Validation of childhood asthma predictive tools: A systematic review.

BACKGROUND: There is uncertainty about the clinical usefulness of currently available asthma predictive tools. Validation of predictive tools in different populations and clinical settings is an essential requirement for the assessment of their predictive performance, reproducibility and generalizability. We aimed to critically appraise asthma predictive tools which have been validated in external studies. METHODS: We searched MEDLINE and EMBASE (1946-2017) for all available childhood asthma prediction models and focused on externally validated predictive tools alongside the studies in which they were originally developed. We excluded non-English and non-original studies. PROSPERO registration number is CRD42016035727. RESULTS: From 946 screened papers, eight were included in the review. Statistical approaches for creation of prediction tools included chi-square tests, logistic regression models and the least absolute shrinkage and selection operator. Predictive models were developed and validated in general and high-risk populations. Only three prediction tools were externally validated: the Asthma Predictive Index, the PIAMA and the Leicester asthma prediction tool. A variety of predictors has been tested, but no studies examined the same combination. There was heterogeneity in definition of the primary outcome among development and validation studies, and no objective measurements were used for asthma diagnosis. The performance of tools varied at different ages of outcome assessment. We observed a discrepancy between the development and validation studies in the tools' predictive performance in terms of sensitivity and positive predictive values. CONCLUSIONS: Validated asthma predictive tools, reviewed in this paper, provided poor predictive accuracy with performance variation in sensitivity and positive predictive value.

Transforming growth factor beta in human milk and allergic outcomes in children: A systematic review.

BACKGROUND: Human milk (HM) transforming growth factor beta (TGF-ß) is critical for inflammation regulation and oral tolerance promotion. Previous reports suggested that variations in HM TGF-ß levels are associated with allergic outcomes. OBJECTIVE: We undertook a systematic review (PROSPERO 2017 CRD42017069920) to reassess the evidence on the relationships between HM TGF-ß and allergic outcomes in children. METHODS: Electronic bibliographic databases (MEDLINE, EMBASE and Cochrane Library) were systematically searched. Two independent reviewers screened reference lists, extracted the data and assessed risk of bias using the National Institute for Clinical Excellence methodological checklist. RESULTS: A total of 21 studies were identified. Sixteen studies assessed relationships between HM TGF-ß and risk of eczema; 14, allergic sensitization; nine, wheezing/asthma; six, food allergy; three, allergic rhinitis/conjunctivitis. Five cohorts (5/18, 28%) reported a protective effect of TGF-ß1, while 3 (3/10, 30%) suggested increased risk of allergic outcomes development and 1 (1/10, 10%), a protective effect of TGF-ß2 on eczema. Meta-analysis was not possible due to significant heterogeneity in methodology, age of outcome assessment and differing statistical approaches. 71% (15/21) of studies carried a high risk of bias. CONCLUSION AND CLINICAL RELEVANCE: In contrast with previous findings, we did not find strong evidence of associations between HM TGF-ß and allergic outcomes. Differences in studies' methodology and outcomes do not allow unconditional rejection or acceptance of the hypothesis that HM TGF-ß influences the risk of allergy development. Future studies on diverse populations employing standardized methods, accurate phenotyping of outcomes and evaluation of the effect of TGF-ß in combination with other HM immune markers, microbiome and oligosaccharides are required.

Effects of environmental noise exposure on DNA methylation in the brain and metabolic health.

Environmental noise exposure is associated with adverse effects on human health including hearing loss, heart disease, and changes in stress-related hormone levels. Alteration in DNA methylation in response to environmental exposures is a well-known phenomenon and it is implicated in many human diseases. Understanding how environmental noise exposures affect DNA methylation patterns may help to elucidate the link between noise and adverse effects on health. In this pilot study we examined the effects of environmental noise exposure on DNA methylation of genes related to brain function and investigated whether these changes are related with metabolic health. We exposed four groups of male Wistar rats to moderate intensity noise (70-75dB with 20-4000Hz) at night for three days as short-term exposure, and for three weeks as long-term exposure. Noise exposure was limited to 45dB during the daytime. Control groups were exposed to only 45dB, day and night. We measured DNA methylation in the Bdnf, Comt, Crhr1, Mc2r, and Snca genes in tissue from four brain regions of the rats (hippocampus, frontal lobe, medulla oblongata, and inferior colliculus). Further, we measured blood pressure and body weight after long-term noise exposure. We found that environmental noise exposure is associated with gene-specific DNA methylation changes in specific regions of the brain. Changes in DNA methylation are significantly associated with changes in body weight (between Bdnf DNA methylation and Δ body weight: r=0.59, p=0.018; and between LINE-1 ORF DNA methylation and Δ body weight: =-0.80, p=0.0004). We also observed that noise exposure decreased blood pressure (p=0.038 for SBP, p=0.017 for DBP and p 0. 017 for MAP) and decreased body weight (ß=-26g, p=0.008). In conclusion, environmental noise exposures can induce changes in DNA methylation in the brain, which may be associated with adverse effects upon metabolic health through modulation of response to stress-related hormones.

Immune Components in Human Milk Are Associated with Early Infant Immunological Health Outcomes: A Prospective Three-Country Analysis.

The role of breastfeeding in improving allergy outcomes in early childhood is still unclear. Evidence suggests that immune mediators in human milk (HM) play a critical role in infant immune maturation as well as protection against atopy/allergy development. We investigated relationships between levels of immune mediators in colostrum and mature milk and infant outcomes in the first year of life. In a large prospective study of 398 pregnant/lactating women in the United Kingdom, Russia and Italy, colostrum and mature human milk (HM) samples were analysed for immune active molecules. Statistical analyses used models adjusting for the site of collection, colostrum collection time, parity and maternal atopic status. Preliminary univariate analysis showed detectable interleukin (IL) 2 and IL13 in HM to be associated with less eczema. This finding was further confirmed in multivariate analysis, with detectable HM IL13 showing protective effect OR 0.18 (95% CI 0.04-0.92). In contrast, a higher risk of eczema was associated with higher HM concentrations of transforming growth factor ß (TGFß) 2 OR 1.04 (95% CI 1.01-1.06) per ng/mL. Parental-reported food allergy was reported less often when IL13 was detectable in colostrum OR 0.10 (95% CI 0.01-0.83). HM hepatocyte growth factor (HGF) was protective for common cold incidence at 12 months OR 0.19 (95% CI 0.04-0.92) per ng/mL. Data from this study suggests that differences in the individual immune composition of HM may have an influence on early life infant health outcomes. Increased TGFß2 levels in HM are associated with a higher incidence of reported eczema, with detectable IL13 in colostrum showing protective effects for food allergy and sensitization. HGF shows some protective effect on common cold incidence at one year of age. Future studies should be focused on maternal genotype, human milk microbiome and diet influence on human milk immune composition and both short- and long-term health outcomes in the infant.

Colostrum and Mature Human Milk of Women from London, Moscow, and Verona: Determinants of Immune Composition.

Cytokines and growth factors in colostrum and mature milk may play an important role in infant immune maturation, and may vary significantly between populations. We aimed to examine associations between environmental and maternal factors, and human milk (HM) cytokine and growth factor levels. We recruited 398 pregnant/lactating women in the United Kingdom, Russia, and Italy. Participants underwent skin prick testing, questionnaire interview, and colostrum and mature milk sampling. HM cytokine and growth factor levels were quantified by electro-chemiluminescence. We found significant geographical variation in growth factor levels, but no evidence of variation between sites in cytokine detectability. There was an inverse correlation between time of milk sampling and growth factor levels in colostrum for Hepatocyte Growth Factor (HGF) and TGFß1 and TGFß3, but not TGFß2, and levels were significantly higher in colostrum than mature milk for all growth factors. The kinetics of decline were different for each growth factor. Cytokines were present at much lower levels than growth factors, and the decline over time was less consistent. HM growth factors and cytokine levels vary between populations for unknown reasons. Levels of HM mediators decline at different rates postpartum, and these findings suggest specific biological roles for HM growth factors and cytokines in early postnatal development.

Effects of short-term exposure to inhalable particulate matter on DNA methylation of tandem repeats.

There is compelling evidence that particulate matter (PM) increases lung cancer risk by triggering systemic inflammation, and leukocyte DNA hypomethylation. However, previous investigations focused on repeated element sequences from LINE-1 and Alu families. Tandem repeats, which display a greater propensity to mutate, and are often hypomethylated in cancer patients, have never been investigated in individuals exposed to PM. We measured methylation of three tandem repeats (SATα, NBL2, and D4Z4) by polymerase chain reaction-pyrosequencing on blood samples from truck drivers and office workers (60 per group) in Beijing, China. We used lightweight monitors to measure personal PM2.5 (PM with aerodynamic diameter ≤2.5 µm) and elemental carbon (a tracer of PM from vehicular traffic). Ambient PM10 data were obtained from air quality measuring stations. Overall, an interquartile increase in personal PM2.5 and ambient PM10 levels was associated with a significant covariate-adjusted decrease in SATα methylation (-1.35% 5-methyl cytosine [5mC], P = 0.01; and -1.33%5mC; P = 0.01, respectively). Effects from personal PM2.5 and ambient PM10 on SATα methylation were stronger in truck drivers (-2.34%5mC, P = 0.02; -1.44%5mC, P = 0.06) than office workers (-0.95%5mC, P = 0.26; -1.25%5mC, P = 0.12, respectively). Ambient PM10 was negatively correlated with NBL2 methylation in truck drivers (-1.38%5mC, P = 0.03) but not in office workers (1.04%5mC, P = 0.13). Our result suggests that PM exposure is associated with hypomethylation of selected tandem repeats. Measuring tandem-repeat hypomethylation in easy-to-obtain blood specimens might identify individuals with biological effects and potential cancer risk from PM exposure.