Search

Rationale Infants born prematurely have impaired capacity to deal with oxidative stress shortly after birth. Objectives We hypothesize that the relative impact of exposure to air pollution on lung function is higher in preterm than in term infants. Methods In the prospective BILD-birth-cohort of 254 preterm and 517 term infants, we investigated associations of particulate matter (PM10) and nitrogen dioxide with lung function at 44 weeks postconceptional age and exhaled markers of inflammation and oxidative stress response (fraction of exhaled nitric oxide (FeNO)) in an explorative hypothesis-driven study design. Multilevel mixed-effects models were used and adjusted for known confounders. Measurements and Main Results Significant associations of PM10 during the second trimester of pregnancy with lung function and FeNO were found in term and preterm infants. Importantly, we observed stronger positive associations in preterm infants (born 32 - 36 weeks), with an increase of [184.9 (79.1, 290.7) mL/min] minute ventilation per 10 ��g/m3 increase in PM10 than in term infants [75.3 (19.7, 130.8) mL/min] (pprematurity �� PM10 interaction = 0.04, after multiple comparison adjustment padj = 0.09). Associations of PM10 and FeNO differed between moderate to late preterm [3.4 (-0.1, 6.8) ppb] and term [-0.3 (-1.5, 0.9) ppb] infants, the interaction with prematurity was significant (pprematurity �� PM10 interaction = 0.006, padj = 0.036). Conclusion Preterm infants showed significant higher susceptibility even to low-to-moderate prenatal air pollution exposure than term infants, leading to increased impairment of postnatal lung function. FeNO results further elucidate differences in inflammatory/oxidative stress response comparing preterms to terms.

The medical challenges caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV‑2) pose a tremendous burden on the healthcare system. This study aimed to analyze the effects of a SARS-CoV‑2 infections or disease progression on inpatient mortality of geriatric patients after proximal femoral fracture surgery.A retrospective analysis was conducted in all patients with a proximal femoral fracture surgically treated in an urban regional trauma center from 01/01/2020 to 01/31/2021. According to PCR test results detecting SARS-CoV‑2, the patients were divided into two groups (SARS-CoV‑2 positive vs. SARS-CoV‑2 negative). Patient data, disease progression data, and treatment-related information were evaluated for all patients. Statistical data analysis was performed using unpaired Student's t test or non-parametric Mann-Whitney U test.A total of 311 patients (women: 70.4%, age: 82.0 ± 11.0 years) were included in this study. Of these 3.9% (12/311) had a positive test result for SARS-CoV‑2. Significantly more deceased patients were found in the group tested positive for SARS-CoV‑2 (SARS-CoV‑2 positive: 41.7%, SARS-CoV‑2 negative: 5.4%, p 0.001). In addition, the number of proximal femoral fracture associated deaths correlated with the number of positive test results performed in the Clinic. The length of stay of SARS-CoV‑2 COVID-19 survivors tended to be greater than in those who were tested negative (SARS-CoV‑2 COVID-19 positive: 15.6 ± 13.1 days, SARS-CoV‑2 COVID-19 negative: 11.5 ± 6.5 days, p = 0.683). Furthermore, a significant difference in age was found in SARS-CoV‑2 survivors and SARS-CoV‑2 decedents (deceased: 95.5 ± 7.5 years, alive: 83.5 ± 7.3 years, p = 0.020).The study was conducted before the introduction of SARS-CoV‑2 vaccination. The results therefore refer to immune naive (unvaccinated) patients. In our study, more than 40% of all patients with proximal femoral fractures who tested positive for SARS-CoV‑2 died during hospitalization. An additional, critical factor in this respect was the age of the infected patients. Nonetheless, a positive correlation was demonstrated between the mortality rate and the number of positive SARS-CoV‑2 detections. Regarding the greater length of stay of patients tested positive for SARS-CoV‑2, the limited transfer options (further rehabilitation, skilled nursing facility) of the infected ones can be considered as causal. Particularly the vulnerable older patients are increasingly endangered by a combination of proximal femoral fracture and SARS-CoV‑2.HINTERGRUND: Die medizinischen Herausforderungen, die durch das Schwere Akute Respiratorische Syndrom durch Coronavirus 2 (SARS-CoV‑2) verursacht werden, stellen eine enorme Belastung für das deutsche Gesundheitssystem dar. Ziel dieser Studie war es, die Auswirkungen einer SARS-CoV‑2-Infektion oder eines asymptomatischen Krankheitsverlaufs auf die stationäre Mortalität geriatrischer Patienten nach einer proximalen Femurfraktur zu analysieren.Es erfolgte eine retrospektive Analyse aller Patienten mit proximaler Femurfraktur, die vom 1. Januar 2020 bis zum 31.01.2021 in einem städtischen regionalen Traumazentrum operiert wurden. Anhand der PCR-Testergebnisse zum Nachweis von SARS-CoV‑2 wurden die Patienten in zwei Gruppen eingeteilt (SARS-CoV‑2 positiv vs. SARS-CoV‑2 negativ). Für alle Patienten wurden Patientendaten, Daten zum Krankheitsverlauf und Informationen zur Behandlung ausgewertet. Die statistische Datenanalyse wurde mit dem ungepaarten Student’s t-Test oder dem nichtparametrischen Mann-Whitney-U-Test durchgeführt.Insgesamt wurden 311 Patienten (Frauen: 70,4 %, Alter: 82,0 ± 11,0 Jahre) in die Studie aufgenommen. Von diesen hatten 3,9 % (12/311) ein positives Testergebnis für SARS-CoV‑2. In der positiv auf SARS-CoV‑2 getesteten Gruppe befanden sich signifikant mehr verstorbene Patienten (SARS-CoV‑2 positiv: 41,7 %, SARS-CoV‑2 negativ: 5,4 %, p 0,001). Darüber hinaus korrelierte die Zahl der Todesfälle im Zusammenhang mit proximalen Femurfrakturen mit der Zahl der positiven Testergebnisse in der Klinik . Die Verweildauer der Überlebenden von SARS-CoV‑2 COVID-19 war tendenziell länger als bei denjenigen, die negativ getestet wurden (SARS-CoV‑2 COVID-19 positiv: 15,6 ± 13,1 Tage, SARS-CoV‑2 COVID-19 negativ: 11,5 ± 6,5 Tage, p = 0,683). Darüber hinaus wurde ein signifikanter Altersunterschied zwischen den Überlebenden von SARS-CoV‑2 und den Verstorbenen von SARS-CoV‑2 festgestellt (verstorben: 95,5 ± 7,5 Jahre, lebend: 83,5 ± 7,3 Jahre, p = 0,020).Die Studie wurde vor der Einführung der COVID-19-SARS-CoV‑2-Impfung durchgeführt. Die Ergebnisse beziehen sich daher auf immun-naive (nicht geimpfte) Patienten. In unserer Studie starben mehr als 40 % aller Patienten mit proximalen Femurfrakturen, die positiv auf SARS-CoV‑2 getestet wurden, während des Krankenhausaufenthalts. Ein zusätzlicher, kritischer Faktor in dieser Hinsicht war das Alter der infizierten Patienten. Dennoch wurde eine positive Korrelation zwischen der Sterblichkeitsrate und der Anzahl der positiven SARS-CoV‑2- nachgewiesen. Hinsichtlich der längeren Verweildauer der positiv auf SARS-CoV‑2 getesteten Patienten können die eingeschränkten Verlegungsmöglichkeiten (Weiterrehabilitation, Fachpflegeeinrichtung) der Infizierten als ursächlich angesehen werden. Insbesondere die vulnerablen älteren Patienten sind durch eine Kombination aus proximaler Femurfraktur und SARS-CoV‑2 zunehmend gefährdet.

RationaleIn adults, personalised asthma treatment targets patients with type 2 (T2)-high and eosinophilic asthma phenotypes. It is unclear whether such classification is achievable in children.ObjectivesTo define T2-high asthma with easily accessible biomarkers and compare resulting phenotypes across all ages.MethodsIn the multicentre clinical All Age Asthma Cohort (ALLIANCE), 1125 participants (n=776 asthmatics, n=349 controls) were recruited and followed for 2 years (1 year in adults). Extensive clinical characterisation (questionnaires, blood differential count, allergy testing, lung function and sputum induction (in adults)) was performed at baseline and follow-ups. Interleukin (IL)-4, IL-5 and IL-13 were measured after stimulation of whole blood with lipopolysaccharide (LPS) or anti-CD3/CD28.Measurements and main resultsBased on blood eosinophil counts and allergen-specific serum IgE antibodies, patients were categorised into four mutually exclusive phenotypes: “atopy-only”, “eosinophils-only”, “T2-high” (eosinophilia + atopy) and “T2-low” (neither eosinophilia nor atopy). The T2-high phenotype was found across all ages, even in very young children in whom it persisted to a large degree even after 2 years of follow-up. T2-high asthma in adults was associated with childhood onset, suggesting early origins of this asthma phenotype. In both children and adults, the T2-high phenotype was characterised by excessive production of specific IgE to allergens (pConclusionsUsing easily accessible biomarkers, patients with T2-high asthma can be identified across all ages delineating a distinct phenotype. These patients may benefit from therapy with biologicals even at a younger age.

Comprehensive studies investigated the role of T-cells in asthma which led to personalised treatment options targeting severe eosinophilic asthma. However, little is known about the contribution of B-cells to this chronic inflammatory disease. In this study we investigated the contribution of various B-cell populations to specific clinical features in asthma.In the All Age Asthma Cohort (ALLIANCE), a subgroup of 154 adult asthma patients and 28 healthy controls were included for B-cell characterisation by flow cytometry. Questionnaires, lung function measurements, blood differential counts and allergy testing of participants were analysed together with comprehensive data on B-cells using association studies and multivariate linear models.Patients with severe asthma showed decreased immature B-cell populations while memory B-cells were significantly increased compared with both mild-moderate asthma patients and healthy controls. Furthermore, increased frequencies of IgAWith this study we demonstrate for the first time a significant association of increased IgA

Background Exposure to indoor moisture damage and visible mold has been found to be associated with asthma and respiratory symptoms in several questionnaire-based studies by self-report. We aimed to define the prospective association between the early life exposure to residential moisture damage or mold and fractional exhaled nitric oxide (FeNO) and lung function parameters as objective markers for airway inflammation and asthma in 6-year-old children. Methods Home inspections were performed in children's homes when infants were on average 5 months old. At age 6 years, data on FeNO (n = 322) as well as lung function (n = 216) measurements were collected. Logistic regression and generalized additive models were used for statistical analyses. Results Early age major moisture damage and moisture damage or mold in the child's main living areas were significantly associated with increased FeNO levels (>75th percentile) at the age of 6 years (adjusted odds ratios, 95% confidence intervals, aOR (95% CI): 3.10 (1.35-7.07) and 3.16 (1.43-6.98), respectively. Effects were more pronounced in those who did not change residential address throughout the study period. For lung function, major structural damage within the whole home was associated with reduced FEV1 and FVC, but not with FEV1/FVC. No association with lung function was observed with early moisture damage or mold in the child's main living areas. Conclusion These results underline the importance of prevention and remediation efforts of moisture and mold-damaged buildings in order to avoid harmful effects within the vulnerable phase of the infants and children's immunologic development.

BackgroundImprovement of paediatric healthcare is hampered by inefficient processes of generating new evidence. Clinical research often requires extra encounters with patients, is costly, takes place in an artificial situation with a biased selection of patients, and entails long delays until new evidence is implemented into health care. Electronic health records (EHR) contain detailed information on real patients and cover the entirety of patients. However, the use of EHR for research is limited because they are not standardized between hospitals. This leads to disproportionate amounts of work for extracting data of interest and frequently data are incomplete and of poor quality.AimsSwissPedData aims to lay the foundation for a paediatric learning health system in Switzerland by facilitating EHR-based research. In this project, we aimed to assess the way routine clinical data are currently recorded in large paediatric clinics in Switzerland and to develop a national EHR-based common data model (CDM) that covers all processes of routine paediatric care in hospitals.MethodsA taskforce of paediatricians from large Swiss children’s hospitals reviewed the current status of routine data documentation in paediatric clinical care and the extent of digitalization. We then used a modified Delphi method to reach a broad consensus on a national EHR-based CDM.ResultsAll Swiss children’s hospitals use EHR to document some or all aspects of care. 119 paediatricians, representing eight hospitals and all paediatric subspecialties, participated in an extended Delphi process to create SwissPedData. The group agreed on a national CDM that comprises a main module with general paediatric data and sub-modules relevant to paediatric subspecialties. The data dictionary includes 336 common data elements (CDEs): 76 in the main module on general paediatrics and between 11 and 59 CDEs per subspecialty module. Among these, 266 were classified as mandatory, 52 as recommended and 18 as optional.ConclusionSwissPedData is a CDM for information to be collected in EHR of Swiss children’s hospitals. It covers all care processes including clinical and paraclinical assessment, diagnosis, treatment, disposition and care site. All participating hospitals agreed to implement SwissPedData in their clinical routine and clinic information systems. This will pave the way for a national paediatric learning health system in Switzerland that enables fast and efficient answers to urgent clinical questions by facilitating high-quality nationwide retrospective and prospective observational studies and recruitment of patients for nested prospective studies and clinical trials.

Introduction: Remodeling of the airway wall is a hallmark feature of asthma. Under physiological conditions, a finely tuned balance maintains a functional state of the extracellular matrix. This balance is disrupted in asthma. COL4A3 is reduced 18-fold in lung tissue from asthmatics, however, the mechanism leading to the diminished levels of COL4A3 has remained elusive. Methods: The COL4A3 fibrolysis marker C4Ma3 (Nordic Bioscience, Denmark) was measured in the ALLIANCE cohort study participants (Fuchs et al. 2018). Pediatric controls/cases: 34/134; Adult control/cases 31/149. C4Ma3 data was correlated with clinical data, serum cytokine profiles (27-Bioplex, Biorad). Female 6-8 week old Balb/C mice were sensitized (OVA i.p., day 1, 14, 21) and challenged with aerosol (OVA i.n., day 26, 27, 28) to induce acute allergic airway inflammation. Acute exacerbations were provoked by instillation of poly(cytidylic-inosinic, i.n. day 28). Murine precision cut lung slices (PCLS) were used to elucidate the role of sensitisation for COL4A3 degradation. Results: Increased C4Ma3 correlated with asthma exacerbation (pl0.01) and elevated levels of Th2/Th9 cytokines in the ALLIANCE cohort. Serum levels of C4Ma3 were elevated in OVA challenged mice (pl0.0001) and correlated with lung tissue levels of mast cell chymase (pl0.01), but not with neutrophils or matrix-metallo-proteinase 9. C4MA3 was elevated in PCLS of allergic, HDM challenged mice (pl0.05) with no further increase after PolyIC. Conclusion: COL4A3 degradation (circulating C4Ma3), is elevated in severe, exacerbating type 2 asthmatics. C4Ma3 levels correlate with chymase positive mast cells in a mouse model of asthma exacerbation. These data highlight that the degradation of COL4A3 is a central part of the pathology of asthma.

Background Globally, the number of children born by cesarean delivery is constantly increasing. However, hormonal and physiological changes associated with labor and vaginal delivery are considered necessary for lung maturation. Objective We aimed to assess whether the mode of delivery is associated with changes in respiratory and atopic outcomes during infancy and at school age. Study Design We included 578 children, born at ≥37 weeks of gestation, from a prospective birth cohort study. We compared weekly respiratory symptoms throughout the first year of life and infant lung function (tidal breathing and multiple-breath washout) at 5 weeks of age between children born by cesarean delivery (N=114) and those born by vaginal delivery (N=464) after term pregnancy in healthy women. At a follow-up visit conducted at 6 years of age (N=371, of which 65 were delivered by cesarean delivery), we assessed respiratory, atopic, and lung function outcomes (spirometry, body plethysmography, and multiple-breath washout). We performed adjusted regression analyses to examine the association between cesarean delivery and respiratory and atopic outcomes. To account for multiple testing, we used the Bonferroni correction, which led to an adapted significance level of P Results During infancy, children born by cesarean delivery did not have more respiratory symptoms than those born by vaginal delivery (median, 4 weeks; interquartile range, 7 weeks vs median, 5 weeks; interquartile range, 7 weeks; adjusted incidence rate ratio, 0.8; 95% confidence interval, 0.6–1.0; P=.02). Infant lung function was similar between the groups. Children born by cesarean delivery did not have a higher incidence of “ever wheezing” (adjusted odds ratio, 0.9; 95% confidence interval, 0.5–1.8; P=.78) or current asthma (adjusted odds ratio, 0.4; 95% confidence interval, 0.0–3.5; P=.42) at school age than those born by vaginal delivery. There was no difference in the lung function parameters between the groups. Conclusion Cesarean delivery was not associated with respiratory symptoms in the first year of life, nor with different respiratory or atopic outcomes at school age, when compared with vaginal delivery. Our results indicate that there are no long-term consequences on the respiratory health of the child associated with cesarean delivery.

“Breathomics” in asthma is a rapidly growing area of significant scientific interest, as indicated by a recently published review, two research articles, and their accompanying editorials in high impact pneumology journals [1–5]. The repeatedly observed associations between breath volatile organic compounds (VOCs) and sputum or blood inflammatory cells [2, 3] suggest that breathomics are on the brink of introduction as a valuable clinically tool. However, there are also major concerns about unresolved methodological issues and a general paucity of high-quality data [1, 6]. In this letter we detail our concerns with breathomics based on data from a cohort of adult asthma patients with a broad spectrum of clinical phenotypes., Despite recent publications, we are not close to finding a clinically valuable breath VOC biomarker for asthma or asthma phenotypes https://bit.ly/3heTgtK

RationaleAsthma in pregnancy is associated with respiratory diseases in the offspring.ObjectiveTo investigate if maternal asthma is associated with lung function in early life.MethodsData on lung function measured at 5–6 weeks of age were combined from two large birth cohorts: the Bern Infant Lung Development (BILD) and the Australian Breathing for Life Trial (BLT) birth cohorts conducted at three study sites (Bern, Switzerland; Newcastle and Sydney, Australia). The main outcome variable was time to reach peak tidal expiratory flow as a percentage of total expiratory time(tPTEF:tE%). Bayesian linear hierarchical regression analyses controlling for study site as random effect were performed to estimate the effect of maternal asthma on the main outcome, adjusting for sex, birth order, breast feeding, weight gain and gestational age. In separate adjusted Bayesian models an interaction between maternal asthma and sex was investigated by including an interaction term.Measurements and main resultsAll 406 BLT infants were born to mothers with asthma in pregnancy, while 193 of the 213 (91%) BILD infants were born to mothers without asthma. A significant interaction between maternal asthma and male sex was negatively associated with tPTEF:tE% (intercept 37.5; estimate: –3.5; 95% credible interval –6.8 to –0.1). Comparing the model posterior probabilities provided decisive evidence in favour of an interaction between maternal asthma and male sex (Bayes factor 33.5).ConclusionsMaternal asthma is associated with lower lung function in male babies, which may have lifelong implications on their lung function trajectories and future risk of wheezing and asthma.

BACKGROUND Current in vitro allergen-specific IgE (sIgE) detection assays measure IgE against allergen extracts or molecules in a single- or multiplex approach. Direct comparisons of the performance of such assays among young children with common presentations of allergic diseases regardless of sensitization status are largely missing. OBJECTIVES The aim of this study was a comparison of the analytical and diagnostic performance for common clinical questions of three commonly used technologies which rely upon different laboratory methodologies among children of the All Age Asthma (ALLIANCE) cohort (clinicaltrials.gov: NCT02496468). METHODS Sera from 106 paediatric study participants (mean age 4 years) were assessed for the presence of sIgE by means of the ImmunoCAP™ sx1 and fx5 mixes, the ImmunoCAP ISAC™ 112 microarray and a Euroline™ panel. RESULTS Total and negative concordance was high (>82%->89%), while positive concordance varied considerably (0%-100%) but was also >50% for the most common sensitizations analysed (house dust mite and birch). All three test systems showed good sensitivity and specificity (AUC consistently > 0.7). However, no significant differences with regard to identifying sIgE sensitizations associated with symptoms in children with suspected pollen- or dust-triggered wheeze or presenting with symptoms of allergic rhinoconjunctivitis or food allergy were detected. Extending the number of allergens did not change the similar performance of the three assay systems. CONCLUSION AND CLINICAL RELEVANCE Among young children, the three sIgE assays showed good analytical and diagnostic concordance. Our results caution that the identification of larger numbers of sensitizations by more comprehensive multiplex approaches may not improve the clinical utility of sIgE testing in this age group.

BackgroundAsthma is a heterogeneous syndrome substantiating the urgent requirement for endotype-specific biomarkers. Dysbalance of fibrosis and fibrolysis in asthmatic lung tissue leads to reduced levels of the inflammation-protective collagen 4 (COL4A3).ObjectiveTo delineate the degradation of COL4A3 in allergic airway inflammation and evaluate the resultant product as a biomarker for anti-IgE therapy response.MethodsThe serological COL4A3 degradation marker C4Ma3 (Nordic Bioscience, Denmark) and serum cytokines were measured in the ALLIANCE cohort (paediatric cases/controls: n=134/n=35; adult cases/controls: n=149/n=31). Exacerbation of allergic airway disease in mice was induced by sensitising to ovalbumin (OVA), challenge with OVA aerosol and instillation of poly(cytidylic-inosinic). Fulacimstat (chymase inhibitor; Bayer) was used to determine the role of mast cell chymase in COL4A3 degradation. Patients with cystic fibrosis (n=14) and cystic fibrosis with allergic bronchopulmonary aspergillosis (ABPA; n=9) as well as patients with severe allergic uncontrolled asthma (n=19) were tested for COL4A3 degradation. Omalizumab (anti-IgE) treatment was assessed using the Asthma Control Test.ResultsSerum levels of C4Ma3 were increased in asthma in adults and children alike and linked to a more severe, exacerbating allergic asthma phenotype. In an experimental asthma mouse model, C4Ma3 was dependent on mast cell chymase. Serum C4Ma3 was significantly elevated in cystic fibrosis plus ABPA and at baseline predicted the success of the anti-IgE therapy in allergic, uncontrolled asthmatics (diagnostic OR 31.5).ConclusionC4Ma3 levels depend on lung mast cell chymase and are increased in a severe, exacerbating allergic asthma phenotype. C4Ma3 may serve as a novel biomarker to predict anti-IgE therapy response.

BackgroundIn recent years, YouTube has become a recognized source of medical information for health care consumers. Although YouTube has advantages in this context, there are potential dangers as videos may contain nonscientific, misleading, or even harmful information.ObjectiveAs little is known about YouTube as a source of information on atopic dermatitis (AD), we investigated the content-related quality of AD videos and their perception among YouTube users.MethodsThe quality of the 100 most viewed AD videos was assessed by using the Global Quality Scale (GQS) and the DISCERN instrument. Videos were classified as “useful,” “misleading,” and “potentially harmful,” and the correlations of viewers’ ratings (likes) with the GQS and DISCERN scores were assessed.ResultsAmong the 100 videos, 68.0% (68/100) and 62.0% (62/100) were of poor and very poor scientific quality, respectively. Additionally, 32.0% (32/100) of the videos were classified as useful, 48.0% (48/100) were classified as misleading, and 34.0% (34/100) were classified as potentially harmful. Viewers’ ratings did not correlate with the GQS and DISCERN scores. Overall, 50.0% (50/100) of the videos were posted by private individuals and promoters of complementary/alternative treatments, 42.0% (42/100) by therapeutical advertisers, and only 8.0% (8/100) by nonprofit organizations/universities.ConclusionsOur study demonstrated that two-thirds of the videos analyzed were below acceptable medical quality standards and that many videos were disseminating misleading or even dangerous content. Subjective and anecdotal content was overrepresented, and viewers did not appear to be able to distinguish between high- and low-quality videos. Health promotion strategies by professional medical organizations are needed to improve their presence and visibility on YouTube.

Background: Exhaled nitric oxide (eNO) is a biomarker of airway inflammation and seems to precede respiratory symptoms, such as asthma, in childhood. Identifying genetic determinants of postnatal eNO levels might aid in unraveling the role of eNO in epithelial function or airway inflammation and disease. Objective: We sought to identify genetic determinants of early postnatal eNO levels and subsequent respiratory symptoms during the first year of life. Methods: Within a population-based birth cohort, eNO levels were measured in healthy term infants aged 5 weeks during quiet tidal breathing in unsedated sleep. We assessed associations of single nucleotide polymorphisms with eNO levels in a genome-wide association study and subsequent symptoms of lower respiratory tract infections during the first year of life and asked whether this was modified by prenatal and early-life environmental factors. Results: We identified thus far unknown determinants of infant eNO levels: rs208515 (P = 3.3 x 10(-8)), which is located at 6q12, probably acting in "trans'' and explaining 10.3% of eNO level variance, and rs1441519 (P = 1.6 x 10(-6)), which is located at 11p14, potentially affecting nitric oxide synthase 3 (NOS3) expression, as shown by means of in vitro functional analyses. Moreover, the 6q12 locus was inversely associated with subsequent respiratory symptoms (P < .05) and time to recovery after first respiratory symptoms during the first year of life (P < .05). Conclusion: The identification of novel genetic determinants of infant eNO levels might implicate that postnatal eNO metabolism in healthy infants before first viral infections and sensitization is related to mechanisms other than those associated with asthma, atopy, or increased risk thereof later in life.

Background Asthma and wheezing disorders in childhood and adulthood are clinically heterogeneous regarding disease presentation, natural course, and response to treatment. Deciphering common disease mechanisms in distinct subgroups requires harmonized molecular (endo-) phenotyping of both children and adult patients with asthma in a prospective, longitudinal setting. Methods The ALL Age Asthma Cohort (ALLIANCE) of the German Center for Lung Research (DZL) is a prospective, multi-center, observational cohort study with seven recruiting sites across Germany. Data are derived from four sources: (a) patient history from medical records, (b) standardized questionnaires and structured interviews, (c) telephone interviews, and (d) objective measurements. Objective measurements include amongst others lung function and quantitative assessment of airway inflammation and exhaled breath, peripheral blood, skin, nasal, pharyngeal, and nasopharyngeal swabs, nasal secretions, primary nasal epithelial cells, and induced sputum. In cases, objective measurements and biomaterial collection are performed regularly, while control subjects are only examined once at baseline. Discussion The standardized and detailed collection of epidemiological and physiological data, and the molecular deep phenotyping of a comprehensive range of biomaterials in a considerable number of study participants across all ages are the outstanding characteristics of this multi-center cohort. Despite extensive biomaterial sampling, and a recruitment strategy that also includes pre-school children as young as 6 months, attrition is low. In children 83.9%, and in adults 90.5% attended the 12-month follow-up. The earliest time-point to include cases, however, is disease manifestation. Therefore, unraveling mechanisms that drive disease onset is limited, as this question can only be answered in a population-based birth cohort. Nonetheless, ALLIANCE offers a unique, integrative and inter-disciplinary framework with a comprehensive molecular approach in a prospective and identical fashion across ages in order to identify biomarkers and predictors for distinct childhood wheeze and asthma trajectories as well as their further course during adulthood. Ultimately, this approach aims to translate its most significant findings into clinical practice, and to improve asthma transition from adolescence to adulthood. Trial registration NCT02496468 for pediatric arm, NCT02419274 for adult arm.

Gene expression data are accumulating exponentially in public repositories. Reanalysis and integration of themed collections from these studies may provide new insights, but requires further human curation. Here we report a crowdsourcing project to annotate and reanalyse a large number of gene expression profiles from Gene Expression Omnibus (GEO). Through a massive open online course on Coursera, over 70 participants from over 25 countries identify and annotate 2,460 single-gene perturbation signatures, 839 disease versus normal signatures, and 906 drug perturbation signatures. All these signatures are unique and are manually validated for quality. Global analysis of these signatures confirms known associations and identifies novel associations between genes, diseases and drugs. The manually curated signatures are used as a training set to develop classifiers for extracting similar signatures from the entire GEO repository. We develop a web portal to serve these signatures for query, download and visualization., A wealth of gene expression data is publicly available, yet is little use without additional human curation. Ma'ayan and colleagues report a crowdsourcing project involving over 70 participants to annotate and analyse thousands of human disease-related gene expression datasets.

F eNO in newborns before exposure to environmental factors is not associated with school-age asthma development http://ow.ly/ShQQ300xiN2

RationaleAsthma is characterised by inflammation and reversible airway obstruction. However, these features are not always closely related. Fluctuations of daily lung function contain information on asthma phenotypes, exacerbation risk and response to long-acting β-agonists.ObjectivesIn search of subgroups of asthmatic participants with specific lung functional features, we developed and validated a novel clustering approach to asthma phenotyping, which exploits the information contained within the fluctuating behaviour of twice-daily lung function measurements.MethodsForced expiratory volume during the first second (FEV1) and peak expiratory flow (PEF) were prospectively measured over 4 weeks in 696 healthy and asthmatic school children (Protection Against Allergy – Study in Rural Environments (PASTURE)/EFRAIM cohort), and over 1 year in 138 asthmatic adults with mild-to-moderate or severe asthma (Pan-European Longitudinal Assessment of Clinical Course and BIOmarkers in Severe Chronic AIRway Disease (BIOAIR) cohort). Using enrichment analysis, we explored whether the method identifies clinically meaningful, distinct clusters of participants with different lung functional fluctuation patterns.Measurements and main resultsIn the PASTURE/EFRAIM dataset, we found four distinct clusters. Two clusters were enriched in children with well-known clinical characteristics of asthma. In cluster 3, children from a farming environment predominated, whereas cluster 4 mainly consisted of healthy controls. About 79% of cluster 3 carried the asthma-risk allele rs7216389 of the17q21locus. In the BIOAIR dataset, we found two distinct clusters clearly discriminating between individuals with mild-to-moderate and severe asthma.ConclusionsOur method identified dynamic functional asthma and healthy phenotypes, partly independent of atopy and inflammation but related to genetic markers on the17q21locus. The method can be used for disease phenotyping and possibly endotyping. It may identify participants with specific functional abnormalities, potentially needing a different therapeutic approach.

© 2017 Author(s). An endstation with two high-efficiency soft x-ray spectrographs was developed at Beamline 8.0.1 of the Advanced Light Source, Lawrence Berkeley National Laboratory. The endstation is capable of performing soft x-ray absorption spectroscopy, emission spectroscopy, and, in particular, resonant inelastic soft x-ray scattering (RIXS). Two slit-less variable line-spacing grating spectrographs are installed at different detection geometries. The endstation covers the photon energy range from 80 to 1500 eV. For studying transition-metal oxides, the large detection energy window allows a simultaneous collection of x-ray emission spectra with energies ranging from the O K-edge to the Ni L-edge without moving any mechanical components. The record-high efficiency enables the recording of comprehensive two-dimensional RIXS maps with good statistics within a short acquisition time. By virtue of the large energy window and high throughput of the spectrographs, partial fluorescence yield and inverse partial fluorescence yield signals could be obtained for all transition metal L-edges including Mn. Moreover, the different geometries of these two spectrographs (parallel and perpendicular to the horizontal polarization of the beamline) provide contrasts in RIXS features with two different momentum transfers.

The term “precision medicine” has become very popular over recent years, fuelled by scientific as well as political perspectives. Despite its popularity, its exact meaning, and how it is different from other popular terms such as “stratified medicine”, “targeted therapy” or “deep phenotyping” remains unclear. Commonly applied definitions focus on the stratification of patients, sometimes referred to as a novel taxonomy, and this is derived using large-scale data including clinical, lifestyle, genetic and further biomarker information, thus going beyond the classical “signs-and-symptoms” approach.While these aspects are relevant, this description leaves open a number of questions. For example, when does precision medicine begin? In which way does the stratification of patients translate into better healthcare? And can precision medicine be viewed as the end-point of a novel stratification of patients, as implied, or is it rather a greater whole?To clarify this, the aim of this paper is to provide a more comprehensive definition that focuses on precision medicine as a process. It will be shown that this proposed framework incorporates the derivation of novel taxonomies and their role in healthcare as part of the cycle, but also covers related terms.

BACKGROUND: The fraction of exhaled nitric oxide (Feno) value is a biomarker of eosinophilic airway inflammation and is associated with childhood asthma. Identification of common genetic variants associated with childhood Feno values might help to define biological mechanisms related to specific asthma phenotypes. OBJECTIVE: We sought to identify the genetic variants associated with childhood Feno values and their relation with asthma. METHODS: Feno values were measured in children age 5 to 15 years. In 14 genome-wide association studies (N = 8,858), we examined the associations of approximately 2.5 million single nucleotide polymorphisms (SNPs) with Feno values. Subsequently, we assessed whether significant SNPs were expression quantitative trait loci in genome-wide expression data sets of lymphoblastoid cell lines (n = 1,830) and were related to asthma in a previously published genome-wide association data set (cases, n = 10,365; control subjects: n = 16,110). RESULTS: We identified 3 SNPs associated with Feno values: rs3751972 in LYR motif containing 9 (LYRM9; P = 1.97 × 10(-10)) and rs944722 in inducible nitric oxide synthase 2 (NOS2; P = 1.28 × 10(-9)), both of which are located at 17q11.2-q12, and rs8069176 near gasdermin B (GSDMB; P = 1.88 × 10(-8)) at 17q12-q21. We found a cis expression quantitative trait locus for the transcript soluble galactoside-binding lectin 9 (LGALS9) that is in linkage disequilibrium with rs944722. rs8069176 was associated with GSDMB and ORM1-like 3 (ORMDL3) expression. rs8069176 at 17q12-q21, but not rs3751972 and rs944722 at 17q11.2-q12, were associated with physician-diagnosed asthma. CONCLUSION: This study identified 3 variants associated with Feno values, explaining 0.95% of the variance. Identification of functional SNPs and haplotypes in these regions might provide novel insight into the regulation of Feno values. This study highlights that both shared and distinct genetic factors affect Feno values and childhood asthma. C.O. is supported by a NIH grant that supported the Hutterite studies (R01 HL085197). D.E. is supported by UK Medical Research Council Centre (G0600705). G.S. is supported by UK Medical Research Council Centre (G0600705). J.K. is funded by a Wellcome Trust 4-year PhD studentship in molecular, genetic, and life course epidemiology (WT083431MA). L.D. is supported by a European Respiratory Society/Marie Curie Joint Research Fellowship of the European Respiratory Society and the European Community’s Seventh Framework Programme FP7/2007-2013–Marie Curie Actions under grant agreement RESPIRE, PCOFUND-GA-2008-229571 (no. MC 1226- 2009). N.T. is supported by UK Medical Research Council Centre (G0600705). R.V. was partly supported by an unrestricted personal grant from GlaxoSmithKline, NL. V.J. is supported by the Netherlands Organization for Health Research and Development (ZonMw 90700303, 916.10159). L. Duijts is supported by a European Respiratory Society/Marie Curie Joint Research Fellowship of the European Respiratory Society and the European Community’s Seventh Framework Programme (FP7/2007-2013-Marie Curie Actions under grant agreement RESPIRE, PCOFUND-GA-2008-229571 [no. MC 1226-2009]). M. T. Salam has received research support from the National Heart, Lung, and Blood Institute (NHLBI; 5R01HL61768 and 5R01HL76647); the Southern California Environmental Health Sciences Center funded by the National Institute of Environmental Health Sciences (5P30ES007048); and the Environmental Protection Agency (EPA; 5P01ES009581, R826708-01, and RD831861-01), the National Institute of Environmental Health Sciences (5P01ES011627), and the Hastings Foundation. J. Genuneit has received grant EuFP6 (018996 under IP LSH-2004-1.25- 1). Evans has received a grant in the form of the MRC New Investigator Award G0600705. B. St Pourcain has received research support with Autism Speaks (7132). O. Fuchs has received research support from the European Commission within Seventh Framework Programme (theme FP7-KBBE-2007- 1) as part of EFRAIM (Impact of exogenous factors in the development of Allergy, contract no. 211911), the European Respiratory Society for a long-term research fellowship (no. 675). F. D. Gilliand has received research support from the NHLBI (5R01HL61768 and 5R01HL76647), Southern California Environmental Health Sciences Center funded by the National Institute of Environmental Health Sciences (5P30ES007048), the Children’s Environmental Health Center funded by the National Institute of Environmental Health Sciences and the Environmental Protection Agency (5P01Es009581, R826708-01, and RD831861-01), the National Institute of Environmental Health Sciences (5P01ES011627)

Summary Bacterial and viral infections occur early and recurrently in life and thereby impose a substantial disease burden. Besides causing clinical symptoms, a potential role of infection in the development of the asthma syndrome later in life has also been suggested. However, whether bacterial and viral infections unmask host factors in children at risk of asthma or whether they directly cause asthma remains unclear; both viewpoints could be justified, but the underlying mechanisms are complex and poorly understood. Recently, the role of the bacterial microbiome has been emphasised. But data are still sparse and future studies are needed for definitive conclusions to be made. In this Review, we discuss present knowledge of viruses and bacteria that infect and colonise the respiratory tract and mucosal surfaces, including their timepoint of action, host factors related to infection, and their effect on childhood asthma. Childhood asthma could be the result of a combination of altered host susceptibility and infectious agents.

Resonant inelastic soft X-ray scattering (RIXS) has been used to study the electronic structure of glycine and lysine in aqueous solution. Upon variation of the pH value of the solution from acidic to basic, major changes of the nitrogen K edge RIXS data are observed for both amino acids, which are associated with the protonation and deprotonation of the amino groups. The experimental results are compared with simulations based on density functional theory, yielding a detailed understanding of the spectral changes, as well as insights into the ultrafast proton dynamics in the intermediate core-excited/ionized state of the RIXS process.

Background: Phenotypes of childhood-onset asthma are characterized by distinct trajectories and functional features. For atopy, definition of phenotypes during childhood is less clear. Objective: We sought to define phenotypes of atopic sensitization over the first 6 years of life using a latent class analysis (LCA) integrating 3 dimensions of atopy: allergen specificity, time course, and levels of specific IgE (sIgE). Methods: Phenotypes were defined by means of LCA in 680 children of the Multizentrische Allergiestudie (MAS) and 766 children of the Protection against allergy: Study in Rural Environments (PASTURE) birth cohorts and compared with classical nondisjunctive definitions of seasonal, perennial, and food sensitization with respect to atopic diseases and lung function. Cytokine levels were measured in the PASTURE cohort. Results: The LCA classified predominantly by type and multiplicity of sensitization (food vs inhalant), allergen combinations, and sIgE levels. Latent classes were related to atopic disease manifestations with higher sensitivity and specificity than the classical definitions. LCA detected consistently in both cohorts a distinct group of children with severe atopy characterized by high seasonal sIgE levels and a strong propensity for asthma; hay fever; eczema; and impaired lung function, also in children without an established asthma diagnosis. Severe atopy was associated with an increased IL-5/IFN-gamma ratio. A path analysis among sensitized children revealed that among all features of severe atopy, only excessive sIgE production early in life affected asthma risk. Conclusions: LCA revealed a set of benign, symptomatic, and severe atopy phenotypes. The severe phenotype emerged as a latent condition with signs of a dysbalanced immune response. It determined high asthma risk through excessive sIgE production and directly affected impaired lung function.

BACKGROUND: Although lung clearance index (LCI) is a sensitive indicator of mild cystic fibrosis (CF) lung disease, it is rarely measured due to lengthy protocols and the commercial unavailability of multiple-breath washout (MBW) setups and tracer gases. We used a newly validated, commercially available nitrogen (N(2) ) MBW setup to assess success rate, duration, and variability of LCI within a 20 min timeframe, during clinical routine. We also evaluated the relationship between LCI and other clinical markers of CF lung disease. METHODS: One hundred thirty six children (83 with CF) between 4 and 16 years were studied in a pediatric CF outpatient setting. One hundred eighteen out of 136 children were naive to MBW. Within 20 min, each child was trained, N(2) MBW was performed, and LCI was analyzed. We assessed intra- and between-test reproducibility in a subgroup of children. RESULTS: At least one LCI was feasible in 123 (90%) children, with a mean (range) of 3.3 (1.2-6.4) min per test. Two or more measurements were feasible in 56 (41%) children. Comparing LCI in CF versus controls, LCI mean (SD) was 12.0 (3.9) versus 6.1 (0.9), and the intra- and inter-test coefficient of repeatability was 1.00 versus 0.81 and 0.96 versus 0.62, respectively. LCI was correlated with spirometry, blood gases, and Pseudomonas aeruginosa infection. CONCLUSIONS: Using available N(2) MBW equipment, LCI measurements are practical and fast in children. LCI is correlated with markers of CF lung disease. Longer timeframes would be required for triplicate N(2) MBW tests in inexperienced children. Pediatr Pulmonol. © 2012 Wiley Periodicals, Inc.

Introduction: Standards for online multiple breath (mb) exhaled nitric oxie (eNO) measurements and studies comparing them with online single breath (sb) eNO measurements are lacking although eNOmb requires less cooperation in children at school age or younger. Methods: Online eNOmb and eNOsb were measured in 99 healthy children and (in order to observe higher values) in 21 children with suspected asthma at a median age of 6.1 and 11.7 y respectively. For eNOmb we aimed for 20 tidal breathing maneuvers; eNOsb was measured according to standards. The two techniques were compared by standard methods after computing NO output or extrapolating eNOmb to the standard flow of 50ml/s (eNOmb 50). Results: Measurements were acceptable in 82 (eNOmb) and 81 (eNOsb) children. Paired data were available for 65 children. On a log log scale eNOmb 50 (geometric mean SD ± 13.1 ± 15.5 parts per billion ppb) was correlated with eNOsb (12.5 ± 15.8 ppb) with r 2 = 0.87. The mean difference between eNOsb and eNOmb 50 was 0.7 ppb with limits of agreement (LOAs) of 4.0 and 5.3 ppb. Discussion: Despite its correlation with eNOsb the LOA range hampers eNOmb use in research where exact values across the whole range are warranted. However eNOmb might be an alternative tool especially at preschool age when cooperation during measurements is crucial. © 2012 International Pediatric Research Foundation Inc.

Studies in cystic fibrosis (CF) generally focus on inflammation present in the airway lumen. Little is known about inflammation occurring in the airway wall, the site ultimately destroyed in end-stage disease.To test the hypothesis that inflammatory patterns in the lumen do not reflect those in the airway wall of children with CF.Bronchoalveolar lavage (BAL) fluid and endobronchial biopsies were obtained from 46 children with CF and 16 disease-free controls. BAL cell differential was assessed using May-Gruenwald-stained cytospins. Area profile counts of bronchial tissue immunopositive inflammatory cells were determined.BAL fluid from children with CF had a predominance of neutrophils compared with controls (median 810×10(3)/ml vs 1×10(3)/ml, p0.0001). In contrast, subepithelial bronchial tissue from children with CF was characterised by a predominance of lymphocytes (median 961 vs 717 cells/mm(2), p=0.014), of which 82% were (CD3) T lymphocytes. In chest exacerbations, BAL fluid from children with CF had more inflammatory cells of all types compared with those with stable disease whereas, in biopsies, only the numbers of lymphocytes and macrophages, but not of neutrophils, were higher. A positive culture of Pseudomonas aeruginosa was associated with higher numbers of T lymphocytes in subepithelial bronchial tissue (median 1174 vs 714 cells/mm(2), p=0.029), but no changes were seen in BAL fluid. Cell counts in BAL fluid and biopsies were positively correlated with age but were unrelated to each other.The inflammatory response in the CF airway is compartmentalised. In contrast to the neutrophil-dominated inflammation present in the airway lumen, the bronchial mucosa is characterised by the recruitment and accumulation of lymphocytes.

Techniques to study the electronic structure of liquids are rare. Most recently, resonant X-ray emission spectroscopy (XES) has been shown to be an extremely versatile spectroscopy to study both occupied and unoccupied electronic states for liquids in thermodynamic equilibrium. However, XES requires high-brilliance soft X-ray synchrotron radiation and poses significant technical challenges to maintain a liquid sample in an ultra-high vacuum environment. Our group has therefore developed and constructed a novel experimental setup for the study of liquids, with the long-term goal of investigating the electronic structure of biological systems in aqueous environments. We have developed a flow-through liquid cell in which the liquid is separated from vacuum by a thin Si 3 N 4 or SiC window and which allows a precise control of temperature. This approach has significant advantages compared to static liquids cells used in the past. Furthermore, we have designed a dedicated high-transmission, high-resolution soft X-ray spectrometer. The high transmission makes it possible to measure complete resonant XES “maps” in less than an hour, giving unprecedented detailed insight into the electronic structure of the investigated sample. Using this new equipment we have investigated the electronic structure of liquid water. Furthermore, our XES spectra and maps give information about ultra-fast dissociation on the timescale of the O 1s core hole lifetime, which is strongly affected by the initial state hydrogen bonding configuration.

High and low volume sampling of paticulate matter at sites with different traffic profiles in the Netherlands and Germany: Results from the HEPMEAP study