Microbial colonization programs are structured by breastfeeding and guide healthy respiratory development.

Breastfeeding and microbial colonization during infancy occur within a critical time window for development, and both are thought to influence the risk of respiratory illness. However, the mechanisms underlying the protective effects of breastfeeding and the regulation of microbial colonization are poorly understood. Here, we profiled the nasal and gut microbiomes, breastfeeding characteristics, and maternal milk composition of 2,227 children from the CHILD Cohort Study. We identified robust colonization patterns that, together with milk components, predict preschool asthma and mediate the protective effects of breastfeeding. We found that early cessation of breastfeeding (before 3 months) leads to the premature acquisition of microbial species and functions, including Ruminococcus gnavus and tryptophan biosynthesis, which were previously linked to immune modulation and asthma. Conversely, longer exclusive breastfeeding supports a paced microbial development, protecting against asthma. These findings underscore the importance of extended breastfeeding for respiratory health and highlight potential microbial targets for intervention.

From Fetus to Eight: the CHILD Cohort Study.

The CHILD Cohort Study is an active multi-center longitudinal, prospective, population pregnancy cohort study following Canadian infants from fetal life until adulthood. We hypothesized that early life physical and psychosocial environments interact with biological factors (e.g. immunologic, genetic, physiologic, and metabolic) influencing burdensome non-communicable disease outcomes, including asthma and allergic disorders, growth and development, cardio-metabolic health, and neurodevelopmental outcomes that manifest during the life-course. Detailed clinical and physiologic phenotyping at strategic intervals was complemented by environmental sampling, actigraphy and global positioning system measures, biological sampling including gut, breastmilk and nasal microbiome, nutritional studies, genetics, and epigenetic profiling. Of 3,454 families recruited from 2008 to 2012, study retention was 96.0% at 1-year, 93.2% at 5-years and 90.7% at 8-years. Data collection during the SARS-2 COVID-19 pandemic was partially completed via virtual visits. A sub-cohort was implemented, capturing detailed information on the prevalence and predictors of SARS-CoV-2 infection and the health and psychosocial impact of the pandemic on Canadian families. The 13-year clinical assessment launched in 2022 will be completed in 2025. Ultimately, the CHILD Cohort Study provides a data science platform designed to enable a deep understanding of early life factors associated with the development of chronic non-communicable diseases and multimorbidity.

Early prediction of pediatric asthma in the Canadian Healthy Infant Longitudinal Development (CHILD) birth cohort using machine learning.

BACKGROUND: Early identification of children at risk of asthma can have significant clinical implications for effective intervention and treatment. This study aims to disentangle the relative timing and importance of early markers of asthma. METHODS: Using the CHILD Cohort Study, 132 variables measured in 1754 multi-ethnic children were included in the analysis for asthma prediction. Data up to 4 years of age was used in multiple machine learning models to predict physician-diagnosed asthma at age 5 years. Both predictive performance and variable importance was assessed in these models. RESULTS: Early-life data (≤1 year) has limited predictive ability for physician-diagnosed asthma at age 5 years (area under the precision-recall curve (AUPRC) < 0.35). The earliest reliable prediction of asthma is achieved at age 3 years, (area under the receiver-operator curve (AUROC) > 0.90) and (AUPRC > 0.80). Maternal asthma, antibiotic exposure, and lower respiratory tract infections remained highly predictive throughout childhood. Wheezing status and atopy are the most important predictors of early childhood asthma from among the factors included in this study. CONCLUSIONS: Childhood asthma is predictable from non-biological measurements from the age of 3 years, primarily using parental asthma and patient history of wheezing, atopy, antibiotic exposure, and lower respiratory tract infections. IMPACT: Machine learning models can predict physician-diagnosed asthma in early childhood (AUROC > 0.90 and AUPRC > 0.80) using ≥3 years of non-biological and non-genetic information, whereas prediction with the same patient information available before 1 year of age is challenging. Wheezing, atopy, antibiotic exposure, lower respiratory tract infections, and the child's mother having asthma were the strongest early markers of 5-year asthma diagnosis, suggesting an opportunity for earlier diagnosis and intervention and focused assessment of patients at risk for asthma, with an evolving risk stratification over time.

Wheeze trajectories: Determinants and outcomes in the CHILD Cohort Study.

BACKGROUND: Wheezing in early life is associated with asthma in adulthood; however, the determinants of wheezing trajectories and their associations with asthma and lung function in childhood remain poorly understood. OBJECTIVE: In the CHILD Cohort Study, we aimed to identify wheezing trajectories and examine the associations between these trajectories, risk factors, and clinical outcomes at age 5 years. METHODS: Wheeze data were collected at 8 time points from 3 months to 5 years of age. We used group-based trajectory models to derive wheeze trajectories among 3154 children. Associations with risk factors and clinical outcomes were analyzed by weighted regression models. RESULTS: We identified 4 trajectories: a never/infrequent trajectory, transient wheeze, intermediate-onset (preschool) wheeze, and persistent wheeze. Higher body mass index was a common risk factor for all wheeze trajectories compared with that in the never/infrequent group. The unique predictors for specific wheeze trajectories included male sex, lower respiratory tract infections, and day care attendance for transient wheeze; paternal history of asthma, atopic sensitization, and child genetic risk score of asthma for intermediate wheeze; and maternal asthma for persistent wheeze. Blood eosinophil counts were higher in children with the intermediate wheeze trajectory than in those children with the other trajectories at the ages of 1 and 5 years. All wheeze trajectories were associated with decreased lung function and increased risk of asthma at age 5 years. CONCLUSIONS: We identified 4 distinct trajectories in children from 3 months to 5 years of age, reflecting different phenotypes of early childhood wheeze. These trajectories were characterized by different biologic and physiologic traits and risk factors.

Longitudinal body mass index trajectories at preschool age: children with rapid growth have differential composition of the gut microbiota in the first year of life.

BACKGROUND/OBJECTIVE: The steep rise in childhood obesity has emerged as a worldwide public health problem. The first 4 years of life are a critical window where long-term developmental patterns of body mass index (BMI) are established and a critical period for microbiota maturation. Understanding how the early-life microbiota relate to preschool growth may be useful for identifying preventive interventions for childhood obesity. We aim to investigate whether longitudinal shifts within the bacterial community between 3 months and 1 year of life are associated with preschool BMI z-score trajectories. METHODS: BMI trajectories from birth to 5 years of age were identified using group-based trajectory modeling in 3059 children. Their association with familial and environmental factors were analyzed. Infant gut microbiota at 3 months and 1 year was defined by 16S RNA sequencing and changes in diversity and composition within each BMIz trajectory were analyzed. RESULTS: Four BMIz trajectories were identified: low stable, normative, high stable, and rapid growth. Infants in the rapid growth trajectory were less likely to have been breastfed, and gained less microbiota diversity in the first year of life. Relative abundance of Akkermansia increased with age in children with stable growth, but decreased in those with rapid growth, abundance of Ruminococcus and Clostridium at 1 year were elevated in children with rapid growth. Children who were breastfed at 6 months had increased levels of Sutterella, and decreased levels of Ruminococcus and Clostridium. CONCLUSION: This study provides new insights into the relationship between the gut microbiota in infancy and patterns of growth in a cohort of preschool Canadian children. We highlight that rapid growth since birth is associated with bacteria shown in animal models to have a causative role in weight gain. Our findings support a novel avenue of research targeted on tangible interventions to reduce childhood obesity.

V367F Mutation in SARS-CoV-2 Spike RBD Emerging during the Early Transmission Phase Enhances Viral Infectivity through Increased Human ACE2 Receptor Binding Affinity.

The current pandemic of COVID-19 is caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The SARS-CoV-2 spike protein receptor-binding domain (RBD) is the critical determinant of viral tropism and infectivity. To investigate whether naturally occurring RBD mutations during the early transmission phase have altered the receptor binding affinity and infectivity, we first analyzed in silico the binding dynamics between SARS-CoV-2 RBD mutants and the human angiotensin-converting enzyme 2 (ACE2) receptor. Among 32,123 genomes of SARS-CoV-2 isolates (December 2019 through March 2020), 302 nonsynonymous RBD mutants were identified and clustered into 96 mutant types. The six dominant mutations were analyzed applying molecular dynamics simulations (MDS). The mutant type V367F continuously circulating worldwide displayed higher binding affinity to human ACE2 due to the enhanced structural stabilization of the RBD beta-sheet scaffold. The MDS also indicated that it would be difficult for bat SARS-like CoV to infect humans. However, the pangolin CoV is potentially infectious to humans. The increased infectivity of V367 mutants was further validated by performing receptor-ligand binding enzyme-linked immunosorbent assay (ELISA), surface plasmon resonance, and pseudotyped virus assays. Phylogenetic analysis of the genomes of V367F mutants showed that during the early transmission phase, most V367F mutants clustered more closely with the SARS-CoV-2 prototype strain than the dual-mutation variants (V367F+D614G), which may derivate from recombination. The analysis of critical RBD mutations provides further insights into the evolutionary trajectory of early SARS-CoV-2 variants of zoonotic origin under negative selection pressure and supports the continuing surveillance of spike mutations to aid in the development of new COVID-19 drugs and vaccines. IMPORTANCE A novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused the pandemic of COVID-19. The origin of SARS-CoV-2 was associated with zoonotic infections. The spike protein receptor-binding domain (RBD) is identified as the critical determinant of viral tropism and infectivity. Thus, whether mutations in the RBD of the circulating SARS-CoV-2 isolates have altered the receptor binding affinity and made them more infectious has been the research hot spot. Given that SARS-CoV-2 is a novel coronavirus, the significance of our research is in identifying and validating the RBD mutant types emerging during the early transmission phase and increasing human angiotensin-converting enzyme 2 (ACE2) receptor binding affinity and infectivity. Our study provides insights into the evolutionary trajectory of early SARS-CoV-2 variants of zoonotic origin. The continuing surveillance of RBD mutations with increased human ACE2 affinity in human or other animals is critical to the development of new COVID-19 drugs and vaccines against these variants during the sustained COVID-19 pandemic.

Lung clearance index predicts persistence of preschool wheeze.

BACKGROUND: The lung clearance index (LCI) is a measure of pulmonary function. Variable feasibility (50->80%) in preschool children has been reported. There are limited studies exploring its relationship to respiratory symptoms and how it predicts persistent wheeze. We aimed to assess the association with respiratory symptoms in preschool-aged children with LCI and determine its utility in predicting persistent wheeze. METHODS: LCI was measured in a subcohort of the CHILD Cohort Study at age 3 years using SF6  multiple breath washout test mass spectrometry. Respiratory symptom phenotypes at age 3 were derived from children's respiratory symptoms reported by their parents. Responses were used to categorize children into 4 symptom groups: recurrent wheeze (3RW), recurrent cough (3RC), infrequent symptoms (IS), and no current symptoms (NCS). At age 5 years, these children were seen by a specialist clinician and assessed for persistent wheeze (PW). RESULTS: At age 3 years, 69% (234/340) had feasible LCI. Excluding two children with missing data, 232 participants were categorized as follows: 33 (14%) 3RW; 28 (12%) 3RC; 17 (7%) IS; and 154 (66%) NCS. LCI z-score at age 3 years was highest in children with 3RW compared to 3RC (mean (SD): 1.14 (1.56) vs. 0.09 (0.95), p < .01), IS (mean (SD): -0.14 (0.59), p < .01), and NCS (mean (SD): -0.08 (1.06), p < .01). LCI z-score at age 3 was predictive of persistent wheeze at age 5 (PW) (AUROC: 0.87). CONCLUSIONS: LCI at age 3 was strongly associated with recurrent wheeze at age 3, and predictive of its persistence to age 5.

Modeling the conversion between specific IgE test platforms for nut allergens in children and adolescents.

BACKGROUND: Multiplex tests allow for measurement of allergen-specific IgE responses to multiple extracts and molecular allergens and have several advantages for large cohort studies. Due to significant methodological differences, test systems are difficult to integrate in meta-analyses/systematic reviews since there is a lack of datasets with direct comparison. We aimed to create models for statistical integration of allergen-specific IgE to peanut/tree nut allergens from three IgE test platforms. METHODS: Plasma from Canadian and Austrian children/adolescents with peanut/tree nut sensitization and a cohort of sensitized, high-risk, pre-school asthmatics (total n = 166) were measured with three R&D multiplex IgE test platforms: Allergy Explorer version 1 (ALEX) (Macro Array Dx), MeDALL-chip (Mechanisms of Development of Allergy) (Thermo Fisher), and EUROLINE (EUROIMMUN). Skin prick test (n = 51) and ImmunoCAP (Thermo Fisher) (n = 62) results for extracts were available in a subset. Regression models (Multivariate Adaptive Regression Splines, local polynomial regression) were applied if >30% of samples were positive to the allergen. Intra-test correlations between PR-10 and nsLTP allergens were assessed. RESULTS: Using two regression methods, we demonstrated the ability to model allergen-specific relationships with acceptable measures of fit (r2  = 94%-56%) for peanut and tree nut sIgE testing at the extract and molecular-level, in order from highest to lowest: Ara h 2, Ara h 6, Jug r 1, Ana o 3, Ara h 1, Jug r 2, and Cor a 9. CONCLUSION: Our models support the notion that quantitative conversion is possible between sIgE multiplex platforms for extracts and molecular allergens and may provide options to aggregate data for future meta-analysis.

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

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 (ntotal = 129) and recurrent wheeze between 2 and 5 years (ntotal = 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 (mediansubcohort = 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.

Neurodevelopmental outcome at 1 year in offspring of women with gestational diabetes mellitus.

OBJECTIVE: To study the metabolic derangements in the second half of pregnancy caused by gestational diabetes mellitus(GDM), on the short term neurodevelopment of infants. DESIGN: A prospective cohort study of 555 mother-child pairs were recruited, which included 177 GDM patients and 378 pregnant women with normal glucose tolerance as controls. Clinical and demographic characteristics were obtained at enrollment, birth and follow-up. Neurodevelopment was examined with the Bayley Scales of Infant Development V.1 mental development index (MDI) and psychomotor development index (PDI). Fatty acids (FA) were analyzed by gas chromatography mass spectrometry (GC-MS). RESULTS: Statistically significant differences were found between the two groups in fasting plasma glucose (FPG) and triglyceride (TG). The scores of MDI and PDI of control group were higher than those of GDM group. The regression analysis showed that maternal age and saturated fatty acid (SFA) were independently associated with lower scores on the MDI whereas gestational age and docosahexaenoic acid (DHA) were associated with higher scores; in addition, lower scores on the PDI were associated with FPG and neonatal weigh associated with higher scores. CONCLUSION: SFA, DHA and FPG as indicators of lipid metabolism were associated with neurodevelopmental outcome at 1 year in offspring of women with gestational diabetes mellitus. Control the level of blood glucose and lipid during pregnancy and the appropriate supplementation of DHA during pregnancy in the second half of pregnancy may be beneficial to the neurodevelopment of infants.

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

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 6 years 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 12 weeks 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 4.32 years (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.

Identification of the streptothricin and tunicamycin biosynthetic gene clusters by genome mining in Streptomyces sp. strain fd1-xmd.

The genus Streptomyces have been highly regarded for their important source of natural products. Combined with the technology of genome sequencing and mining, we could identify the active ingredients from fermentation broth quickly. Here, we report on Streptomyces sp. strain fd1-xmd, which was isolated from a soil sample collected in Shanghai. Interestingly, the fermentation broth derived from this strain demonstrated broad-spectrum antimicrobial activity against gram-positive bacteria, gram-negative bacteria, and eukaryotes. To identify the antimicrobial substances and their biosynthetic gene clusters, we sequenced the fd1-xmd strain and obtained a genome 7,929,999 bp in length. The average GC content of the chromosome was 72.5 mol%. Knockout experiments demonstrated that out of eight biosynthetic gene clusters we could identify, two are responsible for the biosynthesis of the antibiotics streptothricin (ST) and tunicamycin (TM). The ST biosynthetic gene cluster from fd1-xmd was verified via successful heterologous expression in Streptomyces coelicolor M1146. ST production had a yield of up to 0.5 g/L after the optimization of culture conditions. This study describes a novel producer of ST and TM and outlines the complete process undertaken for Streptomyces sp. strain fd1-xmd genome mining.

Maternal pre-pregnancy obesity and the risk of macrosomia: a meta-analysis.

PURPOSE: The aim of our meta-analysis was to explore whether pre-pregnancy obesity is regarded as an important risk factor for predicting macrosomia or not. METHODS: Three databases were systematically reviewed and reference lists of relevant articles were checked. Meta-analysis of published cohort studies comparing whether pre-pregnancy obesity was associated with macrosomia and adjusting for potential confounding factors. Calculations of pooled estimates were conducted in random-effect model. Heterogeneity was tested by using Chi-square test and I 2 statistics. Publication bias was estimated from Egger's test (linear regression method) and Begg's test (rank correlation method). RESULTS: Sixteen cohort studies met the inclusion criteria. The meta-analysis showed that pre-pregnancy obesity was associated with macrosomia as an important risk factor. The adjusted odds ratio was 1.93, 95% CI (1.65, 2.27) in random-effect model, stratified analyses showed no differences regarding different quality grade, definition of macrosomia, location of study and number of confounding factors adjusted for. There was no indication of a publication bias either from the result of Egger's test or Begg's test. CONCLUSION: Our findings indicated that pre-pregnancy obesity should be considered as an important risk factor for macrosomia. The effect of pre-pregnancy obesity on macrosomia need to be carefully assessed and monitored.

[The mechanisms of hippocampal neurons exposed to PBDE-209 induce oxidative stress and apoptosis].

OBJECTIVE: To determine the potential mechanisms of PBDE-209 induce apoptosis of the hippocampal neurons. METHODS: The primary fetal hippocampal neurons and hippocampus neurons cell line HT-22 were exposed to the concentrations of 0( solvent control), 6. 25, 12. 5, 25, 50 and 100 µg/mL PBDE-209 for 24 h. The SOD activity, MDA, NO and GSH contents in primary fetal hippocampal neurons were examined. The apoptosis of hippocampus neurons cell line HT-22 was observed using Annexin V/PI. The expressions of Bax, Bcl-2, CHOP, GRP78, PERK, Caspase-12 were measured by Western blot. RESULTS: The results showed that the difference was significant( P < 0. 05)of neuronal survival between the experimental groups and control groups and the difference was more obvious with the increasing dose of PBDE-209 which was observed in primary fetal hippocampal neurons and HT-22 cell lines. The increasing of Bax/Bcl-2( P < 0. 05), expression of CHOP and Caspase-12 in primary fetal hippocampal neurons( P < 0. 05), malondialdehyde( MDA) content and NO content( P < 0. 01) were also observed. Additionally, the results also indicated that PBDE-209 deceased activity of superoxidedismutase( SOD) and glutathione( GSH)( P < 0. 05). Meanwhile, the experiments of the HT-22 cell line showed that PBDE-209 could increase the expression of GRP78, PERK and Caspase-12 and apoptosis. CONCLUSION: The oxidative stress and endoplasmic reticulum stress may involve in the apoptosis of nerve cells caused by PBDE-209.

A trispecific antibody induces potent tumor-directed T-cell activation and antitumor activity by CD3/CD28 co-engagement.

Aim: A novel CD19xCD3xCD28 trispecific antibody with a tandem single-chain variable fragments (scFv) structure was developed for the treatment of B-cell malignancies. Methods: The trispecific antibody in inducing tumor-directed T-cell activation and cytotoxicity was evaluated in vitro and in vivo and compared with its bispecific counterpart BiTE-CD19xCD3 lacking a CD28-targeting domain. Results: The trispecific antibody with a co-stimulatory domain exhibited augmented T-cell activation and memory T-cell differentiation capability and it induced faster tumor cell lysis than the bispecific antibody. RNAseq analysis revealed that the trispecific antibody modulates CD3/TCR complex-derived signal and upregulates antiapoptotic factors to influence the survival of T cells. Conclusion: By CD3/CD28 co-engagement, the trispecific antibody demonstrated its advantages in T-cell immunity and potential use as a more powerful and long-lasting T-cell engager.

T-cell based immunotherapies are a type of treatment that stimulates the body's own immune system to fight cancer. They have grown in popularity in recent years and have had impressive results in cancer treatment. One type of T-cell immunotherapy is a T-cell engager antibody. This is a type of molecule that redirects the body's immune cells to recognise and kill cancer cells. In this study, we developed a new type of T-cell engager antibody to treat two types of blood and bone marrow cancer. The antibody works by joining immune cells and cancer cells close together, to help activate the immune cells for cancer killing. This new type of T-cell engager antibody worked better than previous versions. It helped the immune cells survive longer and kill cancer more effectively. This means the new antibody might be better at treating people who have these types of cancers, but more testing in humans needs to be done.

CTLA-4 polymorphisms and systemic lupus erythematosus (SLE): a meta-analysis.

The aim of this study was to summarize results on the association of cytotoxic T-lymphocyte antigen-4 (CTLA-4) promoter exon-1 +49 and 1722T/C polymorphism with systemic lupus erythematosus (SLE) susceptibility by using the meta-analysis. We searched all the publications about the association between CTLA-4) promoter exon-1 +49 and 1722T/C polymorphism and SLE from PubMed, Elsevier Science Direct, Chinese Biomedical Literature Database (CBM), Chinese National Knowledge Infrastructure (CNKI), and Wanfang (Chinese). Previous CTLA-4 association studies with SLE, however, have produced inconsistent results. We have performed a meta-analysis to better assess the purported associations. A total of 17 independent studies (to June 2012) testing association between one or more CTLA-4 polymorphisms and SLE were used in this analysis. We have compared allele and genotype frequencies at two polymorphic sites found in exon-1 (at +49) and the promoter region (at -1722). The data demonstrate that the exon-1 +49 polymorphism is associated with SLE susceptibility in Asian population. The overall risk, measured by odds ratio (OR), stratification by ethnicity indicates the exon-1 +49 GG+GA genotype is associated with SLE, at least in Asians (OR = 0.85, 95 % CI = 0.73-0.99, P = 0.04 for GG+GA vs. AA; OR = 0.85, 95 % CI = 0.72-1.00, P = 0.05 for AG vs. AA). Similar trends are found in allele-specific risk estimates and disease association. Overall, there was significant association between the 1722T/C polymorphism and overall SLE risks (OR = 0.78, 95 % CI = 0.63-0.97, P = 0.04 for GG+GA vs. AA, OR = 0.87, 95 % CI = 0.76-0.99, P = 0.04 for G vs. A) in Asian population.In summary, this meta-analysis demonstrates that the CTLA-4 promoter +49A/G and promoter -1722C/T polymorphism may confer susceptibility to SLE, especially in Asian-derived population.

Moderate-to-severe lower respiratory tract infection in early life is associated with increased risk of polysensitization and atopic dermatitis: Findings from the CHILD Study.

Background: Respiratory infections in infancy are associated with the development of allergic asthma and atopy. Delineating whether symptomatic infections are a marker of atopic predisposition or contribute to atopic development is important for preventive strategies. We hypothesized that early, severe lower respiratory tract infections (LRTIs) may be a risk factor for the development of atopic disease. Objective: Our aim was to determine whether clinically defined, moderate-to-severe LRTIs in infancy are associated with the development of atopic dermatitis and allergic sensitization at preschool age. Methods: LRTI timing and severity in the first 18 months of life was defined by using the Canadian Healthy Infant Longitudinal Development study questionnaires. Polysensitization and atopic dermatitis were determined by standardized skin prick testing and structured clinical assessments. Longitudinal associations between LRTI severity and clinical outcomes at ages 3 years and 5 years were determined by adjusted repeated measures generalized estimation equations. Results: Moderate-to-severe LRTIs were associated with increased odds of polysensitization (odds ratio = 1.91 [95% CI = 1.16-3.15]; P = .014) and atopic dermatitis (odds ratio = 2.19 [95% CI 1.41-3.39]; P < .001) as compared with the odds in children with no history of LRTI in the first 18 months of life. The association between moderate-to-severe LRTI and polysensitization or atopic dermatitis remained robust after adjusting for sex; study site; breast-feeding duration; and mother, father, or both-parent atopy or asthma. Conclusions: These results highlight severe infant LRTI as an important risk factor for allergic and atopic disease (ie, polysensitization and atopic dermatitis), and they suggest that this risk is independent of maternal in utero environment, both-parent history of asthma, and both-parent genetic predisposition.

Development of a Symptom-Based Tool for Screening of Children at High Risk of Preschool Asthma.

Importance: Despite advances in asthma therapeutics, the burden remains highest in preschool children; therefore, it is critical to identify primary care tools that distinguish preschool children at high risk for burdensome disease for further evaluation. Current asthma prediction tools, such as the modified Asthma Predictive Index (mAPI), require invasive tests, limiting their applicability in primary care and low-resource settings. Objective: To develop and evaluate the use of a symptom-based screening tool to detect children at high risk of asthma, persistent wheeze symptoms, and health care burden. Design, Setting, and Participants: The cohort for this diagnostic study included participants from the CHILD Study (n = 2511) from January 1, 2008, to December 31, 2012, the Raine Study from January 1, 1989, to December 31, 2012 (n = 2185), and the Canadian Asthma Primary Prevention Study (CAPPS) from January 1, 1989, to December 31, 1995 (n = 349), with active follow-up to date. Data analysis was performed from November 1, 2019, to May 31, 2022. Exposures: The CHILDhood Asthma Risk Tool (CHART) identified factors associated with asthma in patients at 3 years of age (timing and number of wheeze or cough episodes, use of asthma medications, and emergency department visits or hospitalizations for asthma or wheeze) to identify children with asthma or persistent symptoms at 5 years of age. Main Outcomes and Measures: Within the CHILD Study cohort, CHART was evaluated against specialist clinician diagnosis and the mAPI. External validation was performed in both a general population cohort (Raine Study [Australia]) and a high-risk cohort (CAPPS [Canada]). Predictive accuracy was measured by sensitivity, specificity, area under the receiver operating characteristic curve (AUROC), and positive and negative predicted values. Results: Among 2511 children (mean [SD] age at 3-year clinic visit, 3.08 [0.17] years; 1324 [52.7%] male; 1608 of 2476 [64.9%] White) with sufficient questionnaire data to apply CHART at 3 years of age, 2354 (93.7%) had available outcome data at 5 years of age. CHART applied in the CHILD Study at 3 years of age outperformed physician assessments and the mAPI in predicting persistent wheeze (AUROC, 0.94; 95% CI, 0.90-0.97), asthma diagnosis (AUROC, 0.73; 95% CI, 0.69-0.77), and health care use (emergency department visits or hospitalization for wheeze or asthma) (AUROC, 0.70; 95% CI, 0.61-0.78). CHART had a similar predictive performance for persistent wheeze in the Raine Study (N = 2185) in children at 5 years of age (AUROC, 0.82; 95% CI, 0.79-0.86) and CAPPS (N = 349) at 7 years of age (AUROC, 0.87; 95% CI, 0.80-0.94). Conclusions and Relevance: In this diagnostic study, CHART was able to identify children at high risk of asthma at as early as 3 years of age. CHART could be easily incorporated as a routine screening tool in primary care to identify children who need monitoring, timely symptom control, and introduction of preventive therapies.

Evaluating post-bronchodilator response in well-controlled paediatric severe asthma using hyperpolarised 129Xe-MRI: A pilot study.

INTRODUCTION: Pulmonary function tests (PFTs) are the main objective measures used to assess asthma in children. However, PFTs provide a global measure of lung function. Hyperpolarised xenon-129 magnetic resonance imaging (129Xe-MRI) can assess lung function spatially. This cross-sectional cohort study aimed to evaluate the use of 129Xe-MRI in detecting ventilation abnormalities in children with well-controlled severe asthma pre- and post-bronchodilator (BD). METHOD: Six healthy children (aged 11 ± 3) and six with well-controlled severe asthma (14 ± 1) underwent spirometry, multiple breath washout (MBW), and 129Xe-MRI. These tests were repeated post-BD in the asthma cohort. Image analysis was performed in MATLAB. Wilcoxon signed-rank test, repeated measures analysis of variance (ANOVA), and Spearman's rank correlation coefficient were used for statistical analysis. RESULTS: A significantly higher number of ventilation defects were found in the asthma cohort pre-BD compared to the healthy participants and post-BD within the asthma cohort (p = 0.02 and 0.01). A greater number of wedge-shaped defects were detected in the asthma cohort pre-BD compared to healthy participants and post-BD within the asthma cohort (p = 0.01 and 0.008, respectively). 129Xe ventilation defect percentage (VDP) and coefficient of variation (CoV) were significantly higher in the asthma cohort pre-BD compared to the healthy cohort (p = 0.006 for both). VDP and CoV were reduced significantly post-BD in the asthma cohort, to a level where there was no longer a significant difference between the two cohorts. CONCLUSION: 129Xe-MRI is a sensitive marker of ventilation inhomogeneity in paediatric severe asthma and may potentially be used as a biomarker to assess disease progression and therapeutic response.