Diagnostic and Monitoring CERN Accelerator Controls Infrastructure : The DIAMON Project First Deployment in Operation

The CERN accelerator controls infrastructure spans over several machines and several thousands of devices are used to collect and transmit piece of control data. Each of these remote devices might fail and therefore prevent correct operation. A complete diagnostic and monitoring infrastructure has been developed in order to provide Operation crews with complete and easy to use graphical interface presenting the state of the controls system. Simple agents running in each surveyed item periodically report monitoring information to a central server. Graphical JAVA clients in the operation centers subscribe to this monitoring data and display a view of the current state of the machines. Mouse actions from these clients allows for diagnostic commands to be sent to the agent to get additional details or to repair a faulty situation. This presentation will describe the overall architecture of DIAMON, present the different agents running in the controls system and a few views of the graphical clients. The outcome of the first months in operation of the DIAMON tools will also be presented. Finally, the future plans will be exposed

Exhaled nitric oxide decreases after positive food-allergen challenge

Background: Exhaled nitric oxide (FeNO) is a well described marker of airway inflammation in asthma and is also known to increase after chronic exposure to inhaled allergens. It is not known whether monitoring FeNO could be useful during food challenges to detect early or subclinical reactions. Methods: Forty children aged 3 to 16 years undergoing an allergen-food challenge at two centres were prospectively recruited for this study. FeNO was assessed before and repeatedly after the food-challenge. Results: Data were obtained from a total of 53 challenges (16 positive, 37 negative) and were compared between the two groups. Half of the patients with a positive food challenge exhibited clinical upper respiratory symptoms. The FeNO significantly decreased in 7 of 16 patients with a positive challenge test within 60 to 90 minutes after the first symptoms of an allergic reaction. Conclusion: Our results show a significant decrease in FeNO after a positive food challenge suggesting involvement of the lower airways despite absence of clinical and functional changes of lower airways. Prospective blinded studies are needed to confirm these results

Electrical impedance spectroscopy detects skin barrier dysfunction in childhood atopic dermatitis

Background Skin barrier dysfunction is associated with the development of atopic dermatitis (AD), however methods to assess skin barrier function are limited. We investigated the use of electrical impedance spectroscopy (EIS) to detect skin barrier dysfunction in children with AD of the CARE (Childhood AlleRgy, nutrition, and Environment) cohort. Methods EIS measurements taken at multiple time points from 4 months to 3‐year‐old children, who developed AD (n = 66) and those who did not (n = 49) were investigated. Using only the EIS measurement and the AD status, we developed a machine learning algorithm that produces a score (EIS/AD score) which reflects the probability that a given measurement is from a child with active AD. We investigated the diagnostic ability of this score and its association with clinical characteristics and age. Results Based on the EIS/AD score, the EIS algorithm was able to clearly discriminate between healthy skin and clinically unaffected skin of children with active AD (area under the curve 0.92, 95% CI 0.85–0.99). It was also able to detect a difference between healthy skin and AD skin when the child did not have active AD. There was no clear association between the EIS/AD score and the severity of AD or sensitisation to the tested allergens. The performance of the algorithm was not affected by age. Conclusions This study shows that EIS can detect skin barrier dysfunction and differentiate skin of children with AD from healthy skin and suggests that EIS may have the ability to predict future AD development

Chitinase-Induced Airway Hyperreactivity and Inflammation in a Mouse Model of Nonallergic Asthma.

INTRODUCTION Environmental exposure to mites and fungi has been proposed to critically contribute to the development of IgE-mediated asthma. A common denominator of such organisms is chitin. Human chitinases have been reported to be upregulated by interleukin-13 secreted in the context of Th2-type immune responses and to induce asthma. We assessed whether chitin-containing components induced chitinases in an innate immune-dependent way and whether this results in bronchial hyperresponsiveness. MATERIALS AND METHODS Monocyte/macrophage cell lines were stimulated with chitin-containing or bacterial components in vitro. Chitinase activity in the supernatant and the expression of the chitotriosidase gene were measured by enzyme assay and quantitative PCR, respectively. Non-sensitized mice were stimulated with chitin-containing components intranasally, and a chitinase inhibitor was administered intraperitoneally. As markers for inflammation leukocytes were counted in the bronchoalveolar lavage (BAL) fluid, and airway hyperresponsiveness was assessed via methacholine challenge. RESULTS We found both whole chitin-containing dust mites as well as the fungal cell wall component zymosan A but not endotoxin-induced chitinase activity and chitotriosidase gene expression in vitro. The intranasal application of zymosan A into mice led to the induction of chitinase activity in the BAL fluid and to bronchial hyperresponsiveness, which could be reduced by applying the chitinase inhibitor allosamidin. DISCUSSION We propose that environmental exposure to mites and fungi leads to the induction of chitinase, which in turn favors the development of bronchial hyperreactivity in an IgE-independent manner

Electrical impedance spectroscopy detects skin barrier dysfunction in childhood atopic dermatitis.

BACKGROUND Skin barrier dysfunction is associated with the development of atopic dermatitis (AD), however methods to assess skin barrier function are limited. We investigated the use of electrical impedance spectroscopy (EIS) to detect skin barrier dysfunction in children with AD of the CARE (Childhood AlleRgy, nutrition, and Environment) cohort. METHODS EIS measurements taken at multiple time points from 4 months to 3-year-old children, who developed AD (n = 66) and those who did not (n = 49) were investigated. Using only the EIS measurement and the AD status, we developed a machine learning algorithm that produces a score (EIS/AD score) which reflects the probability that a given measurement is from a child with active AD. We investigated the diagnostic ability of this score and its association with clinical characteristics and age. RESULTS Based on the EIS/AD score, the EIS algorithm was able to clearly discriminate between healthy skin and clinically unaffected skin of children with active AD (area under the curve 0.92, 95% CI 0.85-0.99). It was also able to detect a difference between healthy skin and AD skin when the child did not have active AD. There was no clear association between the EIS/AD score and the severity of AD or sensitisation to the tested allergens. The performance of the algorithm was not affected by age. CONCLUSIONS This study shows that EIS can detect skin barrier dysfunction and differentiate skin of children with AD from healthy skin and suggests that EIS may have the ability to predict future AD development

MHC Class II Molecules Enhance Toll-Like Receptor Mediated Innate Immune Responses

BACKGROUND: Major histocompatibility complex (MHC) class II molecules play crucial roles in immune activation by presenting foreign peptides to antigen-specific T helper cells and thereby inducing adaptive immune responses. Although adaptive immunity is a highly effective defense system, it takes several days to become fully operational and needs to be triggered by danger-signals generated during the preceding innate immune response. Here we show that MHC class II molecules synergize with Toll-like receptor (TLR) 2 and TLR4 in inducing an innate immune response. METHODOLOGY/PRINCIPAL FINDINGS: We found that co-expression of MHC class II molecules and TLR2 or TLR4 in human embryonic kidney (HEK) cells 293 leads to enhanced production of the anti-microbial peptide human-beta-defensin (hBD) 2 after treatment with TLR2 stimulus bacterial lipoprotein (BLP) or TLR4 ligand lipopolysaccharide (LPS), respectively. Furthermore, we found that peritoneal macrophages of MHC class II knock-out mice show a decreased responsiveness to TLR2 and TLR4 stimuli compared to macrophages of wild-type mice. Finally, we show that MHC class II molecules are physically and functionally associated with TLR2 in lipid raft domains of the cell membrane. CONCLUSIONS/SIGNIFICANCE: These results demonstrate that MHC class II molecules are, in addition to their central role in adaptive immunity, also implicated in generating optimal innate immune responses

Clinical data for paediatric research: the Swiss approach : Proceedings of the National Symposium in Bern, Switzerland, Dec 5-6, 2019.

Continuous improvement of health and healthcare system is hampered by inefficient processes of generating new evidence, particularly in the case of rare diseases and paediatrics. Currently, most evidence is generated through specific research projects, which typically require extra encounters with patients, are costly and entail long delays between the recognition of specific needs in healthcare and the generation of necessary evidence to address those needs. The Swiss Personalised Health Network (SPHN) aims to improve the use of data obtained during routine healthcare encounters by harmonizing data across Switzerland and facilitating accessibility for research. The project "Harmonising the collection of health-related data and biospecimens in paediatric hospitals throughout Switzerland (SwissPedData)" was an infrastructure development project funded by the SPHN, which aimed to identify and describe available data on child health in Switzerland and to agree on a standardised core dataset for electronic health records across all paediatric teaching hospitals. Here, we describe the results of a two-day symposium that aimed to summarise what had been achieved in the SwissPedData project, to put it in an international context, and to discuss the next steps for a sustainable future. The target audience included clinicians and researchers who produce and use health-related data on children in Switzerland. The symposium consisted of state-of-the-art lectures from national and international keynote speakers, workshops and plenary discussions. This manuscript summarises the talks and discussions in four sections: (I) a description of the Swiss Personalized Health Network and the results of the SwissPedData project; (II) examples of similar initiatives from other countries; (III) an overview of existing health-related datasets and projects in Switzerland; and (IV) a summary of the lessons learned and future prospective from workshops and plenary discussions. Streamlined processes linking initial collection of information during routine healthcare encounters, standardised recording of this information in electronic health records and fast accessibility for research are essential to accelerate research in child health and make it affordable. Ongoing projects prove that this is feasible in Switzerland and elsewhere. International collaboration is vital to success. The next steps include the implementation of the SwissPedData core dataset in the clinical information systems of Swiss hospitals, the use of this data to address priority research questions, and the acquisition of sustainable funding to support a slim central infrastructure and local support in each hospital. This will lay the foundation for a national paediatric learning health system in Switzerland

An integrated molecular risk score early in life for subsequent childhood asthma risk.

BACKGROUND Numerous children present with early wheeze symptoms, yet solely a subgroup develops childhood asthma. Early identification of children at risk is key for clinical monitoring, timely patient-tailored treatment, and preventing chronic, severe sequelae. For early prediction of childhood asthma, we aimed to define an integrated risk score combining established risk factors with genome-wide molecular markers at birth, complemented by subsequent clinical symptoms/diagnoses (wheezing, atopic dermatitis, food allergy). METHODS Three longitudinal birth cohorts (PAULINA/PAULCHEN, n = 190 + 93 = 283, PASTURE, n = 1133) were used to predict childhood asthma (age 5-11) including epidemiological characteristics and molecular markers: genotype, DNA methylation and mRNA expression (RNASeq/NanoString). Apparent (ap) and optimism-corrected (oc) performance (AUC/R2) was assessed leveraging evidence from independent studies (Naïve-Bayes approach) combined with high-dimensional logistic regression models (LASSO). RESULTS Asthma prediction with epidemiological characteristics at birth (maternal asthma, sex, farm environment) yielded an ocAUC = 0.65. Inclusion of molecular markers as predictors resulted in an improvement in apparent prediction performance, however, for optimism-corrected performance only a moderate increase was observed (upto ocAUC = 0.68). The greatest discriminate power was reached by adding the first symptoms/diagnosis (up to ocAUC = 0.76; increase of 0.08, p = .002). Longitudinal analysis of selected mRNA expression in PASTURE (cord blood, 1, 4.5, 6 years) showed that expression at age six had the strongest association with asthma and correlation of genes getting larger over time (r = .59, p < .001, 4.5-6 years). CONCLUSION Applying epidemiological predictors alone showed moderate predictive abilities. Molecular markers from birth modestly improved prediction. Allergic symptoms/diagnoses enhanced the power of prediction, which is important for clinical practice and for the design of future studies with molecular markers

Toll-like receptor 2 expression is decreased on alveolar macrophages in cigarette smokers and COPD patients

BACKROUND: Cigarette smoke exposure including biologically active lipopolysaccharide (LPS) in the particulate phase of cigarette smoke induces activation of alveolar macrophages (AM) and alveolar epithelial cells leading to production of inflammatory mediators. This represents a crucial mechanism in the pathogenesis of chronic obstructive pulmonary disease (COPD). Respiratory pathogens are a major cause of exacerbations leading to recurrent cycles of injury and repair. The interaction between pathogen-associated molecular patterns and the host is mediated by pattern recognition receptors (PRR's). In the present study we characterized the expression of Toll-like receptor (TLR)- 2, TLR4 and CD14 on human AM compared to autologous monocytes obtained from patients with COPD, healthy smokers and non-smokers. METHODS: The study population consisted of 14 COPD patients without evidence for acute exacerbation, 10 healthy smokers and 17 healthy non-smokers stratified according to age. The expression of TLR2, TLR4 and CD14 surface molecules on human AM compared to autologous monocytes was assessed ex vivo using FACS analysis. In situ hybridization was performed on bronchoalveolar lavage (BAL) cells by application of the new developed HOPE-fixative. RESULTS: The expression of TLR2, TLR4 and CD14 on AM from COPD patients, smokers and non-smokers was reduced as compared to autologous monocytes. Comparing AM we detected a reduced expression of TLR2 in COPD patients and smokers. In addition TLR2 mRNA and protein expression was increased after LPS stimulation on non-smokers AM in contrast to smokers and COPD patients. CONCLUSION: Our data suggest a smoke related change in the phenotype of AM's and the cellular response to microbial stimulation which may be associated with impairment of host defenses in the lower respiratory tract