Adiponectin, leptin and insulin in breast milk: associations with maternal characteristics and infant body composition in the first year of life.

BACKGROUND/OBJECTIVES: Breastfeeding may protect against excessive weight gain during infancy. However, the breast milk components responsible for this effect are unknown. We examined the variation of three breast milk hormones (adiponectin, leptin and insulin) according to maternal characteristics and determined their association with infant body composition. SUBJECTS/METHODS: We studied a representative subset of 430 breastfed infants in the CHILD birth cohort. Breast milk was collected at 4 months postpartum and hormone concentrations were measured using the MesoScale Discovery System. Weight-for-length (WFL) and body mass index (BMI) z-scores were calculated according to the World Health Organization reference standard from infant anthropometrics measured at 4 months and 1 year. Maternal BMI and demographics were self-reported. RESULTS: Breast milk hormone concentrations varied widely between mothers. The geometric mean (range) was 19.4 (3.7-74.4) ngml-1 for adiponectin; 361 (31-3968) pgml-1 for leptin; and 589 (53-5557) pgml-1 for insulin. Maternal BMI was positively correlated with breast milk insulin (r=+0.40, P<0.0001) and leptin (r=+0.71, P<0.0001), but not adiponectin (r=-0.02, P=0.68). Breast milk hormone concentrations were also associated with maternal ethnicity, parity and breastfeeding exclusivity at sample collection. Independent of these factors and maternal diabetes, smoking and breastfeeding duration, higher breast milk leptin was associated with lower infant WFL z-score at 4 months (ß -0.67, 95% confidence interval (CI): -1.17, -0.17 for highest vs lowest quintile) and 1 year (ß -0.58, 95% CI: -1.02, -0.14). Insulin showed a U-shaped association, with intermediate concentrations predicting the lowest infant WFL z-score at 4 months (ß -0.51, 95% CI: -0.87, -0.15 for third vs lowest quintile) and 1 year (ß -0.35, 95% CI: -0.66, -0.04). Similar results were seen with infant BMI. Breast milk adiponectin was not significantly associated with infant body composition. CONCLUSIONS: Breast milk hormone concentrations were associated with several fixed and modifiable maternal characteristics. Higher concentrations of leptin and intermediate concentrations of insulin were associated with lower infant WFL in the first year of life.

Patterns of allergic sensitization and atopic dermatitis from 1 to 3 years: Effects on allergic diseases.

BACKGROUND: While allergic sensitization and atopic dermatitis (AD) are known to increase the risk for allergic diseases, the impact of different temporal and clinical patterns of sensitization and AD is less well defined. OBJECTIVE: We investigated patterns of sensitization and AD from early infancy to age 3, and the differential risk of developing allergic diseases within each pattern in a general cohort. METHODS: Children (n = 2629) from the Canadian Healthy Infant Longitudinal Development (CHILD) Study underwent skin prick tests and were assessed clinically for AD at ages 1 and 3 years. We applied an unsupervised latent class analysis (LCA) to the following 5 factors at these ages: AD, food sensitization, inhalant sensitization, poly-sensitization to foods and poly-sensitization to inhalants. The risks for developing asthma, allergic rhinitis and food allergy at 3 years were evaluated for each identified group. RESULTS: Five distinct classes were revealed by LCA: healthy (81.8%), atopic dermatitis (7.6%), inhalant sensitization (3.5%), transient sensitization (4.1%) and persistent sensitization (3.2%). Using healthy children as the baseline, children in the "atopic dermatitis" group had the next lowest risk for all allergic outcomes at 3 years; those in the "inhalant sensitization" group had the highest risk for allergic rhinitis; children in the "transient sensitization" group were at an increased risk for food allergy; while children in the "persistent sensitization" group had the highest risk for all allergic diseases. CONCLUSION AND CLINICAL RELEVANCE: There is substantial heterogeneity among allergen-sensitized children. Researchers and clinicians need to be aware of the non-specificity associated with labelling children simply as "atopic" and "non-atopic" without considering the timing of their atopic history, type of sensitization and AD status. Children with AD who were poly-sensitized to foods at an early age appear to be at greatest risk of developing other allergic diseases.

Impact of maternal intrapartum antibiotics, method of birth and breastfeeding on gut microbiota during the first year of life: a prospective cohort study.

OBJECTIVE: Dysbiosis of the infant gut microbiota may have long-term health consequences. This study aimed to determine the impact of maternal intrapartum antibiotic prophylaxis (IAP) on infant gut microbiota, and to explore whether breastfeeding modifies these effects. DESIGN: Prospective pregnancy cohort of Canadian infants born in 2010-2012: the Canadian Healthy Infant Longitudinal Development (CHILD) Study. SETTING: General community. SAMPLE: Representative sub-sample of 198 healthy term infants from the CHILD Study. METHODS: Maternal IAP exposures and birth method were documented from hospital records and breastfeeding was reported by mothers. Infant gut microbiota was characterised by Illumina 16S rRNA sequencing of faecal samples at 3 and 12 months. MAIN OUTCOME MEASURES: Infant gut microbiota profiles. RESULTS: In this cohort, 21% of mothers received IAP for Group B Streptococcus prophylaxis or pre-labour rupture of membranes; another 23% received IAP for elective or emergency caesarean section (CS). Infant gut microbiota community structures at 3 months differed significantly with all IAP exposures, and differences persisted to 12 months for infants delivered by emergency CS. Taxon-specific composition also differed, with the genera Bacteroides and Parabacteroides under-represented, and Enterococcus and Clostridium over-represented at 3 months following maternal IAP. Microbiota differences were especially evident following IAP with emergency CS, with some changes (increased Clostridiales and decreased Bacteroidaceae) persisting to 12 months, particularly among non-breastfed infants. CONCLUSIONS: Intrapartum antibiotics in caesarean and vaginal delivery are associated with infant gut microbiota dysbiosis, and breastfeeding modifies some of these effects. Further research is warranted to explore the health consequences of these associations. TWEETABLE ABSTRACT: Maternal #antibiotics during childbirth alter the infant gut #microbiome.

Infant gut microbiota and food sensitization: associations in the first year of life.

BACKGROUND: The gut microbiota is established during infancy and plays a fundamental role in shaping host immunity. Colonization patterns may influence the development of atopic disease, but existing evidence is limited and conflicting. OBJECTIVE: To explore associations of infant gut microbiota and food sensitization. METHODS: Food sensitization at 1 year was determined by skin prick testing in 166 infants from the population-based Canadian Healthy Infant Longitudinal Development (CHILD) study. Faecal samples were collected at 3 and 12 months, and microbiota was characterized by Illumina 16S rRNA sequencing. RESULTS: Twelve infants (7.2%) were sensitized to ≥ 1 common food allergen at 1 year. Enterobacteriaceae were overrepresented and Bacteroidaceae were underrepresented in the gut microbiota of food-sensitized infants at 3 months and 1 year, whereas lower microbiota richness was evident only at 3 months. Each quartile increase in richness at 3 months was associated with a 55% reduction in risk for food sensitization by 1 year (adjusted odds ratio 0.45, 95% confidence interval 0.23-0.87). Independently, each quartile increase in Enterobacteriaceae/Bacteroidaceae ratio was associated with a twofold increase in risk (2.02, 1.07-3.80). These associations were upheld in a sensitivity analysis among infants who were vaginally delivered, exclusively breastfed and unexposed to antibiotics. At 1 year, the Enterobacteriaceae/Bacteroidaceae ratio remained elevated among sensitized infants, who also tended to have decreased abundance of Ruminococcaceae. CONCLUSIONS AND CLINICAL RELEVANCE: Low gut microbiota richness and an elevated Enterobacteriaceae/Bacteroidaceae ratio in early infancy are associated with subsequent food sensitization, suggesting that early gut colonization may contribute to the development of atopic disease, including food allergy.

The Canadian healthy infant longitudinal development birth cohort study: biological samples and biobanking.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Associations between bacterial communities of house dust and infant gut.

The human gut is host to a diverse and abundant community of bacteria that influence health and disease susceptibility. This community develops in infancy, and its composition is strongly influenced by environmental factors, notably perinatal anthropogenic exposures such as delivery mode (Cesarean vs. vaginal) and feeding method (breast vs. formula); however, the built environment as a possible source of exposure has not been considered. Here we report on a preliminary investigation of the associations between bacteria in house dust and the nascent fecal microbiota from 20 subjects from the Canadian Healthy Infant Longitudinal Development (CHILD) Study using high-throughput sequence analysis of portions of the 16S rRNA gene. Despite significant differences between the dust and fecal microbiota revealed by Nonmetric Multidimensional Scaling (NMDS) analysis, permutation analysis confirmed that 14 bacterial OTUs representing the classes Actinobacteria (3), Bacilli (3), Clostridia (6) and Gammaproteobacteria (2) co-occurred at a significantly higher frequency in matched dust-stool pairs than in randomly permuted pairs, indicating an association between these dust and stool communities. These associations could indicate a role for the indoor environment in shaping the nascent gut microbiota, but future studies will be needed to confirm that our findings do not solely reflect a reverse pathway. Although pet ownership was strongly associated with the presence of certain genera in the dust for dogs (Agrococcus, Carnobacterium, Exiguobacterium, Herbaspirillum, Leifsonia and Neisseria) and cats (Escherichia), no clear patterns were observed in the NMDS-resolved stool community profiles as a function of pet ownership.

Forceps birth delivery, allergic sensitisation and asthma: a population-based cohort study.

BACKGROUND: Studies indicate an increased risk of allergies among children born by caesarean section, possibly because immune development is altered by avoiding exposure to maternal vaginal flora. It is unknown if other obstetric interventions are associated with allergies. OBJECTIVE: To assess associations between delivery with forceps assistance and development of atopy and asthma. METHODS: In a population-based cohort of 1037 individuals born in 1972/73, atopy was assessed by skin-prick tests for common allergens at ages 13 and 32 years. A history of asthma was obtained at the same ages. Associations between birth with forceps assistance, atopy and asthma were assessed with adjustments for sex, head circumference at birth, parental atopy disease, birth order and socio-economic status. RESULTS: Children born using forceps were more likely to have atopy at ages 13 (53% vs. 44%) and 32 (68% vs 59%). They were also more likely to have asthma (21% vs. 11% and 23% vs. 16% at ages 13 and 32 respectively). Except for asthma at age 13, these associations were not statistically significant after adjustment for multiple confounding factors. CONCLUSIONS & CLINICAL RELEVANCE: Delivery with forceps assistance is associated with an increased risk of atopy and asthma, but the associations were weaker after adjustment for confounding factors. The previously reported association between caesarean birth and atopic disease may be due to confounding rather than altered exposure to maternal flora, although other factors associated with a difficult labour cannot be ruled out.

Effect of different asthma treatments on risk of cold-related exacerbations.

Common colds often trigger asthma exacerbations. The present study compared cold-related severe exacerbations during budesonide/formoterol maintenance and reliever therapy, and different regimens of maintenance inhaled corticosteroids (ICS), with or without long-acting ß(2)-agonists (LABA), and with as-needed short-acting ß(2)-agonists (SABA) or LABA. Reported colds and severe exacerbations (defined by oral corticosteroid use and/or hospitalisation/emergency room visit) were assessed for 12,507 patients during 6-12 months of double-blind treatment. Exacerbations occurring ≤14 days after onset of reported colds were analysed by a Poisson model. The incidence of colds was similar across treatments. Asthma symptoms and reliever use increased during colds. Budesonide/formoterol maintenance and reliever therapy reduced severe cold-related exacerbations by 36% versus pooled comparators plus SABA (rate ratio (RR) 0.64; p=0.002), and for individual treatment comparisons, by 52% versus the same maintenance dose of ICS/LABA (RR 0.48; p<0.001); there were nonsignificant reductions versus higher maintenance doses of ICS or ICS/LABA (RR 0.83 and 0.72, respectively). As-needed LABA did not reduce cold-related exacerbations versus as-needed SABA (RR 0.96). Severe cold-related exacerbations were reduced by budesonide/formoterol maintenance and reliever therapy compared with ICS with or without LABA and with as-needed SABA. Subanalyses suggested the importance of the ICS component in reducing cold-related exacerbations. Future studies should document the cause of exacerbations, in order to allow identification of different treatment effects.

Measuring asthma control: a comparison of three classification systems.

There are various ways to classify asthma control; however, no classification is universally accepted. This retrospective analysis compared asthma control as assessed by the Asthma Control Questionnaire (5-item version; ACQ-5), Global Initiative for Asthma (GINA) or Gaining Optimal Asthma Control (GOAL) study criteria. Pooled data at the final study week (n = 8,188) from three budesonide/formoterol maintenance and reliever therapy studies which measured ACQ-5 were stratified according to GINA or GOAL criteria and ACQ-5 score distribution. The percentages of patients with a controlled/partly controlled week (GINA), totally/well-controlled week (GOAL) and range of ACQ-5 cut-off points were compared. Patients with GINA controlled, partly controlled and uncontrolled asthma had mean ACQ-5 scores of 0.43, 0.75 and 1.62, respectively. Patients with GOAL totally controlled, well-controlled and uncontrolled asthma had ACQ-5 scores of 0.39, 0.78 and 1.63. The kappa measure of agreement was 0.80 for GINA and GOAL criteria, and 0.63 for GINA controlled/partly controlled and ACQ-5 <1.00. ACQ-5 detected clinically important improvements in 49% of patients who, according to GINA criteria, remained uncontrolled at the end of the study. Asthma control measured by GINA or GOAL criteria provides similar results. GINA Controlled/Partly Controlled and GOAL Totally Controlled/Well-Controlled correspond to ACQ-5 <1.00. The ACQ-5 is more responsive to change in a clinical trial setting than a categorical scale.

Effects of cannabis on lung function: a population-based cohort study.

The effects of cannabis on lung function remain unclear and may be different from those of tobacco. We compared the associations between use of these substances and lung function in a population-based cohort (n = 1,037). Cannabis and tobacco use were reported at ages 18, 21, 26 and 32 yrs. Spirometry, plethysmography and carbon monoxide transfer factor were measured at 32 yrs. Associations between lung function and exposure to each substance were adjusted for exposure to the other substance. Cumulative cannabis use was associated with higher forced vital capacity, total lung capacity, functional residual capacity and residual volume. Cannabis was also associated with higher airway resistance but not with forced expiratory volume in 1 s, forced expiratory ratio or transfer factor. These findings were similar among those who did not smoke tobacco. In contrast, tobacco use was associated with lower forced expiratory volume in 1 s, lower forced expiratory ratio, lower transfer factor and higher static lung volumes, but not with airway resistance. Cannabis appears to have different effects on lung function from those of tobacco. Cannabis use was associated with higher lung volumes, suggesting hyperinflation and increased large-airways resistance, but there was little evidence for airflow obstruction or impairment of gas transfer.

Geographical variations in the prevalence of atopic sensitization in six study sites across Canada.

BACKGROUND: Geographical variations in atopic sensitization in Canada have not been described previously. This study used the standardized protocol of the European Community Respiratory Health Survey-1 (ECRHS-1) to investigate the distribution and predictors of atopic sensitization in six sites across Canada and to compare the results with some ECRHS-1 centers. METHODS: Adults aged 20-44 years in six study sites across Canada underwent allergy skin testing using 14 allergens (Dermatophagoides pteronyssinus, Dermatophagoides farinae) cat, cockroach, grasses (Timothy grass, Kentucky grass), molds (Cladosporium herbarium, Alternaria alternata, Aspergillus fumigatus, Penicillium), trees (tree mix, birch, Olea europea), and common ragweed. RESULTS: The overall prevalence of atopy (skin test over 0 mm to any allergen) was 62.7%. There was significant geographical variation in the prevalence of atopy in the six study sites (lowest 55.6% [95% C.I.51.3-59.9] in Prince Edward Island, highest 66.0 [61.7-70.3] in Montreal) and of sensitization to each of the allergens tested even after adjustment for confounders. When the first eight of the nine allergens in the ECRHS were used to estimate the prevalence of atopic sensitization, the prevalence of atopy in Canada was 57% compared with 35.2% overall for centers in the ECRHS. The prevalence of atopy in Vancouver (57% [52.3-61.8]) was close to that of Portland, Oregon (52.1% [46.2-58.0]). CONCLUSION: There was a significant variation in atopic sensitization among different study sites across Canada. The prevalence of atopic sensitization is relatively high in Canada compared with sites in the ECRHS and this may, in part, account for the high prevalence of asthma and asthma symptoms in Canada.

Associations between birth weight, early childhood weight gain and adult lung function.

BACKGROUND: Low birth weight is associated with lower values for spirometry in adults but it is not known if birth weight influences other measures of pulmonary function. It is also unclear whether postnatal growth affects adult lung function. The associations between birth weight, postnatal growth and adult lung function were assessed in an unselected birth cohort of 1037 children. METHODS: Birth weight, weight gain between birth and age 3 years, and lung function at age 32 years were measured. Analyses were adjusted for adult height and sex and further adjusted for multiple other potential confounding factors. RESULTS: Birth weight was positively correlated with spirometric (forced expiratory volume in 1 s and forced vital capacity) and plethysmographic (total lung capacity and functional residual capacity) lung function and with lung diffusing capacity. These associations persisted after adjustment for confounding factors including adult weight, exposure to cigarette smoke in utero and during childhood, personal smoking, socioeconomic status, asthma and gestational age. Weight gain between birth and age 3 years was also positively associated with lung diffusing capacity, and with higher values of lung volumes in men after adjustment for covariates. Neither birth weight nor postnatal weight gain was associated with airflow obstruction. CONCLUSIONS: Low birth weight and lower weight gain in early childhood are associated with modest reductions in adult lung function across a broad range of measures of lung volumes and with lower diffusing capacity. These findings are independent of a number of potential confounding factors and support the hypothesis that fetal and infant growth is a determinant of adult lung function.

Long-acting beta-agonists: a review of formoterol safety data from asthma clinical trials.

The safety of long-acting beta(2)-agonist (LABA) treatment in asthma has been questioned following reported increased respiratory deaths when salmeterol was added to usual pharmacotherapy. The aim of this study was to examine whether asthma, cardiac or all-cause mortality and morbidity were increased with formoterol use. The analysis included all AstraZeneca randomised controlled parallel-group asthma trials of 3-12-months duration involving formoterol. Risks associated with formoterol use compared with non-LABA treatment, overall and in combination with inhaled corticosteroids (ICS), were assessed using an intention-to-treat analysis of the rates and rate ratios of deaths and serious adverse events (SAEs). The main objective of this study was to compare asthma-related mortality in patients using formoterol and those not using formoterol. There were eight asthma-related deaths (0.34 per 1,000 person-yrs) among 49,906 formoterol-randomised patients (92% using ICS), and two (0.22 per 1,000 person-yrs) among 18,098 patients (83% using ICS) not randomised to formoterol, which was nonsignificant. Asthma-related SAEs (>90% of which were hospitalisations) were significantly fewer among formoterol-randomised patients (0.75 versus 1.10%). There was no increase in asthma-related SAEs with increased daily doses of formoterol (9, 18 or 36 microg). There was no significant difference in cardiac mortality or noncardiac nonasthma-related mortality in formoterol-randomised compared to non-LABA-treated patients. All-cause mortality was similar. In the data set in which all subjects were prescribed ICS at baseline, there were seven asthma-related deaths (0.32 per 1,000 person-yrs) among 46,003 formoterol-randomised patients and one (0.14 per 1,000 person-yrs) among 13,905 patients not randomised to formoterol, which was also nonsignificant. There were few asthma-related or cardiac-related deaths among patients randomised to formoterol, and all differences were nonsignificant compared with non-long-acting beta(2)-agonist-randomised patients. However, despite data on >68,000 patients, the power was insufficient to conclude that there was no increased mortality with formoterol. Cardiac-related serious adverse events were not increased, and asthma-related serious adverse events were significantly reduced with formoterol.

The validity of the family history screen for assessing family history of mental disorders.

There is a need to collect psychiatric family history information quickly and economically (e.g., for genome-wide studies and primary care practice). We sought to evaluate the validity of family history reports using a brief screening instrument, the Family History Screen (FHS). We assessed the validity of parents' reports of seven psychiatric disorders in their adult children probands from the Dunedin Study (n = 959, 52% male), using the proband's diagnosis as the criterion outcome. We also investigated whether there were informant characteristics that enhanced accuracy of reporting or were associated with reporting biases. Using reports from multiple informants, we obtained sensitivities ranging from 31.7% (alcohol dependence) to 60.0% (conduct disorder) and specificities ranging from 76.0% (major depressive episode) to 97.1% (suicide attempt). There was little evidence that any informant characteristics enhanced accuracy of reporting. However, three reporting biases were found: the probability of reporting disorder in the proband was greater for informants with versus without a disorder, for female versus male informants, and for younger versus older informants. We conclude that the FHS is as valid as other family history instruments (e.g., the FH-RDC, FISC), and its brief administration time makes it a cost-effective method for collecting family history data. To avoid biasing results, researchers who aim to compare groups in terms of their family history should ensure that the informants reporting on these groups do not differ in terms of age, sex or personal history of disorder.

The influence of maternal and infant nutrition on cardiometabolic traits: novel findings and future research directions from four Canadian birth cohort studies.

A mother's nutritional choices while pregnant may have a great influence on her baby's development in the womb and during infancy. There is evidence that what a mother eats during pregnancy interacts with her genes to affect her child's susceptibility to poor health outcomes including childhood obesity, pre-diabetes, allergy and asthma. Furthermore, after what an infant eats can change his or her intestinal bacteria, which can further influence the development of these poor outcomes. In the present paper, we review the importance of birth cohorts, the formation and early findings from a multi-ethnic birth cohort alliance in Canada and summarise our future research directions for this birth cohort alliance. We summarise a method for harmonising collection and analysis of self-reported dietary data across multiple cohorts and provide examples of how this birth cohort alliance has contributed to our understanding of gestational diabetes risk; ethnic and diet-influences differences in the healthy infant microbiome; and the interplay between diet, ethnicity and birth weight. Ongoing work in this birth cohort alliance will focus on the use of metabolomic profiling to measure dietary intake, discovery of unique diet-gene and diet-epigenome interactions, and qualitative interviews with families of children at risk of metabolic syndrome. Our findings to-date and future areas of research will advance the evidence base that informs dietary guidelines in pregnancy, infancy and childhood, and will be relevant to diverse and high-risk populations of Canada and other high-income countries.

Budesonide/formoterol maintenance and reliever therapy: impact on airway inflammation in asthma.

The aim of the present study was to compare the effectiveness, safety and health economics of budesonide/formoterol maintenance and a novel reliever therapy with conventional best practice in patients with persistent asthma in Canada. After 2 weeks of usual therapy, 1,538 patients were randomised for 6 months to open-label budesonide/formoterol maintenance and reliever therapy 160/4.5 microg twice daily and as needed, or to guideline-based conventional best practice. Severe asthma exacerbations, reliever medication use and total inhaled corticosteroid dose were analysed in all patients and airway inflammation was assessed in a sub-study of 115 patients. No differences were seen in time to first severe exacerbation and severe asthma exacerbation rate. There were numerically fewer emergency room visits or hospitalisations with budesonide/formoterol maintenance and reliever therapy (4.4 versus 7.5 events per 100 patients x yr(-1), 41% reduction); however, this did not reach statistical significance. Mean total inhaled corticosteroid dose, reliever use, asthma medication costs and total annual costs per patient were all significantly lower with budesonide/formoterol maintenance and reliever therapy. Mean sputum eosinophil cell counts remained in the range for controlled inflammation in both groups. In conclusion, budesonide/formoterol maintenance and reliever therapy achieved similar or improved clinical control compared with conventional best practice, with significantly lower total inhaled corticosteroid dose and lower cost, while maintaining similar control of eosinophilic inflammation.

A new perspective on concepts of asthma severity and control.

Concepts of asthma severity and control are important in the evaluation of patients and their response to treatment but the terminology is not standardised and the terms are often used interchangeably. This review, arising from the work of an American Thoracic Society/European Respiratory Society Task Force, identifies the need for separate concepts of control and severity, describes their evolution in asthma guidelines and provides a framework for understanding the relationship between current concepts of asthma phenotype, severity and control. "Asthma control" refers to the extent to which the manifestations of asthma have been reduced or removed by treatment. Its assessment should incorporate the dual components of current clinical control (e.g. symptoms, reliever use and lung function) and future risk (e.g. exacerbations and lung function decline). The most clinically useful concept of asthma severity is based on the intensity of treatment required to achieve good asthma control, i.e. severity is assessed during treatment. Severe asthma is defined as the requirement for (not necessarily just prescription or use of) high-intensity treatment. Asthma severity may be influenced by the underlying disease activity and by the patient's phenotype, both of which may be further described using pathological and physiological markers. These markers can also act as surrogate measures for future risk.

Impact of maternal pre-pregnancy overweight on infant overweight at 1 year of age: associations and sex-specific differences.

BACKGROUND: Maternal overweight or obesity (OWOB) is linked to gestational diabetes, fetal macrosomia and higher rates of caesarean delivery. OBJECTIVES: The study aims to assess whether maternal pre-pregnancy OWOB is associated with infant overweight in a sex-dependent manner, independent of microbiota-altering variables. METHODS: Weight and length measurements of 955 mother-infant pairs were obtained from the Canadian Healthy Infant Longitudinal Development cohort. Maternal pre-pregnancy weight was defined as follows: normal, overweight (25 ≤ body mass index < 30) and obese (body mass index ≥ 30). Age and sex-adjusted weight-for-length z-scores >97th percentile were classified as infant overweight at age 1 year. Associations between pre-pregnancy and infant overweight were determined by linear and logistic regression, adjusting for covariates. RESULTS: Maternal pre-pregnancy OWOB were associated with infant weight-for-length and overweight risk at 1 year. Except for pre-pregnancy obesity, these associations were not attenuated appreciably after adjustment for birth mode, exclusivity of breastfeeding, exposure to antibiotics and infant sex. Yet only boys born to mothers with obesity were three times more likely to become overweight at age 1 independent of microbiota-altering variables. Pre-pregnancy obesity was associated with weight-for-length in male and female infants. CONCLUSIONS: Maternal pre-pregnancy OWOB increases the risk of infant overweight, and this association is more evident in male infants.

Effect of experimental pneumococcal meningitis on respiration and circulation in the rabbit.

Pathophysiological studies in bacterial meningitis in man have been limited by clinical variability and the necessity for immediate therapy. After the development of a reliable animal model of pneumococcal meningitis, we studied respiration and circulation in 25 anesthetized New Zealand white rabbits during untreated pneumococcal meningitis and in 33 healthy controls. In meningitis, we found increased lactic acid in cerebrospinal fluid (CSF). Increased ventilation, perhaps due to CSF lactic acid accumulation, resulted in respiratory alkalosis; the concomitant lowering of Pco(2) acted as a homeostatic mechanism to restore pH toward normality in the CSF. Hyperventilation increased with the duration of the illness. Cardiac output was also increased with decreased peripheral vascular resistance but with only slight reduction in mean systemic and pulmonary arterial pressures. In the final hour of life, peripheral vascular resistance fell further; ventilation declined and then abruptly ceased while cardiac activity continued. Lactic acid accumulation in the CSF, found in both experimental and human pneumococcal meningitis, may cause the hyperventilation found in this disease and may contribute to death.