Publications by authors named "Stuart E Turvey"

188 Publications

Mechanistic understanding of the combined immunodeficiency in complete human CARD11 deficiency.

J Allergy Clin Immunol 2021 Apr 16. Epub 2021 Apr 16.

Department of Pediatrics, British Columbia Children's Hospital, The University of British Columbia, Vancouver, BC, Canada; Experimental Medicine Program, Faculty of Medicine, The University of British Columbia, Vancouver, BC, Canada. Electronic address:

Background: Germline pathogenic variants impairing the caspase recruitment domain family member 11 (CARD11)-B cell CLL/lymphoma 10 (BCL10)-MALT1 paracaspase (MALT1) [CBM] complex are associated with diverse human diseases including combined immunodeficiency (CID), atopy, and lymphoproliferation. However, the impact of CARD11 deficiency on human B cell development, signalling, and function is incompletely understood.

Objective: We sought to determine the cellular, immunological, and biochemical basis of disease for two unrelated patients who presented with profound CID associated with viral and fungal respiratory infections, interstitial lung disease, and severe colitis.

Methods: Patients underwent next-generation sequencing, immunophenotyping by flow cytometry, signalling assays by immunoblot, and transcriptome profiling by RNA-Seq.

Results: Both patients carried identical novel pathogenic biallelic loss-of-function variants in CARD11 (c.2509C>T; p.Arg837*) leading to undetectable protein expression. This variant prevented CBM complex formation, severely impairing the activation of NF-κB, JNK, and MALT1 paracaspase activity in B and T cells. This functional defect resulted in a developmental block in B cells at the naïve and type 1 (T1) transitional B cell stage and impaired circulating T follicular helper cell (cTfh) development, which was associated with impaired antibody responses and absent germinal centre structures on lymph node histology. Transcriptomics indicated that CARD11-dependent signalling is essential for immune signalling pathways involved in the development of these cells. Both patients underwent hematopoietic stem cell transplantations (HSCT), which led to functional normalization.

Conclusion: Complete human CARD11 deficiency causes profound CID by impairing naïve/T1 B cell and cTfh cell development, and abolishing activation of MALT1 paracaspase, NF-κB, and JNK activity. HSCT functionally restores impaired signalling pathways.
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http://dx.doi.org/10.1016/j.jaci.2021.04.006DOI Listing
April 2021

Influence of Neighborhood Characteristics and Weather on Movement Behaviors at Age 3 and 5 Years in a Longitudinal Birth Cohort.

J Phys Act Health 2021 Apr 8:1-9. Epub 2021 Apr 8.

Background: Movement behaviors (physical activity, sedentary time, and sleep) established in early childhood track into adulthood and interact to influence health outcomes. This study examined the associations between neighborhood characteristics and weather with movement behaviors in preschoolers.

Methods: A subset of Canadian Healthy Infant Longitudinal Development birth cohort (n = 385, 50.6% boys) with valid movement behaviors data were enrolled at age 3 years and followed through to age 5 years. Objective measures of neighborhood characteristics were derived by ArcGIS software, and weather variables were derived from the Government of Canada weather website. Random forest and linear mixed models were used to examine predictors of movement behaviors. Cross-sectional analyses were stratified by age and season (winter and nonwinter).

Results: Neighborhood safety, temperature, green space, and roads were important neighborhood characteristics for movement behaviors in 3- and 5-year-olds. An increase in temperature was associated with greater light physical activity longitudinally from age 3 to 5 years and also in the winter at age 5 years in stratified analysis. A higher percentage of expressways was associated with less nonwinter moderate to vigorous physical activity at age 3 years.

Conclusions: Future initiatives to promote healthy movement behaviors in the early years should consider age differences, neighborhood characteristics, and season.
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http://dx.doi.org/10.1123/jpah.2020-0827DOI Listing
April 2021

Age trends in direct medical costs of pediatric asthma: A population study.

Pediatr Allergy Immunol 2021 Apr 4. Epub 2021 Apr 4.

Respiratory Evaluation Sciences Program, Collaboration for Outcomes Research and Evaluation, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada.

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http://dx.doi.org/10.1111/pai.13515DOI Listing
April 2021

Ethnicity associations with food sensitization are mediated by gut microbiota development in the first year of life.

Gastroenterology 2021 Mar 16. Epub 2021 Mar 16.

Department of Pediatrics, University of Alberta, Edmonton, AB, Canada. Electronic address:

Background And Aims: Increasing evidence supports the role of early-life gut microbiota in developing atopic diseases, but ecological changes to gut microbiota during infancy in relation to food sensitization remain unclear. We aimed to characterize and associate these changes with the development of food sensitization in children.

Methods: In this observational study, using 16S rRNA amplicon sequencing, we characterized the composition of 2844 fecal microbiota in 1422 Canadian full-term infants. Atopic sensitization outcomes were measured by skin prick tests at age 1 year and 3 years. The association between gut microbiota trajectories, based on longitudinal shifts in community clusters, and atopic sensitization outcomes at age 1 and 3 years was determined. Ethnicity and early life exposures influencing microbiota trajectories were initially examined, and post hoc analyses were conducted.

Results: Four identified developmental trajectories of gut microbiota were shaped by birth mode and varying by ethnicity. The trajectory with persistently-low Bacteroides abundance and high Enterobacteriaceae/Bacteroidaceae ratio throughout infancy increased the risk of sensitization to food allergens, particularly peanut at age 3 years by 3-fold (adjusted OR, 2.82; 95% CI, 1.13-7.01); a much higher likelihood for peanut sensitization was found if infants with this trajectory were born to Asian mothers (adjusted OR, 7.87; 95% CI, 2.75-22.55). It was characterized by a deficiency in sphingolipid metabolism and persistent C. difficile colonization. Importantly, this trajectory of depleted Bacteroides abundance mediated the association between Asian ethnicity and food sensitization.

Conclusions: This study documented an association between persistently-low gut Bacteroides abundance throughout infancy and sensitization to peanut in childhood. It is the first to show a mediation role for infant gut microbiota in ethnicity-associated development of food sensitization.
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http://dx.doi.org/10.1053/j.gastro.2021.03.016DOI Listing
March 2021

Human MALT1 deficiency and predisposition to infections.

Curr Opin Immunol 2021 Mar 11;72:1-12. Epub 2021 Mar 11.

Department of Pediatrics, British Columbia Children's Hospital, The University of British Columbia, Vancouver, BC, Canada. Electronic address:

Human germline MALT1 deficiency is an inborn error of immunity characterized by recurrent bacterial, viral, and fungal infections, periodontal disease, enteropathy, dermatitis, and failure to thrive. The number of identified MALT1-deficient patients have greatly increased in the past two years, which has significantly improved our understanding of the clinical features of this disorder. Patients frequently experience infections affecting the respiratory, skin, gastrointestinal, and blood systems. The most frequently detected pathogens are Staphylococcus aureus, Candida albicans, and cytomegalovirus. Enhanced susceptibility to S. aureus and C. albicans is likely due to impaired Th17 immunity, similar to STAT3 and IL-17 pathway deficiencies.
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http://dx.doi.org/10.1016/j.coi.2021.02.008DOI Listing
March 2021

Early life exposure to phthalates and the development of childhood asthma among Canadian children.

Environ Res 2021 Mar 7;197:110981. Epub 2021 Mar 7.

University of Toronto, Toronto, ON, Canada. Electronic address:

Background: Studies have demonstrated an association between phthalate exposure and childhood asthma, although results have been inconsistent. No epidemiological studies have examined exposure during the first year of life.

Objective: To investigate the association between phthalate exposures in the home environment during the first year of life, and subsequent development of childhood asthma and related symptoms.

Methods: This study used a case-cohort design including 436 randomly selected children and all additional cases of asthma at 5 years (n = 129) and recurrent wheeze between 2 and 5 years (n = 332) within the CHILD Cohort Study, a general population Canadian birth cohort of 3455 children. Phthalate exposure was assessed using house dust samples collected during a standardized home visit when children were 3-4 months of age. All children were assessed by specialist clinicians for asthma and allergy at 1, 3 and 5 years. Logistic regression was used to assess the association between exposure to five phthalates and asthma diagnosis at 5 years, and recurrent wheeze between 2 and 5 years, with further stratification by wheeze subtypes (late onset, persistent, transient) based on the timing of onset and persistence of wheeze symptoms.

Results: Di(2-ethylhexyl) phthalate (DEHP) had the highest concentration in dust (median = 217 μg/g), followed by benzyl butyl phthalate (BzBP) (20 μg/g). A nearly four-fold increase in risk of developing asthma was associated with the highest concentration quartile of DEHP (OR = 3.92, 95% CI: 1.87-8.24) including a positive dose-response relationship. A two-fold increase in risk of recurrent wheeze was observed across all quartiles compared to the lowest quartile of DEHP concentrations. Compared to other wheeze subtypes, stronger associations for DEHP were observed with the late onset wheezing subtype, while stronger associations for di-iso-butyl phthalate (DiBP) and BzBP were observed with the transient subtype.

Discussion: DEHP exposure at 3-4 months, at concentrations lower than other studies that reported an association, were associated with increased risks of asthma and recurrent wheeze among children at 5 years. These findings suggest the need to assess whether more stringent regulations are required to protect children's health, which can be informed by future work exploring the main sources of DEHP exposure.
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http://dx.doi.org/10.1016/j.envres.2021.110981DOI Listing
March 2021

Newly developed multiple-breath washout reference equations from the CHILD Cohort Study: implications of poorly fitting equations.

ERJ Open Res 2021 Jan 25;7(1). Epub 2021 Jan 25.

Division of Respiratory Medicine, Dept of Pediatrics and Program in Translational Medicine, SickKids Research Institute, The Hospital for Sick Children, and University of Toronto, Toronto, Canada.

https://bit.ly/3dcNZ5p.
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http://dx.doi.org/10.1183/23120541.00301-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836672PMC
January 2021

Idiopathic splenomegaly in childhood and the spectrum of RAS-associated lymphoproliferative disease: a case report.

BMC Pediatr 2021 Jan 21;21(1):45. Epub 2021 Jan 21.

Department of Pediatrics, British Columbia Children's Hospital, The University of British Columbia, 950 West 28th Avenue, V5Z 4H4, Vancouver, BC, Canada.

Background: KRAS (KRAS proto-oncogene, GTPase; OMIM: 190,070) encodes one of three small guanosine triphosphatase proteins belonging to the RAS family. This group of proteins is responsible for cell proliferation, differentiation and inhibition of apoptosis. Gain-of-function variants in KRAS are commonly found in human cancers. Non-malignant somatic KRAS variants underlie a subset of RAS-associated autoimmune leukoproliferative disorders (RALD). RALD is characterized by splenomegaly, persistent monocytosis, hypergammaglobulinemia and cytopenia, but can also include autoimmune features and lymphadenopathy. In this report, we describe a non-malignant somatic variant in KRAS with prominent clinical features of massive splenomegaly, thrombocytopenia and lymphopenia.

Case Presentation: A now-11-year-old girl presented in early childhood with easy bruising and bleeding, but had an otherwise unremarkable medical history. After consulting for the first time at 5 years of age, she was discovered to have massive splenomegaly. Clinical follow-up revealed thrombocytopenia, lymphopenia and increased polyclonal immunoglobulins and C-reactive protein. The patient had an unremarkable bone marrow biopsy, flow cytometry showed no indication of expanded double negative T-cells, while malignancy and storage disorders were also excluded. When the patient was 8 years old, whole exome sequencing performed on DNA derived from whole blood revealed a heterozygous gain-of-function variant in KRAS (NM_004985.5:c.37G > T; (p.G13C)). The variant was absent from DNA derived from a buccal swab and was thus determined to be somatic.

Conclusions: This case of idiopathic splenomegaly in childhood due to a somatic variant in KRAS expands our understanding of the clinical spectrum of RAS-associated autoimmune leukoproliferative disorder and emphasizes the value of securing a molecular diagnosis in children with unusual early-onset presentations with a suspected monogenic origin.
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http://dx.doi.org/10.1186/s12887-021-02508-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819237PMC
January 2021

Exome sequencing enables diagnosis of X-linked hypohidrotic ectodermal dysplasia in patient with eosinophilic esophagitis and severe atopy.

Allergy Asthma Clin Immunol 2021 Jan 14;17(1). Epub 2021 Jan 14.

BC Children's Hospital, University of British Columbia, 950 W 28th Ave, Vancouver, BC, V5Z 4H4, Canada.

X-linked hypohidrotic ectodermal dysplasia (XLHED) is the most common form of ectodermal dysplasia. Clinical and genetic heterogeneity between different ectodermal dysplasia types and evidence of incomplete penetrance and variable expressivity increase the potential for misdiagnosis. We describe a family with X-linked hypohidrotic ectodermal dysplasia (XLHED) presenting with variable expressivity of symptoms between affected siblings. In addition to the classical signs of hypohidrosis, hypotrichosis and hypodontia, the index patient-a 5 year old boy, also presented with a severe atopy phenotype that was not observed in the other two affected brothers. Exome sequencing in the index and the mother identified a pathogenic nonsense variant in EDA (NM_001399.4: c.766 C>T; p. Gln256Ter). This study highlights how exome sequencing was crucial in establishing a precise molecular diagnosis of XLHED by enabling us to rule out other differential diagnoses including NEMO deficiency syndrome, that was initially presented as a clinical diagnosis to the family.
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http://dx.doi.org/10.1186/s13223-021-00510-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809757PMC
January 2021

Maternal consumption of artificially sweetened beverages during pregnancy is associated with infant gut microbiota and metabolic modifications and increased infant body mass index.

Gut Microbes 2021 Jan-Dec;13(1):1-15

Physiology and Pharmacology, University of Calgary , Calgary, Alberta, Canada.

Artificial sweetener consumption by pregnant women has been associated with an increased risk of infant obesity, but the underlying mechanisms are unknown. We aimed to determine if maternal consumption of artificially sweetened beverages (ASB) during pregnancy is associated with modifications of infant gut bacterial community composition and function during the first year of life, and whether these alterations are linked with infant body mass index (BMI) at one year of age. We studied 100 infants from the prospective Canadian CHILD Cohort Study, selected based on maternal ASB consumption during pregnancy (50 non-consumers and 50 daily consumers). BMI was higher among ASB-exposed infants. Infant stool (16S rRNA gene sequencing) and urine (untargeted metabolomics) were acquired in early (3-4 months) and late (12 months) infancy. We identified four microbiome clusters, of which two recapitulated the maturation trajectory of the infant gut bacterial communities from immature (Cluster 1) to mature (Cluster 4) and two deviated from this trajectory (Clusters 2 and 3). Maternal ASB consumption did not differ between clusters, but was associated with community-level shifts in infant gut bacterial taxonomy structure and depletion of several sp. in Cluster 2. In the complete dataset, urine succinate and spermidine levels at 3 months were higher in ASB-exposed infants, and urine succinate was positively associated with BMI at one-year-old. Overall, gestational exposure to ASB was associated with gut microbiota structure in infants from Cluster 2, and gut microbiota structure was associated with infant BMI. Gestational exposure to ASB was positively associated with infant urine succinate and spermidine. Succinate was found to mediate 29% of the effect of ASB exposure on BMI at one-year-old, revealing a potential role of this metabolite in increased infant weight linked to gestational ASB consumption. As we face an unprecedented rise in childhood obesity, future studies should evaluate the causal relationships between maternal ASB consumption (a modifiable exposure), gut microbiota and metabolites, infant metabolism, and body composition.
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http://dx.doi.org/10.1080/19490976.2020.1857513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781635PMC
December 2020

Prenatal egg consumption and infant sensitization and allergy to egg, peanut, and cow's milk in the CHILD Cohort.

J Allergy Clin Immunol Pract 2020 Dec 13. Epub 2020 Dec 13.

Section of Allergy & Immunology, Department of Pediatrics & Child Health, University of Manitoba and Children's Hospital Research Institute of Manitoba DEVOTION Network, Winnipeg, MB, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.jaip.2020.11.061DOI Listing
December 2020

Reduced peanut sensitization with maternal peanut consumption and early peanut introduction while breastfeeding.

J Dev Orig Health Dis 2020 Dec 9:1-8. Epub 2020 Dec 9.

Department of Medicine, McMaster University, Hamilton, ON, Canada.

New guidelines for peanut allergy prevention in high-risk infants recommend introducing peanut during infancy but do not address breastfeeding or maternal peanut consumption. We assessed the independent and combined association of these factors with peanut sensitization in the general population CHILD birth cohort (N = 2759 mother-child dyads). Mothers reported peanut consumption during pregnancy, timing of first infant peanut consumption, and length of breastfeeding duration. Child peanut sensitization was determined by skin prick testing at 1, 3, and 5 years. Overall, 69% of mothers regularly consumed peanuts and 36% of infants were fed peanut in the first year (20% while breastfeeding and 16% after breastfeeding cessation). Infants who were introduced to peanut early (before 1 year) after breastfeeding cessation had a 66% reduced risk of sensitization at 5 years compared to those who were not (1.9% vs. 5.8% sensitization; aOR 0.34, 95% CI 0.14-0.68). This risk was further reduced if mothers introduced peanut early while breastfeeding and regularly consumed peanut themselves (0.3% sensitization; aOR 0.07, 0.01-0.25). In longitudinal analyses, these associations were driven by a higher odds of outgrowing early sensitization and a lower odds of late-onset sensitization. There was no apparent benefit (or harm) from maternal peanut consumption without breastfeeding. Taken together, these results suggest the combination of maternal peanut consumption and breastfeeding at the time of peanut introduction during infancy may help to decrease the risk of peanut sensitization. Mechanistic and clinical intervention studies are needed to confirm and understand this "triple exposure" hypothesis.
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http://dx.doi.org/10.1017/S2040174420001129DOI Listing
December 2020

Maternal Diet and the Serum Metabolome in Pregnancy: Robust Dietary Biomarkers Generalizable to a Multiethnic Birth Cohort.

Curr Dev Nutr 2020 Oct 2;4(10):nzaa144. Epub 2020 Sep 2.

Department of Health Research Methods, Evidence, and Impact, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada.

Background: Advances in metabolomics are anticipated to decipher associations between dietary exposures and health. Replication biomarker studies in different populations are critical to demonstrate generalizability.

Objectives: To identify and validate robust serum metabolites associated with diet quality and specific foods in a multiethnic cohort of pregnant women.

Design: In this cross-sectional analysis of 3 multiethnic Canadian birth cohorts, we collected semiquantitative FFQ and serum data from 900 women at the second trimester of pregnancy. We calculated a diet quality score (DQS), defined as daily servings of "healthy" minus "unhealthy" foods. Serum metabolomics was performed by multisegment injection-capillary electrophoresis-mass spectrometry, and specific serum metabolites associated with maternal DQSs were identified. We combined the results across all 3 cohorts using meta-analysis to classify robust dietary biomarkers ( > ± 0.1; < 0.05).

Results: Diet quality was higher in the South Asian birth cohort (mean DQS = 7.1) than the 2 white Caucasian birth cohorts (mean DQS <3.2). Sixty-six metabolites were detected with high frequency (>75%) and adequate precision (CV <30%), and 47 were common to all cohorts. Hippuric acid was positively associated with healthy diet score in all cohorts, and with the overall DQS only in the primarily white Caucasian cohorts. We observed robust correlations between: ) proline betaine-citrus foods; ) 3-methylhistidine-red meat, chicken, and eggs; ) hippuric acid-fruits and vegetables; ) trimethylamine -oxide (TMAO)-seafood, meat, and eggs; and ) tryptophan betaine-nuts/legumes.

Conclusions: Specific serum metabolites reflect intake of citrus fruit/juice, vegetables, animal foods, and nuts/legumes in pregnant women independent of ethnicity, fasting status, and delays to storage across multiple collection centers. Robust biomarkers of overall diet quality varied by cohort. Proline betaine, 3-methylhistidine, hippuric acid, TMAO, and tryptophan betaine were robust dietary biomarkers for investigations of maternal nutrition in diverse populations.
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http://dx.doi.org/10.1093/cdn/nzaa144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547851PMC
October 2020

Soluble Low-density Lipoprotein Receptor-related Protein 1 in Juvenile Idiopathic Arthritis.

J Rheumatol 2020 Oct 15. Epub 2020 Oct 15.

The BBOP Study was supported by The Canadian Institutes of Health Research (FRN #82517); The Arthritis Society (Canada), Canadian Arthritis Network (SRI-IJD-01); University of Saskatchewan; The Clinical Research Centre of the Centre Hospitalier Universitaire de Sherbrooke; University of British Columbia; McGill University; Memorial University; Manitoba Institute of Child Health; Children's Health Research Trust Fund; Jim Pattison Children's Hospital Foundation of Saskatchewan; The Pediatric Rheumatic Disease Research and Innovation Laboratory, University of Saskatchewan; The Haslam Research Fund, University of Saskatchewan; and The Kleiman Fund, University of Saskatchewan. E. Rezaei, MD, PhD, A.M. Rosenberg, MD, Departments of Pediatrics, University of Saskatchewan, Saskatoon, Saskatchewan; M.M. Newkirk, PhD, Department of Medicine, McGill University Health Center, Montreal, Quebec; Z. Li, MSc, RC-CHUM, University of Montreal, Montreal, Quebec; J.R. Gordon, PhD, Department of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan; K.G. Oen, MD, Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba; S.M. Benseler, MD, PhD, Department of Pediatrics, Alberta Children's Hospital, University of Calgary, Calgary, Alberta; G. Boire, MD, Département de Médecine, Université de Sherbrooke, Sherbrooke, Quebec; D.A. Cabral, MD, K. Houghton, MD, K.A. Morishita, MD, R.E. Petty, MD, PhD, L.B. Tucker, MD, S.E. Turvey, MD, Department of Pediatrics, British Columbia Children's Hospital, Vancouver, British Columbia; S. Campillo, MD, G. Chédeville, MD, R. Scuccimarri, MD, Department of Pediatrics, McGill University Health Center, Montreal, Quebec; A.L. Chetaille, MD, Département de Médecine le Centre Hospitalier Universitaire de Quebec, Quebec City, Quebec; P. Dancey, MD, Department of Pediatrics, Janeway Children's Health and Rehabilitation Centre, St. John's, Newfoundland; C. Duffy, MD, R. Jurencak, MD, Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, Ontario; K. Watanabe Duffy, MD, Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, Ontario; A.M. Huber, MD, B. Lang, MD, S.E. Ramsey, MD, E. Stringer, MD, Department of Pediatrics, IWK Health Centre and Dalhousie University, Halifax, Nova Scotia; J. Roth, MD, Department of Pediatrics, Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario; R. Schneider, MD, L. Spiegel, MD, S.M. Tse, MD, R.S. Yeung, MD, PhD, Department of Paediatrics, University of Toronto and the Hospital for Sick Children, Toronto, Ontario, Canada. The authors declare no conflict of interest. Address correspondence to Dr. A.M. Rosenberg, Department of Pediatrics, Royal University Hospital, 103 Hospital Drive, Saskatoon, SK S7N 0W8, Canada. Email: Accepted for publication October 2, 2020.

Objective: This study aimed to expand knowledge about soluble low-density lipoprotein receptor-related protein 1 (sLRP1) in juvenile idiopathic arthritis ( JIA) by determining associations of sLRP1 levels in nonsystemic JIA patients with clinical and inflammatory biomarker indicators of disease activity.

Methods: Plasma sLRP1 and 44 inflammation-related biomarkers were measured at enrollment and 6 months later in a cohort of 96 newly diagnosed Canadian patients with nonsystemic JIA. Relationships between sLRP1 levels and indicators of disease activity and biomarker levels were analyzed at both visits.

Results: At enrollment, sLRP1 levels correlated negatively with age and active joint counts. Children showed significantly higher levels of sLRP1 than adolescents (mean ranks: 55.4 and 41.9, respectively; = 0.02). Participants with 4 or fewer active joints, compared to those with 5 or more active joints, had significantly higher sLRP1 levels (mean ranks: 56.2 and 40.7, respectively; = 0.006). At enrollment, considering the entire cohort, sLRP1 correlated negatively with the number of active joints (r = -0.235, = 0.017). In the entire cohort, sLRP1 levels at enrollment and 6 months later correlated with 13 and 6 pro- and antiinflammatory biomarkers, respectively. In JIA categories, sLRP1 correlations with inflammatory markers were significant in rheumatoid factor-negative polyarticular JIA, oligoarticular JIA, enthesitis-related arthritis, and psoriatic arthritis at enrollment. Higher sLRP1 levels at enrollment increased the likelihood of absence of active joints 6 months later.

Conclusion: Plasma sLRP1 levels correlate with clinical and biomarker indicators of short-term improvement in JIA disease activity, supporting sLRP1 as an upstream biomarker of potential utility for assessing JIA disease activity and outcome prediction.
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http://dx.doi.org/10.3899/jrheum.200391DOI Listing
October 2020

Can we prevent allergic disease? Understanding the links between the early life microbiome and allergic diseases of childhood.

Curr Opin Pediatr 2020 12;32(6):790-797

Department of Pediatrics, University of British Columbia.

Purpose Of Review: The microbiome and immune system are intrinsically linked, and during infancy these crucial biological systems undergo a concurrent and expansive maturation process. As these maturation processes progress, some children develop a sequence of IgE-mediated immune disorders termed the 'Allergic March', and unfortunately the prevalence of these lifelong and burdensome allergic conditions has increased over the past half century. Our current treatment strategies are unable to prevent or cure components of the Allergic March. However, recent discoveries have enhanced our mechanistic understanding of early-life microbiota-immune interactions with exciting implications for preventing these allergic disorders.

Recent Findings: The current review will detail recent literature regarding perinatal factors (e.g. birth mode, antibiotic exposure, breastmilk seeding of the microbiota, built environment) that shape the infant gut microbiota composition. Furthermore, we will discuss new findings that have highlighted immune cells which are particularly sensitive to microbial influences in utero and during the early-life window of development.

Summary: As our understanding of the dynamic relationship between the developing infant microbiota and immune system grows, a priority toward preserving critical early-life interactions may provide life-long protection to these diseases in the future.
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http://dx.doi.org/10.1097/MOP.0000000000000956DOI Listing
December 2020

From Birth to Overweight and Atopic Disease: Multiple and Common Pathways of the Infant Gut Microbiome.

Gastroenterology 2021 Jan 16;160(1):128-144.e10. Epub 2020 Sep 16.

Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada; Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Alberta, Canada; School of Public Health, University of Alberta, Edmonton, Alberta, Canada. Electronic address:

Background & Aims: Few studies, even those with cohort designs, test the mediating effects of infant gut microbes and metabolites on the onset of disease. We undertook such a study.

Methods: Using structural equation modeling path analysis, we tested directional relationships between first pregnancy, birth mode, prolonged labor and breastfeeding; infant gut microbiota, metabolites, and IgA; and childhood body mass index and atopy in 1667 infants.

Results: After both cesarean birth and prolonged labor with a first pregnancy, a higher Enterobacteriaceae/Bacteroidaceae ratio at 3 months was the dominant path to overweight; higher Enterobacteriaceae/Bacteroidaceae ratios and Clostridioides difficile colonization at 12 months were the main pathway to atopic sensitization. Depletion of Bifidobacterium after prolonged labor was a secondary pathway to overweight. Influenced by C difficile colonization at 3 months, metabolites propionate and formate were secondary pathways to child outcomes, with a key finding that formate was at the intersection of several paths.

Conclusions: Pathways from cesarean section and first pregnancy to child overweight and atopy share many common mediators of the infant gut microbiome, notably C difficile colonization.
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http://dx.doi.org/10.1053/j.gastro.2020.08.053DOI Listing
January 2021

Development and Validation of SDBeasy Score as a Predictor of Behavioral Outcomes in Childhood.

Am J Respir Crit Care Med 2021 03;203(6):718-725

Department of Pediatrics and.

There are limited tools to identify which children are at greatest risk for developing sleep-disordered breathing (SDB)-associated behavioral morbidity. To examine associations between age of onset and duration of parent-reported symptoms of SDB and behavioral problems at the age of 5 years. Data were collected and analyses were completed for participants in the CHILD (Canadian Healthy Infant Longitudinal Development) cohort at the Edmonton and Toronto sites. We generated an SDBeasy score on the basis of the age of onset and duration of SDB symptoms as reported by parents completing the Pediatric Sleep Questionnaire. Using CHILD-Edmonton data, we completed multivariate linear regression to determine whether the SDBeasy score was associated with behavioral problems at the age 5 years of age as assessed by using the Child Behavior Checklist (CBCL). We then validated the SDBeasy score using CHILD-Toronto data. At the 5-year visit, 581 of 716 (81%) CHILD-Edmonton participants still enrolled had CBCL data. Of the 581 children with data, 77% (446 of 581) had an SDBeasy score of 0 (never had SDB symptoms), whereas 20 of 581 children (3.4%) had persistent SDB symptoms from infancy through 5 years of age (SDBeasy score of 24). Children had a 0.35-point-higher CBCL total behavioral score at 5 years for each 1-point increase in their SDBeasy score (95% confidence interval, 0.24-0. 5;  < 0.01). We found consistent results among CHILD-Toronto participants; children had a 0.26-point-higher CBCL total behavioral score at 5 years for each 1-point increase in their SDBeasy score (95% confidence interval, 0.08-0.44;  = 0.005). The SDBeasy score, based on the Pediatric Sleep Questionnaire, enables identification of children with higher behavioral-problem scores.
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http://dx.doi.org/10.1164/rccm.202002-0363OCDOI Listing
March 2021

Vitamin D supplementation in pregnancy and early infancy in relation to gut microbiota composition and colonization: implications for viral respiratory infections.

Gut Microbes 2020 11;12(1):1799734

Departments of Pediatrics, Obstetrics & Gynecology, University of Alberta , Edmonton, AB, Canada.

In Canada and the US, the infant diet is supplemented with vitamin D via supplement drops or formula. Pregnant and nursing mothers often take vitamin D supplements. Since little is known about the impact of this supplementation on infant gut microbiota, we undertook a study to determine the association between maternal and infant vitamin D supplementation, infant gut microbiota composition and colonization in 1,157 mother-infant pairs of the CHILD (Canadian Healthy Infant Longitudinal Development) Cohort Study over 2009-2012. Logistic and MaAsLin regression were employed to assess associations between vitamin D supplementation, and colonization, or other gut microbiota, respectively. Sixty-five percent of infants received a vitamin D supplement. Among all infants, infant vitamin D supplementation was associated with a lower abundance of genus (q = 0.01) in gut microbiota. Among those exclusively breastfed, maternal prenatal supplementation was associated with lower abundance of (q = 0.01) and of Lachnospiraceae (q = 0.02) but higher abundance of (q = 0.02). There were no differences in microbiota composition with vitamin D supplementation among partially and not breastfed infants. Neither infant nor maternal vitamin D supplementation were associated with colonization, after adjusting for breastfeeding status and other factors. However, maternal consumption of vitamin-D fortified milk reduced the likelihood of colonization in infants (adjustedOR: 0.40, 95% CI: 0.19-0.82). The impact of this compositional difference on later childhood health, especially defense against viral respiratory infection, may go beyond the expected effects of vitamin D supplements and remains to be ascertained.
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http://dx.doi.org/10.1080/19490976.2020.1799734DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524344PMC
November 2020

Rhinovirus Infection Drives Complex Host Airway Molecular Responses in Children With Cystic Fibrosis.

Front Immunol 2020 16;11:1327. Epub 2020 Jul 16.

Telethon Kids Institute, Respiratory Research Centre, Nedlands, WA, Australia.

Early-life viral infections are responsible for pulmonary exacerbations that can contribute to disease progression in young children with cystic fibrosis (CF). The most common respiratory viruses detected in the CF airway are human rhinoviruses (RV), and augmented airway inflammation in CF has been attributed to dysregulated airway epithelial responses although evidence has been conflicting. Here, we exposed airway epithelial cells from children with and without CF to RV . Using RNA-Seq, we profiled the transcriptomic differences of CF and non-CF airway epithelial cells at baseline and in response to RV. There were only modest differences between CF and non-CF cells at baseline. In response to RV, there were 1,442 and 896 differentially expressed genes in CF and non-CF airway epithelial cells, respectively. The core antiviral responses in CF and non-CF airway epithelial cells were mediated through interferon signaling although type 1 and 3 interferon signaling, when measured, were reduced in CF airway epithelial cells following viral challenge consistent with previous reports. The transcriptional responses in CF airway epithelial cells were more complex than in non-CF airway epithelial cells with diverse over-represented biological pathways, such as cytokine signaling and metabolic and biosynthetic pathways. Network analysis highlighted that the differentially expressed genes of CF airway epithelial cells' transcriptional responses were highly interconnected and formed a more complex network than observed in non-CF airway epithelial cells. We corroborate observations in fully differentiated air-liquid interface (ALI) cultures, identifying genes involved in IL-1 signaling and mucin glycosylation that are only dysregulated in the CF airway epithelial response to RV infection. These data provide novel insights into the CF airway epithelial cells' responses to RV infection and highlight potential pathways that could be targeted to improve antiviral and anti-inflammatory responses in CF.
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http://dx.doi.org/10.3389/fimmu.2020.01327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378398PMC
April 2021

Cardiorespiratory Monitoring Data during Sleep in Healthy Canadian Infants.

Ann Am Thorac Soc 2020 10;17(10):1238-1246

Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada.

Sleep study interpretation in children needs to be based on age-specific normal values. Although several studies have reported normal cardiorespiratory parameters during sleep in children and adolescents, few have included younger children. To describe cardiopulmonary indices, specifically oxygen saturation and heart rate, as well as frequency of obstructive and central apneas in healthy 1-year-old Canadian infants during sleep. Home sleep cardiorespiratory monitoring was performed among infants participating in the Edmonton subcohort of the CHILD (Canadian Healthy Infant Longitudinal Development) study at their 1-year follow-up visit. A portable sleep monitoring device, which included a nasal pressure cannula, an oronasal thermal airflow sensor, a pulse oximeter, and respiratory inductance plethysmography belts, was used to collect sleep architecture and cardiorespiratory data during one night of monitoring in the home. Sleep scoring was done in blocks of 5 minutes using a novel pilot sleep scoring algorithm. Among the 562 subjects (mean ± standard deviation age 1.1 ± 0.2 yr) who attempted home sleep cardiorespiratory monitoring, 91% provided technically acceptable data with no loss of signal preventing analysis of any parameter. Obstructive and central apneas were rare, with a median obstructive apnea index of 0.0 events/h (10th percentile, 0.0; 90th percentile, 0.5) and a median central apnea index of 2.5 events/h (10th percentile, 0.6; 90th percentile, 7.1). Median oxygen saturation was 97.0% (10th percentile, 95.4; 90th percentile, 97.9). The oxygen desaturation index was 6.7 events/h (10th percentile, 1.4; 90th percentile, 15.8), with infants spending only 0.1% (10th percentile, 0.0; 90th percentile, 0.6) of the time with an oxygen saturation below 92%. These results provide important reference data for healthy infants undergoing cardiorespiratory monitoring during sleep.
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http://dx.doi.org/10.1513/AnnalsATS.201909-703OCDOI Listing
October 2020

Breastmilk Feeding Practices Are Associated with the Co-Occurrence of Bacteria in Mothers' Milk and the Infant Gut: the CHILD Cohort Study.

Cell Host Microbe 2020 08 10;28(2):285-297.e4. Epub 2020 Jul 10.

Children's Hospital Research Institute of Manitoba and Developmental Origins of Chronic Diseases in Children Network (DEVOTION), Winnipeg, MB, Canada; Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, MB, Canada. Electronic address:

Gut microbiota play a critical role in infant health. It is now accepted that breastmilk contains live bacteria from endogenous and exogenous sources, but it remains unclear whether these bacteria transfer to the infant gut and whether this process is influenced by breastmilk feeding practices. Here, we show that certain bacteria, including Streptococcus spp. and Veillonella dispar, co-occur in mothers' milk and their infants' stool, and co-occurrence is reduced when infants receive pumped breastmilk. The relative abundances of commonly shared species are positively correlated between breastmilk and stool. Overall, gut microbiota composition is strongly associated with breastfeeding exclusivity and duration but not breastmilk feeding mode (nursing versus pumping). Moreover, breastmilk bacteria contributed to overall gut microbiota variation to a similar extent as other modifiers of the infant microbiome, such as birth mode. These results provide evidence that breastmilk may transfer bacteria to the infant gut and influence microbiota development.
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http://dx.doi.org/10.1016/j.chom.2020.06.009DOI Listing
August 2020

Natural environments in the urban context and gut microbiota in infants.

Environ Int 2020 09 28;142:105881. Epub 2020 Jun 28.

Department of Pediatrics, University of Alberta, Edmonton, AB, Canada; Department of Obstetrics & Gynecology, University of Alberta, AB, Canada; School of Public Health, University of Alberta, AB, Canada; inVIVO Planetary Health, Canada. Electronic address:

The biodiversity hypothesis that contact with natural environments (e.g. native vegetation) and biodiversity, through the influence of environmental microbes, may be beneficial for human commensal microbiota has been insufficiently tested. We aimed to study the association between living near natural environments in the urban context, and gut microbiota diversity and composition in young infants. Based on data linkage between the unique Urban Primary Land and Vegetation Inventory (uPLVI) for the city of Edmonton and 355 infants in the CHILD Cohort Study, infant exposure to natural environments (any and specific types, yes/no) was determined within 500 m and 1000 m of their home residence. Gut microbiota composition and diversity at age 4 months was assessed in infant fecal samples. Adjusted for covariates, we observed a reduced odds of high microbial alpha-diversity in the gut of infants exposed to any natural environment within 500 m [Shannon index aOR (95%CI) = 0.63 (0.40, 0.98) and Simpson index = 0.63 (0.41, 0.98)]. In stratified analyses, these associations remained only among infants not breastfed or living with household pets. When doubly stratifying by these variables, the reduced likelihood of high alpha-diversity was present only among infants who were not breastfed and lived with household pets [9% of the study population, Shannon index = 0.07 (0.01, 0.49) and Simpson index = 0.11 (0.02, 0.66)]. Differences in beta-diversity was also seen (p = 0.04) with proximity to a nature space in not breastfed and pets-exposed infants. No associations were observed among infants who were fully formula-fed but without pets at home. When families and their pets had close access to a natural environment, Verrucomicrobiales colonization was reduced in the gut microbiota of formula-fed infants, the abundance of Clostridiales was depleted, whereas the abundance of Enterobacteriales was enriched. Our double-stratified results indicate that proximity to a natural environment plus pet ownership has the capacity to alter the gut microbiota of formula-fed infants. Further research is needed to replicate and better interpret these results, as well as to understand their health consequences.
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http://dx.doi.org/10.1016/j.envint.2020.105881DOI Listing
September 2020

STIM1-mediated calcium influx controls antifungal immunity and the metabolic function of non-pathogenic Th17 cells.

EMBO Mol Med 2020 08 1;12(8):e11592. Epub 2020 Jul 1.

Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA.

Immunity to fungal infections is mediated by cells of the innate and adaptive immune system including Th17 cells. Ca influx in immune cells is regulated by stromal interaction molecule 1 (STIM1) and its activation of the Ca channel ORAI1. We here identify patients with a novel mutation in STIM1 (p.L374P) that abolished Ca influx and resulted in increased susceptibility to fungal and other infections. In mice, deletion of STIM1 in all immune cells enhanced susceptibility to mucosal C. albicans infection, whereas T cell-specific deletion of STIM1 impaired immunity to systemic C. albicans infection. STIM1 deletion impaired the production of Th17 cytokines essential for antifungal immunity and compromised the expression of genes in several metabolic pathways including Foxo and HIF1α signaling that regulate glycolysis and oxidative phosphorylation (OXPHOS). Our study further revealed distinct roles of STIM1 in regulating transcription and metabolic programs in non-pathogenic Th17 cells compared to pathogenic, proinflammatory Th17 cells, a finding that may potentially be exploited for the treatment of Th17 cell-mediated inflammatory diseases.
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http://dx.doi.org/10.15252/emmm.201911592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7411566PMC
August 2020

Clinical IRAK4 deficiency caused by homozygosity for the novel (c.1049delG, p.Gly350Glufs*15) variant.

Cold Spring Harb Mol Case Stud 2020 06 12;6(3). Epub 2020 Jun 12.

Division of Allergy and Clinical Immunology, Department of Pediatrics, BC Children's Hospital, Vancouver, British Columbia V5Z 4H4, Canada.

The innate immune system allows for rapid recognition of pathogens. Toll-like receptor (TLR) signaling is a key aspect of the innate immune response, and interleukin-1 receptor-associated kinase 4 (IRAK4) plays a vital role in the TLR signaling cascade. Each TLR recognizes a distinct set of pathogen-associated molecular patterns (PAMPs) that encompass conserved microbial components such as lipopolysaccharides and flagellin. Upon binding of PAMPs and TLR activation, TLR intracellular domains initiate the oligomerization of the myeloid differentiation primary response 88 (MyD88), IRAK1, IRAK2, and IRAK4 signaling platform known as the Myddosome complex while also triggering the Toll/IL-1R domain-containing adaptor-inducing IFN-β (TRIF)-dependent pathway. The Myddosome complex initiates signal transduction pathways enabling the activation of NF-κB and mitogen-activated protein kinase (MAPK) transcription factors and the subsequent production of inflammatory cytokines. Human IRAK4 deficiency is an autosomal recessive inborn error of immunity that classically presents with blunted or delayed inflammatory response to infection and susceptibility to a narrow spectrum of pyogenic bacteria, particularly We describe a case of IRAK4 deficiency in an 11-mo-old boy with concurrent bacteremia and cervical lymphadenitis with a blunted inflammatory response to invasive infection. Although initial clinical immune profiling was unremarkable, a high degree of suspicion for an innate immune defect prompted genetic sequencing. Genetic testing revealed a novel variant in the gene (c.1049delG, p.(Gly350Glufs*15)) predicted to be likely pathogenic. Functional testing showed a loss of IRAK4 protein expression and abolished TLR signaling, confirming the pathogenicity of this novel IRAK4 variant.
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http://dx.doi.org/10.1101/mcs.a005298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7304365PMC
June 2020

The relationship between machine-learning-derived sleep parameters and behavior problems in 3- and 5-year-old children: results from the CHILD Cohort study.

Sleep 2020 12;43(12)

Department of Pediatrics, University of Alberta, Edmonton, AB, Canada.

Study Objectives: Machine learning (ML) may provide insights into the underlying sleep stages of accelerometer-assessed sleep duration. We examined associations between ML-sleep patterns and behavior problems among preschool children.

Methods: Children from the CHILD Cohort Edmonton site with actigraphy and behavior data at 3-years (n = 330) and 5-years (n = 304) were included. Parent-reported behavior problems were assessed by the Child Behavior Checklist. The Hidden Markov Model (HMM) classification method was used for ML analysis of the accelerometer sleep period. The average time each participant spent in each HMM-derived sleep state was expressed in hours per day. We analyzed associations between sleep and behavior problems stratified by children with and without sleep-disordered breathing (SDB).

Results: Four hidden sleep states were identified at 3 years and six hidden sleep states at 5 years using HMM. The first sleep state identified for both ages (HMM-0) had zero counts (no movement). The remaining hidden states were merged together (HMM-mov). Children spent an average of 8.2 ± 1.2 h/day in HMM-0 and 2.6 ± 0.8 h/day in HMM-mov at 3 years. At age 5, children spent an average of 8.2 ± 0.9 h/day in HMM-0 and 1.9 ± 0.7 h/day in HMM-mov. Among SDB children, each hour in HMM-0 was associated with 0.79-point reduced externalizing behavior problems (95% CI -1.4, -0.12; p < 0.05), and a 1.27-point lower internalizing behavior problems (95% CI -2.02, -0.53; p < 0.01).

Conclusions: ML-sleep states were not associated with behavior problems in the general population of children. Children with SDB who had greater sleep duration without movement had lower behavioral problems. The ML-sleep states require validation with polysomnography.
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http://dx.doi.org/10.1093/sleep/zsaa117DOI Listing
December 2020

Human milk fungi: environmental determinants and inter-kingdom associations with milk bacteria in the CHILD Cohort Study.

BMC Microbiol 2020 06 5;20(1):146. Epub 2020 Jun 5.

Children's Hospital Research Institute of Manitoba, Developmental Origins of Chronic Diseases in Children Network (DEVOTION), Winnipeg, MB, Canada.

Background: Fungi constitute an important yet frequently neglected component of the human microbiota with a possible role in health and disease. Fungi and bacteria colonise the infant gastrointestinal tract in parallel, yet most infant microbiome studies have ignored fungi. Milk is a source of diverse and viable bacteria, but few studies have assessed the diversity of fungi in human milk.

Results: Here we profiled mycobiota in milk from 271 mothers in the CHILD birth cohort and detected fungi in 58 (21.4%). Samples containing detectable fungi were dominated by Candida, Alternaria, and Rhodotorula, and had lower concentrations of two human milk oligosaccharides (disialyllacto-N-tetraose and lacto-N-hexaose). The presence of milk fungi was associated with multiple outdoor environmental features (city, population density, and season), maternal atopy, and early-life antibiotic exposure. In addition, despite a strong positive correlation between bacterial and fungal richness, there was a co-exclusion pattern between the most abundant fungus (Candida) and most of the core bacterial genera.

Conclusion: We profiled human milk mycobiota in a well-characterised cohort of mother-infant dyads and provide evidence of possible host-environment interactions in fungal inoculation. Further research is required to establish the role of breastfeeding in delivering fungi to the developing infant, and to assess the health impact of the milk microbiota in its entirety, including both bacterial and fungal components.
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http://dx.doi.org/10.1186/s12866-020-01829-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275434PMC
June 2020

Polygenic risk score for atopic dermatitis in the Canadian population.

J Allergy Clin Immunol 2021 Jan 19;147(1):406-409. Epub 2020 May 19.

Département des sciences fondamentales, Université du Québec à Chicoutimi, Saguenay, Quebec, Canada; Centre intersectoriel en santé durable, Université du Québec à Chicoutimi, Saguenay, Quebec, Canada; Department of Pediatrics, Centre intégré universitaire de santé et de services sociaux du Saguenay-Lac-Saint-Jean, Saguenay, Quebec, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2020.04.057DOI Listing
January 2021

Ethnic differences in maternal diet in pregnancy and infant eczema.

PLoS One 2020 14;15(5):e0232170. Epub 2020 May 14.

Department of Medicine, McMaster University, Hamilton, Ontario, Canada.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0232170PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7224524PMC
July 2020

Nonnutritive sweetener consumption during pregnancy, adiposity, and adipocyte differentiation in offspring: evidence from humans, mice, and cells.

Int J Obes (Lond) 2020 10 4;44(10):2137-2148. Epub 2020 May 4.

Developmental Origins of Chronic Diseases in Children Network (DEVOTION) and the Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Theme of the Children's Hospital Research Institute of Manitoba, Winnipeg, MB, Canada.

Background: Obesity often originates in early life, and is linked to excess sugar intake. Nonnutritive sweeteners (NNS) are widely consumed as "healthier" alternatives to sugar, yet recent evidence suggests NNS may adversely influence weight gain and metabolic health. The impact of NNS during critical periods of early development has rarely been studied. We investigated the effect of prenatal NNS exposure on postnatal adiposity and adipocyte development.

Methods: In the CHILD birth cohort (N = 2298), we assessed maternal NNS beverage intake during pregnancy and child body composition at 3 years, controlling for maternal BMI and other potential confounders. To investigate causal mechanisms, we fed NNS to pregnant C57BL6J mice at doses relevant to human consumption (42 mg/kg/day aspartame or 6.3 mg/kg/day sucralose), and assessed offspring until 12 weeks of age for: body weight, adiposity, adipose tissue morphology and gene expression, glucose and insulin tolerance. We also studied the effect of sucralose on lipid accumulation and gene expression in cultured 3T3-L1 pre-adipocyte cells.

Results: In the CHILD cohort, children born to mothers who regularly consumed NNS beverages had elevated body mass index (mean z-score difference +0.23, 95% CI 0.05-0.42 for daily vs. no consumption, adjusted for maternal BMI). In mice, maternal NNS caused elevated body weight, adiposity, and insulin resistance in offspring, especially in males (e.g., 47% and 15% increase in body fat for aspartame and sucralose vs. controls, p < 0.001). In cultured adipocytes, sucralose exposure at early stages of differentiation caused increased lipid accumulation and expression of adipocyte differentiation genes (e.g., C/EBP-α, FABP4, and FASN). These genes were also upregulated in adipose tissue of male mouse offspring born to sucralose-fed dams.

Conclusion: By triangulating evidence from humans, mice, and cultured adipocytes, this study provides new evidence that maternal NNS consumption during pregnancy may program obesity risk in offspring through effects on adiposity and adipocyte differentiation.
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http://dx.doi.org/10.1038/s41366-020-0575-xDOI Listing
October 2020

Associations of clinical and inflammatory biomarker clusters with juvenile idiopathic arthritis categories.

Rheumatology (Oxford) 2020 05;59(5):1066-1075

Department of Pediatrics, University of Saskatchewan, Saskatoon, Canada.

Objective: To identify discrete clusters comprising clinical features and inflammatory biomarkers in children with JIA and to determine cluster alignment with JIA categories.

Methods: A Canadian prospective inception cohort comprising 150 children with JIA was evaluated at baseline (visit 1) and after six months (visit 2). Data included clinical manifestations and inflammation-related biomarkers. Probabilistic principal component analysis identified sets of composite variables, or principal components, from 191 original variables. To discern new clinical-biomarker clusters (clusters), Gaussian mixture models were fit to the data. Newly-defined clusters and JIA categories were compared. Agreement between the two was assessed using Kruskal-Wallis analyses and contingency plots.

Results: Three principal components recovered 35% (three clusters) and 40% (five clusters) of the variance in patient profiles in visits 1 and 2, respectively. None of the clusters aligned precisely with any of the seven JIA categories but rather spanned multiple categories. Results demonstrated that the newly defined clinical-biomarker lustres are more homogeneous than JIA categories.

Conclusion: Applying unsupervised data mining to clinical and inflammatory biomarker data discerns discrete clusters that intersect multiple JIA categories. Results suggest that certain groups of patients within different JIA categories are more aligned pathobiologically than their separate clinical categorizations suggest. Applying data mining analyses to complex datasets can generate insights into JIA pathogenesis and could contribute to biologically based refinements in JIA classification.
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http://dx.doi.org/10.1093/rheumatology/kez382DOI Listing
May 2020