A new platform for high-throughput therapy testing on iPSC-derived lung progenitor cells from cystic fibrosis patients

For those people with cystic fibrosis carrying rare CFTR mutations not responding to currently available therapies, there is an unmet need for relevant tissue models for therapy development. Here, we describe a new testing platform that employs patient-specific induced pluripotent stem cells (iPSCs) differentiated to lung progenitor cells that can be studied using a dynamic, high-throughput fluorescence-based assay of CFTR channel activity. Our proof-of-concept studies support the potential use of this platform, together with a Canadian bioresource that contains iPSC lines and matched nasal cultures from people with rare mutations, to advance patient-oriented therapy development. Interventions identified in the high-throughput, stem cell-based model and validated in primary nasal cultures from the same person have the potential to be advanced as therapies

Pediatric home mechanical ventilation: A Canadian Thoracic Society clinical practice guideline executive summary

Over the last 30 to 40 years, improvements in technology, as well as changing clinical practice regarding the appropriateness of long-term ventilation in patients with “non-curable” disorders, have resulted in increasing numbers of children surviving what were previously considered fatal conditions. This has come but at the expense of requiring ongoing, long-term prolonged mechanical ventilation (both invasive and noninvasive). Although there are many publications pertaining to specific aspects of home mechanical ventilation (HMV) in children, there are few comprehensive guidelines that bring together all of the current literature. In 2011 the Canadian Thoracic Society HMV Guideline Committee published a review of the available English literature on topics related to HMV in adults, and completed a detailed guideline that will help standardize and improve the assessment and management of individuals requiring noninvasive or invasive HMV. This current document is intended to be a companion to the 2011 guidelines, concentrating on the issues that are either unique to children on HMV (individuals under 18 years of age), or where common pediatric practice diverges significantly from that employed in adults on long-term home ventilation. As with the adult guidelines,1 this document provides a disease-specific review of illnesses associated with the necessity for long-term ventilation in children, including children with chronic lung disease, spinal muscle atrophy, muscular dystrophies, kyphoscoliosis, obesity hypoventilation syndrome, and central hypoventilation syndromes. It also covers important common themes such as airway clearance, the ethics of initiation of long-term ventilation in individuals unable to give consent, the process of transition to home and to adult centers, and the impact, both financial, as well as social, that this may have on the child\u27s families and caregivers. The guidelines have been extensively reviewed by international experts, allied health professionals and target audiences. They will be updated on a regular basis to incorporate any new information

Ethnic differences in maternal diet in pregnancy and infant eczema

Background The global prevalence of childhood eczema has increased over the last few decades, with a marked increase in high-income countries. Differences in prevalence of childhood eczema between countries and ethnicities suggest that genetic and early modifiable environmental factors, such as dietary intake, may underlie this observation. To investigate the association between pregnancy diet and infant eczema in a consortium of prospective Canadian birth cohorts predominantly comprised of white Europeans and South Asians. Methods We evaluated the association of maternal dietary patterns reported during pregnancy (assessed at 24–28 weeks gestation using a semi-quantitiative food-frequency questionnaire) with parent-reported physician-diagnosed infant eczema at 1-year from 2,160 mother-infant pairs. Using three dietary patterns (“Western”, “plant-based”, and “Balanced”) previously derived in this cohort using principal component analysis, we used multivariable logistic regression to determine the association of these dietary patterns with infant eczema, adjusted for potential confounders. Results We observed a lower odds of eczema in the full sample combining white Europeans and South Asians with greater adherence to a plant-based (OR = 0.65; 95% CI: 0.55, 0.76; <0.001) and Western dietary pattern (OR = 0.73; 95% CI: 0.60, 0.89; P<0.01), after adjusting for other known predictors of eczema, including ethnicity, which was not significant. No associations were observed for the balanced diet. An interaction between the Western diet and ethnicity was observed (P<0.001). Following stratification by ethnicity, a protective association between the plant-based diet and infant eczema was confirmed in both white Europeans (OR = 0.59; 95% CI: 0.47, 0.74; P<0.001) and South Asians (OR = 0.77; 95% CI: 0.61, 0.97; P = 0.025). In white Europeans only, a Western diet was associated with a lower odds of infant eczema (OR = 0.69; 95% CI: 0.56, 0.87; P = 0.001) while a balanced diet increased the odds of infant eczema (OR = 1.23; 95% CI: 1.02, 1.49; P = 0.03). Beyond a plant-based diet, no significant associations with other dietary patterns were observed in South Asians. Conclusion A plant-based diet during pregnancy is associated with a lowered odds of infant eczema at 1 year in all participants. Future studies of the components of plant-based diet which underlie the lower risk of eczema are needed

Polygenic risk score for atopic dermatitis in the Canadian population

Atopic dermatitis (AD) is characterized by a damaged skin barrier that allows allergens to penetrate the body, leading to sensitization and a higher risk of developing food allergies (relative risk [RR], 33.79), asthma (RR, 7.04), and/or rhinitis (RR, 11.75), all features of the atopic march.1 Recent evidence has shown that the atopic march can be modified in high-risk infants with early interventions directed at reestablishing and/or maintaining skin barrier function with intense use of simple emollients, and introducing food allergens early into the diet.2, 3, 4, 5 Although these constitute examples of low-intensity, high-impact interventions for health care systems, their successful and indiscriminate implementation in the whole population is neither feasible nor realistic. In this context, building a predictive tool to identify children at high risk of developing moderate to severe AD (MSAD) would allow targeted interventions with maximized impact. In this study, a polygenic risk score (PRS) with an area under the curve (AUC) of 88% and explaining 37% of MSAD variance was established for the Canadian population

The human milk proteome and allergy of mother and child: Exploring associations with protein abundances and protein network connectivity

BackgroundThe human milk proteome comprises a vast number of proteins with immunomodulatory functions, but it is not clear how this relates to allergy of the mother or allergy development in the breastfed infant. This study aimed to explore the relation between the human milk proteome and allergy of both mother and child.MethodsProteins were analyzed in milk samples from a subset of 300 mother-child dyads from the Canadian CHILD Cohort Study, selected based on maternal and child allergy phenotypes. For this selection, the definition of “allergy” included food allergy, eczema, allergic rhinitis, and asthma. Proteins were analyzed with non-targeted shotgun proteomics using filter-aided sample preparation (FASP) and nanoLC-Orbitrap-MS/MS. Protein abundances, based on label-free quantification, were compared using multiple statistical approaches, including univariate, multivariate, and network analyses.ResultsUsing univariate analysis, we observed a trend that milk for infants who develop an allergy by 3 years of age contains higher abundances of immunoglobulin chains, irrespective of the allergy status of the mother. This observation suggests a difference in the milk’s immunological potential, which might be related to the development of the infant’s immune system. Furthermore, network analysis showed overall increased connectivity of proteins in the milk of allergic mothers and milk for infants who ultimately develop an allergy. This difference in connectivity was especially noted for proteins involved in the protein translation machinery and may be due to the physiological status of the mother, which is reflected in the interconnectedness of proteins in her milk. In addition, it was shown that network analysis complements the other methods for data analysis by revealing complex associations between the milk proteome and mother-child allergy status.ConclusionTogether, these findings give new insights into how the human milk proteome, through differences in the abundance of individual proteins and protein-protein associations, relates to the allergy status of mother and child. In addition, these results inspire new research directions into the complex interplay of the mother-milk-infant triad and allergy

Persistent ventilation inhomogeneity after an acute exacerbation in preschool children with recurrent wheezing

© 2020 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd. Background: Preschool children with recurrent wheezing suffer high morbidity. It is unclear whether objective measures of asthma control, such as pulmonary function tests (PFTs), provide additional information to the clinical assessment. Methods: We recruited children between 3 and 6years old, with a history of recurrent wheezing in the preceding year and treated for acute wheezing exacerbation in the emergency department (ED) into an observational cohort study. Children attended two outpatient visits: the first study visit within five days of discharge from the ED and the second study visit 12weeks after the ED visit. We performed standardized symptom score (test for respiratory and asthma control in kids (TRACK)), multiple breath washout (MBW), spirometry, and clinical assessment at both visits. Results: Seventy-four children, mean (standard deviation (SD)) age of 4.32years (0.84), attended both visits. Paired FEV0.75 and lung clearance index (LCI) measurements at both time points were obtained in 37 and 34 subjects, respectively. Feasibility for all tests improved at visit 2 and was not age-dependent. At the second study visit, a third had controlled asthma based on the TRACK score, and the mean lung clearance index (LCI) improved from 9.86 to 8.31 (P=.003); however, 46% had an LCI in the abnormal range. FEV0.75 z-score improved from −1.66 to −1.17 (P=.05) but remained in the abnormal range in 24%. LCI was abnormal in more than half of the children with “well-controlled” asthma based on the TRACK score. There was no correlation between PFT measures and TRACK scores at either visit. Conclusions: Lung clearance index demonstrates a persistent deficit post-exacerbation in a large proportion of preschoolers with recurrent wheezing, highlighting that symptom scores alone may not suffice for monitoring these children

Integrated Analysis of Human Milk Microbiota With Oligosaccharides and Fatty Acids in the CHILD Cohort

Background: Human milk contains many bioactive components that are typically studied in isolation, including bacteria. We performed an integrated analysis of human milk oligosaccharides and fatty acids to explore their associations with milk microbiota.Methods: We studied a sub-sample of 393 mothers in the CHILD birth cohort. Milk was collected at 3–4 months postpartum. Microbiota was analyzed by 16S rRNA gene V4 sequencing. Oligosaccharides and fatty acids were analyzed by rapid high-throughput high performance and gas liquid chromatography, respectively. Dimension reduction was performed with principal component analysis for oligosaccharides and fatty acids. Center log-ratio transformation was applied to all three components. Associations between components were assessed using Spearman rank correlation, network visualization, multivariable linear regression, redundancy analysis, and structural equation modeling. P-values were adjusted for multiple comparisons. Key covariates were considered, including fucosyltransferase-2 (FUT2) secretor status of mother and infant, method of feeding (direct breastfeeding or pumped breast milk), and maternal fish oil supplement use.Results: Overall, correlations were strongest between milk components of the same type. For example, FUT2-dependent HMOs were positively correlated with each other, and Staphylococcus was negatively correlated with other core taxa. Some associations were also observed between components of different types. Using redundancy analysis and structural equation modeling, the overall milk fatty acid profile was significantly associated with milk microbiota composition. In addition, some individual fatty acids [22:6n3 (docosahexaenoic acid), 22:5n3, 20:5n3, 17:0, 18:0] and oligosaccharides (fucosyl-lacto-N-hexaose, lacto-N-hexaose, lacto-N-fucopentaose I) were associated with microbiota α diversity, while others (C18:0, 3′-sialyllactose, disialyl-lacto-N-tetraose) were associated with overall microbiota composition. Only a few significant associations between individual HMOs and microbiota were observed; notably, among mothers using breast pumps, Bifidobacterium prevalence was associated with lower abundances of disialyl-lacto-N-hexaose. Additionally, among non-secretor mothers, Staphylococcus was positively correlated with sialylated HMOs.Conclusion: Using multiple approaches to integrate and analyse milk microbiota, oligosaccharides, and fatty acids, we observed several associations between different milk components and microbiota, some of which were modified by secretor status and/or breastfeeding practices. Additional research is needed to further validate and mechanistically characterize these associations and determine their relevance to infant gut and respiratory microbiota development and health

Pseudorapidity distributions of charged hadrons in proton-lead collisions at root s(NN)=5:02 and 8.16 TeV

The pseudorapidity distributions of charged hadrons in proton-lead collisions at nucleon-nucleon center-of-mass energies root s(NN) = 5.02 and 8.16 TeV are presented. The measurements are based on data samples collected by the CMS experiment at the LHC. The number of primary charged hadrons produced in non-single-diffractive proton-lead collisions is determined in the pseudorapidity range vertical bar eta(lab)vertical bar vertical bar(vertical bar eta cm vertical bar) <0.5 are 17.1 +/- 0.01 (stat) +/- 0.59 (syst) and 20.10 +/- 0.01 (stat) +/- 0.5(syst) at root s(NN) = 5.02 and 8.16 TeV, respectively. The particle densities per participant nucleon are compared to similar measurements in proton-proton, proton-nucleus, and nucleus-nucleus collisions.Peer reviewe

Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016

As mortality rates decline, life expectancy increases, and populations age, non-fatal outcomes of diseases and injuries are becoming a larger component of the global burden of disease. The Global Burden of Diseases, Injuries, and Risk Factors Study 2016 (GBD 2016) provides a comprehensive assessment of prevalence, incidence, and years lived with disability (YLDs) for 328 causes in 195 countries and territories from 1990 to 2016