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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.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.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.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.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.

ImportanceDespite 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.ObjectiveTo 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 ParticipantsThe 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.ExposuresThe 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 MeasuresWithin 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.ResultsAmong 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 RelevanceIn 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.

BACKGROUND Maternal pre-postnatal psychosocial distress increases the risk for childhood allergic disease. This may occur through a host immunity pathway that involves intestinal secretory immunoglobulin A (sIgA). Experimental animal models show changes in the gut microbiome and immunity of offspring when exposed to direct or prenatal maternal stress, but little is known in humans. OBJECTIVE We determined the association between maternal depression and stress symptom trajectories and infant fecal sIgA concentrations. METHODS 1043 term infants from the Canadian Healthy Infant Longitudinal Development (CHILD) birth cohort were studied. Trajectories of maternal perceived stress and depression were based on scored scales administered in pregnancy and postpartum. sIgA was quantified in infant stool (mean age 3.7 months) with Immundiagnostik ELISA. Linear regression and logistic regression were employed to test associations. RESULTS Very low fecal sIgA concentrations were more common in infants of mothers in the antepartum and persistent depression trajectories (6% and 2% of women, respectively). Independent of breastfeeding status at fecal sampling, infant antibiotic exposure or other covariates, the antepartum depressive symptom trajectory was associated with reduced mean infant sIgA concentrations (β=-0.07, P

Background Fatty acids are a vital component of human milk. They influence infant neurodevelopment and immune function, and they provide ∼50% of milk's energy content. Objectives The objectives of this study were to characterize the composition of human milk fatty acids in a large Canadian birth cohort and identify factors influencing their variability. Methods In a subset of the CHILD cohort (n = 1094), we analyzed milk fatty acids at 3-4 mo postpartum using GLC. Individual and total SFAs, MUFAs, and n-3 and n-6 PUFAs were analyzed using SD scores and principal component analysis (PCA). Maternal diet, sociodemographic, health, and environmental factors were self-reported. Single-nucleotide polymorphisms were assessed in the fatty acid desaturase 1 (FADS1-rs174556) and 2 (FADS2-rs174575) genes. Results Fatty acid profiles were variable, with individual fatty acid proportions varying from 2- to >30-fold between women. Using PCA, we identified 4 milk fatty acid patterns: "MUFA and low SFA," "high n-6 PUFA," "high n-3 PUFA," and "high medium-chain fatty acids." In multivariable-adjusted analyses, fish oil supplementation and fatty cold water fish intake were positively associated with DHA and the "high n-3 PUFA" pattern. Mothers carrying the minor allele of FADS1-rs174556 had lower proportions of arachidonic acid (ARA; 20:4n-6). Independent of selected dietary variables and genetic variants, Asian ethnicity was associated with higher linoleic acid (18:2n-6) and total n-3 PUFAs. Ethnic differences in ARA were explained by FADS1 genotype. Maternal obesity was independently associated with higher total SFAs, the "high medium-chain fatty acid" pattern, and lower total MUFAs. Lactation stage, season, study site, and maternal education were also independently associated with some milk fatty acids. No associations were observed for maternal age, parity, delivery mode, or infant sex. Conclusions This study provides unique insights about the "normal" variation in the composition of human milk fatty acids and the contributing dietary, genetic, sociodemographic, health, and environmental factors. Further research is required to assess implications for infant health.

Few studies have examined phthalate exposure during infancy and early life, critical windows of development. The Canadian Healthy Infant Longitudinal Development (CHILD) study, a population-based birth cohort, ascertained multiple exposures during early life. To characterize exposure to phthalates during infancy and early childhood. Environmental questionnaires were administered, and urine samples collected at 3, 12, and 36 months. In the first 1578 children, urine was analyzed for eight phthalate metabolites: mono-methyl phthalate (MMP), mono-ethyl phthalate (MEP), mono-butyl phthalate (MBP), mono-benzyl phthalate (MBzP), mono-2-ethylhexyl phthalate (MEHP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), and mono-3-carboxypropyl phthalate (MCPP). Geometric mean (GM) concentrations were calculated by age, together with factors that may influence concentrations. Trends with age were examined using mixed models and differences within factors examined using ANOVA. The highest urinary concentration was for the metabolite MBP at all ages (GM: 15–32 ng/mL). Concentrations of all phthalate metabolites significantly increased with age ranging from GM: 0.5–15.1 ng/mL at 3 months and 1.9–32.1 ng/mL at 36 months. Concentrations of all metabolites were higher in the lowest income categories except for MEHP at 3 months, among children with any breastfeeding at 12 months, and in urine collected on dates with warmer outdoor temperatures (>17 °C), except for MBzP at 3 months and MEHP at 3 and 12 months. No consistent differences were found by gender, study site, or maternal age. Higher phthalate metabolite concentrations were observed among children in lower income families. Examination of factors associated with income could inform interventions aimed to reduce infant phthalate exposure.

Objectives Primary: examine associations between meeting the 24-Hour Movement Guidelines for the Early Years and behavioral and emotional problems in a large sample of 3-year-old children. Secondary: determine the proportion of children meeting the Canadian 24-Hour Movement Guidelines. Design Cross-sectional. Methods Participants were 3-year olds (n = 539) from the Edmonton site of the Canadian Healthy Infant Longitudinal Development (CHILD) birth cohort. Physical activity and sleep duration were accelerometer-derived while screen time was parent-reported. Meeting the overall guidelines was defined as: (1) ≥180 min/day of total physical activity, including 60 min/day of moderate- to vigorous-intensity physical activity, (2) ≤1 h/day of screen time, and (3) 10–13 h of sleep per 24-hour period. Externalizing, internalizing, and total problem scores (lower scores representing fewer problems) were calculated from the parent-reported Child Behavior Checklist (CBCL). Descriptive statistics and linear regression models were completed. Results Only 5% of children met the overall guidelines (all three recommendations), with 19.3%, 50.5%, and 83.1% meeting the physical activity, screen time, and sleep recommendations, respectively. Meeting more recommendations was associated with lower scores for total (B = −1.78, 95%CI: −3.03, −0.54), externalizing (B = −1.51, 95%CI: −2.80, −0.22) and internalizing (B = −1.35, 95%CI: −2.60, −0.01) problems. Similar findings were also observed for the specific combinations of: (1) physical activity and screen time and (2) sleep duration and screen time. Conclusions Meeting more recommendations within the 24-hour Movement Guidelines was associated with fewer behavioral and emotional problems at 3-years. Few 3-year-olds met the overall guidelines. Findings support an integrated approach for healthy growth and development.

Rationale Sleep duration is critical to growth, learning, and immune function development in infancy. Strategies to ensure that national recommendations for sleep duration in infants are met require knowledge of perinatal factors that affect infant sleep. Objectives To investigate the mechanistic pathways linking maternal education and infant sleep. Methods An observational study was conducted on 619 infants whose mothers were enrolled at the Edmonton site of the CHILD birth cohort. Infant sleep duration at three months was assessed using the Brief Infant Sleep Questionnaire. Maternal education was collected via maternal report. Prenatal and postnatal depression scores were obtained from the 20-item Center for Epidemiologic Studies Depression Scale (CES-D). Birth records and maternal report were the source of covariate measures. Mediation analysis (PROCESS v3.0) was used to examine the indirect effects of maternal education on infant sleep duration mediated through prenatal depression and birth mode. Measurements and main results At three months of age, infants slept on average 14.1 h. Lower maternal education and prenatal depression were associated with significantly shorter infant sleep duration. Emergency cesarean section birth was associated with 1-hour shorter sleep duration at three months compared to vaginal birth [without intrapartum antibiotic prophylaxis] (β: −0.99 h; 95% CI: −1.51, −0.48). Thirty percent of the effect of lower maternal education on infant total sleep duration was mediated sequentially through prenatal depression and birth mode (Total Indirect Effects: −0.12, 95% CI: −0.22, −0.03, p Conclusions Prenatal depression and birth mode sequentially mediate the effect of maternal education on infant sleep duration.

The objective of this population-based retrospective cohort study was to identify factors associated with lifespan in pet dogs evaluated at primary care veterinary hospitals. Dogs ≥3 mo of age that visited any of 787 US hospitals at least twice from January 1, 2010, through December 31, 2012, were included. Survival curves were constructed for dogs by reproductive status, breed, body size, and purebreed (versus mixed-breed) status. Multivariate Cox proportional hazard regression was performed to identify factors associated with lifespan. There were 2,370,078 dogs included in the study, of whom 179,466 (7.6%) died during the study period. Mixed-breed dogs lived significantly longer than purebred dogs, and this difference was more pronounced as body size increased. Controlling for other factors, dogs of either sex had a greater hazard of death over the study follow-up period if sexually intact rather than gonadectomized. For dogs who lived to 2 yr of age, the hazard of death decreased with increasing frequency of dental scaling. Our findings support previous reports of the impact of body size and gonadectomy on lifespan and provide new evidence in support of ultrasonic dental scaling and mixed breeding.

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.

Inhibitory interneurons integrate into developing circuits in specific ratios and distributions. In the neocortex, inhibitory network formation occurs concurrently with the apoptotic elimination of a third of GABAergic interneurons. The cell surface molecules that select interneurons to survive or die are unknown. Here, we report that members of the clustered Protocadherins (cPCDHs) control GABAergic interneuron survival during developmentally-regulated cell death. Conditional deletion of the gene cluster encoding the γ-Protocadherins(Pcdhgs)from developing GABAergic neurons in mice of either sex causes a severe loss of inhibitory populations in multiple brain regions and results in neurologic deficits such as seizures. By focusing on the neocortex and the cerebellar cortex, we demonstrate that reductions of inhibitory interneurons result from elevated apoptosis during the critical postnatal period of programmed cell death (PCD). By contrast, cortical interneuron (cIN) populations are not affected by removal ofPcdhgsfrom pyramidal neurons or glial cells. Interneuron loss correlates with reduced AKT signaling inPcdhgmutant interneurons, and is rescued by genetic blockade of the pro-apoptotic factor BAX. Together, these findings identify the PCDHGs as pro-survival transmembrane proteins that select inhibitory interneurons for survival and modulate the extent of PCD. We propose that the PCDHGs contribute to the formation of balanced inhibitory networks by controlling the size of GABAergic interneuron populations in the developing brain.SIGNIFICANCE STATEMENTA pivotal step for establishing appropriate excitatory-inhibitory ratios is adjustment of neuronal populations by cell death. In the mouse neocortex, a third of GABAergic interneurons are eliminated by BAX-dependent apoptosis during the first postnatal week. Interneuron cell death is modulated by neural activity and pro-survival pathways but the cell-surface molecules that select interneurons for survival or death are unknown. We demonstrate that members of the cadherin superfamily, the clustered γ-Protocadherins (PCDHGs), regulate the survival of inhibitory interneurons and the balance of cell death. Deletion of thePcdhgsin mice causes inhibitory interneuron loss in the cortex and cerebellum, and leads to motor deficits and seizures. Our findings provide a molecular basis for controlling inhibitory interneuron population size during circuit formation.

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 Clostridioides difficile 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 C. difficile 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 Megamonas (q = 0.01) in gut microbiota. Among those exclusively breastfed, maternal prenatal supplementation was associated with lower abundance of Bilophila (q = 0.01) and of Lachnospiraceae (q = 0.02) but higher abundance of Haemophilus (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 C. difficile colonization, after adjusting for breastfeeding status and other factors. However, maternal consumption of vitamin-D fortified milk reduced the likelihood of C. difficile 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.

Objectives Prenatal maternal metabolic problems such as pre-pregnancy adiposity, excess gestational weight gain, and gestational diabetes mellitus (GDM) are associated with an increased risk of psychopathology in offspring. We examined whether these exposures were linked to symptoms of emotional and behavioral problems in offspring at 2 years of age, or if associations were due to confounding variables. Methods Data from 815 mother–child pairs enrolled at the Edmonton site of the Canadian Healthy Infant Longitudinal Development cohort were used to examine associations between gestational metabolic complications and scores on the externalizing and internalizing scales of the Child Behavior Checklist (CBCL-1½ to 5) at age two. Associations between maternal metabolic complications and offspring psychopathology were assessed before and after adjustment for gestational diet, socioeconomic status (SES), postpartum depression (PPD), prenatal smoking and breastfeeding. Results Pre-pregnancy body mass index and GDM, but not gestational weight gain, predicted more offspring externalizing and internalizing problems. However, after adjustment for confounding variables, these associations were no longer statistically significant. Post-hoc analyses revealed that gestational diet accounted for unique variance in both externalizing (semi-partial rdiet = − 0.20, p

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.

BACKGROUND: Comprehensive longitudinal studies are important for understanding the complex risk factors, pathways, exposures and interactions that lead to the development and persistence of asthma. We aimed to examine associations between use of household cleaning products in early life and childhood respiratory and allergic disease using data from the Canadian Healthy Infant Longitudinal Development (CHILD) Cohort Study. METHODS: We summed responses from parental questionnaires that indicated the frequency of use of 26 household cleaning products in the homes of 2022 children from this birth cohort when they were 3–4 months of age to create a cumulative Frequency of Use Score (FUS). We used multivariable logistic regression models to assess whether frequent compared with less frequent use was associated with recurrent wheeze, atopy or asthma diagnosis, as defined by the questionnaire and clinical assessments at age 3 years. Data were collected between 2008 and 2015. RESULTS: Children in homes with a higher frequency of use of cleaning products in infancy, as determined by an interquartile range increase, had higher odds of recurrent wheeze (adjusted odds ratio [OR] 1.35, 95% confidence interval [CI] 1.11–1.64), recurrent wheeze with atopy (adjusted OR 1.49, 95% CI 1.02–2.16) and asthma diagnosis (adjusted OR 1.37, 95% CI 1.09–1.70), but no increase in the odds of atopy at age 3 years (adjusted OR 1.14, 95% CI 0.96–1.35). Compared with the lowest tertile of FUS exposure, infants in the highest tertile had higher odds of acquiring asthma. Stratification of the results showed that females had higher ORs than males for all outcomes, although the p values for this sex difference did not reach statistical significance. INTERPRETATION: Frequent use of household cleaning products in early life was associated with an increased risk for childhood wheeze and asthma but not atopy at age 3 years. Our findings add to the understanding of how early life exposures to cleaning products may be associated with the development of allergic airway disease and help to identify household behaviours as a potential area for intervention.

Background Persisting atopic dermatitis (AD) is known to be associated with more serious allergic diseases at later ages; however, making an accurate diagnosis during infancy is challenging. We assessed the diagnostic performance of questionnaire-based AD measures with criteria-based in-person clinical assessments at age 1 year and evaluated the ability of these diagnostic methods to predict asthma, allergic rhinitis and food allergies at age 5 years. Methods Data relate to 3014 children participating in the Canadian Healthy Infant Longitudinal Development (CHILD) Study who were directly observed in a clinical assessment by an experienced healthcare professional using the UK Working Party criteria. The majority (2221; 73.7%) of these children also provided multiple other methods of AD ascertainment: a parent reporting a characteristic rash on a questionnaire, a parent reporting the diagnosis provided by an external physician and a combination of these two reports. Results Relative to the direct clinical assessment, the area under the Receiver Operating Characteristic curve for a parental report of a characteristic rash, reported physician diagnosis and a combination of both were, respectively, 0.60, 0.69 and 0.70. The strongest predictor of asthma at 5 years was AD determined by criteria-based in-person clinical assessment followed by the combination of parental and physician report. Conclusions These findings suggest that questionnaire data cannot accurately substitute for assessment by experienced healthcare professionals using validated criteria for diagnosis of atopic dermatitis. Combining the parental report with diagnosis by a family physician might sometimes be appropriate (eg to avoid costs of a clinical assessment).

Background Both short sleep duration and sleep-disordered breathing (SDB) are associated with poor neurocognitive development. However, the co-contributions of short sleep duration and SDB on neurodevelopment in pre-school children are relatively unknown. Methods We assessed both sleep duration and SDB by quarterly questionnaire from three months to two years of age among Canadian Healthy Infant Longitudinal Development (CHILD) birth cohort participants. Group-based modeling determined trajectories of total, daytime, and nighttime sleep duration and SDB. Linear regression was used to assess the impact of sleep duration and SDB trajectories on cognitive (primary outcome) and language (secondary) development at two years of age as assessed by the Bayley Scale of Infant Development (BSID-III) (mean 100; standard deviation of 15). Results Of the 822 CHILD Edmonton participants, 703 (86%) were still enrolled at two years of age with 593 having BSID-III data at two years of age. Trajectory analysis identified four total sleep durations phenotypes [short sleepers (17.9%), decline to short sleepers (21.1%), intermediate sleepers (36.9%) and long sleepers (24.1%)]. Compared to children with intermediate sleep durations, short sleepers had a 5.2-point lower cognitive development score at two years of age [standard error (SE) 1.7; p = 0.002]. Nocturnal sleep duration, compared to daytime sleep duration had the greatest effect on cognitive development. We also identified three SDB symptom trajectories [early-onset SDB (15.7%), late-onset SDB (14.2%), and persistent SDB (5.3%)] and 79.5% of children had no SDB symptoms. Children with persistent SDB also had a 5.3-point lower language score (SE 2.7; p = 0.05) compared to children with no SDB. SDB trajectories were not associated with cognitive development. Conclusion In a population-representative birth cohort study, both short sleep duration and SDB were associated with adverse neurodevelopment at two years of age. Children with short nighttime sleep duration had lowered cognitive and language scores and children with persistent SDB also had lower language scores.

Childhood sleep-disordered breathing (SDB) symptoms may comprise multiple phenotypes depending on craniofacial anatomy, tonsil and adenoid growth, body habitus, and rhinitis symptoms. The primary objective of this study is to identify and characterize the different SDB phenotypes to two years of age.Data from 770 infants in the Edmonton sub-cohort of the Canadian Healthy Infant Longitudinal Study (CHILD) were analyzed to identify SDB phenotypes based on age of onset and duration of symptoms. Parents completed the 22-item sleep-related breathing disorder (SRBD) scale. Children with a SRBD ratio greater than 0.33 were considered positive for SDB at each quarterly assessment between three months and two years. The STATA Proc trajectory extension identified SDB phenotypes based on their age of onset and duration of symptoms and attributed the percentage chance of a participant being assigned to each phenotype. Multivariate linear regression identified factors associated with increased risk of being assigned to each SDB phenotype.Trajectory analysis identified four phenotypes: no SDB (65.7%), early-onset SDB (15.7%) with peak symptoms at nine months, late-onset SDB (14.2%) with peak symptoms at 18 months, and persistent SDB (5.3%) with symptoms from 3 to 24 months. Rhinitis was associated with all three SDB symptom trajectories (p 0.05). Children with gastroesophageal reflux disease presented with early (p = 0.03) and late SDB (p 0.001). Maternal obstructive sleep apnea syndrome (OSAS) was associated with persistent (p = 0.01) and late SDB (p 0.001). Atopy (positive skin prick test at one year) was associated with persistent SDB (p = 0.04). Infants born prior to 36.5 weeks gestational age were more likely to present with late SDB (p = 0.03).Childhood SDB symptoms, rather than being a homogenous disorder, may comprise multiple overlapping phenotypes each with unique risk factors.

Background Breastfeeding has many established health benefits for women and children. We examined the association between maternal education, newborn feeding in hospital, and long-term breastfeeding duration. Methods We studied 3195 Canadian mother-infant dyads in the CHILD pregnancy cohort. Newborn feeding was documented from hospital records. Caregivers reported sociodemographic factors and infant feeding at 3, 6, 12, 18, and 24 months. Results Overall, 97% of newborns initiated breastfeeding and 74% were exclusively breastfed in hospital. Exclusively breastfed newborns were ultimately breastfed longer compared with those who received formula supplementation during their hospital stay (median 11.0 vs 7.0 months, P

The clustered protocadherins (Pcdhs) comprise 58 cadherin-related proteins encoded by three tandemly arrayed gene clusters,Pcdh-α,Pcdh-β, andPcdh-γ (Pcdha,Pcdhb, andPcdhg, respectively). Pcdh isoforms from different clusters are combinatorially expressed in neurons. They form multimers that interact homophilically and mediate a variety of developmental processes, including neuronal survival, synaptic maintenance, axonal tiling, and dendritic self-avoidance. Most studies have analyzed clusters individually. Here, we assessed functional interactions betweenPcdhaandPcdhgclusters. To circumvent neonatal lethality associated with deletion ofPcdhgs, we used Crispr-Cas9 genome editing in mice to combine a constitutivePcdhamutant allele with a conditionalPcdhgallele. We analyzed roles of Pcdhas and Pcdhgs in the retina and cerebellum from mice (both sexes) lacking one or both clusters. In retina, Pcdhgs are essential for survival of inner retinal neurons and dendritic self-avoidance of starburst amacrine cells, whereas Pcdhas are dispensable for both processes. Deletion of bothPcdhaandPcdhgclusters led to far more dramatic defects in survival and self-avoidance thanPcdhgdeletion alone. Comparisons of an allelic series of mutants support the conclusion that Pcdhas and Pcdhgs function together in a dose-dependent and cell-type-specific manner to provide a critical threshold of Pcdh activity. In the cerebellum, Pcdhas and Pcdhgs also cooperate to mediate self-avoidance of Purkinje cell dendrites, with modest but significant defects in either single mutant and dramatic defects in the double mutant. Together, our results demonstrate complex patterns of redundancy between Pcdh clusters and the importance of Pcdh cluster diversity in postnatal CNS development.SIGNIFICANCE STATEMENTThe formation of neural circuits requires diversification and combinatorial actions of cell surface proteins. Prominent among them are the clustered protocadherins (Pcdhs), a family of ∼60 neuronal recognition molecules. Pcdhs are encoded by three closely linked gene clusters calledPcdh-α,Pcdh-β, andPcdh-γ. The Pcdhs mediate a variety of developmental processes, including neuronal survival, synaptic maintenance, and spatial patterning of axons and dendrites. Most studies to date have been limited to single clusters. Here, we used genome editing to assess interactions betweenPcdh-α andPcdh-γ gene clusters. We examined two regions of the CNS, the retina and cerebellum and show that the 14 α-Pcdhs and 22 γ-Pcdhs act synergistically to mediate neuronal survival and dendrite patterning.

Objectives To identify distinctive patterns of respiratory-related health services use (HSU) between birth and 3 years of age, and to examine associated symptom and risk profiles. Methods This study included 729 mother and child pairs enrolled in the Toronto site of the Canadian Healthy Infant Longitudinal Development study in 2009-2012; they were linked to Ontario health administrative databases (2009-2016). A model-based cluster analysis was performed to identify distinct groups of children who followed a similar pattern of respiratory-related HSU between birth and 3 years of age, regarding hospitalization, emergency department (ED) and physician office visits for respiratory conditions and total health care costs (2016 Canadian dollars). Results The majority (estimated cluster weight = 0.905) showed a pattern of low and stable respiratory care use (low HSU) while the remainder (weight = 0.095) showed a pattern of high use (high HSU). From 0 to 3 years of age, the low- and high-HSU groups differed in mean trajectories of total health care costs ($783 per 6 months decreased to $114, vs $1796 to $177, respectively). Compared to low-HSU, the high-HSU group was associated with a constant risk of hospitalizations, early high ED utilization and physician visits for respiratory problems. The two groups differed significantly in the timing of wheezing (late onset in low-HSU vs early in high-HSU) and future total costs (stable vs increased). Conclusions One in ten children had high respiratory care use in early life. Such information can help identify high-risk young children in a large population, monitor their long-term health, and inform resource allocation.

Asthma is a chronic disease of the airways affecting one in ten children in Westernized countries. Recently, our group showed that specific bacterial genera in early life are associated with atopy and wheezing in 1-year-old children. However, little is known about the link between the early life gut microbiome and the diagnosis of asthma in preschool age children. To determine the role of the gut microbiota in preschool age asthma, children up to 4 years of age enrolled in the Canadian Healthy Infant Longitudinal Development (CHILD) study were classified as asthmatic (n=39) or matched healthy controls (n=37). 16S rRNA sequencing and quantitative PCR (qPCR) were used to analyse the composition of the 3-month and 1-year gut microbiome of these children. At 3 months the abundance of the genus, Lachnospira (L), was decreased (P=0.008), whereas the abundance of the species, Clostridium neonatale (C), was increased (P=0.07) in asthmatics. Quartile analysis of stool composition at 3-months revealed a negative association between the ratio of these two bacteria (L/C) and asthma risk by 4 years of age [quartile 1: odds ratio (OR)=15, P=0.02, CI (confidence interval)= 1.8–124.7; quartile 2: OR=1.0, ns; quartile 3: OR=0.37, ns]. We conclude that opposing shifts in the relative abundances of Lachnospira and C. neonatale in the first 3 months of life are associated with preschool age asthma, and that the L/C ratio may serve as a potential early life biomarker to predict asthma development.

BackgroundPre-school children spend an average of two-hours daily using screens. We examined associations between screen-time on pre-school behavior using data from the Canadian Healthy Infant Longitudinal Development (CHILD) study.MethodsCHILD participant parents completed the Child Behavior Checklist (CBCL) at five-years of age. Parents reported their child's total screen-time including gaming and mobile devices. Screen-time was categorized using the recommended threshold of two-hours/day for five-years or one-hour/day for three-years. Multiple linear regression examined associations between screen-time and externalizing behavior (e.g. inattention and aggression). Multiple logistic regression identified characteristics of children at risk for clinically significant externalizing problems (CBCL T-score≥65).ResultsScreen-time was available for over 95% of children (2,322/2,427) with CBCL data. Mean screen-time was 1·4 hours/day (95%CI 1·4, 1·5) at five-years and 1·5 hours/day (95%CI: 1·5, 1·6) at three-years. Compared to children with less than 30-minutes/day screen-time, those watching more than two-hours/day (13·7%) had a 2·2-point increase in externalizing T-score (95%CI: 0·9, 3·5, p≤0·001); a five-fold increased odd for reporting clinically significant externalizing problems (95%CI: 1·0, 25·0, p = 0·05); and were 5·9 times more likely to report clinically significant inattention problems (95%CI: 1·6, 21·5, p = 0·01). Children with a DSM-5 ADHD T-score above the 65 clinical cut-off were considered to have significant ADHD type symptoms (n = 24). Children with more than 2-hours of screen-time/day had a 7·7-fold increased risk of meeting criteria for ADHD (95%CI: 1·6, 38·1, p = 0·01). There was no significant association between screen-time and aggressive behaviors (p>0.05).ConclusionIncreased screen-time in pre-school is associated with worse inattention problems.

Objectives The aim of the study was to identify any dietary, signalment, geographic and clinical factors associated with hematuric struvite crystalluria (HSC) in a population of cats that visit general care veterinary hospitals in the USA. Methods In total, 4032 cats that had a first-time diagnosis of HSC and 8064 control cats with no history of hematuria or crystalluria were identified from medical records of all cats examined between 2007 and 2011 at 790 US veterinary hospitals. Extracted variables included age, sex, neuter status, breed, diet, urinalysis results and history of cystitis. Potential associations between these variables and HSC were estimated. Results Controlling for other factors, young cats fed a dry diet had an increased likelihood of HSC relative to young cats fed a non-dry diet. However, as age increased, the likelihood of HSC declined for cats fed a dry diet and increased for cats fed a non-dry diet. Moreover, the odds of HSC were significantly greater when cats were unneutered (vs neutered; odds ratio [OR] 45.52) or had a thin (vs heavy) body condition (OR 23.81), diagnosis of cystitis (OR 2.84), urine protein concentration >30 mg/dl (OR 4.72), alkaline (vs neutral) urine pH (OR 3.34), pyuria (OR 23.67) or bacteriuria (OR 2.24). Conclusions and relevance The present study provides estimates of the strengths of association between HSC and certain signalment and clinical characteristics of cats. This information could help clinicians to perform a more directed screening for struvite crystalluria in certain cat populations. Follow-up studies that build on the findings of this study could explore the clinical importance of HSC in cats.

OBJECTIVES: Studies addressing breastfeeding and obesity rarely document the method of breast milk feeding, type of supplementation, or feeding in hospital. We investigated these practices in the CHILD birth cohort. METHODS: Feeding was reported by mothers and documented from hospital records. Weight and BMI z scores (BMIzs) were measured at 12 months. Analyses controlled for maternal BMI and other confounders. RESULTS: Among 2553 mother-infant dyads, 97% initiated breastfeeding, and the median breastfeeding duration was 11.0 months. Most infants (74%) received solids before 6 months. Among “exclusively breastfed” infants, 55% received some expressed breast milk, and 27% briefly received formula in hospital. Compared with exclusive direct breastfeeding at 3 months, all other feeding styles were associated with higher BMIzs: adjusted β: +.12 (95% confidence interval [CI]: .01 to .23) for some expressed milk, +.28 (95% CI: .16 to .39) for partial breastfeeding, and +.45 (95% CI: .30 to .59) for exclusive formula feeding. Brief formula supplementation in hospital did not alter these associations so long as exclusive breastfeeding was established and sustained for at least 3 months. Formula supplementation by 6 months was associated with higher BMIzs (adjusted β: +.25; 95% CI: .13 to .38), whereas supplementation with solid foods was not. Results were similar for weight gain velocity. CONCLUSIONS: Breastfeeding is inversely associated with weight gain velocity and BMI. These associations are dose dependent, partially diminished when breast milk is fed from a bottle, and substantially weakened by formula supplementation after the neonatal period.

Summary Breastmilk contains a complex community of bacteria that may help seed the infant gut microbiota. The composition and determinants of milk microbiota are poorly understood. Among 393 mother-infant dyads from the CHILD cohort, we found that milk microbiota at 3–4 months postpartum was dominated by inversely correlated Proteobacteria and Firmicutes, and exhibited discrete compositional patterns. Milk microbiota composition and diversity were associated with maternal factors (BMI, parity, and mode of delivery), breastfeeding practices, and other milk components in a sex-specific manner. Causal modeling identified mode of breastfeeding as a key determinant of milk microbiota composition. Specifically, providing pumped breastmilk was consistently associated with multiple microbiota parameters including enrichment of potential pathogens and depletion of bifidobacteria. Further, these data support the retrograde inoculation hypothesis, whereby the infant oral cavity impacts the milk microbiota. Collectively, these results identify features and determinants of human milk microbiota composition, with potential implications for infant health and development.

Importance The effect of neonatal and infant feeding practices on childhood obesity is unclear. The gut microbiome is strongly influenced by feeding practices and has been linked to obesity. Objective To characterize the association between breastfeeding, microbiota, and risk of overweight during infancy, accounting for the type and timing of supplementary feeding. Design, Setting, and Participants In this study of a subset of 1087 infants from the prospective CHILD pregnancy cohort, mothers were recruited between January 1, 2009, and December 31, 2012. Statistical analysis was performed from February 1 to December 20, 2017. Main Outcomes and Measures Feeding was reported by mothers and documented from hospital records. Fecal microbiota at 3 to 4 months (from 996 infants) and/or 12 months (from 821 infants) were characterized by 16S ribosomal RNA sequencing. Infants with a weight for length exceeding the 85th percentile were considered to be at risk for overweight. Results There were 1087 infants in the study (507 girls and 580 boys); at 3 months, 579 of 1077 (53.8%) were exclusively breastfed according to maternal report. Infants who were exclusively formula fed at 3 months had an increased risk of overweight in covariate-adjusted models (53 of 159 [33.3%] vs 74 of 386 [19.2%]; adjusted odds ratio, 2.04; 95% CI, 1.25-3.32). This association was attenuated (adjusted odds ratio, 1.33; 95% CI, 0.79-2.24) after further adjustment for microbiota features characteristic of formula feeding at 3 to 4 months, including higher overall richness and enrichment of Lachnospiraceae. A total of 179 of 579 infants who were exclusively breastfed (30.9%) received formula as neonates; this brief supplementation was associated with lower relative abundance of Bifidobacteriaceae and higher relative abundance of Enterobacteriaceae at 3 to 4 months but did not influence the risk of overweight. At 12 months, microbiota profiles differed significantly according to feeding practices at 6 months; among partially breastfed infants, formula supplementation was associated with a profile similar to that of nonbreastfed infants (higher diversity and enrichment of Bacteroidaceae ), whereas the introduction of complementary foods without formula was associated with a profile more similar to that of exclusively breastfed infants (lower diversity and enrichment of Bifidobacteriaceae and Veillonellaceae ). Microbiota profiles at 3 months were more strongly associated with risk of overweight than were microbiota profiles at 12 months. Conclusions and Relevance Breastfeeding may be protective against overweight, and gut microbiota may contribute to this effect. Formula feeding appears to stimulate changes in microbiota that are associated with overweight, whereas other complementary foods do not. Subtle microbiota differences emerge after brief exposure to formula in the hospital. These results identify important areas for future research and distinguish early infancy as a critical period when transient gut dysbiosis may lead to increased risk of overweight.

OBJECTIVE To examine potential associations between periodontal disease (PD) and the risk of development of chronic azotemic kidney disease (CKD) among cats and determine whether the risk of CKD increases with severity of PD. DESIGN Retrospective cohort study. ANIMALS 169, 242 cats. PROCEDURES Cats were evaluated ≥ 3 times at any of 829 hospitals from January 1, 2002, through June 30, 2013. Cats with an initial diagnosis of PD of any stage (n = 56,414) were frequency matched with cats that had no history or evidence of PD (112,828) by age and year of study entry. Data on signalment, PD, and other conditions potentially related to CKD were extracted from electronic medical records. Cox proportional hazards modeling was used to estimate the association of PD with CKD after controlling for covariates. RESULTS PD was associated with increased risk of CKD; risk was highest for cats with stage 3 or 4 PD. Risk of CKD increased with age. Purebred cats had greater risk of CKD than mixed-breed cats. General anesthesia within the year before study exit and diagnosis of cystitis at any point prior to study exit (including prior to study entry) were each associated with increased CKD risk. Diagnosis of diabetes mellitus or hepatic lipidosis at any point prior to study exit was associated with decreased CKD risk. CONCLUSIONS AND CLINICAL RELEVANCE The findings supported the benefit of maintaining good oral health and can be useful to veterinarians for educating owners on the importance of preventing PD in cats.

BACKGROUND Pulmonary function testing is commonly performed for diagnosis and clinical management of respiratory diseases. It is important to use appropriate reference equations from healthy subjects for interpretation of data from infants with lung disease. This study aimed to determine if published reference equations were similar to forced flow measures and plethysmographic infant pulmonary function testing data collected in the Canadian Healthy Infant Longitudinal Development (CHILD) Study. METHODS Reference equations for five pulmonary function variables (FEV0.5 , FVC, FEF25-75 , FEV0.5 /FVC ratio and plethysmography (FRCpleth )) were developed using data from the nSpire system. New reference equations developed using healthy data from the CHILD Study were compared to previously published reference equations for forced flow and plethysmographic measures. RESULTS The current analysis included 131 infants (on 181 test occasions) with forced flow measures and 161 infants (on 246 test occasions) with plethysmography measures, aged 3-24 months. Age and length were major determinants of both forced flow and plethysmography measures. In addition, ethnicity (Caucasian vs non-Caucasian) was significantly associated with FEV0.5 /FVC and FEF25-75 measures. We found that the published reference equations based on custom-built equipment or commercially available systems provided poor fit to our current pulmonary function testing data, resulting in placing a large proportion of our healthy population outside the normal ranges. CONCLUSIONS Our current data support the need for population and device specific reference data for infant pulmonary function studies. By deriving new equipment-specific reference equations for our healthy population, we provide normative data to other centers utilizing this equipment.

Study objectives To examine the association between the age of onset and duration of parent-reported symptoms of sleep-disordered breathing (SDB) and behavioral problems at age 2. Methods Parent-reported SDB symptoms were assessed quarterly between 3 months and 2 years among 583 Canadian Healthy Infant Longitudinal Development Edmonton-site participants. Parent-reported SDB symptoms were clustered into phenotypes using group-based trajectory analysis based on age of onset and duration of symptoms. Home-based polysomnography (PSG) was completed at 1 year. The Child Behavior Checklist preschool-version (Mean T-score 50, standard deviation 10 points) assessed total, externalizing (attention), and internalizing (anxiety, depression) behaviors at 2 years. Results Four phenotypes were identified: no SDB (64.7%), early-onset SDB (15.7%, peak symptoms at 9 months), late-onset (14.2%, peak symptoms at 18 months), and persistent SDB symptoms (5.3%, peak symptoms from 3 through 24 months). Persistent SDB (9.5 points, 95% CI 1.7, 17.2; p = .02) predicted the greatest magnitude of effect of total behavior problems, compared with children without SDB. Children with early-onset SDB (3.5 points, 95% CI 1.6, 5.4; p ≤ .001) and late-onset SDB (6.1 points 95% CI 4.0, 8.3; p ≤ .001) had increased total behavioral problems than children without SDB to 2 years. Additional analyses showed that the SDB phenotypes' trajectories were important for internalizing but not for externalizing behavior problems. There were no significant associations between home-PSG and parent-reported behavior problems. Conclusions Findings suggest that the age of onset and duration of parent-reported SDB symptoms prior to age 2 have adverse consequences for overall behavior problems.

Background The atopic march describes the progression from atopic dermatitis during infancy to asthma and allergic rhinitis in later childhood. In a Canadian birth cohort we investigated whether concomitant allergic sensitization enhances subsequent development of these allergic diseases at age 3 years. Methods Children completed skin prick testing at age 1 year. Children were considered sensitized if they produced a wheal 2 mm or larger than that elicited by the negative control to any of 10 inhalant or food allergens. Children were also assessed for atopic dermatitis by using the diagnostic criteria of the UK Working Party. At age 3 years, children were assessed for asthma, allergic rhinitis, food allergy, and atopic dermatitis. Data from 2311 children were available. Results Atopic dermatitis without allergic sensitization was not associated with an increased risk of asthma at age 3 years after adjusting for common confounders (relative risk [RR], 0.46; 95% CI, 0.11-1.93). Conversely, atopic dermatitis with allergic sensitization increased the risk of asthma more than 7-fold (RR, 7.04; 95% CI, 4.13-11.99). Atopic dermatitis and allergic sensitization had significant interactions on both the additive (relative excess risk due to interaction, 5.06; 95% CI, 1.33-11.04) and multiplicative (ratio of RRs, 5.80; 95% CI, 1.20-27.83) scales in association with asthma risk. There was also a positive additive interaction between atopic dermatitis and allergic sensitization in their effects on food allergy risk (relative excess risk due to interaction, 15.11; 95% CI, 4.19-35.36). Conclusions Atopic dermatitis without concomitant allergic sensitization was not associated with an increased risk of asthma. In combination, atopic dermatitis and allergic sensitization had strong interactive effects on both asthma and food allergy risk at age 3 years.

Objective To determine whether different modes of infant feeding are associated with childhood asthma, including differentiating between direct breastfeeding and expressed breast milk. Study design We studied 3296 children in the Canadian Healthy Infant Longitudinal Development birth cohort. The primary exposure was infant feeding mode at 3 months, reported by mothers and categorized as direct breastfeeding only, breastfeeding with some expressed breast milk, breast milk and formula, or formula only. The primary outcome was asthma at 3 years of age, diagnosed by trained healthcare professionals. Results At 3 months of age, the distribution of feeding modes was 27% direct breastfeeding, 32% breastfeeding with some expressed breast milk, 26% breast milk and formula, and 15% formula only. At 3 years of age, 12% of children were diagnosed with possible or probable asthma. Compared with direct breastfeeding, any other mode of infant feeding was associated with an increased risk of asthma. These associations persisted after adjusting for maternal asthma, ethnicity, method of birth, infant sex, gestational age, and daycare attendance (some expressed breast milk: aOR, 1.64, 95% CI, 1.12-2.39; breast milk and formula, aOR, 1.73, 95% CI, 1.17-2.57; formula only: aOR, 2.14, 95% CI, 1.37-3.35). Results were similar after further adjustment for total breastfeeding duration and respiratory infections. Conclusions Modes of infant feeding are associated with asthma development. Direct breastfeeding is most protective compared with formula feeding; indirect breast milk confers intermediate protection. Policies that facilitate and promote direct breastfeeding could have impact on the primary prevention of asthma.

Calcium oxalate urolithiasis results from the formation of aggregates of calcium salts in the urinary tract. Difficulties associated with effectively treating calcium oxalate urolithiasis and the proportional increase in the prevalence of calcium oxalate uroliths relative to other urolith types over the last 2 decades has increased the concern of clinicians about this disease. To determine factors associated with the development of calcium oxalate urolithiasis in dogs evaluated at general care veterinary hospitals in the United States, a retrospective case-control study was performed. A national electronic database of medical records of all dogs evaluated between October 1, 2007 and December 31, 2010 at 787 general care veterinary hospitals in the United States was reviewed. Dogs were selected as cases at the first-time diagnosis of a laboratory-confirmed urolith comprised of at least 70% calcium oxalate (n=452). Two sets of control dogs with no history of urolithiasis diagnosis were randomly selected after the medical records of all remaining dogs were reviewed: urinalysis examination was a requirement in the selection of one set (n=1808) but was not required in the other set (n=1808). Historical information extracted included urolith composition, dog's diet, age, sex, neuter status, breed size category, hospital location, date of diagnosis, and urinalysis results. Multivariable analysis showed that the odds of first-time diagnosis of calcium oxalate urolithiasis were significantly (P0.05) greater for dogs7 years, males (OR: 7.77, 95% CI: 4.93-12.26), neutered (OR: 2.58, 1.44-4.63), toy- vs. medium-sized breeds (OR: 3.15, 1.90-5.22), small- vs. medium-sized breeds (OR: 3.05, 1.83-5.08), large- vs. medium-sized breeds (OR: 0.05, 0.01-0.19), and those with a diagnosis of cystitis within the previous year (OR: 6.49, 4.14-10.16). Urinary factors significantly associated with first-time diagnosis of calcium oxalate urolithiasis were acidic vs. basic pH (OR: 1.94, 1.22-3.10), presence of RBCs (OR: 6.20, 3.91-9.83) or WBCs (OR: 1.62, 1.03-2.54), and protein concentration30 mg/dL (OR: 1.55, 1.04-2.30). Patient demographics and urinalysis results are important factors that can support risk assessment and early identification of canine oxalate urolithiasis. Therefore, periodic urolith screening and monitoring of urine parameters should be encouraged for dogs at risk of developing these uroliths.

Background Allergic disease is the most frequent chronic health issue in children and has been linked to early-life gut microbiome dysbiosis. Many lines of evidence suggest that microbially derived short-chain fatty acids, and particularly butyrate, can promote immune tolerance. Objective We sought to determine whether bacterial butyrate production in the gut during early infancy is protective against the development of atopic disease in children. Methods We used shotgun metagenomic analysis to determine whether dysbiosis in butyrate fermentation could be identified in human infants, before their developing allergic disease. Results We found that the microbiome of infants who went on to develop allergic sensitization later in childhood lacked genes encoding key enzymes for carbohydrate breakdown and butyrate production. Conclusions Our findings support the importance of microbial carbohydrate metabolism during early infancy in protecting against the development of allergies.

Objective—To identify factors associated with development of struvite urolithiasis in dogs evaluated at general care veterinary hospitals in the United States. Design—Retrospective case-control study. Animals—508 dogs with a first-time diagnosis of struvite urolithiasis and 7,135 control dogs. Procedures—Electronic medical records of all dogs evaluated at 787 general care veterinary hospitals in the United States between October 2007 and December 2010 were reviewed to identify dogs that developed struvite urolithiasis and 2 groups of control dogs with no history of urolithiasis. Information extracted included diet, age, sex, neuter status, breed size category, hospital location, and date of diagnosis. Urinalysis results, urolith composition, and other disease conditions were recorded if applicable. Potential risk factors were assessed with univariable and multivariable regression analysis. Results—Toy- or small-sized breeds had significantly greater odds of struvite urolithiasis, compared with medium- or large-sized breeds. Neutering significantly increased the odds of this outcome in females only; sexually intact females were more likely to develop struvite urolithiasis than were sexually intact males, but only up to 5 years of age. Urinary factors significantly associated with the outcome were basic (vs acidic) pH, presence of RBCs or WBCs, protein concentration > 30 mg/dL, and ketone concentration ≥ 5 mg/dL. Conclusions and Clinical Relevance—Evaluation of demographic characteristics and urinalysis results may be useful in the early identification of struvite urolithiasis in dogs. Periodic urinalysis in dogs is recommended because of the potential health impact of a late diagnosis of urolithiasis.

Objective—To determine whether gonadectomy or age at gonadectomy was associated with the risk that dogs would subsequently become overweight. Design—Retrospective cohort study. Animals—1,930 dogs gonadectomized between 1998 and 2001 at ≤ 6 months of age (n = 782), > 6 months to ≤ 1 year of age (861), or > 1 to ≤ 5 years of age (287) and 1,669 sexually intact dogs. Procedures—Dogs were followed-up through medical records for ≥ 10 years or until a diagnosis of overweight (defined as overweight, obese, or having a body condition score ≥ 4/5) was recorded. Information extracted included age at study entry, sex, breed, breed-size category, hospital visit frequency, and diagnosis (yes or no) of overweight or diseases that might affect body condition. Relative risk of a diagnosis of overweight was assessed among age groups of gonadectomized dogs and between gonadectomized and sexually intact dogs. Results—No difference was detected among dogs grouped according to age at gonadectomy with respect to the risk of being overweight. This risk was significantly greater in gonadectomized dogs than in sexually intact dogs, but only during the first 2 years after gonadectomy. Sexually intact male dogs were approximately 40% less likely to have this diagnosis (hazard ratio, 0.61; 95% confidence interval, 0.52 to 0.72) than were sexually intact female dogs; no difference in risk between the sexes was evident for gonadectomized dogs. Conclusions and Clinical Relevance—Gonadectomized dogs had a greater risk of being overweight than did sexually intact dogs, but this risk was not influenced by age at gonadectomy. Opportunities exist for veterinarians to provide counseling during the first years after gonadectomy to help dogs maintain a healthy weight.

The impact of breastfeeding on respiratory health is uncertain, particularly when the mother has asthma. We examined the association of breastfeeding and wheezing in the first year of life.We studied 2773 infants from the Canadian Healthy Infant Longitudinal Development (CHILD) birth cohort. Caregivers reported on infant feeding and wheezing episodes at 3, 6 and 12 months. Breastfeeding was classified as exclusive, partial (supplemented with formula or complementary foods) or none.Overall, 21% of mothers had asthma, 46% breastfed for at least 12 months and 21% of infants experienced wheezing. Among mothers with asthma, breastfeeding was inversely associated with infant wheezing, independent of maternal smoking, education and other risk factors (adjusted rate ratio (aRR) 0.52; 95% CI 0.35–0.77 for ≥12 versus Breastfeeding appears to confer protection against wheezing in a dose-dependent manner among infants born to mothers with asthma.

A community surgery group was reviewed for 1 year after completion of a laparoscopic colon surgery mentoring program.A formal mentoring protocol had been established between a university center and two surgeons at a community hospital. Over 18 months, concluding August 2007, surgeons were mentored and telementored through 20 laparoscopic colon resections in their local setting. Surgeons tracked their cases for a further 12 months after the mentoring.From September 2007 to August 2008, 30 colon resections were performed. Three of these resections (1 laparoscopic sigmoid colectomy for fistula and 2 laparoscopic subtotal colectomies) were mentored and telementored as advanced procedures. Of the remaining 27 resections, 15 (56%) were laparoscopic procedures including 9 right and 5 sigmoid colectomies as well as 1 subtotal colectomy. The 15 laparascopic colon resections were performed for cancer (n = 6), polyps (n = 5), diverticular disease (n = 2), Crohn's disease (n = 1), and colonic inertia (n = 1). Five cases were converted to open surgery (33%) due to adhesions (n = 3), unclear anatomy (n = 1), and equipment failure (n = 1). The mean number of lymph nodes in the cancer cases was 15.3 + or - 3.8. Minor postoperative complications occurred in seven cases (47%), three of which involved conversions. These complications included ileus (n = 4), wound abscess (n = 2), cardiac arrhythmia (n = 1), anastomotic bleed (n = 1), and abscess (n = 1). The patients selected for open surgery consisted of seven right and three sigmoid colectomies as well as a splenic flexure resection and a dual resection. The rationale for these open surgeries were transverse colon cancer (n = 4), medical comorbidity (n = 3), colovesicle fistulas (n = 2), rectal lesion (n = 2), and carcinoid tumor (n = 1). The laparoscopic patients were younger (58.2 + or - 13.2 vs 73.8 + or - 10.6 years; P = 0.003), had longer operating times (124 + or - 28 vs 94 + or - 38 min; P = 0.026), and a shorter median hospital stay (3 vs 7 days; P = 0.006). The laparoscopic operating time improved over the mentoring experience (124 + or - 28 vs 150 + or - 43 min; P = 0.046).The 1-year follow-up evaluation after a longitudinal mentoring program demonstrates excellent incorporation of laparoscopic colon surgery into a community practice with appropriate case selection, quality cancer surgery, and a moderate conversion rate.

Objective—To characterize and evaluate risk factors for suture-associated cystoliths in dogs and cats. Design—Retrospective case-control study. Animals—163 dogs and 13 cats with suture-associated cystoliths and 326 control dogs and 26 control cats with non–suture-associated cystoliths. Procedures—Submissions to the Canadian Veterinary Urolith Centre received from 1999 to 2006 were reviewed. Case dogs and cats had cystoliths associated with visible suture or with hollow, cylindrical channels or suture knot impressions consistent with dissolved suture. Control dogs and cats had at least a single recurrent non–suture-associated cystolith submitted closest in time to the sample case. Associations among cystolith composition, recurrence times, sex, age, and breed were evaluated. Results—Cases consisted of 92 dogs and 7 cats with visible suture and 71 dogs and 6 cats with dissolved suture. Suture-associated cystoliths represented 0.6% of canine cystoliths, 9.4% of recurrent canine cystoliths, 0.17% of feline cystoliths, and 4% of recurrent feline cystoliths. Sexually intact and neutered males were at increased odds of suture-associated cystoliths, relative to spayed female dogs. Shih Tzus, Lhasa Apsos, and Pomeranians were significantly predisposed to form suture-associated cystoliths. In dogs, compound suture-associated cystoliths were significantly more likely than other cystolith types (OR, 8.6). Dogs with suture-associated cystoliths had significantly shorter recurrence times than did control dogs. Conclusions and Clinical Relevance—Suture remnants in the bladder have an important role in recurrent cystolithiasis in dogs. Identification of risk factors is important for avoiding recurrence of iatrogenic cystoliths.

The Canadian Healthy Infant Longitudinal Development (CHILD) birth cohort study recruited 3624 pregnant women, most partners and 3542 eligible offspring. We hypothesise that early life physical and psychosocial environments, immunological, physiological, nutritional, hormonal and metabolic influences interact with genetics influencing allergic diseases, including asthma. Environmental and biological sampling, innate and adaptive immune responses, gene expression, DNA methylation, gut microbiome and nutrition studies complement repeated environmental and clinical assessments to age 5. This rich data set, linking prenatal and postnatal environments, diverse biological samples and rigorous phenotyping, will inform early developmental pathways to allergy, asthma and other chronic inflammatory diseases.

Lymph node metastases of squamous cell carcinomas in the neck can appear cystic. Without a clinically apparent primary tumour they can classically be considered to originate in a branchial cleft. We report two cases of cystic squamous cell carcinoma with histopathologic criteria of branchial cleft carcinoma. After a review of the literature, diagnostic strategies, histopathologic features, and therapeutic options for this very controversial clinical situation are discussed. We conclude by suggesting that Martin's criteria, largely used to differentiate between a cystic metastasis of a squamous cell carcinoma and a very theoretical branchial cleft carcinoma should be abandoned for lack of applicability.

It is hypothesised that complex interactions between genetic and environmental factors give rise to allergy and asthma in childhood. The Canadian Healthy Infant Longitudinal Development (CHILD) study was designed to explore these factors.CHILD is a longitudinal, general population birth cohort study following infants from mid-pregnancy to age 5 years. Over this time period, biological samples, questionnaires, clinical measures and environmental data are collected.A total of 3624 families have been recruited, and many thousands of samples and questionnaires have been collected, annotated, and archived. This report outlines the rationale and methodology for collecting and storing diverse biological samples from parents and children in this study, and the mechanisms for their release for analyses.The CHILD sample and data repository is a tremendous current and future resource and will provide a wealth of information not only informing studies of asthma and allergy, but also potentially in many other aspects of health relevant for Canadian infants and children.

This phase II study determined response rate of patients with locally advanced or metastatic head and neck cancer treated with pemetrexed disodium, a new multitargeted antifolate that inhibits thymidylate synthase, dihydrofolate reductase and glycinamide ribonucleotide formyl transferase. 35 patients with local or metastatic relapse of squamous cell carcinoma of the head and neck (31 male, 4 female; median age 53 years) were treated with pemetrexed 500 mg m2 administered as a 10-minute infusion on day 1 of a 21-day cycle. Patients received 1 to 8 cycles of therapy. 9 patients (26.5%) had an objective response, with a median response duration of 5.6 months (range 2.9–20 months). 15 (44.1%) had stable disease, and 8 (23.5%) had progressive disease. 2 patients were not assessable for response. Median overall survival was 6.4 months (range 0.7–28.1 months; 95% CI: 3.9–7.7 months). 24 patients (68.6%) experienced grade 3/4 neutropenia, with febrile neutropenia in 4 (11.4%). Grade 3/4 anaemia and thrombocytopenia occurred in 11 (34.3%) and 6 (17.1%) patients, respectively. The most frequent non-haematological toxicity was grade 3/4 mucositis (17.1%; 6 patients). In conclusion, pemetrexed is active in squamous cell carcinoma of the head and neck. Although substantial haematological toxicities were experienced by patients, subsequent studies have shown that these toxicities can be proactively managed by folic acid and vitamin B12 supplementation. © 2001 Cancer Research Campaign http://www.bjcancer.com

The purpose of the present article was to evaluate indications, regimens, treatment modalities, and predictive factors of response to treatment in locally advanced squamous cell carcinoma of the head and neck (SCCHN).An expert panel including otolaryngology and head and neck surgery specialists, oncologists, radiotherapists and biologists analyzed the literature providing a synthesis and giving some recommendations.Findings from the main randomized phase III trials highlight that the TPF regimen (docetaxel, cisplatin, fluorouracil) represent a preferential option when induction chemotherapy is indicated in either operable or non-operable patients. Given the potential fragility of patients presenting with SCCHN, treatment modalities in routine use require applying preventive measures and tailored follow-up according to each patient's profile. As regards predictive factors of response to TPF regimen, no factor is currently validated, but ongoing trials should provide better knowledge.Progresses in induction chemotherapy have allowed improving the prognosis of patients with locally advanced SCCHN. The TPF regimen represents a major improvement in this indication, and ongoing strategic clinical trials should refine its indications.

Background: Both induction chemotherapy followed by irradiation and concurrent chemotherapy and radiotherapy have been reported as valuable alternatives to total laryngectomy in patients with advanced larynx or hypopharynx cancer. We report results of the randomized phase 3 trial 24954 from the European Organization for Research and Treatment of Cancer. Methods: Patients with resectable advanced squamous cell carcinoma of the larynx (tumor stage T3T4) or hypopharynx (T2T4), with regional lymph nodes in the neck staged as N0N2 and with no metastasis, were randomly assigned to treatment in the sequential (or control) or the alternating (or experimental) arm. In the sequential arm, patients with a 50% or more reduction in primary tumor size after two cycles of cisplatin and 5-fluorouracil received another two cycles, followed by radiotherapy (70 Gy total). In the alternating arm, a total of four cycles of cisplatin and 5-fluorouracil (in weeks 1, 4, 7, and 10) were alternated with radiotherapy with 20 Gy during the three 2-week intervals between chemotherapy cycles (60 Gy total). All nonresponders underwent salvage surgery and postoperative radiotherapy. The KaplanMeier method was used to obtain time-to-event data. Results: The 450 patients were randomly assigned to treatment (224 to the sequential arm and 226 to the alternating arm). Median follow-up was 6.5 years. Survival with a functional larynx was similar in sequential and alternating arms (hazard ratio of death and/or event = 0.85, 95% confidence interval = 0.68 to 1.06), as were median overall survival (4.4 and 5.1 years, respectively) and median progression-free interval (3.0 and 3.1 years, respectively). Grade 3 or 4 mucositis occurred in 64 (32%) of the 200 patients in the sequential arm who received radiotherapy and in 47 (21%) of the 220 patients in the alternating arm. Late severe edema and/or fibrosis was observed in 32 (16%) patients in the sequential arm and in 25 (11%) in the alternating arm. Conclusions: Larynx preservation, progression-free interval, and overall survival were similar in both arms, as were acute and late toxic effects.

A case-control study was conducted to investigate occupational risk factors for upper respiratory and digestive tract cancers (nose, lips, buccal cavity, pharynx, and larynx) in the north of France. Two hundred and eighty three cases of histologically confirmed cancer in men treated during the first semester of 1983 at the Regional Cancer Institute were included in the study. Two controls per case were chosen from patients in the medical wards of the local general hospitals in the same geographical area as the case, who did not have cancer. Controls were individually matched for sex, age (+/- 18 months), ethnic group, area of residence, and smoking and alcohol drinking history. All subjects were questioned about occupations in which they had worked for at least 15 years. Odds ratios for major occupational categories were estimated using conditional logistic regression for matched samples. Significant associations were found between wood work and nasal cancer (four cases, no control) and farming and lip cancer (odds ratio 5.3, 95% confidence interval 1.1-26.8). Pharyngeal cancer was associated with the textile industry (OR 2.4, 95% CI 1.0-5.7) and the building industry (OR 2.0, 95% CI 1.1-3.9). Coal miners showed a threefold excess risk for cancer of the lip (4 cases, no control), buccal cavity (OR 3.5, 95% CI 1.1-11.8), and larynx (OR 3.2, 95% CI 1.1-9.7).

The facial artery musculomucosal (FAMM) flap described by Pribaz in 1992 is a musculomucosa flap of the cheek plugged into the higher or lower facial pedicle artery. Indications in terms of substance losses in the oral cavity are numerous.Twenty cases carried out from 2003 to 2006 at the Oscar-Lambret Neck Surgery Cancer Center are reported with a study first on record, then a study on 15 patients (three deaths, two flaps take away for local recurrence). The dimensions of the flap, its epicritic sensitivity, its sensitivity to hot and cold temperatures, the Semmes-Weinstein test and a key test of pique were analyzed. A neck dissection was most often done in the cases studied, and did not advise against the flap.The main indication was represented by tumors of the floor of the mouth. Individual susceptibility testing were broadly similar to the flap and on the opposite side healthy. The results seem to show that, as with skin flaps, there is a complete recovery of sensation.This flap is very reliable and most often resensitizes. The low ligation of the artery during neck dissection does not jeopardize the survival (rich regional anastomoses). The FAMM flap makes up for the loss of medium size substance, it represents a very good solution between directed healing and more consistent skin flaps.

Gastrointestinal diseases pose significant risks to captive cheetah survival and welfare. Multiple factors are thought to be associated with these diseases, but to date a comprehensive epidemiological survey of disease risk factors has not been conducted. A survey of diet and health parameters was completed for 184 captive cheetahs in 86 international facilities. Comparisons were made among dietary factors with respect to disease status and observed faecal consistency, incidence of vomiting and diarrhoea in the past 4 weeks. Extremely dry faeces were most common in cheetahs fed carcasses, but was still of low incidence (15%). Contrastingly, cheetahs fed commercially prepared diets had the highest prevalence of liquid faeces “always” or “often” (9%). Cheetahs fed raw meat diets had the highest prevalence of soft faeces with no shape (22%), as well as of firm and dry faeces (40%). No broad category of diet exerted any influence on the health parameters investigated. However, feeding of ribs at least once per week reduced the odds of diarrhoea (P = 0.020) and feeding of long bones (limbs) at least once per week was associated with a lower odds of vomiting (P = 0.008). Cheetahs fed muscle meat at least once per week had reduced odds of suffering from chronic gastritis (P = 0.005) or non-specific gastrointestinal disease (P < 0.001). The only factor identified as increasing the odds of chronic gastritis was feeding of horse “often” or “always” (P = 0.023). The findings of the current study build on existing empirical research to support a recommendation towards a greater inclusion of skeletal components. Current husbandry guidelines advocating the use of supplemented raw meat diets are likewise supported, but the use of horse meat, as well as commercially prepared diets for captive cheetahs, warrants caution until further research is conducted.

In 1991, a retrospective study was conducted by the French Cancer Centers Group. It concerned 752 cancers of the nasal cavities and paranasal sinuses, among which 61 were adenoid cystic carcinomas and 64 esthesioneuroblastomas. Local aggressiveness and high metastatic potential of adenoid cystic carcinomas were confirmed: 27 local relapses, 26 metastases, overall 5-year survival rate at 55%. Concerning esthesioneuroblastomas, the 5-year survival rate was 56% for patients treated with surgery and radiotherapy (7/27 went through combined surgical approaches), and 26% for those treated with radiotherapy alone. Two main factors of poor prognosis can be emphasized: a) intracranial extension: 5-year survival rate at 18% vs 59%, b) immediate node metastases: 5-year survival rate at 11% vs 63%.

Based on activity in a case report, mitoxantrone was studied in a phase II study in adenoid cystic carcinoma.Patients with symptomatic and/or rapidly progressive metastatic or recurrent adenoid cystic carcinoma were eligible for this study. They were treated with mitoxantrone given intravenously by bolus injection at a dose of 14 mg/m2, cycles repeated every 3 weeks.Thirty-six chemotherapy-naive patients entered on trial, 4 were ineligible. A median of 6 cycles per patient were given. Leucocytopenia (in 97% of patients) was the most important side effect and tended to be cumulative. Other side effects were mainly mild to moderate and consisted of nausea (62%), vomiting (29%), alopecia (53%) and mucositis (41%). Four of 32 patients had a partial response (12%; 95% CI 4%-29%) lasting 3-13 months, 22 patients (69%) had a stable disease.Mitoxantrone at this dose and schedule has modest activity in adenoid cystic carcinomas.

The assessment of quality of life is an element that is now taken into account in the evaluation of therapies in oncology and especially for treatments connected with important sequellae. The lack of a specific tool measuring the quality of life of patients with head and neck cancers (HN), validated in French, leads us to develop and to validate a self-questionnaire. The construction of this questionnaire has been realised following a strict procedure (identification of aspects to explore, formulation and selection of items) conducting to a specific module of 17 questions with 4 modes of reply. The validation of the questionnaire has been undertaken on 116 patients that filled the specific module HN and the general self-questionnaire QLQ-C30 of the EORTC. The acceptability is excellent since only 4% of the patients have refused to participate to this study and that the number of missing data is very low. The value of the Cronbach alpha coefficient with the global score equal to 0.85, reflects a good reliability of the questionnaire. Global score correlation of the module HN with the different scales (functional and symptoms) of the QLQ-C30 are coherent. Global scores are correlated to the nature of the treatment (p0.001), to the evolution of the disease (p = 0.01), to the tumour site (p = 0.015) but not to the code WHO neither to the performance of a laryngectomy. The whole results indicate that we have a specific tool, reliable, and validated. Associated to a general quality of life questionnaire, this specific tool will be useful to complete the evaluation of therapies, especially during of comparative clinical trials.