School-age outcomes among IVF-conceived children: A population-wide cohort study.

BACKGROUND: In vitro fertilisation (IVF) is a common mode of conception. Understanding the long-term implications for these children is important. The aim of this study was to determine the causal effect of IVF conception on primary school-age childhood developmental and educational outcomes, compared with outcomes following spontaneous conception. METHODS AND FINDINGS: Causal inference methods were used to analyse observational data in a way that emulates a target randomised clinical trial. The study cohort comprised statewide linked maternal and childhood administrative data. Participants included singleton infants conceived spontaneously or via IVF, born in Victoria, Australia between 2005 and 2014 and who had school-age developmental and educational outcomes assessed. The exposure examined was conception via IVF, with spontaneous conception the control condition. Two outcome measures were assessed. The first, childhood developmental vulnerability at school entry (age 4 to 6), was assessed using the Australian Early Developmental Census (AEDC) (n = 173,200) and defined as scoring <10th percentile in ≥2/5 developmental domains (physical health and wellbeing, social competence, emotional maturity, language and cognitive skills, communication skills, and general knowledge). The second, educational outcome at age 7 to 9, was assessed using National Assessment Program-Literacy and Numeracy (NAPLAN) data (n = 342,311) and defined by overall z-score across 5 domains (grammar and punctuation, reading, writing, spelling, and numeracy). Inverse probability weighting with regression adjustment was used to estimate population average causal effects. The study included 412,713 children across the 2 outcome cohorts. Linked records were available for 4,697 IVF-conceived cases and 168,503 controls for AEDC, and 8,976 cases and 333,335 controls for NAPLAN. There was no causal effect of IVF-conception on the risk of developmental vulnerability at school-entry compared with spontaneously conceived children (AEDC metrics), with an adjusted risk difference of -0.3% (95% CI -3.7% to 3.1%) and an adjusted risk ratio of 0.97 (95% CI 0.77 to 1.25). At age 7 to 9 years, there was no causal effect of IVF-conception on the NAPLAN overall z-score, with an adjusted mean difference of 0.030 (95% CI -0.018 to 0.077) between IVF- and spontaneously conceived children. The models were adjusted for sex at birth, age at assessment, language background other than English, socioeconomic status, maternal age, parity, and education. Study limitations included the use of observational data, the potential for unmeasured confounding, the presence of missing data, and the necessary restriction of the cohort to children attending school. CONCLUSIONS: In this analysis, under the given causal assumptions, the school-age developmental and educational outcomes for children conceived by IVF are equivalent to those of spontaneously conceived children. These findings provide important reassurance for current and prospective parents and for clinicians.

The natural history of peanut and egg allergy in children up to age 6 years in the HealthNuts population-based longitudinal study.

BACKGROUND: Prospectively collected data on the natural history of food allergy are lacking. OBJECTIVE: We examined the natural history of egg and peanut allergy in children from age 1 to 6 years and assessed whether a skin prick test (SPT) result or other clinical factors at diagnosis are associated with the persistence or resolution of food allergy in early childhood. METHODS: The HealthNuts cohort consists of 5276 children who were recruited at age 1 year and have been followed prospectively. Children with food allergy at age 1 year (peanut [n = 156] or raw egg [n = 471] allergy ) and children who developed new sensitizations or food reactions after age 1 year were assessed for food sensitization and allergy (confirmed by oral food challenge when indicated) at the 6-year follow-up. RESULTS: New-onset food allergy developed by age 6 years was more common for peanut (0.7% [95% CI = 0.5%-1.1%]) than egg (0.09% [95% CI = 0.03%-0.3%]). Egg allergy resolved more commonly (89% [95% CI = 85%-92%]) than peanut allergy (29% [95% CI = 22%-38%]) by age 6 years. The overall weighted prevalence of peanut allergy at age 6 years was 3.1% (95% CI = 2.6-3.7%) and that of egg allergy was 1.2% (95% = CI 0.9%-1.6%). The factors at age 1 year associated with persistence of peanut allergy were peanut SPT result of 8 mm or larger (odds ratio [OR] = 2.35 [95% CI 1.08-5.12]), sensitization to tree nuts (adjusted OR [aOR] = 2.51 [95% CI = 1.00-6.35]), and early-onset severe eczema (aOR = 3.23, [95% CI 1.17-8.88]). Factors at age 1 associated with persistence of egg allergy at age 6 were egg SPT result of 4 mm or larger (OR = 2.98 [95% CI 1.35-6.36]), other (peanut and/or sesame) food sensitizations (aOR = 2.80 [95% CI = 1.11-7.03]), baked egg allergy (aOR = 7.41 [95% CI = 2.16-25.3]), and early-onset severe eczema (aOR = 3.77 [95% CI = 1.35-10.52]). CONCLUSION: Most egg allergy and nearly one-third of peanut allergy resolves naturally by age 6 years. The prevalence of peanut allergy at age 6 years was similar to that observed at age 1 year, largely owing to new-onset food peanut allergy after age 1 year. Infants with early-onset eczema, larger SPT wheals, or multiple food sensitizations and/or allergies were less likely to acquire tolerance to either peanut or egg.

Violation of research integrity principles occurs more often than we think.

The science community generally believes that the violation of research integrity is rare. Built upon this belief, the scientific system makes little effort to examine the trustworthiness of research. Research misconduct refers to an intentional violation of research integrity principles, which has an extensive and far-reaching impact on the trustworthiness and reputation of science. Emerging evidence has suggested that research misconduct is far more common than we normally perceive. Far more problematic papers should be retracted than are being retracted because of poor actions when confronting research misconduct. Research misconduct is usually driven by incentives in the form of pursuing publications for researchers' career needs and is further facilitated by poor research governance. The current strategy that tackles potential research misconduct focuses on protecting the reputation of authors and their institutions but neglects the interests of patients, clinicians and honest researchers. Removing improper incentives, training researchers and imposing better governance are vital to reducing research misconduct. Awareness of the possibility of misconduct and formalized procedures that scrutinize study trustworthiness are important during peer review and in systematic reviews.

Association Between Earlier Introduction of Peanut and Prevalence of Peanut Allergy in Infants in Australia.

Importance: Randomized clinical trials showed that earlier peanut introduction can prevent peanut allergy in select high-risk populations. This led to changes in infant feeding guidelines in 2016 to recommend early peanut introduction for all infants to reduce the risk of peanut allergy. Objective: To measure the change in population prevalence of peanut allergy in infants after the introduction of these new guidelines and evaluate the association between early peanut introduction and peanut allergy. Design: Two population-based cross-sectional samples of infants aged 12 months were recruited 10 years apart using the same sampling frame and methods to allow comparison of changes over time. Infants were recruited from immunization centers around Melbourne, Australia. Infants attending their 12-month immunization visit were eligible to participate (eligible age range, 11-15 months), regardless of history of peanut exposure or allergy history. Exposures: Questionnaires collected data on demographics, food allergy risk factors, peanut introduction, and reactions. Main Outcome and Measures: All infants underwent skin prick tests to peanut and those with positive results underwent oral food challenges. Prevalence estimates were standardized to account for changes in population demographics over time. Results: This study included 7209 infants (1933 in 2018-2019 and 5276 in 2007-2011). Of the participants in the older vs more recent cohort, 51.8% vs 50.8% were male; median (IQR) ages were 12.5 (12.2-13.0) months vs 12.4 (12.2-12.9) months. There was an increase in infants of East Asian ancestry over time (16.5% in 2018-2019 vs 10.5% in 2007-2011), which is a food allergy risk factor. After standardizing for infant ancestry and other demographics changes, peanut allergy prevalence was 2.6% (95% CI, 1.8%-3.4%) in 2018-2019, compared with 3.1% in 2007-2011 (difference, -0.5% [95% CI, -1.4% to 0.4%]; P = .26). Earlier age of peanut introduction was significantly associated with a lower risk of peanut allergy among infants of Australian ancestry in 2018-2019 (age 12 months compared with age 6 months or younger: adjusted odds ratio, 0.08 [05% CI, 0.02-0.36]; age 12 months compared with 7 to less than 10 months: adjusted odds ratio, 0.09 [95% CI, 0.02-0.53]), but not significant among infants of East Asian ancestry (P for interaction = .002). Conclusions and Relevance: In cross-sectional analyses, introduction of a guideline recommending early peanut introduction in Australia was not associated with a statistically significant lower or higher prevalence of peanut allergy across the population.

Adiposity and estrogen receptor-positive, postmenopausal breast cancer risk: Quantification of the mediating effects of fasting insulin and free estradiol.

Adiposity increases estrogen receptor (ER)-positive postmenopausal breast cancer risk. While mechanisms underlying this relationship are uncertain, dysregulated sex-steroid hormone production and insulin signaling are likely pathways. Our aim was to quantify mediating effects of fasting insulin and free estradiol in the adiposity and ER-positive postmenopausal breast cancer association. We used data from a case-cohort study of sex hormones and insulin signaling nested within the Melbourne Collaborative Cohort Study. Eligible women, at baseline, were not diagnosed with cancer, were postmenopausal, did not use hormone therapy and had no history of diabetes or diabetes medication use. Women with ER-negative disease or breast cancer diagnosis within the first follow-up year were excluded. We analyzed the study as a cumulative sampling case-control study with 149 cases and 1,029 controls. Missing values for insulin and free estradiol were multiply imputed with chained equations. Interventional direct (IDE) and indirect (IIE) effects were estimated using regression-based multiple-mediator approach. For women with body mass index (BMI) >30 kg/m2 compared to women with BMI 18.5-25 kg/m2 , the risk ratio (RR) of breast cancer was 1.75 (95% confidence interval [CI] 1.05-2.91). The estimated IDE (RR) not through the mediators was 1.03 (95% CI 0.43-2.48). Percentage mediated effect through free estradiol was 72% (IIE-RR 1.56; 95% CI 1.11-2.19). There was no evidence for an indirect effect through insulin (IIE-RR 1.12; 95% CI 0.68-1.84; 28% mediated). Our results suggest that circulating free estradiol plays an important mediating role in the adiposity-breast cancer relationship but does not explain all of the association.

Childhood pneumonia, pleurisy and lung function: a cohort study from the first to sixth decade of life.

INTRODUCTION: Adult spirometry following community-acquired childhood pneumonia has variably been reported as showing obstructive or non-obstructive deficits. We analysed associations between doctor-diagnosed childhood pneumonia/pleurisy and more comprehensive lung function in a middle-aged general population cohort born in 1961. METHODS: Data were from the prospective population-based Tasmanian Longitudinal Health Study cohort. Analysed lung function was from ages 7 years (prebronchodilator spirometry only, n=7097), 45 years (postbronchodilator spirometry, carbon monoxide transfer factor and static lung volumes, n=1220) and 53 years (postbronchodilator spirometry and transfer factor, n=2485). Parent-recalled histories of doctor-diagnosed childhood pneumonia and/or pleurisy were recorded at age 7. Multivariable linear and logistic regression were used. RESULTS: At age 7, compared with no episodes, childhood pneumonia/pleurisy-ever was associated with reduced FEV1:FVC for only those with current asthma (beta-coefficient or change in z-score=-0.20 SD, 95% CI -0.38 to -0.02, p=0.028, p interaction=0.036). At age 45, for all participants, childhood pneumonia/pleurisy-ever was associated with a restrictive pattern: OR 3.02 (1.5 to 6.0), p=0.002 for spirometric restriction (FVC less than the lower limit of normal plus FEV1:FVC greater than the lower limit of normal); total lung capacity z-score -0.26 SD (95% CI -0.38 to -0.13), p<0.001; functional residual capacity -0.16 SD (-0.34 to -0.08), p=0.001; and residual volume -0.18 SD (-0.31 to -0.05), p=0.008. Reduced lung volumes were accompanied by increased carbon monoxide transfer coefficient at both time points (z-score +0.29 SD (0.11 to 0.49), p=0.001 and +0.17 SD (0.04 to 0.29), p=0.008, respectively). DISCUSSION: For this community-based population, doctor-diagnosed childhood pneumonia and/or pleurisy were associated with obstructed lung function at age 7 for children who had current asthma symptoms, but with evidence of 'smaller lungs' when in middle age.

Earlier ingestion of peanut after changes to infant feeding guidelines: The EarlyNuts study.

BACKGROUND: Randomized controlled trials demonstrate that timely introduction of peanut to infants reduces the risk of peanut allergy. However, much debate remains regarding how to best achieve earlier peanut introduction at the population level. Our previous study in 2007-2011 (HealthNuts, n = 5300) indicated that few infants were consuming peanut in the first year. Australian infant feeding guidelines were updated in 2016 to recommend introducing peanut before 12 months for all infants. There were no data available on the subsequent effect on peanut introduction or peanut reactions. OBJECTIVE: We sought to assess the consequences of a nonscreening approach to allergenic food introduction in a population-based sample of infants in their first year of life. METHODS: EarlyNuts is a population-based, cross-sectional study of 12-month-old infants in Melbourne, Australia, recruited by using an identical sampling frame and methods to HealthNuts (72% response rate vs 73% response rate in HealthNuts). We report here on the first 860 participants recruited between November 2016 and October 2018. RESULTS: Most infants (88.6%; 95% CI, 86.1% to 90.7%) had introduced peanut by 12 months (median age, 6 months), an increase from 28.4% (95% CI, 27.2% to 29.7%) in the HealthNuts study. By 12 months, the majority of these (76.4%) had consumed peanut more than 4 times, and 28% were eating peanut more than once per week. Preliminary results on parent-reported reactions show that 4.0% of those consuming peanut by 12 months had possible IgE-mediated reactions. CONCLUSIONS: There has been a striking shift toward earlier peanut introduction, with a 3-fold increase in peanut introduction by age 1 year in 2018 compared with 2007-2011.

Egg allergen specific IgE diversity predicts resolution of egg allergy in the population cohort HealthNuts.

BACKGROUND: IgE-mediated egg allergy presents as one of the most common food allergies in children. Measurement of egg white specific IgE (sIgE) levels in serum or skin prick test has been shown to be a poor predictor of clinical allergy to raw egg white, and also to baked or cooked egg. Recent developments in component resolved diagnostic (CRD) technology have enabled us to improve the way in which we diagnose and predict peanut allergy by examining IgE specificity to individual peptides. OBJECTIVES: We aimed to investigate whether egg CRD could improve current methods to diagnose various egg allergy phenotypes as well as predict the development of tolerance to egg. METHODS: Using the HealthNuts cohort of food challenge-proven egg allergic and egg-sensitized and egg-tolerant, age-matched 12-month infants with longitudinal follow-up at 2 and 4 years (n = 451), we measured serum egg white, Gal d 1, 2, 3 and 5 sIgE using ImmunoCAP. RESULTS: Gal d 1 sensitization increased the risk of persistent egg allergy by 2.5-fold. The production of sIgE to all four egg allergens (Gal d 1, 2, 3 or 5) increased the risk of having persistent raw egg allergy fourfold (OR 4.19 (95% CI: 1.25-14.07). We did not find any improvements of using Gal d 1, 2, 3 or 5 to diagnose current egg allergy compared to egg white sIgE. CONCLUSION: Sensitization to multiple egg allergens Gal d 1, 2, 3 or 5 may be a prognostic marker that could be useful for patient management and identifying individuals at risk of developing persistent egg allergy.

Effect decomposition through multiple causally nonordered mediators in the presence of exposure-induced mediator-outcome confounding.

Avin et al (2005) showed that, in the presence of exposure-induced mediator-outcome confounding, decomposing the total causal effect (TCE) using standard conditional exchangeability assumptions is not possible even under a nonparametric structural equation model with all confounders observed. Subsequent research has investigated the assumptions required for such a decomposition to be identifiable and estimable from observed data. One approach was proposed by VanderWeele et al (2014). They decomposed the TCE under three different scenarios: (1) treating the mediator and the exposure-induced confounder as joint mediators; (2) generating path-specific effects albeit without distinguishing between multiple distinct paths through the exposure-induced confounder; and (3) using so-called randomised interventional analogues where sampling values from the distribution of the mediator within the levels of the exposure effectively marginalises over the exposure-induced confounder. In this paper, we extend their approach to the case where there are multiple mediators that do not influence each other directly but which are all influenced by an exposure-induced mediator-outcome confounder. We provide a motivating example and results from a simulation study based on from our work in dental epidemiology featuring the 1982 Pelotas Birth Cohort in Brazil.

Prevalence of clinic-defined food allergy in early adolescence: The SchoolNuts study.

BACKGROUND: Rising rates of food-induced anaphylaxis have recently been shown in the adolescent age group, following earlier descriptions of a rise in children younger than 5 years. However, few population-based studies have examined the prevalence of food allergy in adolescence using objective measures such as oral food challenge (OFC). OBJECTIVE: We sought to determine the prevalence of food allergy among a population-based sample of 10- to 14-year-old adolescents using clinical evaluation including OFC to confirm the diagnosis. METHODS: Schools were randomly selected from greater metropolitan Melbourne, Australia. Students aged 10 to 14 years, and their parents, were asked to complete a questionnaire regarding the adolescent's food allergy or food-related reactions. Clinic evaluation, which consisted of skin prick tests and OFC where eligible, was undertaken if students were suspected to have current food allergy from parent response. Among 9816 students assessed, 5016 had complete parent response and clinic evaluation when eligible. An additional 4800 students had student questionnaires only. RESULTS: The prevalence of clinic-defined current food allergy based on history, sensitization data, and OFC results was 4.5% (95% CI, 3.9-5.1), with the most common food triggers being peanut, 2.7% (95% CI, 2.3-3.2), and tree nut, 2.3% (95% CI, 1.9-2.8). Among the additional group of 4800 adolescents who had only self-reported food allergy status available, the prevalence of self-reported current food allergy was 5.5% (95% CI, 4.9-6.2), with peanut, 2.8% (95% CI, 2.3-3.3), and tree nut, 2.3% (95% CI, 1.9-2.8), the most common. CONCLUSIONS: Approximately 1 in 20 10- to 14-year-old school students in Melbourne has current food allergy. This high prevalence suggests that the previously reported rise in food-induced anaphylaxis in this age group may reflect an increasing prevalence of food allergy rather than simply increased reporting of anaphylaxis.

Multilevel Regression and Poststratification: A Modeling Approach to Estimating Population Quantities From Highly Selected Survey Samples.

Investigators in large-scale population health studies face increasing difficulties in recruiting representative samples of participants. Nonparticipation, item nonresponse, and attrition, when follow-up is involved, often result in highly selected samples even in well-designed studies. We aimed to assess the potential value of multilevel regression and poststratification, a method previously used to successfully forecast US presidential election results, for addressing biases due to nonparticipation in the estimation of population descriptive quantities in large cohort studies. The investigation was performed as an extensive case study using baseline data (2013-2014) from a large national health survey of Australian males (Ten to Men: The Australian Longitudinal Study on Male Health). Analyses were performed in the open-source Bayesian computational package RStan. Results showed greater consistency and precision across population subsets of varying sizes when compared with estimates obtained using conventional survey sampling weights. Estimates for smaller population subsets exhibited a greater degree of shrinkage towards the national estimate. Multilevel regression and poststratification provides a promising analytical approach to addressing potential participation bias in the estimation of population descriptive quantities from large-scale health surveys and cohort studies.

Clinical penetrance in hereditary hemochromatosis: estimates of the cumulative incidence of severe liver disease among HFE C282Y homozygotes.

Iron overload (hemochromatosis) can cause serious, symptomatic disease that is preventable if detected early and managed appropriately. The leading cause of hemochromatosis in populations of predominantly European ancestry is homozygosity of the C282Y variant in the HFE gene. Screening of adults for iron overload or associated genotypes is controversial, largely because of a belief that severe phenotypes are uncommon, although cascade testing of first-degree relatives of patients is widely endorsed. We contend that severe liver disease (cirrhosis or hepatocellular cancer) is not at all uncommon among older males with hereditary hemochromatosis. Our review of the published data from a variety of empirical sources indicates that roughly 1 in 10 male HFE C282Y homozygotes is likely to develop severe liver disease during his lifetime unless iron overload is detected early and treated. New evidence from a randomized controlled trial of treatment allows for evidence-based management of presymptomatic patients. Although population screening for HFE C282Y homozygosity faces multiple barriers, a potentially effective strategy for increasing the early detection and prevention of clinical iron overload and severe disease is to include HFE C282Y homozygosity in lists of medically actionable gene variants when reporting the results of genome or exome sequencing.

Do Glutathione S-Transferase Genes Modify the Link between Indoor Air Pollution and Asthma, Allergies, and Lung Function? A Systematic Review.

PURPOSE OF REVIEW: Glutathione S-transferase (GST) genes are involved in oxidative stress management and may modify the impact of indoor air pollution. We aimed to assess the influence of GST genes on the relationship between indoor air pollution and allergy/lung function. RECENT FINDINGS: Our systematic review identified 22 eligible studies, with 15 supporting a gene-environment interaction. Carriers of GSTM1/T1 null and GSTP1 val genotypes were more susceptible to indoor air pollution exposures, having a higher risk of asthma and lung function deficits. However, findings differed in terms of risk alleles and specific exposures. High-exposure heterogeneity precluded meta-analysis. We found evidence that respiratory effects of indoor air pollution depend on the individual's GST profile. This may help explain the inconsistent associations found when gene-environment interactions are not considered. Future studies should aim to improve the accuracy of pollution assessment and investigate this finding in different populations.

Childhood measles contributes to post-bronchodilator airflow obstruction in middle-aged adults: A cohort study.

BACKGROUND AND OBJECTIVE: Chronic obstructive pulmonary disease (COPD) has potential origins in childhood but an association between childhood measles and post-bronchodilator (BD) airflow obstruction (AO) has not yet been shown. We investigated whether childhood measles contributed to post-BD AO through interactions with asthma and/or smoking in a non-immunized middle-aged population. METHODS: The population-based Tasmanian Longitudinal Health Study (TAHS) cohort born in 1961 (n = 8583) underwent spirometry in 1968 before immunization was introduced. A history of childhood measles infection was obtained from school medical records. During the fifth decade follow-up (n = 5729 responses), a subgroup underwent further lung function measurements (n = 1389). Relevant main associations and interactions by asthma and/or smoking on post-BD forced expiratory volume in 1 s/forced vital capacity (FEV1 /FVC; continuous variable) and AO (FEV1 /FVC < lower limit of normal) were estimated by multiple regression. RESULTS: Sixty-nine percent (n = 950) had a history of childhood measles. Childhood measles augmented the combined adverse effect of current clinical asthma and smoking at least 10 pack-years on post-BD FEV1 /FVC ratio in middle age (z-score: -0.70 (95% CI: -1.1 to -0.3) vs -1.36 (-1.6 to -1.1), three-way interaction: P = 0.009), especially for those with childhood-onset asthma. For never- and ever-smokers of <10 pack-years who had current asthma symptoms, compared with those without childhood measles, paradoxically, the odds for post-BD AO was not significant in the presence of childhood measles (OR: 12.0 (95% CI: 3.4-42) vs 2.17 (0.9-5.3)). CONCLUSION: Childhood measles infection appears to compound the associations between smoking, current asthma and post-BD AO. Differences between asthma subgroups provide further insight into the complex aetiology of obstructive lung diseases for middle-aged adults.

Cirrhosis in Hemochromatosis: Independent Risk Factors in 368 HFE p.C282Y Homozygotes.

INTRODUCTION AND AIM: We sought to identify independent risk factors for cirrhosis in HFE p.C282Y homozygotes in a cross-sectional study. MATERIAL AND METHODS: We evaluated 368 p.C282Y homozygotes who underwent liver biopsy and compared characteristics of those with and without cirrhosis. We performed multivariable logistic regression on cirrhosis with: age; sex; race/ethnicity; diabetes; blood pints/units donated voluntarily; erythrocyte pints/units received; iron supplement use; alcohol intake, g/d; body mass index, kg/m2; swollen/tender 2nd/3rd metacarpophalangeal joints; elevated alanine aminotransferase; elevated aspartate aminotransferase; steatosis/fatty liver; iron removed by phlebotomy, g; and GNPAT p.D519G positivity. RESULTS: Mean age of 368 participants (73.6% men) was 47 ± 13 (standard deviation) y. Cirrhosis was diagnosed in 86 participants (23.4%). Participants with cirrhosis had significantly greater mean age, proportion of men, diabetes prevalence, mean daily alcohol intake, prevalence of swollen/ tender 2nd/3rd metacarpophalangeal joints, mean serum ferritin, elevated alanine aminotransferase, elevated aspartate aminotransferase, and mean iron removed; and significantly fewer mean blood pints/units donated. GNPAT p.D519G positivity was detected in 82 of 188 participants (43.6%). In a multivariable model for cirrhosis, there were four significant positive associations: age (10-y intervals) (odds ratio 2.2 [95% confidence interval 1.5, 3.3]); diabetes (3.3; [1.1, 9.7]); alcohol intake (14 g alcohol drinks/d) (1.5 [1.2, 1.8]); and iron removed, g (1.3 [1.2, 1.4]). There was no statistical evidence of two-way interactions between these variables. CONCLUSION: In conclusion, cirrhosis in HFE p.C282Y homozygotes is significantly associated with age, diabetes, daily alcohol intake, and iron removed by phlebotomy, taking into account the effect of other variables.

Peanut Allergen Threshold Study (PATS): Novel single-dose oral food challenge study to validate eliciting doses in children with peanut allergy.

BACKGROUND: Eliciting doses (EDs) of allergenic foods can be defined by the distribution of threshold doses for subjects within a specific population. The ED05 is the dose that elicits a reaction in 5% of allergic subjects. The predicted ED05 for peanut is 1.5 mg of peanut protein (6 mg of whole peanut). OBJECTIVE: We sought to validate the predicted peanut ED05 (1.5 mg) with a novel single-dose challenge. METHODS: Consecutive eligible children with peanut allergy in 3 centers were prospectively invited to participate, irrespective of previous reaction severity. Predetermined criteria for objective reactions were used to identify ED05 single-dose reactors. RESULTS: Five hundred eighteen children (mean age, 6.8 years) were eligible. No significant demographic or clinical differences were identified between 381 (74%) participants and 137 (26%) nonparticipants or between subjects recruited at each center. Three hundred seventy-eight children (206 male) completed the study. Almost half the group reported ignoring precautionary allergen labeling. Two hundred forty-five (65%) children experienced no reaction to the single dose of peanut. Sixty-seven (18%) children reported a subjective reaction without objective findings. Fifty-eight (15%) children experienced signs of a mild and transient nature that did not meet the predetermined criteria. Only 8 (2.1%; 95% CI, 0.6%-3.4%) subjects met the predetermined criteria for an objective and likely related event. No child experienced more than a mild reaction, 4 of the 8 received oral antihistamines only, and none received epinephrine. Food allergy-related quality of life improved from baseline to 1 month after challenge regardless of outcome (η2 = 0.2, P < .0001). Peanut skin prick test responses and peanut- and Ara h 2-specific IgE levels were not associated with objective reactivity to peanut ED05. CONCLUSION: A single administration of 1.5 mg of peanut protein elicited objective reactions in fewer than the predicted 5% of patients with peanut allergy. The novel single-dose oral food challenge appears clinically safe and patient acceptable, regardless of the outcome. It identifies the most highly dose-sensitive population with food allergy not otherwise identifiable by using routinely available peanut skin prick test responses or specific IgE levels, but this single-dose approach has not yet been validated for risk assessment of individual patients.

The prevalence of food allergy and other allergic diseases in early childhood in a population-based study: HealthNuts age 4-year follow-up.

BACKGROUND: The HealthNuts study previously reported interim prevalence data showing the highest prevalence of challenge-confirmed food allergy in infants internationally. However, population-derived prevalence data on challenge-confirmed food allergy and other allergic diseases in preschool-aged children remain sparse. OBJECTIVE: This study aimed to report the updated prevalence of food allergy at age 1 year from the whole cohort, and to report the prevalence of food allergy, asthma, eczema, and allergic rhinitis at age 4 years. METHODS: HealthNuts is a population-based cohort study with baseline recruitment of 5276 one-year-old children who underwent skin prick test (SPT) to 4 food allergens and those with detectable SPT results had formal food challenges. At age 4 years, parents completed a questionnaire (81.3% completed) and those who previously attended the HealthNuts clinic at age 1 year or reported symptoms of a new food allergy were invited for an assessment that included SPT and oral food challenges. Data on asthma, eczema, and allergic rhinitis were captured by validated International Study of Asthma and Allergies in Childhood questionnaires. RESULTS: The prevalence of challenge-confirmed food allergy at age 1 and 4 years was 11.0% and 3.8%, respectively. At age 4 years, peanut allergy prevalence was 1.9% (95% CI, 1.6% to 2.3%), egg allergy was 1.2% (95% CI, 0.9% to 1.6%), and sesame allergy was 0.4% (95% CI, 0.3% to 0.6%). Late-onset peanut allergy at age 4 years was rare (0.2%). The prevalence of current asthma was 10.8% (95% CI, 9.7% to 12.1%), current eczema was 16.0% (95% CI, 14.7% to 17.4%), and current allergic rhinitis was 8.3% (95% CI, 7.2% to 9.4%). Forty percent to 50% of this population-based cohort experienced symptoms of an allergic disease in the first 4 years of their life. CONCLUSIONS: Although the prevalence of food allergy decreased between age 1 year and age 4 years in this population-based cohort, the prevalence of any allergic disease among 4-year-old children in Melbourne, Australia, is remarkably high.

Occupational exposure to pesticides are associated with fixed airflow obstruction in middle-age.

RATIONALE: Population-based studies have found evidence of a relationship between occupational exposures and Chronic Obstructive Pulmonary Disease (COPD), but these studies are limited by the use of prebronchodilator spirometry. Establishing this link using postbronchodilator is critical, because occupational exposures are a modifiable risk factor for COPD. OBJECTIVES: To investigate the associations between occupational exposures and fixed airflow obstruction using postbronchodilator spirometry. METHODS: One thousand three hundred and thirty-five participants were included from 2002 to 2008 follow-up of the Tasmanian Longitudinal Health Study (TAHS). Spirometry was performed and lifetime work history calendars were used to collect occupational history. ALOHA plus Job Exposure Matrix was used to assign occupational exposure, and defined as ever exposed and cumulative exposure unit (EU)-years. Fixed airflow obstruction was defined by postbronchodilator FEV1/FVC <0.7 and the lower limit of normal (LLN). Multinomial logistic regressions were used to investigate potential associations while controlling for possible confounders. RESULTS: Ever exposure to biological dust (relative risk (RR)=1.58, 95% CI 1.01 to 2.48), pesticides (RR=1.74,95% CI 1.00 to 3.07) and herbicides (RR=2.09,95% CI 1.18 to 3.70) were associated with fixed airflow obstruction. Cumulative EU-years to all pesticides (RR=1.11,95% CI 1.00 to 1.25) and herbicides (RR=1.15,95% CI 1.00 to 1.32) were also associated with fixed airflow obstruction. In addition, all pesticides exposure was consistently associated with chronic bronchitis and symptoms that are consistent with airflow obstruction. Ever exposure to mineral dust, gases/fumes and vapours, gases, dust or fumes were only associated with fixed airflow obstruction in non-asthmatics only. CONCLUSIONS: Pesticides and herbicides exposures were associated with fixed airflow obstruction and chronic bronchitis. Biological dust exposure was also associated with fixed airflow obstruction in non-asthmatics. Minimising occupational exposure to these agents may help to reduce the burden of COPD.

Traffic-related air pollution exposure over a 5-year period is associated with increased risk of asthma and poor lung function in middle age.

Current evidence concerning the impact of exposure to traffic-related air pollution (TRAP) on adult respiratory morbidity mainly comes from cross-sectional studies. We sought to establish more robust measures of this association and potential gene-environment interactions using longitudinal data from an established cohort study.Associations between measures of TRAP (nitrogen dioxide (NO2) and distance to major roads) and wheeze, asthma prevalence and lung function were investigated in participants of the Tasmanian Longitudinal Health Study at 45- and 50-year follow-ups. Generalised estimating equations were used to quantify associations and the potential modifying effect of glutathione S-transferase gene variants.Living <200 m from a major road was associated with increased prevalence of current asthma and wheeze, and lower lung function. The association between living <200 m from a major road and current asthma and wheeze was more marked for carriers of the GSTT1 null and GSTP1 val/val or ile/val genotypes. Over the 5-year period, higher NO2 exposures were associated with increased current asthma prevalence. Higher NO2 exposure was associated with lower forced vital capacity for carriers of the GSTT1 null genotype.TRAP exposures were associated with increased risk of asthma, wheeze and lower lung function in middle-aged adults. The interaction with the GSTT1 genotype suggests that deficient antioxidant mechanisms may play a role in these adverse health effects.

Bronchial hyperresponsiveness and obesity in middle age: insights from an Australian cohort.

The association between obesity and bronchial hyperresponsiveness (BHR) is incompletely characterised. Using the 2006 follow-up of the Tasmanian Longitudinal Health Study, we measured the association between obesity and BHR and whether it was mediated by small airway closure or modified by asthma and sex of the patient.A methacholine challenge measured BHR. Multivariable logistic regression measured associations between body mass index (BMI) and BHR, adjusting for sex, asthma, smoking, corticosteroid use, family history and lung function. Mediation by airway closure was also measured.Each increase in BMI of 1 kg·m-2 was associated with a 5% increase in the odds of BHR (OR 1.05, 95% CI 1.01-1.09) and 43% of this association was mediated by airway closure. In a multivariable model, BMI (OR 1.06, 95% CI 1.00-1.16) was associated with BHR independent of female sex (OR 3.26, 95% CI 1.95-5.45), atopy (OR 2.30, 95% CI 1.34-3.94), current asthma (OR 5.74, 95% CI 2.79-11.82), remitted asthma (OR 2.35, 95% CI 1.27-4.35), low socioeconomic status (OR 2.11, 95% CI 1.03-4.31) and forced expiratory volume in 1 s/forced vital capacity (OR 0.86, 95% CI 0.82-0.91). Asthma modified the association with an increasing probability of BHR as BMI increased, only in those with no or remitted asthma.An important fraction of the BMI/BHR association was mediated via airway closure. Conflicting findings in previous studies could be explained by failure to consider this intermediate step.