Epigenomic variability is associated with age-specific naïve CD4 T cell response to activation in infants and adolescents.

Childhood is a critical period of immune development. During this time, naïve CD4 (nCD4) T cells undergo programmed cell differentiation, mediated by epigenetic changes, in response to external stimuli leading to a baseline homeostatic state that may determine lifelong disease risk. However, the ontogeny of epigenetic signatures associated with CD4 T cell activation during key developmental periods are yet to be described. We investigated genome-wide DNA methylation (DNAm) changes associated with nCD4 T activation following 72 h culture in media+anti-CD3/CD28 beads in healthy infants (aged 12 months, n = 18) and adolescents (aged 10-15 years, n = 15). We integrated these data with transcriptomic and cytokine profiling from the same samples. nCD4 T cells from both age groups show similar extensive epigenetic reprogramming following activation, with the majority of genes involved in the T cell receptor signaling pathway associated with differential methylation. Additionally, we identified differentially methylated probes showing age-specific responses, that is, responses in only infants or adolescents, including within a cluster of T cell receptor (TCR) genes. These encoded several TCR alpha joining (TRAJ), and TCR alpha variable (TRAV) genes. Cytokine data analysis following stimulation revealed enhanced release of IFN-γ, IL-2 and IL-10, in nCD4 T cells from adolescents compared with infants. Overlapping differential methylation and cytokine responses identified four probes potentially underpinning these age-specific responses. We show that DNAm in nCD4T cells in response to activation is dynamic in infancy and adolescence, with additional evidence for age-specific effects potentially driving variation in cytokine responses between these ages.

Pre-pregnancy obesity is associated with greater systemic inflammation and increased risk of antenatal depression.

BACKGROUND: Pre-pregnancy obesity is an emerging risk factor for perinatal depression. However, the underlying mechanisms remain unclear. We investigated the association between pre-pregnancy body mass index (BMI) and perinatal depressive symptoms in a large population-based pre-birth cohort, the Barwon Infant Study. We also assessed whether the levels of circulating inflammatory markers during pregnancy mediated this relationship. METHODS: Depressive symptoms were assessed in 883 women using the Edinburgh Postnatal Depression Scale (EPDS) and psychological stress using the Perceived Stress Scale (PSS) at 28 weeks gestation and 4 weeks postpartum. Glycoprotein acetyls (GlycA), high-sensitivity C-reactive protein (hsCRP) and cytokines were assessed at 28 weeks gestation. We performed regression analyses, adjusted for potential confounders, and investigated mediation using nested counterfactual models. RESULTS: The estimated effect of pre-pregnancy obesity (BMI ≥ 30 kg/m2) on antenatal EPDS scores was 1.05 points per kg/m2 increase in BMI (95% CI: 0.20, 1.90; p = 0.02). GlycA, hsCRP, interleukin (IL) -1ra and IL-6 were higher in women with obesity, compared to healthy weight women, while eotaxin and IL-4 were lower. Higher GlycA was associated with higher EPDS and PSS scores and partially mediated the association between pre-pregnancy obesity and EPDS/PSS scores in unadjusted models, but this association attenuated upon adjustment for socioeconomic adversity. IL-6 and eotaxin were negatively associated with EPDS/PSS scores, however there was no evidence for mediation. CONCLUSIONS: Pre-pregnancy obesity increases the risk of antenatal depressive symptoms and is also associated with systemic inflammation during pregnancy. While discrete inflammatory markers are associated with antenatal depressive symptoms and perceived stress, their role in mediating the effects of pre-pregnancy obesity on antenatal depression requires further investigation.

Targeting the perinatal diet to modulate the gut microbiota increases dietary variety and prebiotic and probiotic food intakes: results from a randomised controlled trial.

OBJECTIVE: To evaluate the hypothesis that a perinatal educational dietary intervention focused on 'eating for the gut microbiota' improves diet quality of pregnant women pre- and postnatally. DESIGN: The Healthy Parents, Healthy Kids study is a prospectively registered randomised controlled trial designed to evaluate the efficacy of a dietary intervention in altering the maternal and infant gut microbiota and improving perinatal diet quality. Eligible pregnant women were randomised to receive dietary advice from their healthcare provider or to additionally receive a three session dietary intervention. Dietary data were collected at gestation weeks 26, 31, 36 and postnatal week 4. Outcome measures were diet quality, dietary variety, prebiotic and probiotic food intakes, energy, fibre, saturated fat and discretionary food intakes. Between-group differential changes from baseline before and after birth in these dietary measures were assessed using generalised estimating equations. SETTING: Melbourne, Australia. PARTICIPANTS: Healthy pregnant women from gestation week 26. RESULTS: Forty-five women were randomised (twenty-two control, twenty-three intervention). Compared with the control group, the intervention group improved diet quality prior to birth (5·66 (95 % CI 1·65, 9·67), Cohen's d: 0·82 (se 0·33)). The intervention improved dietary variety (1·05 (95 % CI 0·17, 1·94), d: 0·66 (se 0·32)) and increased intakes of prebiotic (0·8 (95 % CI 0·27, 1·33), d: 0·91 (se 0·33)) and probiotic foods (1·05 (95 % CI 0·57, 1·53), d: 1·3(se 0·35)) over the whole study period compared with the control group. CONCLUSION: A dietary intervention focused on 'eating for the gut microbiota' can improve aspects of perinatal diet quality during and after pregnancy.

Burden of infection in Australian infants.

AIM: To determine the incidence, risk factors and health service utilisation for infection in the first 12 months of life in a population-derived Australian pre-birth cohort. METHODS: The Barwon Infant Study is a population-derived pre-birth cohort with antenatal recruitment (n = 1074) based in Geelong, Victoria, Australia. Infection data were collected by parent report, and general practitioner and hospital records at 1, 3, 6, 9 and 12 months of age. We calculated the incidence of infection, attendance at a health service with infection and used multiple negative binomial regression to investigate the effects of a range of exposures on incidence of infection. RESULTS: In the first 12 months of life, infections of the upper and lower respiratory tract (henceforth 'respiratory infections'), conjunctivitis and gastroenteritis occurred at a rate of 0.35, 0.04 and 0.04 episodes per child-month, respectively. A total of 482 (72.4%) infants attended a general practitioner with an infection and 69 (10.4%) infants attended the emergency department. Maternal antibiotic exposure in pregnancy and having older siblings were associated with respiratory infection. Childcare attendance by 12 months of age was associated with respiratory infections and gastroenteritis. Breastfeeding, even if less than 4 weeks in total, was associated with reduced respiratory infection. CONCLUSION: Infection, especially of the respiratory tract, is a common cause of morbidity in Australian infants. Several potentially modifiable risk factors were identified, particularly for respiratory infections. Most infections were managed by general practitioners and 1 in 10 infants attended an emergency department with infection in the first year of life.

Costs and uptake of a community model of paediatric food allergy care versus specialist hospital care: A before-and-after controlled trial.

AIM: To compare the costs of community-based food allergy model of care (intervention cohort, IC) with a tertiary-hospital, specialist allergy clinic model of care (control cohort, CC). METHODS: In this pragmatic controlled trial, children (aged 0-12 years) newly referred to the allergy clinic at Melbourne's Royal Children's Hospital with suspected/known food allergy to three or fewer foods were allocated to see either a community-based paediatrician, trained via online webinars and web-based clinical decision support tools for food allergy diagnosis and management, or a hospital allergist. Per-patient costs to the health-care system and out-of-pocket costs to families seen within 12 months (clinician time, allergy tests and medicare billing) were compared between the two models of care. RESULTS: At 12 months, 54/181 (30%) CC families had been seen in the allergy clinic and 93/115 (81%) of the IC families who chose to see a community paediatrician had been seen. In an intention-to-treat analysis (ITT), health-care system costs per IC patient were higher than the costs per CC patient (mean cost $333 versus $319, respectively; mean difference $14, 95% Confidence Interval (CI) -97 to 118, P = 0.81). Total out-of-pocket costs to family were $129 in the IC compared with $89 in the CC (mean difference $40, 95% CI $4-$77, P = 0.03). CONCLUSIONS: A community-based model of care for simple food allergy showed that costs to the health-care system were similar between the community model and hospital care but did not show reduced out-of-pocket costs to the families 12-months post-enrolment.

Outdoor fungal spores and acute respiratory effects in vulnerable individuals.

BACKGROUND: Many outdoor fungal spores are ubiquitous, respirable and possibly allergenic. They may contribute to asthma symptoms; however, little is known about their effects on respiratory function. OBJECTIVE: To investigate if outdoor fungal spore levels were associated with lung function or airway inflammation, and whether fungal sensitization or current asthma modified any associations. METHODS: Cross-sectional associations between same day (Lag0) and cumulative 3-day lagged (Lag0-3) counts of 12 outdoor fungal spore taxa and pre-bronchodilator spirometry (FEV1, FVC, FEF25%-75%), bronchodilator response (BDR) and airway inflammation (fractional exhaled nitric oxide (FeNO) and exhaled breath condensate (EBC) nitrogen oxides (NOx) and pH were investigated in 936 Melbourne Atopy Cohort Study participants during September 2009 to December 2011. Generalized linear models were used to quantify associations with lung function, FeNO and EBC pH; generalized estimating equations for BDR; and ordinal logistic regression for EBC NOx. Models were adjusted for age, sex, height, temperature, relative humidity, grass pollen and sample storage time. Potential effect modification by fungal sensitization and current asthma were examined using interaction terms. RESULTS: Mixed associations were found. Higher levels of Ustilago/smuts were associated with lower lung function at Lag0 (FEV1: 21ml [95%CI -36, -7]; FEF25%-75%: 39ml [-65, -13]) and Lag0-3 (FEV1: 9ml [-14, -4]; FEF25%-75% -18ml [-27, -9]). Positive BDR was associated with Ustilago/smuts (Lag0 OR = 1.1 [1.04, 1.2]; Lag0-3 OR = 1.04 [1.02, 1.07]), Alternaria (Lag0 OR = 1.3 [1.0, 1.6]) and Drechslera (Lag0 OR = 1.1 [1.03, 1.2]). Higher EBC NOx was associated with Cladosporium (Lag0-3 OR = 1.1 [1.0, 1.2]), Alternaria (Lag0-3 OR = 1.1 [1.0, 1.3]). No associations were found with higher FeNO. In those with fungal sensitization, Ustilago/smuts and Drechslera were associated with lower FEV1 and FVC; Cladosporium was associated with increased FEV1, FVC and FEF25%-75% but also with higher FeNO and lower EBC pH. In those with current asthma, Alternaria, Ustilago/smuts and Drechslera were associated with lower FEV1, FVC, FEF25-75% and EBC pH. CONCLUSION: Exposure to outdoor fungal spores may be associated with lower lung function and increased airway inflammation, particularly in those with fungal sensitization and/or current asthma.

Probiotics for treating eczema.

BACKGROUND: Eczema is a common chronic skin condition. Probiotics have been proposed as an effective treatment for eczema; their use is increasing, as numerous clinical trials are under way. This is an update of a Cochrane Review first published in 2008, which suggested that probiotics may not be an effective treatment for eczema but identified areas in which evidence was lacking. OBJECTIVES: To assess the effects of probiotics for treating patients of all ages with eczema. SEARCH METHODS: We updated our searches of the following databases to January 2017: the Cochrane Skin Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), in the Cochrane Library, the Global Resource of Eczema Trials (GREAT) database, MEDLINE, Embase, PsycINFO, the Allied and Complementary Medicine Database (AMED), and Latin American Caribbean Health Sciences Literature (LILACS). We searched five trials registers and checked the reference lists of included studies and relevant reviews for further references to relevant randomised controlled trials (RCTs). We also handsearched a number of conference proceedings. We updated the searches of the main databases in January 2018 and of trials registries in March 2018, but we have not yet incorporated these results into the review. SELECTION CRITERIA: Randomised controlled trials of probiotics (live orally ingested micro-organisms) compared with no treatment, placebo, or other active intervention with no probiotics for the treatment of eczema diagnosed by a doctor. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures as expected by Cochrane. We recorded adverse events from the included studies and from a separate adverse events search conducted for the first review. We formally assessed reporting bias by preparing funnel plots, and we performed trial sequential analysis for the first primary outcome - eczema symptoms at the end of active treatment.We used GRADE to assess the quality of the evidence for each outcome (in italic font). MAIN RESULTS: We included 39 randomised controlled trials involving 2599 randomised participants. We included participants of either gender, aged from the first year of life through to 55 years (only six studies assessed adults), who had mild to severe eczema. Trials were undertaken in primary and secondary healthcare settings, mainly in Europe or Asia. Duration of treatment ranged from four weeks to six months, and duration of follow-up after end of treatment ranged from zero to 36 months. We selected no standard dose: researchers used a variety of doses and concentrations of probiotics. The probiotics used were bacteria of the Lactobacillus and Bifidobacteria species, which were taken alone or combined with other probiotics, and were given with or without prebiotics. Comparators were no treatment, placebo, and other treatments with no probiotics.For all results described in this abstract, the comparator was no probiotics. Active treatment ranged from six weeks to three months for all of the following results, apart from the investigator-rated eczema severity outcome, for which the upper limit of active treatment was 16 weeks. With regard to score, the higher the score, the more severe were the symptoms. All key results reported in this abstract were measured at the end of active treatment, except for adverse events, which were measured during the active treatment period.Probiotics probably make little or no difference in participant- or parent-rated symptoms of eczema (13 trials; 754 participants): symptom severity on a scale from 0 to 20 was 0.44 points lower after probiotic treatment (95% confidence interval (CI) -1.22 to 0.33; moderate-quality evidence). Trial sequential analysis shows that target sample sizes of 258 and 456, which are necessary to demonstrate a minimum mean difference of -2 and -1.5, respectively, with 90% power, have been exceeded, suggesting that further trials with similar probiotic strains for this outcome at the end of active treatment may be futile.We found no evidence suggesting that probiotics make a difference in QoL for patients with eczema (six studies; 552 participants; standardised mean difference (SMD) 0.03, 95% CI -0.36 to 0.42; low-quality evidence) when measured by the participant or the parent using validated disease-specific QoL instruments.Probiotics may slightly reduce investigator-rated eczema severity scores (24 trials; 1596 participants). On a scale of 0 to 103 for total Severity Scoring of Atopic Dermatitis (SCORAD), a score combining investigator-rated eczema severity score and participant scoring for eczema symptoms of itch and sleep loss was 3.91 points lower after probiotic treatment than after no probiotic treatment (95% CI -5.86 to -1.96; low-quality evidence). The minimum clinically important difference for SCORAD has been estimated to be 8.7 points.We noted significant to extreme levels of unexplainable heterogeneity between the results of individual studies. We judged most studies to be at unclear risk of bias; six studies had high attrition bias, and nine were at low risk of bias overall.We found no evidence to show that probiotics make a difference in the risk of adverse events during active treatment (risk ratio (RR) 1.54, 95% CI 0.90 to 2.63; seven trials; 402 participants; low-quality evidence). Studies in our review that reported adverse effects described gastrointestinal symptoms. AUTHORS' CONCLUSIONS: Evidence suggests that, compared with no probiotic, currently available probiotic strains probably make little or no difference in improving patient-rated eczema symptoms. Probiotics may make little or no difference in QoL for people with eczema nor in investigator-rated eczema severity score (combined with participant scoring for eczema symptoms of itch and sleep loss); for the latter, the observed effect was small and of uncertain clinical significance. Therefore, use of probiotics for the treatment of eczema is currently not evidence-based. This update found no evidence of increased adverse effects with probiotic use during studies, but a separate adverse events search from the first review revealed that probiotic treatment carries a small risk of adverse events.Results show significant, unexplainable heterogeneity between individual trial results. Only a small number of studies measured some outcomes.Future studies should better measure QoL scores and adverse events, and should report on new probiotics. Researchers should also consider studying subgroups of patients (e.g. patients with atopy or food allergies, adults) and standardising doses/concentrations of probiotics given.

Anaphylaxis to packaged foods in Australasia.

AIMS: To examine reports of anaphylaxis in Australasia from consumption of packaged food products with or without precautionary allergen labelling (PAL), where the known allergen triggers were not a listed ingredient. METHODS: A questionnaire was sent to all members of the Australasian Society of Clinical Immunology and Allergy (n = 548). Participants were asked to complete a survey reporting whether they have had seen any patients over the last 3 months reporting anaphylaxis following ingestion of a packaged food where the suspected food allergen was not a listed ingredient. RESULTS: Of the n = 548 members approached, n = 198 responded (response rate 36.1%).There were 14 reports of anaphylaxis to packaged foods (where the suspected allergen was not a listed ingredient), which met the case definition from a total of 198 respondents over the 9-month period. Of those reactions, 50.0% (confidence interval 95% 21-78) were reported from foods that did not have a PAL statement, and 50.0% (confidence interval 95% 21-78) were due to peanuts. CONCLUSION: Anaphylaxis to undeclared allergens was not rare and did not appear to depend on whether the product was labelled with precautionary advice. There is currently no reliable labelling system that can inform food-allergic consumers of safer food choices. Improvements in the regulation of food labelling with PAL are required.

Prevalence and determinants of antibiotic exposure in infants: A population-derived Australian birth cohort study.

AIM: The aim of this study was to describe antibiotic exposure in Australian infants during the first year of life, focusing on antibiotic class, indication, risk factors associated with exposure and comparison with international counterparts. METHODS: The Barwon Infant Study is a birth cohort study (n = 1074) with an unselected antenatal sampling frame from a large regional centre in Victoria, Australia. Longitudinal data on infection and medication were collected at 1, 3, 6, 9 and 12 months by parental questionnaire and from general practitioner and hospital records. Predictors of questionnaire non-completion were identified. A total of 660 infants with complete serial data were comprehensively examined. Antibiotic exposure was calculated as (i) antibiotic prescriptions and (ii) antibiotic days-exposed per person-year. RESULTS: Mean antibiotic prescription rate was 0.92 prescriptions (95% confidence interval (CI), 0.83-1.02) per person-year, with the highest rates in those aged <1 month (1.50 (95% CI, 1.09-1.91) per person-year). A total of 50.0% of infants were exposed to at least one antibiotic in their first year of life. Increasing number of siblings was associated with increased antibiotic exposure. Penicillin with extended spectrum (365 of 661 antibiotic prescriptions, 52.6%) and cephalosporins (12.0%) were the most frequently prescribed antibiotics. One fifth of antibiotics were prescribed for respiratory tract infections and bronchiolitis. CONCLUSION: Australian infants in this large population-based study are exposed to considerably more antibiotics than the majority of their international counterparts. Interventions aimed at addressing avoidable prescribing by medical practitioners and modifiable risk factors associated with antibiotic exposure may reduce antibiotic use.

Formula and breast feeding in infant food allergy: A population-based study.

AIM: To determine whether infant-feeding practices, including duration of exclusive breastfeeding and use of partially hydrolysed formula, modify the risk of developing infant food allergy. METHODS: In an observational population-based study, 1 year olds were recruited from community immunisation clinics in Melbourne, Australia. Parent-reported data on infant-feeding practices and potential confounders were collected prior to infant skin prick testing for four food allergens. Sensitised infants attended hospital-based oral food challenges to establish food allergy status. Multiple logistic regression was used to investigate associations between breastfeeding and formula-feeding and infant food allergy adjusting for possible confounding variables. RESULTS: A total of 5276 (74% response) infants participated. Of the 4537 for whom food allergy status was determined, 515 (11.3%) were food allergic (challenge-proven in the context of skin prick testing positive (≥2 mm)). After adjusting for confounding variables, there was no association between duration of exclusive breastfeeding and food allergy. Use of partially hydrolysed formula did not reduce the risk of food allergy compared with cow's milk formula in the general population (adjusted odds ratios 1.03 (confidence interval 0.67-1.50)). CONCLUSION: Duration of exclusive breastfeeding and use of partially hydrolysed formula were not associated with food allergy at 1 year of age in this large population-based study. These findings have implications for population-based infant-feeding guidelines and do not support the use of partially hydrolysed formula for food allergy prevention.

Medical intervention in parent-reported infant gastro-oesophageal reflux: A population-based study.

AIM: To report the cumulative incidence, health-seeking behaviour and medical intervention of infants with gastro-oesophageal reflux (GOR) in the first year of life. METHODS: The HealthNuts study is a longitudinal, population-based study. At 12 months of age, infants underwent skin prick testing to food allergens, including cows milk. Parents completed a questionnaire on GOR symptoms, food allergy and treatments. Factors associated with seeking health care for infants with GOR were modelled using logistic regression. RESULTS: Of 4674 infants, parents reported GOR in 1054 (23%; 95% confidence interval (CI) 21.4-23.8). Parents consulted a medical practitioner in 662 (64%) cases. Symptoms commenced in the first month in 411 (48%) and resolved within 6 months in 703 (75%) infants. Factors associated with doctor consultation for GOR were prematurity (adjusted odds ratio (aOR) 1.94; 95% CI 1.43-2.63) and family history of atopy (aOR 1.64; 95% CI 1.1-2.43). Eight per cent of infants (371/4674; 95% CI 7.2-8.7) received anti-reflux medication and 6% (296/4674; 95% CI 5.7-7.1) changed formula. Parents were more likely to seek treatment if they perceived their infant to be unsettled (aOR 2.55; 95% CI 1.26-5.17) and if the duration of GOR was prolonged (aOR 3.36 for symptoms >6 months; 95% CI 1.83-6.17). CONCLUSIONS: In the first year of life, approximately 14% of the population seek medical advice for GOR symptoms. The use of anti-reflux medication in the general community remains high, despite the absence of evidence that it is appropriate or effective for uncomplicated GOR.

Probiotic effects in allergic disease.

The increasing prevalence of allergic disease has been linked to reduced microbial exposure in early life. Probiotics have recently been advocated for the prevention and treatment of allergic disease. This article summarises recent publications on probiotics in allergic disease, focusing on clinical studies of prevention or treatment of allergic disease. Studies employing the combined administration of pre-natal and post-natal probiotics suggest a role for certain probiotics (alone or with prebiotics) in the prevention of eczema in early childhood, with the pre-natal component of treatment appearing to be important for beneficial effects. On the other hand, current data are insufficient to support the use of probiotics for the treatment of established allergic disease, although recent studies have highlighted new hope in this area. Probiotic bacteria continue to represent the most promising intervention for primary prevention of allergic disease, and well-designed definitive intervention studies should now be a research priority.

Age-dependent associations of human milk oligosaccharides with body size and composition up to 4 years of age.

BACKGROUND: Human milk oligosaccharides (HMOs) are major components of human milk that may mediate its beneficial effects on infant growth. OBJECTIVES: To investigate relationships between HMO concentrations in milk at 6 wk postpartum and anthropometry to 4 y of age in human milk-fed infants. METHODS: Milk samples were collected from 292 mothers at 6 wk (median 6.0 wk; range 3.3, 11.1] postpartum in a longitudinal, population-derived cohort. Of the infants, 171 were exclusively human milk-fed to 3 mo of age and 127 to 6 mo. Concentrations of 19 HMOs were quantified using high-performance liquid chromatography. Maternal secretor status (n = 221 secretors) was determined from 2'-fucosyllactose (2'FL) concentration. We calculated z-scores for child weight, length, head circumference, summed triceps and subscapular skinfold thicknesses, and weight-for-length at 6 wk, 6 mo, 12 mo, and 4 y. We investigated associations of secretor status and each HMO measure with change from birth for each z-score using linear mixed-effects models. RESULTS: Maternal secretor status was not associated with anthropometric z-scores up to 4 y of age. Several HMOs were associated with z-scores at 6 wk and 6 mo, predominantly within secretor status subgroups. Higher levels of 2'FL were associated with greater weight [ß = 0.91 increase in z-score per SD increase log-2'FL, 95% CI (0.17, 1.65)] and length [ß = 1.22, (0.25, 2.20)] in children born to secretor mothers, but not body composition measures. Higher lacto-N-tetraose was associated with greater weight [ß = 0.22, (0.02, 0.41)] and length (ß = 0.30, (0.07, 0.53)] among children born to nonsecretor mothers. Several HMOs were associated with anthropometric measures at 12 mo and 4 y of age. CONCLUSIONS: Milk HMO composition at 6 wk postpartum is associated with several anthropometry measures up to 6 mo of age in a potential secretor status-specific manner, with largely different HMOs associating with anthropometry from 12 mo to 4 y of age.

A systematic review of quality and consistency of clinical practice guidelines on the primary prevention of food allergy and atopic dermatitis.

Background and aims: With an increasing number of Clinical Practice Guidelines (CPGs) addressing primary prevention of food allergy and atopic dermatitis, it is timely to undertake a comprehensive assessment of the quality and consistency of recommendations and evaluation of their implementability in different geographical settings. Methods: We systematically reviewed CPGs from 8 international databases and extensive website searches. Seven reviewers screened records in any language and then used the AGREE II and AGREE REX instruments to critically appraise CPGs published between January 2011 and April 2022. Results: Our search identified 2138 relevant articles, of which 30 CPGs were eventually included. Eight (27%) CPGs were shortlisted based on our predefined quality criteria of achieving scores >70% in the "Scope and Purpose" and "Rigour of Development" domains of the AGREE II instrument. Among the shortlisted CPGs, scores on the "Applicability" domain were generally low, and only 3 CPGs rated highly in the "Implementability" domain of AGREE-REX, suggesting that the majority of CPGs fared poorly on global applicability. Recommendations on maternal diet and complementary feeding in infants were mostly consistent, but recommendations on use of hydrolysed formula and supplements varied considerably. Conclusion: The overall quality of a CPG for Food Allergy and Atopic Dermatitis prevention did not correlate well with its global applicability. It is imperative that CPG developers consider stakeholders' preferences, local applicability, and adapt existing recommendations to each individual population and healthcare system to ensure successful implementation. There is a need for development of high-quality CPGs for allergy prevention outside of North America and Europe. PROSPERO registration number: CRD42021265689.

A phase I study of daily treatment with a ceramide-dominant triple lipid mixture commencing in neonates.

BACKGROUND: Defects in skin barrier function are associated with an increase risk of eczema and atopic sensitisation. Ceramide-dominant triple lipid mixture may improve and maintain the infant skin barrier function, and if shown to be safe and feasible, may therefore offer an effective approach to reduce the incidence of eczema and subsequent atopic sensitisation. We sort to assess the safety and compliance with daily application of a ceramide-dominant triple lipid formula (EpiCeram™) commencing in the neonatal period for the prevention of eczema. METHODS: Ten infants (0-4 weeks of age) with a family history of allergic disease were recruited into an open-label, phase one trial of daily application of EpiCeram™ for six weeks. The primary outcomes were rate of compliance and adverse events. Data on development of eczema, and physiological properties of the skin (transepidermal water loss, hydration, and surface pH) were also measured. RESULTS: Eighty percent (8/10) of mothers applied the study cream on 80% or more of days during the six week intervention period. Though a number of adverse events unrelated to study product were reported, there were no adverse skin reactions to the study cream. CONCLUSIONS: These preliminary results support the safety and parental compliance with daily applications of a ceramide-dominant formula for the prevention of eczema, providing the necessary ground work for a randomised clinical trial to evaluate EpiCeram™ for the prevention of eczema. TRIAL REGISTRATION: The study was listed at the Australian/New Zealand Clinical Trial Registry (ANZCTR): reg. no. ACTRN12609000727246.

Cord blood immune profile: Associations with higher prenatal plastic chemical levels.

Prenatal exposure to plastic chemicals has been associated with alterations to early-life immune function in children. However, previous studies have generally been small and focused on limited repertoires of immune indices. In a large population-based pre-birth cohort (n = 1074), third-trimester measurements of eight phthalate metabolites and three analogues of bisphenols were used to estimate prenatal exposure to phthalate and bisphenol compounds. In cord blood, immune cell populations were measured by flow cytometry and an extensive panel of cytokines and chemokines were measured by multiplex immunoassay. We used these cord blood analytes to estimate "early life" immune profiles. The full study sample comprises data from 774 infants with prenatal plastic metabolite measurements and any cord blood immune data. Multiple linear regression analysis was used to evaluate whether prenatal phthalate and bisphenol exposure was prospectively associated with cord blood immune cell populations and cytokine and chemokine levels. Generally, inverse associations were observed between prenatal phthalate exposure and cord blood immune indices. Higher exposure to di-n-butyl phthalate was associated with lower cord blood levels of platelet-derived growth factor (PDGF) and interferon gamma-induced protein 10 (IP-10); higher exposure to the sum of dibutyl phthalates was associated with lower cord blood levels of IP-10; and higher exposure to benzyl butyl phthalate was associated with lower cord blood levels of interleukin 1 beta (IL-1ß). There was less evidence of associations between bisphenols and cord blood immune indices. These results extend previous work examining prenatal plastic chemical exposure and early-life immune development and highlight the importance of further examination of potential associations with health-related outcomes.

Study protocol of a phase 2, dual-centre, randomised, controlled trial evaluating the effectiveness of probiotic and egg oral immunotherapy at inducing desensitisation or sustained unresponsiveness (remission) in participants with egg allergy compared with placebo (Probiotic Egg Allergen Oral Immunotherapy for Treatment of Egg Allergy: PEAT study).

INTRODUCTION: Egg allergy is the most common food allergy in children but recent studies have shown persistence or delayed resolution into adolescence. As there is currently no effective long-term treatment, definitive treatments that improve quality of life and prevent fatalities for food allergies are required. We have previously shown that a novel treatment comprising a combination of the probiotic Lactobacillus rhamnosus CGMCC 1.3724 with peanut oral immunotherapy (OIT) is highly effective at inducing sustained unresponsiveness, with benefit persisting to 4 years after treatment cessation in the majority of initial treatment responders. In this study, we plan to extend the probiotic food OIT platform to another allergen, namely egg. We describe the protocol for a phase 2, dual-centre, randomised, controlled trial evaluating the effectiveness of probiotic and egg OIT at inducing desensitisation or sustained unresponsiveness (remission) in participants with egg allergy compared with placebo. METHODS AND ANALYSIS: 80 participants aged 5-30 years of age with current egg allergy confirmed by double-blind placebo-controlled food challenge at study screening will be recruited from Australia and Singapore. There are two intervention arms-probiotic and egg OIT (active) or placebo. Interventions are administered once daily for 18 months. The primary outcome is the proportion of participants who attain 8-week sustained unresponsiveness in the active group versus placebo group. ETHICS AND DISSEMINATION: This study has been approved by the Human Research Ethics Committees at the Royal Children's Hospital (HREC 2019.082) and the National Healthcare Group Domain Specific Review Board (2019/00029). Results will be published in peer-reviewed journals and disseminated via presentations at international conferences. TRIAL REGISTRATION NUMBER: ACTRN12619000480189.

Epigenetic programming underpins B-cell dysfunction in peanut and multi-food allergy.

OBJECTIVE: Rates of IgE-mediated food allergy (FA) have increased over the last few decades, and mounting evidence implicates disruption of epigenetic profiles in various immune cell types in FA development. Recent data implicate B-cell dysfunction in FA; however, few studies have examined epigenetic changes within these cells. METHODS: We assessed epigenetic and transcriptomic profiles in purified B cells from adolescents with FA, comparing single-food-allergic (peanut only), multi-food-allergic (peanut and ≥1 other food) and non-allergic (control) individuals. Adolescents represent a phenotype of persistent and severe FA indicative of a common immune deviation. RESULTS: We identified 144 differentially methylated probes (DMPs) and 116 differentially expressed genes (DEGs) that distinguish B cells of individuals with FA from controls, including differential methylation of the PM20D1 promoter previously associated with allergic disorders. Subgroup comparisons found 729 DMPs specific to either single-food- or multi-food-allergic individuals, suggesting epigenetic distinctions between allergy groups. This included two regions with increased methylation near three S100 genes in multi-food-allergic individuals. Ontology results of DEGs specific to multi-food-allergic individuals revealed enrichment of terms associated with myeloid cell activation. Motif enrichment analysis of promoters associated with DMPs and DEGs showed differential enrichment for motifs recognised by transcription factors regulating B- and T-cell development, B-cell lineage determination and TGF-ß signalling pathway between the multi-food-allergic and single-food-allergic groups. CONCLUSION: Our data highlight epigenetic changes in B cells associated with peanut allergy, distinguishing features of the epigenome between single-food- and multi-food-allergic individuals and revealing differential developmental pathways potentially underpinning these distinct phenotypes.

Targeting the Infant Gut Microbiota Through a Perinatal Educational Dietary Intervention: Protocol for a Randomized Controlled Trial.

BACKGROUND: The early life gut microbiota are an important regulator of the biological pathways contributing toward the pathogenesis of noncommunicable disease. It is unclear whether improvements to perinatal diet quality could alter the infant gut microbiota. OBJECTIVE: The aim of this study is to assess the efficacy of a perinatal educational dietary intervention in influencing gut microbiota in mothers and infants 4 weeks after birth. METHODS: The Healthy Parents, Healthy Kids randomized controlled trial aimed to recruit 90 pregnant women from Melbourne, Victoria, Australia. At week 26 of gestation, women were randomized to receive dietary advice from their doctor (n=45), or additionally receive a dietary intervention (n=45). The intervention included an educational workshop and 2 support calls aiming to align participants' diets with the Australian Dietary Guidelines and increase intakes of prebiotic and probiotic foods. The educational design focused on active learning and self-assessment. Behavior change techniques were used to support dietary adherence, and the target behavior was eating for the gut microbiota. Exclusion criteria were age under 18 years, diagnosed mental illnesses, obesity, diabetes mellitus, diagnosed bowel conditions, exclusion diets, illicit drug use, antibiotic use, prebiotic or probiotic supplementation, and those lacking dietary autonomy. The primary outcome measure is a between-group difference in alpha diversity in infant stool collected 4 weeks after birth. Secondary outcomes include evaluating the efficacy of the intervention in influencing infant and maternal stool microbial composition and short chain fatty acid concentrations, epigenetic profile, and markers of inflammation and stress, as well as changes in maternal dietary intake and well-being. The study and intervention feasibility and acceptance will also be evaluated as secondary outcomes. RESULTS: The study results are yet to be written. The first participant was enrolled on July 28, 2016, and the final follow-up assessment was completed on October 11, 2017. CONCLUSIONS: Data from this study will provide new insights regarding the ability of interventions targeting the perinatal diet to alter the maternal and infant gut microbiota. If this intervention is proven, our findings will support larger studies aiming to guide the assembly of gut microbiota in early life. TRIAL REGISTRATION: Australian Clinical Trials Registration Number ACTRN12616000936426; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=370939. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/14771.