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Objectifs L’alliance therapeutique (AT) se definit comme l’engagement mutuel entre le soignant et le patient au cours du processus therapeutique. L’adhesion therapeutique est un enjeu majeur dans la prise en charge de l’arthrite juvenile idiopathique (AJI) et repose sur la forte capacite de l’enfant a suivre les traitements. Cette etude avait pour objectif d’evaluer l’association entre l’AT et l’adhesion therapeutique chez des patients atteints d’AJI. Methodes Etude observationnelle, transversale, multicentrique. Des enfants atteints d’AJI, âges de 8 a 16 ans ont ete inclus. Les enfants, leurs parents et les medecins ont complete le Helping Alliance Questionnaire (HAq-CP) pour mesurer l’AT. L’observance aux traitements a ete mesuree a l’aide du Child/Parent Adherence Report Questionnaire (CARQ & PARQ). Les donnees demographiques, les caracteristiques de la maladie, les traitements en cours et l’environnement social ont ete recueillis. La relation univariee entre l’AT et l’adhesion a ete mesuree a l’aide du coefficient de correlation de Pearson. L’analyse multivariee a utilise un modele de regression lineaire multiple. Resultats 119 patients ont ete inclus : 68,9 % de filles, l’âge moyen (ET) etait de 12,4 (2,9) ans, avec une duree de la maladie de 73,1 (48,2) mois. L’AJI etait en remission (52 %), de faible activite (32 %) et active (16 %). Les scores de l’AT etaient eleves (≥ 80/100) chez les enfants, les parents et les medecins. Le HAQ-CP a montre une forte correlation avec le CARQ (r = 0,31 ; p Conclusion L’AT exerce une forte influence sur l’adhesion therapeutique et pourrait jouer un role majeur dans l’efficacite du traitement.

Severe SARS-CoV-2 infections are characterized by lymphopenia, but the mechanisms involved are still elusive. Based on our knowledge of HIV pathophysiology, we hypothesized that SARS-CoV-2 infection-mediated lymphopenia could also be related to T cell apoptosis. By comparing intensive care unit (ICU) and non-ICU COVID-19 patients with age-matched healthy donors, we found a strong positive correlation between plasma levels of soluble FasL (sFasL) and T cell surface expression of Fas/CD95 with the propensity of T cells to die and CD4 T cell counts. Plasma levels of sFasL and T cell death are correlated with CXCL10 which is part of the signature of 4 biomarkers of disease severity (ROC, 0.98). We also found that members of the Bcl-2 family had modulated in the T cells of COVID-19 patients. More importantly, we demonstrated that the pan-caspase inhibitor, Q-VD, prevents T cell death by apoptosis and enhances Th1 transcripts. Altogether, our results are compatible with a model in which T-cell apoptosis accounts for T lymphopenia in individuals with severe COVID-19. Therefore, a strategy aimed at blocking caspase activation could be beneficial for preventing immunodeficiency in COVID-19 patients.

Background: Little is known about the natural history of immunoglobulin (Ig) E-mediated diseases in preterm infants, further hampered by the lack of noninvasive investigations. We aimed at developing a non-invasive tool for the study of IgE and eosinophil-derived neurotoxin (EDN) in neonatal fecal samples and evaluating its predictive value for the development of IgE-mediated diseases (cow’s milk allergy, asthma, or atopic dermatitis) during the first year of life. Methods: We developed a stool extraction protocol, followed by freeze-drying and solubilization. sIgE responses were investigated in neonatal fecal samples from 21 preterm infants with a 300-allergen multiplex containing whole and molecular allergens and confirmed by capillary Western blot with nano-immunoassay. The local eosinophilic component was investigated by measuring the concentration of EDN. Results: The multiplexed allergen assay detected sIgE in all samples. Confirmation was obtained with Western blot. Frequency and levels of sIgE in neonatal fecal samples differed between infants who developed IgE-mediated diseases and controls. Neonatal fecal sIgE directed to milk proteins predicted later development of cow’s milk allergy (specificity 88%, sensitivity 78%). Allergen specificity of neonatal fecal sIgE was associated with later development of cow’s milk allergy and asthma. Neonatal fecal EDN levels predicted the development of IgE-mediated diseases (sensitivity 100%, specificity 75%). Conclusion: Non-invasive investigation of neonatal fecal sIgE is a promising tool for the prediction of subsequent development of IgE-mediated diseases.

172-lead (16x16 mm body size) and 100-lead (10x10 mm body size) MAXQFP's and 172 MAXQFP_EP (exposed pad) for automotive industry are introduced. The advantage of MAXQFP as compare to standard LQFP/QFP packages will be outlined. Thermal & mechanical simulation results were performed to prove its advantage over conventional LQFP and LQFP_EP. The challenges in manufacturing, designs and concerns of tighter lead pitches for MAXQFP are briefly addressed. Methods and data to resolve these challenges will be shown. For example, Sn whisker and Sn migration both are concerns to MAXQFP because of smaller distance between adjacent leads. The board-level solder joint reliability (SJR) has been collected to prove it is AEC G1 compliant. Visual inspection methods and requirements on AOI (automatic object inspection) systems on solider joints of J-leads of MAXQFP for are proposed. Standard AEC G1 component level reliability stresses defined at AEC Q100 which are TC (temperature cycling), HTSL (high temperature storage life), THB (Temperature Humidity Biased) and uHAST (un-biased HAST) tests are summarized Since Cu wires were used, AEC Q006 data are also collected. Assembly challenges are described. Future works will be summarized.

Background: Vietnam implemented various public health interventions such as contact tracing and testing, mandatory quarantine, and lockdowns in response to coronavirus disease 2019 (COVID-19). However, the effects of these measures on the epidemic remain unclear. Methods: This article describes the public health interventions in relation to COVID-19 incidence. Maximum likelihood estimations were used to assess containment delays (time between symptom onset and start of isolation) and multivariable regression was employed to identify associated factors between interventions and COVID-19 incidence. The effective reproductive numbers (Rt) were calculated based on transmission pairs. Results: Interventions were introduced periodically in response to the epidemic. Overall, 817 (55.4%) among 1474 COVID-19 cases were imported. Based on a serial interval of 8.72 ± 5.65 days, it was estimated that Rt decreased to below 1 (lowest at 0.02, 95% CI 0–0.12) during periods of strict border control and contact tracing, and increased ahead of new clusters. The main method to detect cases shifted over time from passive notification to active case-finding at immigration or in lockdown areas, with containment delays showing significant differences between modes of case detection. Conclusions: A combination of early, strict, and consistently implemented interventions is crucial to control COVID-19. Low-middle income countries with limited capacity can contain COVID-19 successfully using non-pharmaceutical interventions.

The pyrin inflammasome acts as a guard of RhoA GTPases and is central to immune defenses against RhoA-manipulating pathogens. Pyrin activation proceeds in two steps. Yet, the second step is still poorly understood. Using cells constitutively activated for the pyrin step 1, a chemical screen identifies etiocholanolone and pregnanolone, two catabolites of testosterone and progesterone, acting at low concentrations as specific step 2 activators. High concentrations of these metabolites fully and rapidly activate pyrin, in a human specific, B30.2 domain-dependent manner and without inhibiting RhoA. Mutations in MEFV, encoding pyrin, cause two distinct autoinflammatory diseases pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND) and familial Mediterranean fever (FMF). Monocytes from PAAND patients, and to a lower extent from FMF patients, display increased responses to these metabolites. This study identifies an unconventional pyrin activation mechanism, indicates that endogenous steroid catabolites can drive autoinflammation, through the pyrin inflammasome, and explains the "steroid fever" described in the late 1950s upon steroid injection in humans. ispartof: CELL REPORTS vol:41 issue:2 ispartof: location:United States status: published

Background Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP), a rare disorder affecting young adults, causes gradual weakness of the limbs, areflexia and impaired sensory function. New CIDP phenotypes without pathogenic antibodies but with modified cell profiles have been described. Treatments include corticotherapy, intravenous immunoglobulins, and plasmapheresis but the latter’s action mechanisms remain unclear. Plasmapheresis supposedly removes toxic agents like antibodies from plasma but it is uncertain whether it has an immune-modulating effect. Also, the refining mechanisms of the two main plasmapheresis techniques—single plasma exchange and double filtration plasmapheresis (DFPP) – are different and unclear. This study aims to compare the evolution of peripheral lymphocyte profiles in patients with CIDP according to their treatment (single centrifugation plasmapheresis or DFPP) to better grasp the action mechanisms of both techniques. Method In this proof-of-concept, monocentric, prospective, Single-Case Experimental Design study, 5 patients are evaluated by alternating their treatment type (single plasma exchange or DFPP) for 6 courses of treatment after randomization to their first treatment type. Each course of treatment lasts 2–4 weeks. For single plasma exchange, 60 ml/kg plasma will be removed from the patient and replaced with albumin solutes, with a centrifugation method to avoid the immunological reaction caused by the membrane used with the filtration method. For DFPP, 60 ml/kg plasma will be removed from the patient with a plasma separator membrane, then processed via a fractionator membrane to remove molecules of a greater size than albumin before returning it to the patient. This technique requires no substitution solutes, only 20 g of albumin to replace what would normally be lost during a session. The primary outcome is the difference between the two plasmapheresis techniques in the variation of the TH1/TH17 ratio over the period D0H0-D0H3 and D0H0-D7. Secondary outcomes include the variation in lymphocyte subpopulations at each session and between therapeutic plasmapheresis techniques, the clinical evolution, tolerance and cost of treatments. Discussion Understanding the action mechanisms of single plasma exchange and DFPP will help us to offer the right treatment to each patient with CIPD according to efficacy, tolerance and cost. Trial registration ClinicalTrials.gov under the no. NCT04742374 and date of registration 10 December 2020.

Export market orientation has always been a central issue in the study of international business and marketing. Therefore, it is essential to put effort into understanding the concept and its application in real-life business. Following in-depth studies and critical review papers in previous years, this research paper focuses on synthesizing and analyzing empirical studies in the period from 2015 to 2021, revolving around theoretical issues, context, the main features of the object, and the methodology. Within a predetermined time frame, twenty critical papers on export market orientation were selected and analyzed. The result reveals in detail that there are sixteen antecedents and five outcomes of export market orientation, as well as the total of eight moderators and seven mediators influencing their relationships. Findings have indicated that in recent years, models and theories of earlier eras have been developed and many of them have reached maturity.

Background: Preterm birth is a major cause of morbidity and mortality in infants and children. Non-invasive methods for screening the neonatal immune status are lacking. Archaea, a prokaryotic life domain, comprise methanogenic species that are part of the neonatal human microbiota and contribute to early immune imprinting. However, they have not yet been characterized in preterm neonates. Objective: To characterize the gut immunological and methanogenic Archaeal (MA) signature in preterm neonates, using the presence or absence of atopic conditions at the age of one year as a clinical endpoint. Methods: Meconium and stool were collected from preterm neonates and used to develop a standardized stool preparation method for the assessment of mediators and cytokines and characterize the qPCR kinetics of gut MA. Analysis addressed the relationship between immunological biomarkers, Archaea abundance, and atopic disease at age one. Results: Immunoglobulin E, tryptase, calprotectin, EDN, cytokines, and MA were detectable in the meconium and later samples. Atopic conditions at age of one year were positively associated with neonatal EDN, IL-1β, IL-10, IL-6, and MA abundance. The latter was negatively associated with neonatal EDN, IL-1β, and IL-6. Conclusions: We report a non-invasive method for establishing a gut immunological and Archaeal signature in preterm neonates, predictive of atopic diseases at the age of one year.

Low-dose IL-2 (ld-IL2) selectively activates and expands regulatory T cells (Tregs) and thus has the potential to skew the regulatory/effector T (Treg/Teff) cell balance towards improved regulation. We investigated which low doses of IL-2 would more effectively and safely activate Tregs during a 1 year treatment in children with recently diagnosed type 1 diabetes. Dose Finding Study of IL-2 at Ultra-low Dose in Children With Recently Diagnosed Type 1 Diabetes (DF-IL2-Child) was a multicentre, double-blinded, placebo-controlled, dose-finding Phase I/II clinical trial conducted in four centres at university hospitals in France: 24 children (7–14 years old) with type 1 diabetes diagnosed within the previous 3 months were randomly assigned 1:1:1:1 to treatment by a centralised randomisation system, leading to a 7/5/6/6 patient distribution of placebo or IL-2 at doses of 0.125, 0.250 or 0.500 million international units (MIU)/m2, given daily for a 5 day course and then fortnightly for 1 year. A study number was attributed to patients by an investigator unaware of the randomisation list and all participants as well as investigators and staff involved in the study conduct and analyses were blinded to treatments. The primary outcome was change in Tregs, expressed as a percentage of CD4+ T cells at day 5. It pre-specified that a ≥60% increase in Tregs from baseline would identify Treg high responders. There were no serious adverse events. Non-serious adverse events (NSAEs) were transient and mild to moderate. In treated patients vs placebo, the commonest NSAE was injection site reaction (37.9% vs 3.4%), whereas other NSAEs were at the same level (23.3% vs 19.2%). ld-IL2 induced a dose-dependent increase in the mean proportion of Tregs, from 23.9% (95% CI −11.8, 59.6) at the lowest to 77.2% (44.7, 109.8) at the highest dose, which was significantly different from placebo for all dose groups. However, the individual Treg responses to IL-2 were variable and fluctuated over time. Seven patients, all among those treated with the 0.250 and 0.500 MIU m−2 day−1 doses, were Treg high responders. At baseline, they had lower Treg proportions in CD4+ cells than Treg low responders, and serum soluble IL-2 receptor α (sIL-2RA) and vascular endothelial growth factor receptor 2 (VEGFR2) levels predicted the Treg response after the 5 day course. There was no significant change in glycaemic control in any of the dose groups compared with placebo. However, there was an improved maintenance of induced C-peptide production at 1 year in the seven Treg high responders as compared with low responders. The safety profile at all doses, the dose-dependent effects on Tregs and the observed variability of the Treg response to ld-IL2 in children with newly diagnosed type 1 diabetes call for use of the highest dose in future developments. The better preservation of insulin production in Treg high responders supports the potential of Tregs in regulating autoimmunity in type 1 diabetes, and warrants pursuing the investigation of ld-IL2 for its treatment and prevention. ClinicalTrials.gov NCT01862120. Assistance Publique-Hopitaux de Paris, Investissements d’Avenir programme (ANR-11-IDEX-0004-02, LabEx Transimmunom and ANR-16-RHUS-0001, RHU iMAP) and European Research Council Advanced Grant (FP7-IDEAS-ERC-322856, TRiPoD).

International audience; Background: Lymphopenia is predictive of survival in patients with coronavirus disease 2019 (COVID-19).Objective: The aim of this study was to understand the cause of the lymphocyte count drop in severe forms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.Methods: Monocytic production of reactive oxygen species (ROSs) and T-cell apoptosis were measured by flow cytometry, DNA damage in PBMCs was measured by immunofluorescence, and angiotensin II (AngII) was measured by ELISA in patients infected with SARS-CoV-2 at admission to an intensive care unit (ICU) (n 5 29) or not admitted to an ICU (n 5 29) and in ageand sex-matched healthy controls.Results: We showed that the monocytes of certain patients with COVID-19 spontaneously released ROSs able to induce DNA damage and apoptosis in neighboring cells. Of note, high ROS production was predictive of death in ICU patients. Accordingly, in most patients, we observed the presence of DNA damage in up to 50% of their PBMCs and T-cell apoptosis. Moreover, the intensity of this DNA damage was linked to lymphopenia. SARS-CoV-2 is known to induce the internalization of its receptor, angiotensin-converting enzyme 2, which is a protease capable of catabolizing AngII. Accordingly, in certain patients with COVID-19 we observed high plasma levels of AngII. When looking for the stimulus responsible for their monocytic ROS production, we revealed that AngII triggers ROS production by monocytes via angiotensin receptor I. ROSs released by AngII-activated monocytes induced DNA damage and apoptosis in neighboring lymphocytes.Conclusion: We conclude that T-cell apoptosis provoked via DNA damage due to the release of monocytic ROSs could play a major role in COVID-19 pathogenesis.

Objectives Behçet disease (BD) is a chronic systemic inflammatory disorder of unknown aetiology. The aim of this study was to determine the orientation of T cell subpopulations in paediatric BD and more precisely to look for a regulatory T lymphocyte (Treg)/Th17 imbalance. Methods T cell subpopulations were analysed by flow cytometry in the peripheral blood of paediatric patients with acute BD (aBD; n = 24), remitting BD (rBD; n = 12) and in healthy controls (HCs; n = 24). Tregs (CD4+CD25hiCD127−/loFoxp3+), activated Tregs (GITR, LAP, CTLA-4 and HLA-DR expression), CD4+ and CD8+ T cells producing IFN-γ (Th1 and Tc1) or IL-17 (Th17 and Tc17) under polyclonal (OKT3/IL-2) or antigenic (Streptococcus sanguis KTH-1 peptides and heat shock protein 60) stimulation were enumerated. Results Th17 (1.9- and 5.1-fold) and Tc17 (4.0- and 2.0-fold) frequency under mitogenic stimulation was significantly increased in aBD and rBD patients as compared with HCs. Th17 frequency under antigenic stimulation was also higher in patients than in HCs. The percentage and number of Tregs and activated Tregs in patients and in HCs were similar. However, when Tregs were removed, antigen-driven differentiation into Th1 and Th17 was significantly boosted in BD but not in HC CD4+ T cells. Conclusion There is a bias towards Th17 polarization in aBD and rBD in children. Although we did not observe an increase in the number of Tregs in these patients, their Tregs limit CD4+ T cell differentiation into Th1 and Th17 cells. Thus, in paediatric BD, Tregs seem to incompletely counterbalance a Th17 orientation of the Th cell response.

Highlights • The first ever detection in the meconium of the methanogen M. smithii. • These data position M. smithii among the early inhabitants of the human gut. • These data suggest the contribution of methanogens to the perinatal development of intestinal microbiota and physiology., To understand the dynamics of methanogens in the human intestinal microbiota, we investigated the presence of methanogens in meconium using a polyphasic approach including microscopy and PCR-sequencing in 33 meconium samples collected from 33 pre-term neonates, in accordance with current ethics regulation. In the presence of negative controls, 90.9% samples were real-time PCR-positive for methanogens and 69.7 % were PCR-sequencing positive, identified as Methanobrevibacter (M.) smithii. Further, auto-fluorescent analysis detected methanogens in the two meconium samples analyzed, with a morphology suggesting M. smithii. Multispacer Sequence Typing found M. smithii genotypes ST1 and ST2, previously described as intestinal microbiota inhabitants. C-section delivery and non-use of peripartum antibiotics significantly correlated with PCR-detection of methanogens in meconium. These data position M. smithii among the early inhabitants of the human gut, detectable immediately after birth and suggest the contribution of methanogens to the perinatal development of intestinal microbiota and physiology.

Behçet’s disease (BD) is a systemic variable vessel vasculitis that involves the skin, mucosa, joints, eyes, arteries, veins, nervous system and gastrointestinal system, presenting with remissions and exacerbations. It is a multifactorial disease, and several triggering factors including oral cavity infections and viruses may induce inflammatory attacks in genetically susceptible individuals. BD vasculitis involves different vessel types and sizes of the vascular tree with mixed-cellular perivascular infiltrates and is often complicated by recurrent thrombosis, particularly in the venous compartment. Several new therapeutic modalities with different mechanisms of action have been studied in patients with BD. A substantial amount of new data have been published on the management of BD, especially with biologics, over the last years. These important therapeutic advances in BD have led us to propose French recommendations for the management of Behçet’s disease [Protocole National de Diagnostic et de Soins de la maladie de Behçet (PNDS)]. These recommendations are divided into two parts: (1) the diagnostic process and initial assessment; (2) the therapeutic management. Thirty key points summarize the essence of the recommendations. We highlighted the main differential diagnosis of BD according to the type of clinical involvement; the role of genetics is also discussed, and we indicate the clinical presentations that must lead to the search for a genetic cause.

Background: Methanogens are part of the human microbiota, the intestinal and oral microbiota. They have even been found in colostrum and breast milk, in vagina only in case of vaginosis and in urinary tract during urinary tract infections. They are present in humans from birth. Accordingly, the detection of methanogens in the meconium has not been reported. The objective of this work was to investigate the presence of methanogens in meconium. Methods: We used a polyphasic approach including microscopy and PCR sequencing in 33 meconium samples taken from 33 premature newborns, in accordance with current ethical regulations. Results: In the presence of negative controls, 90.9% samples were real-time PCR-positive for methanogens and 69.7% were PCR-sequencing positive, identified as Methanobrevibacter (M.) smithii. Further, auto-fluorescent analysis detected methanogens in the two meconium samples analyzed, with a morphology suggesting M. smithii. Multispacer Sequence Typing found M. smithii genotypes ST1 and ST2, previously described as intestinal microbiota inhabitants. C-section delivery and non-use of peripartum antibiotics significantly correlated with PCR-detection of methanogens in meconium. Conclusion: These data position M. smithii among the early inhabitants of the human gut, detectable immediately after birth and suggest the contribution of methanogens to the perinatal development of intestinal microbiota and physiology. Trial Registration: NCT02738411. Funding Statement: YS and COG benefit from PhD grants from the Fondation Mediterranee Infection, Marseille, France. This work was supported by the French Government under the «Investissements d’avenir» (Investments for the Future) program managed by the Agence Nationale de la Recherche (ANR, fr: National Agency for Research), (reference: Mediterranee Infection 10-IAHU-03). Declaration of Interests: The authors declare no competing interests in relation to this study. Outside this study, JV reports speaker and consultancy fees in the past 5 years from Meda Pharma (Mylan), Novartis, Sanofi, Thermo Fisher Scientific, outside the submitted work. Ethics Approval Statement: Written informed parental consent was obtained for each preterm. This research project was approved by the Ethics Committee on Clinical Research of Nimes and Montpellier University Hospitals.

International audience; No abstract available

Background International air travel plays an important role in the global spread of SARS-CoV-2, and tracing of close contacts is an integral part of the public health response to COVID-19. We aimed to assess the timeliness of contact tracing among airline passengers arriving in Vietnam on flights containing COVID-19 cases and investigated factors associated with timeliness of contact tracing. Methods We included data from 2228 passengers on 22 incoming flights between 2 and 19 March 2020. Contact tracing duration was assessed separately for the time between the date of index case confirmation and date of contact tracing initiation (interval I), and the date of contact tracing initiation and completion (interval II). We used log-rank tests and multivariable Poisson regression models to identify factors associated with timeliness. Results The median duration of interval I and interval II was one (IQR: 1–2) and 3 days (IQR: 2–5), respectively. The contact tracing duration was shorter for passengers from flights where the index case was identified through mandatory testing directly upon arrival (median = 4; IQR: 3–5) compared to flights with index case detection through self-presentation at health facilities after arrival (median = 7; IQR: 5–8) (p-value = 0.018). Cumulative hazards for successful tracing were higher for Vietnamese nationals compared to non-Vietnamese nationals (p Conclusions Contact tracing among flight passengers in the early stage of the COVID-19 epidemic in Vietnam was timely though delays occurred on high workload days. Mandatory SARS-CoV-2 testing at arrival may reduce contact tracing duration and should be considered as an integrated screening tool for flight passengers from high-risk areas when entering low-transmission settings with limited contact tracing capacity. We recommend a standardized risk-based contact tracing approach for flight passengers during the ongoing COVID-19 epidemic.

Therapeutic alliance (TA) is the agreement between caregiver and patient during the care process. Therapeutic adherence is a major issue for the management of Juvenile Idiopathic Arthritis (JIA) requiring child's strong ability to follow treatments. The aim of this study was to evaluate the relationship between TA and adherence in patients with JIA.Observational, cross-sectional, multicenter study. Children, with JIA, aged 8-16, were included. Children, parents and physicians completed the Helping Alliance Questionnaire (HAQ-CP) for assessing TA. Adherence was measured using the Child/Parent Adherence Report Questionnaire (CARQPARQ). Demographic data, disease characteristics, current treatments and social environment were collected. The univariate relationship between TA and adherence, was studied by Pearson correlation coefficient. The multivariate analysis used a multiple linear regression model.A total of 119 patients were included: 68.9% girls, mean age (SD) 12.4 (2.9) years, disease duration 73.1 (48.2) months. JIA was in remission (52%), in low activity (32%) and active (16%). TA scores were high (≥80/100) for children, parents and physicians. HAQCP was highly correlated with CARQ (r=0.31; P0.001) PARQ (r=0.37; P0.001). In univariate analysis, disease activity (P0.05), place of residence (P0.01) and family status (P0.01) were associated with child's TA. In multivariate analysis, only the place of residence (P0.001) and the family status (P0.05) remained associated with TA.TA strongly influences therapeutic adherence and therefore may be important for treatment effectiveness.

This contribution conceptualizes an evaluation model for data mining approaches for preventive quality assurance in purchasing. Future purchasing heavily relies on data analytics and purchasers need to be equipped with suitable tools and skills. A major prerequisite is to collect the respective data and to apply suitable algorithms to generate added value. This will free human capacity for more strategic initiatives and will provide an increase in flexibility and productivity within the company. To derive a valid evaluation model, data mining methods apt for preventive quality assurance being a binary classification problem are presented. Based on a seven steps data mining approach and a literature analysis, requirements for the data mining methods are derived. Subsequently, the criteria are aligned with exigencies in purchasing. This leads to a weighting of the respective criteria. The application of the evaluation model shows that support vector machines and k-nearest neighbors seem to be the best suitable data mining methods for preventive quality assurance in purchasing.

We propose a joint model for POS tagging and dependency parsing. Our model consists of a BiLSTM-CNN-CRF-based POS tagger [26] and a Deep Biaffine Attention-based dependency parser [24]. A combined objective function is used to jointly train both models. Experiment results show very competitive performance on several languages of the Universal Dependencies (UD) v2.2 Treebanks [11].

We describe a patient exhibiting clinical features of PRAAS due to a homozygous mutation in PSMB10. This gene encodes the only immunoproteasome subunit in which mutations have not yet been associated with PRAAS.

International audience; To understand the dynamics of methanogens in the human intestinal microbiota, we investigated the presence of methanogens in meconium using a polyphasic approach including microscopy and PCR-sequencing in 33 meconium samples collected from 33 pre-term neonates, in accordance with current ethics regulation. In the presence of negative controls, 90.9% samples were real-time PCR-positive for methanogens and 69.7 % were PCR-sequencing positive, identified as Methanobrevibacter (M.) smithii. Further, auto-fluorescent analysis detected methanogens in the two meconium samples analyzed, with a morphology suggesting M. smithii. Multispacer Sequence Typing found M. smithii genotypes ST1 and ST2, previously described as intestinal microbiota inhabitants. C-section delivery and non-use of peripartum antibiotics significantly correlated with PCR-detection of methanogens in meconium. These data position M. smithii among the early inhabitants of the human gut, detectable immediately after birth and suggest the contribution of methanogens to the perinatal development of intestinal microbiota and physiology.

Sai Gon South is the gateway area being focused on developing urban infrastructure of Ho Chi Minh city. However this area have a low-lying terrain and weak geological structure. Therefore the subsidence problems are very serious now due to the urbanization. There is few research obtained to the effects of subsidence in this area the study has been carried out to assess the current situation and forecast the ground subsidence in this area. The study used the geo-statistics method of Kriging and calculation method for subsidence. The interpolated results of 167 boreholes showed the geologycal weakness of the soil layer from 6.5 to 35m which has correlation with the subsidence. (Coefficient r2 = 0.7).

Muckle-Wells syndrome (MWS) is a rare autoinflammatory disorder. It is due to NLRP3 gene mutations, responsible for excessive caspase-1 activation and interleukin 1β processing. MWS is the intermediate phenotype of severity of cryopyrin-associated periodic syndrome. Urticarial rash, conjunctivitis, recurrent fever, arthralgia, and fatigue are the main clinical manifestations of MWS. Yet, sensorineural hearing loss and renal amyloidosis can occur after long term evolution. Patients' quality of life has been drastically improved with the advent of IL-1 inhibitors. This review reports recent findings in MWS, particularly genotype/phenotype correlation, and discusses the clinical perspectives of this disease in a time of efficient treatment.

Highlights • Evocative symptoms and TDM chest scan do not make a diagnosis of COVID-19. • Molecular biology test is mandatory for the diagnosis of SARS-CoV-2 infection. • Call for caution on the differential diagnosis of COVID-19., Here, we report the clinical case of a 12-year-old girl presenting with flu-like symptoms, cough, anosmia, ageusia, breathing difficulties, and patchy ground glass opacities on TDM chest scan who turned out to be Coronavirus 229E-infected. This case draws attention to the risk of false COVID-19 diagnosis when over-relying on CT scan imaging.

The objective of this pilot study was to assess the overall adherence rate of the pediatric population to anti-infective drugs prescribed for acute infection at hospital discharge and to identify risk factors for non-adherence behavior. Pediatric patients discharged from a French university hospital with at least one oral drug prescription for acute infection were included for 3 months. Medication adherence and antibiotic knowledge were assessed through data collected by calling the parents. Overall adherence was assessed according to seven items: medication order filling, administered dose, time of intake, frequency of doses, medication omission, dose modification, and length of treatment. Seventy-five patients were included, and 63 interviews were exploited. The median age was 1.4 years, IQR = [0.7; 3.3]. Overall adherence to anti-infective agents concerned 34.9% of patients. The most frequently prescribed antibiotics were amoxicillin (29.3%), amoxicillin associated with clavulanic acid (25.3%), cotrimoxazole (18.7%), and cefixime (12.0%). A lack of parents' anti-infective knowledge was associated with non-adherence to anti-infective drugs.Conclusion: Two-thirds of outpatients were non-adherent to anti-infectives in acute infectious diseases. The misunderstanding of anti-infective treatment could be a risk factor for non-adherence. Implementation of preventive actions such as therapeutic education or pharmaceutical counseling at hospital discharge could improve adherence to anti-infective agents. What Is Known: • Non-adherence to anti-infective drugs involves the emergence and spread of antibiotic resistance. • Very few studies have assessed medication adherence in acute infectious diseases in pediatrics after hospital discharge. What Is New: • Only 35% of children were overall adherent to anti-infective drugs in acute infectious disease after hospital discharge. • Most patients (89%) had a good primary adherence but very few (40%) had good secondary adherence mainly due to dose omission and dose modification.

Background: Low-dose interleukin 2 (ld-IL2) selectively activates and expands regulatory T cells (Tregs) and thus has the potential to skew the regulatory/effector T (Treg/Teff) cell balance towards improved regulation. Regimens of ld-IL2 are actively investigated as a treatment for various autoimmune diseases, including type 1 diabetes (T1D). We previously reported a dose-dependent specific activation and expansion of Tregs in adults with established T1D receiving a short 5-day treatment with ld-IL2. We report results from the DF-Child trial, in which we investigated which low doses of IL2 would more effectively activate Treg cells during a 1-year treatment in children with recently diagnosed T1D. Methods: DF-Child was a multicentre, double-blinded, phase 1/2 clinical trial: 24 children (7-14 years-old) with T1D diagnosed within the previous 3 months were randomized in a 1:1:1:1 ratio to s.c. injection of placebo or IL2, at doses of 0.125, 0.250, or 0.500 MIU/m2, given daily for a 5-day course and then fortnightly for 1 year. The primary outcome was change in Treg cells expressed as a percentage of CD4+ T cells at day-5, and pre-specified that an increased on Tregs ≥60% from baseline would identify Treg high responders. This trial is registered with ClinicalTrials.gov, NCT01862120. Findings: Twenty-four patients were randomized between June 27, 2013, and Jan 1, 2016. IL2 was well tolerated at all doses, with no serious adverse events. Non-serious adverse events were transient and mild to moderate. Ld-IL2 induced a dose dependent increase in the proportion of Tregs. Although the mean Treg responses of all dose-groups were significantly different from placebo, the individual Treg responses to IL-2 were variable and fluctuated over time. All treated subjects showed an increase in Tregs, and we identified 7 Treg high responders among those treated with the 0.250 and 0.500 MIU/m2/day doses (3 and 4, respectively). There was no significant change in glycaemic control in any of the dose-groups compared to placebo, and no differences reported in insulin doses. However, there was a trend for an improved maintenance of induced C-peptide production at one year in the 7 Treg high responders. Interpretation: The good safety profile at all doses, the dose-dependent effects on Tregs and the observed variability of the Treg response to ld-IL2 in newly diagnosed T1D children call for using the highest dose in future developments. The better preservation of insulin production in Treg high responders supports the potential of Tregs in regulating autoimmunity in T1D and warrants pursuing the investigation of ld-IL2 for its treatment and prevention. Trial Registration Number: This trial is registered with ClinicalTrials.gov, NCT01862120. Funding: Assistance Publique-Hopitaux de Paris, Investissements d’Avenir programme (ANR-11-IDEX-0004-02, LabEx Transimmunom and ANR-16-RHUS-0001, RHU iMAP) and European Research Council Advanced Grant (FP7-IDEAS-ERC-322856, TRiPoD). Declaration of Interest: DK, MR and CB are co-inventor of a patent entitled “IL 2 based therapy” (OEB 11 305269.0) and DK and MR are shareholders in ILTOO pharma, the exclusive licensee of this patent. Ethical Approval: The study was approved by the institutional review board of Pitie-Salpetriere Hospital, and conducted in accordance with the Declaration of Helsinki and good clinical practice guidelines. Written informed consent was obtained from all participants before enrolment in the study.

Introduction L’avenement des biopuces a allergenes a facilite la description de profils de sensibilisation complexes chez les enfants allergiques. Le faible volume necessaire pour une exploration par biopuce facilite l’analyse des prelevements locaux. L’objectif de ce travail etait de developper un protocole experimental pour detecter des IgE specifiques (sIgE) a l’aide de biopuces a allergenes a partir d’echantillons de matieres fecales et d’evaluer sa valeur predictive pour la survenue de maladies allergiques. Methodes L’analyse a ete realisee sur 21 echantillons de selles collectes entre la naissance et l’âge de 14 semaines chez des nourrissons inclus dans le protocole Primibiota ( NCT02738411 ). La survenue d’allergies alimentaires, asthme, ou dermatite atopique (DA) a l’âge de 1 an a ete consignee dans le cadre du suivi de cohorte. Nous avons developpe et optimise un protocole d’extraction de selles, suivi de lyophilisation et solubilisation. L’exploration de la reponse sIgE a ete realisee par biopuce Alex® (MADX, Vienne, Autriche) et confirmee par Western Blot capillaire avec nano-immunoessai (JessTM Simple Western system, Protein Simple, San Jose, CA). La composante eosinophilique locale a ete exploree par mesure de la concentration d’EDN (Eosinophil-Derived Neurotoxin) par la methode ImmunoCAP (Thermo Fisher Scientific, Uppsala, Suede). Resultats La presence de sIgE a ete detectee dans tous les echantillons testes. Par ordre de frequence, les principales sIgE detectees concernaient des extraits et allergenes alimentaires d’origine animale (21/21) et vegetale (20/21), des pollens (19/21) et des phaneres (15/21). La presence de sIgE a ete confirmee par Western blot JessTM pour les proteines du lait de vache. Quantitativement, la concentration d’EDN fecale et de sIgE etaient significativement differentes chez les nourrissons qui developperaient par la suite une maladie atopique. Conclusion L’exploration de la reponse sIgE et eosinophilique peut etre realisee de maniere non invasive dans les selles chez le nourrisson. Nos resultats suggerent une valeur predictive de ce type d’exploration pour la survenue d’asthme, allergies alimentaires ou DA.

This paper has two purposes: first, to investigate centre- periphery, and within-school relationships and processes by which Vietnam schools undertake system reform implementation; second, to develop the explanatory power and complementarity of two theories – complex adaptive system theory and loose-tight coupling. Main findings - schools’ internal enablers driving reforms were shaped by external enablers; a plethora of internal enablers then worked in concert to implement the intended reforms (eg. the take-up of student-centred teaching and learning); in the local adaptation process, school culture and professional development were pre-eminent. Conclusions – complex adaptive system theory was validated in how Vietnam schools locally adapted policy.

Resume La sarcoidose est une granulomatose systemique d’origine indeterminee, dont le diagnostic repose sur une triade classique : un tableau clinique et radiologique evocateur, la mise en evidence de granulomes tuberculoides sans necrose caseeuse a l’histologie et l’elimination des autres granulomatoses, en particulier la tuberculose. Cette maladie est rare dans la population generale, notamment chez l’enfant chez lequel peu de cas avec hypercalcemie ont ete decrits. Nous rapportons le cas d’un enfant de 14 ans ayant presente une sarcoidose ganglionnaire et medullaire revelee par une alteration de l’etat general avec hypercalcemie. En l’absence d’orientation etiologique initiale et devant l’hypercalcemie severe (jusqu’a 3,28 mmol/L), l’adolescent a recu un traitement par hyperhydratation, diuretiques et biphosphonates ayant donne un bon resultat. La revue de litterature des cas similaires publies depuis 1990 a permis de colliger 23 cas (incluant le notre) dont nous avons compare les donnees cliniques, epidemiologiques, biologiques, iconographiques et histopathologiques. Les enfants presentant une sarcoidose associee a une hypercalcemie sont plus jeunes que ceux sans hypercalcemie. Les atteintes classiques, notamment pulmonaires, ganglionnaires et cutanees permettent d’orienter plus rapidement vers le diagnostic. La corticotherapie est proposee habituellement pour traiter la sarcoidose et notamment l’hypercalcemie. En conclusion, la sarcoidose de l’enfant reste difficile a diagnostiquer (delai diagnostique allant de 3 mois a plusieurs annees). Cela est du a sa faible incidence et au caractere non specifique des symptomes ; la classique triade n’est pas toujours presente. Une sarcoidose doit etre recherchee devant une hypercalcemie de cause indeterminee chez l’enfant.

The aim of this study was to visualize improved swallowing mechanics resulting from respiratory-swallow phase training using patient specific computational analysis of Modified Barium Swallow (MBS) videofluoroscopic images. Imaging from a single subject showing improved MBSImP™© scores in 17 of 18 pre- to post-treatment swallows was selected for analysis. Using a semi-automated MATLAB tracker tool, a frame-by-frame annotation of 10 coordinates mapping muscle functional groups was performed during oropharyngeal swallowing. Computational analysis of coordinate shape change was executed using MorphoJ software to determine differences in swallowing mechanics associated with multiple independent variables. Canonical variant analysis indicated significant differences in mechanics associated with respiratory-swallow phase training (D=1.92,p

Introduction La naissance prematuree est la principale cause de morbi-mortalite neonatale. Un substrat genetique, infectieux et immunologique est suspecte. Il n’existe pas actuellement de methode d’exploration non invasive pour caracteriser le statut immunitaire du nouveau-ne. Dans le cadre d’un protocole de recherche clinique sur le developpement du microbiote intestinal et le statut immunitaire dans une cohorte d’enfants prematures, cette etude ancillaire vise a proposer un dosage non invasif de mediateurs et cytokines impliques dans la physiopathologie des maladies allergiques. Methodes Apres mise au point et optimisation methodologique, le protocole experimental associe extraction proteique, concentration des selles et filtration, suivies des dosages suivants : IgE totales, tryptase (ImmunoCAP Thermo Fisher Scientific), calprotectine (BioFlash Werfen), IL-6, IL-10, IL-1 beta, TGF-beta, TNF-alpha, IgA, IgG (R&DSystems, Abcam) dans le meconium de 50 nouveau-nes prematures. Resultats Tous les mediateurs etaient detectables, a l’exception du TNF-alpha. La prevalence maximale de 100 % etait observee pour les IgA, IgG et calprotectine, suivie des IgE totales (92 %), l’IL-6 (76 %) et le TGF-beta (60 %). A l’inverse, la tryptase etait detectee dans 20 % des echantillons, l’IL-1 beta dans 30 % et l’IL-10 dans 6 % d’entre eux. La mediane des valeurs mesurees etait respectivement de 9 ng/mL (IgA), 33 ng/mL (IgG), 5 kUI/L (IgE), 514 ng/mL (calprotectine), 12 pg/mL (Il-6), 37 pg/mL (TGF-beta), 8 pg/mL (IL-1 beta), 49 pg/mL (IL-10), avec des correlations significatives tryptase-IgE totales (r = 0,99, p = 6×10–9), TGF-beta -IL-6 (r = 0,73, p = 0,0005) et TGF-beta-calprotectine (r = 0,73, p = 0,025). Discussion Nous rapportons une methodologie d’exploration immunitaire non invasive du nouveau-ne premature par analyse des mediateurs fecaux, avec des resultats dont la fourchette haute est comparable avec les valeurs disponibles dans la litterature pour des maladies intestinales allergiques et inflammatoires chroniques. Conclusion Nous apportons la preuve de concept de la faisabilite et de l’interet du dosage de mediateurs fecaux pour l’exploration non invasive de l’immunite neonatale. La perspective d’un multiplexage est discutee.