosis, as well as the number of IFs. Results: 78/1,867 participants had at least one IF [4.2%, 95% Confidence Interval (CI) 3.4-5.2%]. IFs requiring medical referral ( n = 38) were observed in 36/1,867 participants (1.9%, 1.4-2.7%), and represented 47.5% of the 80 IFs initially flagged. Referred IFs were retrospectively classified as PSIFs in 25/1,867 participants (1.3%, 0.9-2.0%), accounting for 68.4% of anomalies referred (26/38). The most common final diagnosis was cysts or ventricular abnormalities in all participants (9/1,867; 0.5%, 0.2-0.9%) and in those with referred IFs (9/36; 25.0%, 13.6-41.3%), while it was multiple sclerosis or radiologically isolated syndrome in participants with PSIFs (5/19; 26.3%, 11.5-49.1%) who represented 0.1% (0.0-0.4%) and 0.2% (0.03-0.5%) of all participants, respectively. Final diagnoses were considered serious in 11/1,867 participants (0.6%, 0.3-1.1%). Among participants with referred IFs, 13.9% (5/36) required active intervention, while 50.0% (18/36) were put on clinical surveillance. Conclusions: In a large brain imaging study of young healthy adults participating in research we observed a non-negligible frequency of IFs. The etiological pattern differed from what has been described in older adults., Competing Interests: SD is currently a guest editor for the Research Topic this work will be submitted to, and has collaborated/is collaborating on research projects or publications with the other two editors of this topic. Outside the submitted work, BB served on the scientific advisory board of Biogen, BMS, Novartis, Roche, Merck, and Jansen, received speaker honoraria from Biogen, BMS, and Roche, served as an editorial board member of Multiple Sclerosis International (2019–2020), received research support from Roche, Biogen, Bayer, Sanofi, and Caridian. The remaining 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., (Copyright © 2021 Soumaré, Beguedou, Laurent, Brochet, Bordes, Mournet, Mellet, Pereira, Pollet, Lachaize, Mougin, Tsuchida, Loiseau, Tourdias, Tzourio, Mazoyer and Debette.)

Aims: Eculizumab is an anti-C5 monoclonal antibody approved for rare diseases including atypical haemolytic-uraemic syndrome. The maintenance phase dosing regimen is identical for all adult patients: 1200 mg every 2 weeks. Recent studies reported an overexposure in many patients when considering a target trough concentration range of 50-100 mg/L. The aim of the present work was to validate the feasibility of therapeutic drug monitoring of eculizumab in atypical haemolytic-uraemic syndrome patients., Methods: We performed a 2-step prospective multicentre study. In the first phase, we developed a pharmacokinetic population model using data from 40 patients and identified patients for whom a 1-week lengthening of interval between infusions would lead to a trough concentration above 100 mg/L. In the second phase, selected patients were allocated a 1-week extension and eculizumab trough concentrations were monitored., Results: The model confirmed the previously reported influence of bodyweight on elimination clearance and predicted that 36 (90%) patients would be eligible for interval extension. In the second phase of the study, a 1-week lengthening of interval between infusions was performed in 15 patients whose trough concentration at the next visit was predicted with a Bayesian model to be above 100 mg/L. After interval extension, 10 patients (67%) presented measured trough concentrations over 100 mg/L. No biological or clinical recurrence of disease was observed, even in the 5 patients with concentrations below 100 mg/L in whom the initial dosing regimen was resumed., Conclusion: Safe eculizumab interval adjustment is feasible with a PK monitoring., (© 2020 The British Pharmacological Society.)

This study explored the design of supersaturable self-microemulsifying drug delivery systems (S-SMEDDS) to address poor solubility and oral bioavailability of a novel benzimidazole derivative anticancer drug (BI). Firstly, self-microemulsifying drug delivery systems SMEDDS made of Miglyol® 812, Kolliphor® RH40, Transcutol® HP, and ethanol were prepared and loaded with the BI drug. Upon dispersion, the systems formed neutrally charged droplets of around 20 nm. However, drug precipitation was observed following incubation with simulated gastric fluid (pH 1.2). Aiming at reducing this precipitation and enhancing drug payload, supersaturable systems were then prepared by adding 1% hydroxypropyl cellulose as precipitation inhibitor. Supersaturable systems maintained a higher amount of drug in a supersaturated state in gastric medium compared with conventional formulations and were stable in simulated intestinal medium (pH 6.8). In vitro cell studies using Caco-2 cell line showed that these formulations reduced in a transient manner the transepithelial electrical resistance of the monolayers without toxicity. Accordingly, confocal images revealed that the systems accumulated at tight junctions after a 2 h exposure. In vivo pharmacokinetic studies carried out following oral administration of BI-loaded S-SMEDDS, SMEDDS, and free drug to healthy mice showed that supersaturable systems promoted drug absorption compared with the other formulations. Overall, these data highlight the potential of using the supersaturable approach as an alternative to conventional SMEDDS for improving oral systemic absorption of lipophilic drugs.

White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.

Background: Treatment with eculizumab in Shiga toxin-associated haemolytic and uraemic syndrome (STEC-HUS) remains controversial despite its increasing utilization. The aim of our study was to evaluate the outcomes of children treated with eculizumab for STEC-HUS in a single-centre matched cohort study., Methods: Data were retrospectively collected from medical records of children diagnosed with STEC-HUS. The outcomes of patients treated with eculizumab for STEC-HUS were compared with those of a control group of untreated patients matched for age, sex and severity of acute kidney injury with a 1:2 matching scheme., Results: Eighteen children (median age 40.6 months) with STEC-HUS treated with eculizumab were compared with 36 matched control patients (median age 36.4 months) who did not receive eculizumab. All patients survived in the two groups. Within 1 month of HUS onset, the evolution of haematological and renal parameters did not differ between the two groups. At 12 months of follow-up, renal outcome was not significantly different between the two groups. At the last follow-up, the prevalence of decreased glomerular filtration rate in the eculizumab group (27%) was not statistically different from that in controls (38%), as was the prevalence of proteinuria and high blood pressure. Children who received eculizumab more often had extrarenal sequelae during follow-up. Eculizumab treatment appeared to be safe in children with STEC-HUS., Conclusion: The benefit of eculizumab on renal and extrarenal outcomes in STEC-HUS could not be established based on our findings. However, efficacy and safety are not best assessed by the observational design and small sample size of our study. Randomized controlled trials are thus required to determine the efficacy of eculizumab in this indication., (© The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Background: Microparticles (MPs) are vesicular structures that derive from multiple cellular sources. MPs play important roles in intercellular communication, regulation of cell signaling or initiation of enzymatic processes. While MPs were characterized in Systemic Sclerosis (SSc) patients, their contribution to SSc pathogenesis remains unknown. Our aim was to investigate the potential role of MPs in SSc pathophysiology and their impact on tissue fibrosis., Methods: Ninety-six SSc patients and 37 sex-matched healthy donors (HD) were enrolled in this study in order to quantify and phenotype their plasmatic MPs by flow cytometry. The ability of MPs purified from SSc patients and HD controls to modulate fibroblast's extra-cellular matrix genes expression was evaluated in vitro by reverse transcriptase quantitative polymerase chain reaction., Results: SSc patients exhibited a higher concentration of circulatory MPs compared to HD. This difference was exacerbated when we only considered patients that were not treated with methotrexate or targeted disease-modifying antirheumatic drugs. Total circulatory MPs were associated to interstitial lung disease, lung fibrosis and diminished lung functional capacity, but also to vascular involvement such as active digital ulcers. Finally, contrary to HD MPs, MPs from SSc patients stimulated the production of extracellular matrix by fibroblast, demonstrating their profibrotic potential., Conclusions: In this study, we provide evidence for a direct profibrotic role of MPs from SSc patients, underpinned by strong clinical associations in a large cohort of patients., (Copyright © 2020 Leleu, Levionnois, Laurent, Lazaro, Richez, Duffau, Blanco, Sisirak, Contin-Bordes and Truchetet.)

Background: The use of complementary and alternative medicine including herbal medicine (phytotherapy), vitamins, minerals and food supplements is frequent among people living with HIV/AIDS (PLWHAs) who take antiretroviral (ARV) drugs, but is often not known by their prescribing physicians. Some drug-supplement combinations may result in clinically meaningful interactions., Aims: In this literature review, we aimed to investigate the evidence for complementary and alternative medicine interactions with ARVs., Sources: A bibliographic search of all in vitro, human studies and case reports of the PubMed database was performed to assess the risk of interactions between complementary and alternative self-medication products and ARVs. The 'HIV drug interaction' (https://www.hiv-druginteractions.org) and 'Natural medicines comprehensive database' (https://naturalmedicines.therapeuticresearch.com) interaction checkers were also analysed., Content: St John's wort, some forms of garlic, grapefruit and red rice yeast are known to have significant interaction and thus should not be co-administered, or should be used with caution with certain ARV classes. Data on other plant-based supplements come from in vitro studies or very small size in vivo studies and are thus insufficient to conclude the real in vivo impact in case of concomitant administration with ARVs. Some polyvalent minerals such as calcium, magnesium, and iron salts can reduce the absorption of integrase inhibitors by chelation. Potential interactions with vitamin C and quercetin with some ARVs should be noted and efficacy and tolerance of the treatment should be monitored., Implications: This review shows the importance of screening all PLWHAs for complementary and alternative medicine use to prevent treatment failure or adverse effects related to an interaction with ARVs. Further human studies are warranted to describe the clinical significance of in vitro interactions between numerous complementary and alternative medicine and ARVs., (Copyright © 2020 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Introduction: Cocaine use is associated with multiple complications, some of which can mimic systemic diseases, especially Antineutrophil Cytoplasmic Antibody (ANCA) associated vasculitis. We report a case of Cocaine Induced Midline Destructive Lesions (CIMDL) for which a diagnosis of granulomatosis with polyangiitis (GPA) was discussed., Case Report: A 42-year-old male, cocaine consumer, was admitted in our department for a centrofacial destructive process. He had no extra ear, nose and throat (ENT) involvement. ANCA were positive with a perinuclear fluorescence pattern and an anti-Proteinase 3 specificity. Regarding this unusual immunologic pattern and in the absence of histological argument for a GPA, a diagnosis of CIMDL was made., Conclusion: CIMDL is a centrofacial destructive process due to intranasal cocaine use. It is frequently associated with the presence of p-ANCA with both anti-HNE and anti-PR3 specificity., (Copyright © 2020. Published by Elsevier Masson SAS.)

Antibiotics are well-known disruptive elements of the intestinal microbiota and antibiotic-associated diarrhea appeared as the most common complication related with post-antibiotic dysbiosis. Lactobacillus rhamnosus GG (LGG) strain is very effective in preventing antibiotic-associated diarrhea in children and adults. However, as any probiotics, it is concerned by the loss of viability during storage and gastrointestinal transit. The aim of this study was to develop an encapsulation system suitable for the specific colonic delivery of LGG strain after oral administration. For this purpose, spray-dried Eudragit® S100 microparticles encapsulating LGG bacteria were developed by using an aqueous based spray-drying approach, avoiding the use of organic solvents. Carbohydrates were added to the formulation since they are widely used as protective agents of bacteria against the harmful effect of dehydration stress. Here, both Surface Enhanced Raman Scattering (SERS) and conventional plate count methods showed that carbohydrates increased the survival ratio of bacteria after spray-drying from 3 to more than 50%. Moreover, these protective agents ensured low residual moisture content thus providing great stability of the cells in the spray-dried powder during storage. Significant improvement of the cell viability in simulated gastro intestinal fluid (SGIF) was observed for encapsulated cells as compared with free LGG bacteria for which no viable cell was detectable after 1 h incubation in gastric fluid only. As a consequence, 4.5 × 10 7 CFU/g of encapsulated LGG were found viable after incubation of microparticles 1 h in Simulated Gastric Fluid followed by 6 h in Simulated Intestinal Fluid, corresponding to less than 3 log reduction of viable cells during the 7 h incubation in Simulated Gastro Intestinal Fluid. These results attested that the developed encapsulation system is suitable for its use as a bacteria carrier for specific colonic delivery., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: An altered immune response and decreased vaccine response are observed in patients with chronic renal failure. A preliminary study of 15 non-immunised patients, despite appropriate previous hepatitis B vaccination, showed a 60% seroconversion rate after 3 months of dialysis with a polymethylmethacrylate (PMMA) membrane. This response was associated with circulating soluble CD40 (CD40s) decrease, a natural inhibitor of the humoral immune response. The aim of the study is to confirm these results in a randomised study., Methods: We conducted a multicentre randomised intention-to-treat superiority clinical trial comparing polysulfone and a PMMA membrane in 2 parallel patient groups. The primary end point was the vaccine response rate, as defined by an anti-HBs antibodies titre of >10 IU/L, 1 month after the last vaccination with a double dose of Engerix B20®, performed at weeks 12, 16, 20, and 36., Results: Twenty-five patients were randomised and included in an intention-to-treat analysis. They were dialysed on polysulfone (n = 11) or PMMA (n = 14) for 40 weeks. Fifty percent of the PMMA patients versus 54.5% of the polysulfone patients achieved seroconversion (p = 1.00). The median anti-HBs antibody titre in responders at week 40 was 496 (92-750) versus 395 (43-572) UI/mL for PMMA and polysulfone, respectively (p = 0.46). The median CD40s titre at week 12 was 306 (193-448) versus 491 (281-515) pg/mL (p = 0.21). The CD40s median variation between week 0 and week 12 was 5 (-105 to 90) versus 64 (-63 to 123) pg/mL (p = 0.55). The CD40s level at week 12 in non-responders was slightly inferior to that of the responders: median 193 (168-331) versus 413 (281-512) pg/mL (p = 0.08)., Conclusion: We did not observe a better vaccine response with the PMMA membrane compared to high-flux polysulfone. The PMMA membrane did not decrease the CD40s more than the polysulfone membrane probably because the titre was previously low in the 2 groups., (© 2019 S. Karger AG, Basel.)

Animals in urban environments face challenging situations and have to cope with human activities. This study investigated the ecology and behaviour of a population of European hamsters (Cricetus cricetus) living in the city centre of Vienna (Austria). We recorded the surface activities of 35 hamsters in May 2015. Each focal animal was observed for 15 minutes, and a total of 66 focal samples were analysable. As a prey species in an environment teeming with human activities, we predicted a high level of vigilance by the hamsters. The results show that while animals dedicated a lot of time to vigilance, most of their time was spent foraging. The study also explores whether the frequency of vigilance behaviours differ between males and females. We found that vigilance behaviours were expressed in a different manner by males and females. Finally, we investigated the distribution of the burrows on green spaces depending on proximity to trees and on noise levels. We found a biased distribution of burrows, with a spatial preference for location protected by the vegetation and distant to noise sources. Although burrows were located preferentially under vegetation cover, levels of noise did not determine their positions. Moreover, this species does not respond to disturbances like daily urban noises, probably due to habituation. The common hamster is an endangered species; our results lead to a greater knowledge of its behaviour in a persistent urban population., Competing Interests: The authors have declared that no competing interests exist.

In Western Europe, river water quality can be assessed using sentinel species such as the amphipod Gammarus fossarum. In this work of environmental metabolomics, the objective was to develop suitable chemometrics methods, using a limited number of individuals, to assess the modification of the metabolism of G. fossarum exposed to two human pharmaceuticals. Males and females gammarids were exposed to a mixture of the anxiolytic oxazepam and the antiepileptic carbamazepine (1000 ng L -1 ) for 14 days under laboratory conditions according to a full factorial design 2² (repeated 5 times). They were analyzed at the single individual scale using a method including a μQuEChERS type extraction followed by a nanoliquid chromatography analysis coupled to high-resolution mass spectrometry. The molecular fingerprints obtained were investigated using XCMS. Several corrections of experimental drifts (by using lock mass and Quality Control samples) were tested prior to using APCA + method for the exploitation of the unbalanced designed data. Signal reproducibility was greatly improved by the lock mass normalisation. From the experimental design, a significant effect of both experimental factors "exposure to the mixture" and "gammarid gender" on the signals measured were highlighted by APCA+. Finally, the results obtained made it possible to identify variables responsible for each of the factor effects., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Trypanosoma brucei gambiense, an extracellular eukaryotic flagellate parasite, is the main etiological agent of human African trypanosomiasis (HAT) or sleeping sickness. Dendritic cells (DCs) play a pivotal role at the interface between innate and adaptive immune response and are implicated during HAT. In this study, we investigated the effects of T gambiense and its excreted/secreted factors (ESF) on the phenotype of human monocyte-derived DCs (Mo-DCs). Mo-DCs were cultured with trypanosomes, lipopolysaccharide (LPS), ESF derived from T gambiense bloodstream strain Biyamina (MHOM/SD/82), or both ESF and LPS. Importantly, ESF reduced the expression of the maturation markers HLA-DR and CD83, as well as the secretion of IL-12, TNF-alpha and IL-10, in LPS-stimulated Mo-DCs. During mixed-leucocyte reactions, LPS- plus ESF-exposed DCs induced a non-significant decrease in the IFN-gamma/IL-10 ratio of CD4 + T-cell cytokines. Based on the results presented here, we raise the hypothesis that T gambiense has developed an immune escape strategy through the secretion of paracrine mediators in order to limit maturation and activation of human DCs. The identification of the factor(s) in the T gambiense ESF and of the DCs signalling pathway(s) involved may be important in the development of new therapeutic targets., (© 2019 John Wiley & Sons Ltd.)