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Atopic dermatitis (AD) or eczema is a chronic inflammatory skin disease characterized by dry, itchy, and inflamed skin. We review emerging concepts and clinical evidence addressing the pathogenesis and prevention of AD. We examine several interventions ranging from skin barrier enhancement strategies to probiotics, prebiotics, and synbiotics; and conversely, from antimicrobial exposure to vitamin D and omega fatty acid supplementation; breastfeeding and hydrolyzed formula; and house dust mite avoidance and immunotherapy. We appraise the available evidence base within the context of the Grades of Recommendation, Assessment, Development, and Evaluation approach. We also contextualize our findings in relation to concepts relating AD and individual-patient allergic life trajectories versus a linear concept of the atopic march and provide insights into future knowledge gaps and clinical trial design considerations that must be addressed in forthcoming research. Finally, we provide implementation considerations to detect population-level differences in AD risk. Major international efforts are required to provide definitive evidence regarding what works and what does not for preventing AD.

Standard care for the management of food allergies previously centered on allergen avoidance and the treatment of adverse reactions after allergen exposure. An increase in the development of immunotherapy treatments for food allergy has occurred over the past 2 decades, with many centers now offering immunotherapy. Previous studies mainly focused on school-age children in whom food allergies are likely to be persistent. However, there is increasing evidence that delivering immunotherapy for food allergy to preschool-age children may deliver higher rates of success, and that peanut allergen immunotherapy leads the way. Conversely, the natural resolution of food allergies occurs primarily in these younger age groups, resulting in challenges to selecting patients who will ultimately benefit from these treatments. Both immunotherapy and natural history studies reveal the inherent plasticity of the immune system in early life, which may be more amenable to intervention, but this raises a delicate yet unknown balance between the optimal timing of intervention versus waiting for natural resolution of the food allergy. Here we review the evidence for early food allergen immunotherapy in preschoolers, and present the pros and cons of this approach while acknowledging important research gaps in this age group.

BACKGROUND: Cashew allergy is the most common tree nut allergy in Australia, but there are limited data on the population-level prevalence and risk factors. OBJECTIVE: Describe the prevalence of cashew sensitization and allergy in 12-month-old infants and identify risk factors. METHODS: Data were from the EarlyNuts cohort, a population-based sample of infants recruited in Melbourne, Australia. Families completed a questionnaire and infants underwent a skin prick test (SPT) to cashew. Infants with positive SPTs were offered food challenges. Questionnaires collected demographic data and allergy risk factors. Allergy outcomes were determined by challenge outcomes or a convincing history of an allergic reaction. We used weights to adjust estimated prevalence to reflect the distribution of risk factors among the combined sample of participants and nonparticipants. RESULTS: We recruited 1,933 participants and identified 1,414 cashew allergy outcomes. Of these, 1.96% (95% CI, 1.28-2.99) had an SPT result of 3 mm or greater and 1.49% (95% CI, 0.91-2.44) were allergic to cashew. Infants with eczema or peanut allergy in the first year of life were more likely to be allergic to cashew (adjusted odds ratio = 5.75; 95% CI, 2.08-15.88; P = .001; and adjusted odds ratio = 19.30; 95% CI, 5.44-68.43; P < .001, respectively). Twenty-five percent of participants had cashew introduced before 12 months (95% CI, 22.7-27.8). There was no association between the timing of cashew introduction and cashew allergy. CONCLUSIONS: To our knowledge, this is the first study describing the prevalence of and risk factors for cashew allergy in a population-based infant cohort. Eczema and peanut allergy were associated with an increased risk of cashew allergy. Few infants were introduced to cashew before age 12 months, which suggests that infant feeding guidelines have not yet translated to the earlier introduction of all allergens.

BACKGROUND/OBJECTIVES: Eczema is a common chronic debilitating skin condition in childhood. Data on the epidemiology and natural history of eczema across the life course are lacking. This analysis aimed to describe these epidemiological features in Australian children and adults. METHODS: Data collected on eczema from four Australian cohort studies were analysed: namely HealthNuts, Melbourne Atopic Cohort Study (MACS), Tasmanian Longitudinal Health Study (TAHS) and the Australian arm of the European Community Respiratory Health Survey (ECRHS). RESULTS: Among children aged under 6 years, 28.8%-35.6% have ever-had eczema, and 16.7%-26.6% had 'current eczema'. Among those aged 6-12 years, 14.6%-24.7% had 'current eczema' with 12.0%-18.5% of those at ages of 6 and 10 years classified as having moderate-to-severe eczema according to the Scoring of Atopic Dermatitis (SCORAD) index. In adults, the prevalence of 'eczema ever' ranged between 13.8% and 48.4%. The 12-month period prevalence of eczema was 15.1% at age 18, while current eczema was 8.5% at an average age of 51, and 8.8% at an average age 53 years. Eczema was more common among young boys, but this difference became non-significant for older children and early adolescents. In contrast, eczema was more common for adult women than men. CONCLUSIONS: Eczema is common both in children and adults. The proportion of severe eczema in children was substantial.

BACKGROUND: Oral immunotherapy (OIT) is a promising treatment for food allergies; however, safety is a concern. We synthesized evidence from the best randomized controlled trials (RCTs) on efficacy/safety of OIT for desensitization (DS) and remission (sustained unresponsiveness (SU)) in IgE mediated allergy to peanut, hen's eggs, and cow's milk. BODY: We searched Pubmed, EMBASE, and Cochrane databases (Until Oct 22) identifying 16 eligible RCTs published in English measuring food allergy by food challenge at the beginning and at the end of the study. The Cochrane Risk of Bias tool was used to assess study quality. We found 18 eligible studies. There was evidence of efficacy for DS for all allergens: peanut (RR 11.32; 95% CI 5.93, 21.60, I2 49%, 8 studies); hen's egg (RR 4.67; 2.66, 8.21, I2 0%, 5 studies); cow's milk (RR 13.98; 3.51, 55.65, I2 0%, 4 studies) and evidence for SU for peanut (RR 7.74; 2.90, 20.69, I2 0%, 3 studies) and hen's egg (RR 6.91; 1.67, 28.57, I2 0%, 2 studies). Allergic events were increased with intervention, and risk of adrenaline use increased for peanut RR 2.96; 1.63, 5.35, I2 0%, 8 studies; egg RR 1.71; 0.42, 6.92, I2 0%, 6 studies; and milk RR 8.45; 2.02, 35.27, I2 0%, 4 studies. CONCLUSION: We found strong evidence that peanut, hen's egg, and cow's milk OIT can induce DS and some evidence for remission. There was a high risk of allergic reactions. Generalizability to the entire food allergic population is not known.

The International Society for Stem Cell Research (ISSCR) has recently released the 2021 update of its guidelines. The update includes detailed new recommendations on human-animal chimera research. This paper argues that the ISSCR recommendations fail to address the core ethical concerns raised by neurological chimeras-namely, concerns about moral status. In minimising moral status concerns, the ISSCR both breaks rank with other major reports on human-animal chimera research and rely on controversial claims about the grounds of moral status that many people will rightly reject. A more robust framework for regulating human-animal chimera research still needs to be developed.

BACKGROUND: In the absence of a clear clinical history of reaction, diagnosis of cashew allergy using skin prick tests (SPT) or cashew-specific IgE requires a high number of oral food challenges (OFC). By using Ana o 3 sIgE alone, or a two-step diagnostic algorithm using cashew sIgE followed by Ana o 3 sIgE, there is a reduced need for OFC. We aimed to perform a cost comparison for both of these approaches compared with cashew SPT alone. METHODS: Pooled individual-level data from 6 studies were used to determine diagnostic accuracy and OFC rate. Two studies used cashew SPT (n = 567, 198 allergic), with 95% positive and negative predictive values of ≥12 mm and <3 mm. Four studies were included in the pathways for Ana o 3 sIgE alone or a 2-step algorithm incorporating cashew and Ana o 3 sIgE (n = 271, 156 allergic). Cut-offs used were ≥8.5kUA/L and ≤0.1kUA/L for cashew sIgE and ≥0.35kUA/L and ≤0.1kUA/L for Ana o 3 sIgE. Costs were constructed based on unit prices from hospital inpatient admissions, expenses incurred by families, individual patient data on allergic reaction types and rates, and adrenaline autoinjector carriage, applying a health system perspective. RESULTS: Modeled data through the Ana o 3 pathway resulted in a 46.43% cost reduction (€307,406/1000 patients) compared with using cashew SPT alone (€573,854/1000 patients). The 2-step algorithm resulted in a 44.94% cost reduction compared with SPT alone (€315,952.82/1000 patients). Both the Ana o 3 pathway and 2-step algorithm resulted in a 79%-80% reduction in OFCs compared with SPT. CONCLUSIONS: Using Ana o 3 as a standalone test for cashew allergy diagnosis or a 2-step algorithm incorporating cashew sIgE and Ana o 3 sIgE is accurate and results in a large reduction in both OFCs and health system costs compared with cashew SPT alone.

Genomic sequencing technologies (GS) pose novel challenges not seen in older genetic technologies, making traditional standards for fully informed consent difficult or impossible to meet. This is due to factors including the complexity of the test and the broad range of results it may identify. Meaningful informed consent is even more challenging to secure in contexts involving significant time constraints and emotional distress, such as when rapid genomic testing (RGS) is performed in neonatal intensive care units. In this article, we propose that informed consent matters not for its own sake, but because obtaining it furthers a range of morally important goals, such as promoting autonomy, well-being, and trust in medicine. These goals form the basis of a new framework [PROmoting Morally Important Consent Ends (PROMICE)] for assessing the ethical appropriateness of various informed consent models. We illustrate this framework with two examples: (a) a tiered and layered consent model for obtaining consent for GS, and (b) consent for RGS in critically ill newborns. We conclude that appropriately-rather than fully-informed consent provides the correct standard for genomic medicine and research.

IgE-mediated food allergy is an increasing public health concern in many regions around the world. Although genetics play a role in the development of food allergy, the reported increase has occurred largely within a single generation and therefore it is unlikely that this can be accounted for by changes in the human genome. Environmental factors must play a key role. While there is strong evidence to support the early introduction of allergenic solids to prevent food allergy, this is unlikely to be sufficient to prevent all food allergy. The purpose of this review is to summarize the evidence on risk factors for food allergy with a focus the outdoor physical environment. We discuss emerging evidence of mechanisms that could explain a role for vitamin D, air pollution, environmental greenness, and pollen exposure in the development of food allergy. We also describe the recent extension of the dual allergen exposure hypothesis to potentially include the respiratory epithelial barrier in addition to the skin. Few existing studies have examined the relationship between these environmental factors with objective measures of IgE-mediated food allergy and further research in this area is needed. Future research also needs to consider the complex interplay between multiple environmental factors.

AIM: Adrenaline auto-injector (AAI) dispensing data, a community-based proxy for number of individuals at risk of anaphylaxis, provides complementary information on time trends of anaphylaxis risk in addition to hospital admission data. We examined trends of AAI dispensing over a 10-year period (from January 2005 to December 2014) in Australia. METHODS: Individuals with dispensed AAI were identified from a 10% random sample of Australian Pharmaceutical Benefits Scheme (PBS) data. PBS is the Australian national drug subsidy programme covering all Australians. Cumulative incidence and incidence rates of individuals with AAI were calculated. We assessed difference by age, sex, state and time trends. RESULTS: The cumulative incidence of individuals with AAI in 2005-2014 was 75.43/100 000 (95%CI 75.07-75.80/100 000). Incidence rate of individuals with AAI increased from 2005 to 2014 (from 71.47 to 82.07 per 100 000 person-years) although this varied by state. Over the time assessed, there was a shift to more prescriptions being provided by general practitioners (GP) rather than specialists. Children (0-19 years) were more likely to have been prescribed an AAI from a specialist and adults from a GP. CONCLUSION: Overall, an increase in dispensed AAI mirrored other evidence for a rising prevalence of allergy. This increase could also reflect changes in prescribing practices or increased awareness and education of health-care professionals on anaphylaxis and indications for prescribing AAI. The rising rate of AAI prescribed by GPs compared to decreasing rates by specialists suggests a changing response of the Australian health-care system to the increased burden of anaphylaxis.

DNA databases have significant commercial value. Direct-to-consumer genetic testing companies have built databanks using samples and information voluntarily provided by customers. As the price of genetic analysis falls, there is growing interest in building such databases by paying individuals for their DNA and personal data. This paper maps the ethical issues associated with private companies paying for DNA. We outline the benefits of building better genomic databases and describe possible concerns about crowding out, undue inducement, exploitation, and commodification. While certain objections deserve more empirical and philosophical investigation, we argue that none currently provide decisive reasons against using financial incentives to secure DNA samples.

Early introduction of allergenic foods into an infant's diet is currently the most promising strategy to prevent food allergy, with infant guidelines around the world shifting from promoting avoidance to actively encourage the introduction of allergenic foods in the infant diet. Infant feeding guidelines vary according to regional public health priorities, and knowledge gaps remain, resulting in ongoing challenges for clinicians and families to translate guidelines into practical strategies for the introduction of complementary foods for food allergy prevention. Evidence from Australia demonstrates high community support and uptake of revised guidelines with most parents introducing allergenic foods in the first year of life, although this has not had the expected impact on substantially reducing food allergy prevalence. To uptake of guidelines from other countries is less clear, and several barriers have been noted in infant feeding RCTs, which may warrant intervention strategies. Further research is needed to understand additional strategies for food allergy prevention, particularly in infants who develop food allergy prior to when they are developmentally ready to commence solids. Several RCTs are underway investigating preventative strategies that target the window before allergen ingestion, such as vitamin D supplementation, emollient use, and immunizations that prime the immune response away from a Th2-driven allergic phenotype. Further research is also needed to understand the role of the environment and the host environment in the development of tolerance to foods.

INTRODUCTION: Clinical studies supported by immunological data indicate early life intervention strategies to be promising in reducing the growing global burden of food allergies. The events that predispose to food allergy, including the induction of allergen-specific immune responses, appear to be initiated early in development. Early exposure to food allergens in utero and via breast milk is likely to be important in initiating oral tolerance. We aim to determine the effectiveness of higher maternal food allergen consumption during pregnancy and lactation on infant food allergy outcomes. METHODS AND ANALYSIS: This is a multisite, parallel, two-arm (1:1 allocation), single-blinded (outcome assessors, statistical analyst and investigators), randomised controlled trial. Pregnant women (<23 weeks' gestation) whose (unborn) infants have at least two biological family members (mother, father or siblings) with medically diagnosed allergic disease are eligible to participate. After obtaining written informed consent, pregnant women are randomised to either a high egg and peanut diet (at least 6 eggs and 60 peanuts per week) or standard (low) egg and peanut diet (no more than 3 eggs and 30 peanuts per week). The women are asked to follow their allocated diet from <23 weeks' gestation to 4 months' lactation. The primary outcome is food challenge proven IgE-mediated egg and/or peanut allergy in the infants at 12 months of age. Key secondary outcomes include infant sensitisation to egg and/or peanut and infant eczema. Our target sample size is 2136 women. Analyses will be performed on an intention-to-treat basis according to a pre-specified statistical analysis plan. ETHICS AND DISSEMINATION: Ethical approval has been granted from the Women's and Children's Health Network Human Research Ethics Committee (approval number HREC/18/WCHN/42). Trial results will be presented at scientific conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: Australian New

IgE-mediated food allergies in infants are a significant health concern, with peanut allergy being of particular interest due to its prevalence and severity. Among individuals who produce peanut-specific IgE some experience no adverse reaction on peanut consumption. This asymptomatic phenotype is known as sensitized tolerance. To elucidate the immune environment of peanut sensitized tolerant and clinically allergic one-year-olds, high-dimensional mass cytometry was conducted as part of the HealthNuts study. The resulting data includes peripheral blood mononuclear cells from 36 participants encompassing non-allergic, peanut sensitized with tolerance, and clinically peanut allergic infants. The raw mass cytometry data is described here and freely available for reuse through the Immunology Database and Analysis Portal (ImmPort). Additional allergy information and serum vitamin D levels of the participants were measured and are also included in the data upload. These high-dimensional mass cytometry data, when combined with clinical information, offer a broad immune profile of peanut allergic and sensitized tolerant infants.

BACKGROUND: While the relationship between pollen and respiratory allergies is well-documented, the role of short-term pollen exposure in food allergy and eczema flares has not previously been explored. We aimed to investigate these associations in a population-based sample of children. METHODS: We investigated 1- (n = 1108) and 6-year-old (n = 675) children in the grass pollen season from the HealthNuts cohort. Grass pollen concentrations were considered on the day of testing (lag 0), up to three days before (lag 1-lag 3) and cumulatively (lag 0-3). Associations between grass pollen and food skin-prick test reactivity (SPT ≥ 2 mm at age 1 year and ≥ 3 mm at age 6 years), eczema flares, challenge-confirmed food allergy, reaction threshold to oral food challenges (OFC), and serum food-specific IgE levels were analyzed using either logistic or quantile regression models. Atopy and family history of allergic disease were considered as potent effect modifiers. RESULTS: Grass pollen at lag 0-3 (every 20 grains/m3 increase) was associated with an up to 1.2-fold increased odds of food SPT reactivity and eczema flares in 6-year-olds. In 1-year-olds, the associations were only observed for peanut in those with a family history of food allergy. Increasing grass pollen concentrations were associated with a lower reaction threshold to OFC and higher serum IgE levels in peanut-allergic 1-year-olds only. CONCLUSION: Increasing grass pollen concentration was associated with increased risk of food SPT reactivity and eczema flares in children. The associations in peanut-allergic infants may be related to immune activation and/or peanut and grass pollen cross-reactivity leading to a lower reaction threshold.

BACKGROUND: While exposure to environmental greenness in childhood has shown mixed associations with the development of allergic disease, the relationship with food allergy has not been explored. We investigated the association between exposure to environmental greenness and challenge-confirmed food allergy in a large population-based cohort. METHODS: The HealthNuts study recruited 5276 12-month-old infants in Melbourne, Australia, who underwent skin prick testing to peanut, egg, and sesame; infants with a detectable wheal underwent food challenges to determine food allergy status. Environmental greenness was estimated using the normalized difference vegetation index (NDVI) for five buffer zones around the infant's home address: at the home, 100 m, 500 m, 800 m, and 1600 m radial distances. Environmental greenness was categorized into 3 tertiles and mixed effects logistic regression models quantified the association between greenness and the risk of food allergy, adjusting for confounding and accounting for clustering at the neighborhood level. RESULTS: NDVI data were available for n = 5097. For most buffer zones, medium and high greenness, compared to low greenness, was associated with an increased risk of peanut allergy (eg, 100 m tertile 2 aOR 1.89 95% CI 1.22-2.95, tertile 3 aOR 1.78 95% CI 1.13-2.82). For egg allergy, the effect sizes were smaller (100 m tertile 2 aOR 1.52 95% CI 1.16-1.97, tertile 3 aOR 1.38 95% CI 1.05-1.82). Socioeconomic status (SES) modified the association between greenness and peanut allergy, but not egg allergy; associations were apparent in the low SES group but not in the high SES group (p for interaction 0.08 at 100 m). Air pollution (PM2.5) also modified the associations between environmental greenness and food allergy, with associations present in high air pollution areas but not low (p for interaction at 100 m 0.05 for peanut and 0.06 for egg allergy.) CONCLUSION: Increased exposure to environmental greenness in the first year of

PURPOSE OF REVIEW: In 2015, findings from the Learning Early About Peanut allergy (LEAP) trial provided the first convincing evidence that peanut allergy may be preventable through early peanut introduction into the infant diet. Here we discuss implementation of the LEAP study findings around the world and emerging evidence of the impacts on infant feeding and food allergy. RECENT FINDINGS: The LEAP findings led to rapid changes in allergy prevention guidelines internationally to recommend early peanut introduction. There is now emerging evidence that this has been followed by a substantial increase in early peanut introduction to infants. Studies investigating the impact of these changes in infant feeding practices on the prevalence of peanut allergy are underway. The LEAP trial represented a significant step forwards in food allergy prevention and new research over the past 5 years has provided insights into how best to implement this intervention in the real world.

BACKGROUND: While integrating genomic sequencing into clinical care carries clear medical benefits, it also raises difficult ethical questions. Compared to traditional sequencing technologies, genomic sequencing and analysis is more likely to identify unsolicited findings (UF) and variants that cannot be classified as benign or disease-causing (variants of uncertain significance; VUS). UF and VUS pose new challenges for genetic health professionals (GHPs) who are obtaining informed consent for genomic sequencing from patients. METHODS: We conducted semi-structured interviews with 31 GHPs across Europe, Australia and Canada to identify some of these challenges. RESULTS: Our results show that GHPs find it difficult to prepare patients to receive results because a vast amount of information is required to fully inform patients about VUS and UF. GHPs also struggle to engage patients - many of whom may be focused on ending their 'diagnostic odyssey' - in the informed consent process in a meaningful way. Thus, some questioned how 'informed' patients actually are when they agree to undergo clinical genomic sequencing. CONCLUSIONS: These findings suggest a tension remains between sufficient information provision at the risk of overwhelming the patient and imparting less information at the risk of uninformed decision-making. We suggest that a shift away from 'fully informed consent' toward an approach aimed at realizing, as far as possible, the underlying goals that informed consent is meant to promote.

BACKGROUND: In Western countries, Asian children have higher food allergy risk than Caucasian children. The early-life environmental exposures for this discrepancy are unclear. We aimed to compare prevalence of food allergy and associated risk factors between Asian children in Singapore and Australia. METHODS: We studied children in the Growing Up in Singapore Towards healthy Outcomes (GUSTO) birth cohort (n = 878) and children of Asian ancestry in the HealthNuts cohort (n = 314). Food allergy was defined as a positive SPT ≥3 mm to egg or peanut AND either a convincing history of IgE-mediated reaction at 18 months (GUSTO) or a positive oral food challenge at 14-18 months (HealthNuts). Eczema was defined as parent-reported doctor diagnosis. RESULTS: Food allergy prevalence was 1.1% in Singapore and 15.0% in Australia (P<0.001). Egg introduction was more often delayed (>10 months) in Singapore (63.5%) than Australia (16.3%; P<0.001). Prevalence of early-onset eczema (<6 months) was lower in Singapore (8.4%) than Australia (30.5%) (P<0.001). Children with early-onset eczema were more likely to have food allergy than those without eczema in Australia [aOR 5.11 (2.34-11.14); P<0.001] and Singapore [aOR4.00 (0.62-25.8); P = 0.145]. CONCLUSIONS: Among Asian children, prevalence of early-onset eczema and food allergy was higher in Australia than Singapore. Further research with larger sample sizes and harmonized definitions of food allergy between cohorts is required to confirm and extend these findings. Research on environmental factors influencing eczema onset in Australia and Singapore may aid understanding of food allergy pathogenesis in different parts of the world.

Food allergy is a major public health issue with growing prevalence in the urbanized world and significant impact on the lives of allergic patients and their families. Research into the risk factors that have contributed to this increase and their underlying immune mechanisms could lead us to definitive ways for treatment and prevention of food allergy. For the time being, introduction of peanut and other allergenic foods in the diet at the time of weaning seems to be an effective way to prevent the development of food allergy. Improved diagnosis and appropriate management and support of food allergic patients are central to patient care with food immunotherapy and biologics making the transition to clinical practice. With the new available treatments, it is becoming increasingly important to include patients' and family preferences to provide a management plan tailored to their needs.

The precautionary principle aims to influence decision‐making in contexts where some activity poses uncertain but potentially grave threats. This perfectly describes the controversy surrounding germline gene editing. This article considers whether the precautionary principle should influence how we weigh the risks and benefits of human germline interventions, focusing especially on the possible threats to the health of future generations. We distinguish between several existing forms of the precautionary principle, assess their plausibility and consider their implications for the ethics of germline modification. We also offer a novel form of the precautionary principle: the sufficientarian precautionary principle. Some plausible versions of the precautionary principle recommend placing somewhat greater weight on avoiding threats to future generations than on achieving short‐term benefits. However, no plausible versions of the precautionary principle entail that we should outright reject the use germline gene editing in human reproduction and some, such as the sufficientarian version, might endorse its use.

BACKGROUND: Genomic research can reveal 'unsolicited' or 'incidental' findings that are of potential health or reproductive significance to participants. It is widely thought that researchers have a moral obligation, grounded in the duty of easy rescue, to return certain kinds of unsolicited findings to research participants. It is less widely thought that researchers have a moral obligation to actively look for health-related findings (for example, by conducting additional analyses to search for findings outside the scope of the research question). MAIN TEXT: This paper examines whether there is a moral obligation, grounded in the duty of easy rescue, to actively hunt for genomic secondary findings. We begin by showing how the duty to disclose individual research findings can be grounded in the duty of easy rescue. Next, we describe a parallel moral duty, also grounded in the duty of easy rescue, to actively hunt for such information. We then consider six possible objections to our argument, each of which we find unsuccessful. Some of these objections provide reason to limit the scope of the duty to look for secondary findings, but none provide reason to reject this duty outright. CONCLUSIONS: We argue that under a certain range of circumstances, researchers are morally required to hunt for these kinds of secondary findings. Although these circumstances may not currently obtain, genomic researchers will likely acquire an obligation to hunt for secondary findings as the field of genomics continues to evolve.

BACKGROUND: High folate status in pregnancy has been implicated in the increased prevalence of allergic disease, but there are no published data relating directly measured folate status in pregnancy to challenge-proven food allergy among offspring. The study aim was to examine the association between red blood cell (RBC) folate status in trimester three of pregnancy and allergic disease among offspring. METHODS: Red blood cell folate levels were measured at 28-32 weeks' gestation in a prospective birth cohort (n = 1074). Food allergy outcomes were assessed in 1-year-old infants by skin prick testing and subsequent food challenge. Eczema was assessed by questionnaire and clinical review. High trimester three RBC folate was defined as greater than (>) 1360 nmol/L. Binomial regression was used to examine associations between trimester three RBC folate and allergic outcomes, adjusting for potential confounders. RESULTS: Red blood cell folate levels were measured in 88% (894/1064) of pregnant women. The mean concentration was 1695.6 nmol/L (standard deviation 415.4) with 82% (731/894) >1360 nmol/L. There was no evidence of either linear or non-linear relationships between trimester three RBC folate and allergic outcomes, nor evidence of associations between high RBC folate and food allergy (adjusted risk ratio (aRR) 2.89, 95% CI 0.90-9.35), food sensitization (aRR 1.72, 95% CI 0.85-3.49), or eczema (aRR 0.97, 95% CI 0.67-1.38). CONCLUSION: The majority of pregnant women in this study had high RBC folate levels. There was no evidence of associations between trimester three RBC folate and food allergy, food sensitization, or eczema among the offspring, although larger studies are required.

Despite a recent surge of bioethical attention, ethical analysis of uterine transplantation is still in its early stages, and many of the key ethical issues remain underexamined and unresolved. In this paper, we briefly review some key ethical issues associated with uterine transplantation (beyond those associated with organ transplantation more generally). We structure our discussion in terms of Beauchamp and Childress' four principles of biomedical ethics: beneficence, non-maleficence, autonomy, and justice. Our review highlights some ethical questions that require further bioethical attention before uterine transplantation can be fully embraced as a potential treatment for absolute uterine factor infertility. We close by arguing that the costs and benefits of uterine transplantation need to be considered in the context of other possible treatments for absolute uterine factor infertility and alternative methods of family creation.

Imaging research regularly yields incidental findings that may have personal medical or reproductive decision-making significance to study participants. It is widely assumed that researchers have a moral obligation to disclose at least some kinds of incidental findings to research participants. However, it is also a widely held view that researchers do not have a moral obligation to actively look for abnormalities irrelevant to the aims of their study. This paper challenges that assumption.

BACKGROUND AND OBJECTIVE: As caesarean delivery and childhood allergy continue to rise, their inter-relationships may change. We examined whether caesarean delivery predicts allergic disease and impaired lung function in two contemporary harmonised population-based cohorts. METHODS: Parent-reported asthma and eczema data were drawn from two prospective Australian infant cohorts, HealthNuts (n=5276, born 2006-2010) and the Longitudinal Study of Australian Children (LSAC, n=5107, born 2003-2004) at age 6-7 years, and spirometric lung function from LSAC's Child Health CheckPoint (n=1756) at age 11-12 years. Logistic regression estimated associations between delivery mode and current asthma and eczema at 6-7 years, and linear regression examined lung function at 11-12 years. Models were adjusted for potential confounding factors. RESULTS: Complete case analysis included 3135 HealthNuts and 3654 LSAC children (32.2% and 30.9% born by caesarean, respectively). An association was evident between caesarean delivery and asthma at age 6-7 years in HealthNuts (adjusted OR (aOR) 1.25, 95% CI 1.00 to 1.57) but not in LSAC (aOR 1.05, 95% CI 0.86 to 1.28), while neither study showed clear associations with eczema (HealthNuts: aOR 1.09, 95% CI 0.88 to 1.35; LSAC: aOR 0.89, 95% CI 0.69 to 1.15). Spirometric lung function parameters at age 11-12 years were similar by delivery mode. Associations were not modified by duration of breast feeding, maternal history of asthma/eczema, childcare attendance, number of older siblings or pet exposure. CONCLUSIONS: In two unselected populations using harmonised protocols, the likely association of caesarean delivery with developing childhood allergy was small.

BACKGROUND: Despite an increasing number of publications from individual countries and regions, there is still no systematic review of the global epidemiology of anaphylaxis in the general paediatric population. METHODS: We conducted a systematic review, using a protocol registered and published with the international prospective register of systematic reviews (PROSPERO). Results were reported following PRISMA guidelines. The search strategy was designed in Medline (ovid) and modified for Embase (ovid) and PubMed. Papers were screened by two independent reviewers following selection and exclusion criteria. Data extraction and risk of bias assessment were completed by the same two reviewers. Studies in adults only or those that did not report data in children separately were excluded. RESULTS: A final total of 59 articles were included. Of these, 5 reported cumulative incidence, 39 reported incidence rate and 17 reported prevalence data. The incidence of anaphylaxis in children worldwide varied widely, ranging from 1 to 761 per 100 000 person-years for total anaphylaxis and 1 to 77 per 100 000 person-years for food-induced anaphylaxis. The definition of anaphylaxis from NIAID/FAAN was the most commonly used. Gender and ethnicity were demographic risk factors associated with anaphylaxis in children. Increasing total or food-induced anaphylaxis incidence over time was reported by 19 studies. CONCLUSION: The reported incidence of anaphylaxis in children varied widely. Studies in developing countries are underrepresented. To accurately compare anaphylaxis incidence between countries and investigate the time trends, further studies using a standardized definition across different countries are required.

Systematic reviews of nutritional interventions indicate limited efficacy in reducing childhood obesity, but their blanket conclusions could obscure promising components. This narrative review sought more detail on effective components within nutrition-related interventions involving children aged 2 to 11 years. In May 2016, the World Health Organization (WHO) searched the Cochrane Library and PubMed for relevant reviews. From 36 reviews, we screened 182 nutrition-related randomized trials for inclusion. We then reviewed those that reported at least 1 statistically significant (P < 0.05) treatment benefit on body weight and/or composition outcomes at their longest follow-up assessment. Fourteen trials met inclusion criteria (median n = 554; mean intervention duration = 10.8 mo; follow-up = 4.4 mo). "Effective" approaches included environmental changes such as school water fountain installations and cafeteria menu changes and possibly less sustainable strategies such as health education lessons. However, effect sizes even of these selected significant treatment benefits were modest-significant body mass index z-score effects range from -0.1 to -0.2. Each trial was associated with very small improvements in body composition. Because this is a "best-case" scenario (reflecting our design), trialists should rigorously test these strategies alone and possibly together; be open to novel strategies; and ensure that each strategy is culturally relevant and self-sustainable.

findings from systematic reviews into infant feeding and later adiposity are largely negative. World Health Organization (WHO) is auspicing Healthy Life Trajectories Initiative (HeLTI), a suite of trials aiming to prevent overweight/obesity in childhood. To inform planning, this narrative review sought to detail potentially effective components of nutrition-related interventions involving children aged 0 to 2 years. Systematic searches of PubMed and the Cochrane Library (2006-2016) identified 108 systematic reviews. These included 31 randomized trials in the age group of interest. Of these, 11 reported greater than or equal to 1 statistically significant (P < 0.05) benefit on body weight and/or composition. Six multicomponent trials whose interventions incorporated education to promote breastfeeding (four trials), responsive feeding (two trials), and healthy diet (eg, increasing fruit and vegetables and limiting unhealthy snack foods; five trials), delivered through home visits or at baby health clinics, reported relative reductions in body mass index (BMI) at the end of intervention. Early benefits were not maintained in the two trials reporting follow-up 1 to 3 years later. Other potentially effective approaches included lower protein formulas in formula-fed infants and education around reducing sugar-sweetened beverages. There is some evidence that infant feeding interventions can have a transient positive impact on a child's BMI. It is not known whether ongoing intervention can avoid the subsequent expected wash-out.

BACKGROUND: The genetic determinants of food allergy have not been systematically reviewed. We therefore systematically reviewed the literature on the genetic basis of food allergy, identifying areas for further investigation. METHODS: We searched three electronic databases (MEDLINE, EMBASE and PubMed) on 9 January 2018. Two authors screened retrieved articles for review according to inclusion criteria and extracted relevant information on study characteristics and measures of association. Eligible studies included those that reported an unaffected nonatopic control group, had genetic information and were carried out in children. RESULTS: Of the 2088 studies retrieved, 32 met our inclusion criteria. Five were genome-wide association studies, and the remaining were candidate gene studies. Twenty-two of the studies were carried out in a predominantly Caucasian population with the remaining 10 from Asian-specific populations or unspecified ethnicity. We found FLG, HLA, IL10, IL13, as well as some evidence for other variants (SPINK5, SERPINB and C11orf30) that are associated with food allergy. CONCLUSIONS: Little genetic research has been carried out in food allergy, with FLG, HLA and IL13 being the most reproducible genes for an association with food allergy. Despite promising results, existing genetic studies on food allergy are inundated with issues such as inadequate sample size and absence of multiple testing correction. Few included replication analyses or population stratification measures. Studies addressing these limitations along with functional studies are therefore needed to unravel the mechanisms of action of the identified genes.

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.

It may soon be possible to generate human tissues and organs inside of part-human chimeras via a technique known as interspecies blastocyst complementation. Using Australian legislation as a case study, we show why this technique of creating part-human chimeras falls within the gaps of existing legislation. We give an overview of the key ethical issues raised by part-human chimera research, and we describe how well these issues are met by a range of possible regulatory approaches. We ultimately argue that regulation of part-human chimera research should be (re)designed to balance two key aims: to facilitate ethical research involving part-human chimeras and to prevent unethical experimentation with chimeras that have an uncertain-and potentially substantial-degree of moral status.

Brain organoid research raises ethical challenges not seen in other forms of stem cell research. Given that brain organoids partially recapitulate the development of the human brain, it is plausible that brain organoids could one day attain consciousness and perhaps even higher cognitive abilities. Brain organoid research therefore raises difficult questions about these organoids' moral status - questions that currently fall outside the scope of existing regulations and guidelines. This paper shows how these gaps can be addressed. We outline a moral framework for brain organoid research that can address the relevant ethical concerns without unduly impeding this important area of research.

Vitamin D is critical to children's skeletal development and health. Despite this, the factors which determine vitamin D concentrations during infancy remain incompletely understood. This article reviews the literature assessing the factors which can affect vitamin D status in infancy, including antenatal and postnatal vitamin D supplementation. Observational data supports that dietary intake of vitamin D, UV exposure, and geographic factors contribute significantly to infants' vitamin D status, but the relationship is unclear regarding genetic variation, ethnicity, and maternal vitamin D status. Randomised controlled trials have compared higher versus lower doses of infant vitamin D supplementation, but no studies have compared infant vitamin D supplementation to placebo and eliminated external sources of vitamin D to fully quantify its effect on vitamin D status. Knowledge gaps remain regarding the factors associated with optimal vitamin D concentrations in infants-including key factors such as ethnicity and genetic variation-and further studies are needed.

BACKGROUND: Physical activity may be a potentially modifiable risk factor for asthma and driver of lung function development. This systematic review aimed to summarize the available evidence concerning the longitudinal effect of physical activity on the development of asthma, the persistence of asthma symptoms and lung function outcomes in children and adolescents. METHODS: PubMed and Embase electronic databases were searched for all original articles that investigated the longitudinal association between physical activity and asthma outcomes or lung function outcomes in children and adolescents. The search and data extraction were conducted by two independent researchers. The methodological quality of the included studies was assessed using two critical assessment tools. RESULTS: The literature search retrieved 2298 publications from the electronic databases. All articles were screened, and 2289 were subsequently excluded, resulting in nine longitudinal studies eligible for inclusion in this review. Two studies found no association with incident wheeze, and two of four found no association with various asthma outcomes. Three studies investigated the effect on lung function: one observed an association in boys only, one observed an association in girls only, and one found no associations. CONCLUSION: The evidence was highly inconsistent for the relationship between physical activity and asthma and lung function outcomes. Hence, we conclude that there is insufficient evidence to suggest that physical activity has a long-term effect on the risk of asthma development in youth. Furthermore, there is insufficient evidence to determine the longitudinal effects of physical activity on lung function in children.

INTRODUCTION: Eczema is a common childhood ailment responsible for a considerable disease burden. Both timing of introduction to solid food and allergenic food are believed to be related to childhood eczema. Despite the growing body of evidence, the relationship between timing of any solid food introduction (allergenic and/or non-allergenic) and development of eczema has not previously been systematically reviewed. METHODS: PubMed and EMBASE databases were searched using food and eczema terms. Two authors selected papers according to the inclusion criteria and extracted information on study characteristics and measures of association. Meta-analyses were performed after grouping studies according to the age and type of exposure. RESULTS: A total of 17 papers met the inclusion criteria, reporting results from 16 study populations. Of these, 11 were cohort studies, 2 case-controls, 1 cross-sectional study and 2 randomized controlled trials. Limited meta-analyses were performed due to heterogeneity between studies. Timing of solid food introduction was not associated with eczema. One randomized controlled trial provided weak evidence of an association between early allergenic (around 4 months) food introduction and reduced risk of eczema. CONCLUSIONS: The available evidence is currently insufficient to determine whether the timing of introduction of any solid food influences the risk of eczema.

BACKGROUND: Asian children born in Australia have higher rates of eczema and nut allergy than non-Asian children. However, it is not known whether this country of birth differential exists for other allergies or anaphylaxis risk. OBJECTIVE: We investigated the influence of maternal and child's country of birth on the prevalence of parent-reported eczema, asthma, food allergy and being diagnosed by a doctor as being "at risk of anaphylaxis." METHODS: We assessed the relationship between mother and child country of birth and allergies using the 2010 School Entrant Health Questionnaire, completed for 57 005 5-year old children (85.8% response rate) in Victoria, Australia. Analyses were conducted using logistic regression with results presented as odds ratios (OR) with 95% confidence intervals (CIs). RESULTS: Children born in Australia to Asian-born mothers were more likely to have parent-reported food allergy (OR 2.33, 95%CI 1.96-2.77) and eczema (OR 2.04, 95%CI 1.73-2.41), but not more likely to have asthma (OR 0.87, 95% CI 0.74-1.02) than non-Asian children. By contrast, children born in Asia who subsequently migrated to Australia had a lower risk of food allergy (OR 0.33, 95%CI 0.20-0.55), eczema (OR 0.37, 95%CI 0.24-0.57) and asthma (OR 0.29, 95% CI 0.21-0.40). Patterns of anaphylaxis risk differed depending on the trigger. Compared with Australian-born non-Asian children, Australian-born Asian children were more likely to be diagnosed as being at risk of both food-induced and non-food-induced anaphylaxis. For children born in Asia, risk was lower for anaphylaxis to milk, peanut and tree nuts compared to non-Asian children, but higher for soy, wheat and non-food triggers. CONCLUSIONS AND CLINICAL RELEVANCE: Patterns of allergy/anaphylaxis risk and their triggers differed according to both ethnicity and country of birth, suggesting a gene-environment factor is in play. The difference in patterns for asthma compared with other atopic diseases is surprising and warran

BACKGROUND: The precautionary allergen labelling (PAL) and Voluntary Incidental Trace Allergen Labelling (VITAL® ) tools were designed by industry to assist consumers with selecting safe foods for consumption. However, a sizeable proportion of food products bear no label, and it is unclear whether these products are free from allergens and therefore safe to consume or have simply not undergone a risk assessment and therefore remain unlabelled for that reason. OBJECTIVE: To assess the prevalence of unlabelled products that have undergone a risk assessment process and to examine the factors influencing industry's uptake of the VITAL® process. METHODS: A web-based questionnaire was distributed to Australasian food and grocery manufacturers. RESULTS: One hundred and thirty-seven Australasian manufacturers were contacted, and 59 questionnaires were returned (response rate: 43%). The respondents represented 454 different manufacturing sites. Manufacturers reported that 23% (95% CI 19-28) of products (n=102/434) that had been through the VITAL® risk assessment process had no PAL statement on the label. 34% (95% CI 30-38), (n=204/600) of products that had undergone another (non-VITAL® ) risk assessment process had no PAL statement. In examining the factors that influenced industry's uptake of the VITAL® process, 25 manufacturers reported on factors that influenced the uptake of the VITAL® process, 76% (CI 95% 55-91) reported that VITAL® was an effective tool because it was based on science; 52% (CI 95% 31-72) reported that it was too time-consuming and 36% (CI 95% 18-57) identified a concern with it not being endorsed by the government. CONCLUSION AND CLINICAL RELEVANCE: Currently, we estimate that at least 30% of products may have been through a risk assessment process and yet bear no PAL statement on the label. Permissive labelling could be incorporated onto these products if they have been assessed to be safe for consumption.

Precautionary allergen labelling (PAL) has resulted in consumer confusion. Previous research has shown that interpretive labels (using graphics, symbols, or colours) are better understood than the traditional forms of labels. In this study, we aimed to understand if consumers would use interpretive labels (symbol, mobile phone application and a toll-free number) with or without medical advice that was advocated by the food industry rather than the normal PAL. This is relevant information for industry and clinicians as it provides an insight into the food allergic perception regarding PAL.

BACKGROUND: Ecological evidence suggests vitamin D insufficiency (VDI) due to lower ambient ultraviolet radiation (UVR) exposure may be a risk factor for IgE-mediated food allergy. However, there are no studies relating directly measured VDI during early infancy to subsequent challenge-proven food allergy. OBJECTIVE: To prospectively investigate the association between VDI during infancy and challenge-proven food allergy at 1 year. METHODS: In a birth cohort (n = 1074), we used a case-cohort design to compare 25-hydroxyvitamin D3 (25(OH)D3 ) levels among infants with food allergy vs a random subcohort (n = 274). The primary exposures were VDI (25(OH)D3 <50 nM) at birth and 6 months of age. Ambient UVR and time in the sun were combined to estimate UVR exposure dose. IgE-mediated food allergy status at 1 year was determined by formal challenge. Binomial regression was used to examine associations between VDI, UVR exposure dose and food allergy and investigate potential confounding. RESULTS: Within the random subcohort, VDI was present in 45% (105/233) of newborns and 24% (55/227) of infants at 6 months. Food allergy prevalence at 1 year was 7.7% (61/786), and 6.5% (53/808) were egg-allergic. There was no evidence of an association between VDI at either birth (aRR 1.25, 95% CI 0.70-2.22) or 6 months (aRR 0.93, 95% CI 0.41-2.14) and food allergy at 1 year. CONCLUSIONS: There was no evidence that VDI during the first 6 months of infancy is a risk factor for food allergy at 1 year of age. These findings primarily relate to egg allergy, and larger studies are required.

BACKGROUND: There is a substantial body of evidence on the epidemiology of allergic conditions, which has advanced the understanding of these conditions. We aimed to systematically identify systematic reviews and meta-analyses on the epidemiology of allergic diseases to assess what has been studied comprehensively and what areas might benefit from further research. METHODS: We searched PubMed and EMBASE up to 12/2014 for systematic reviews on epidemiological research on allergic diseases. We indexed diseases and topics covered and extracted data on the search characteristics of each systematic review. RESULTS: The search resulted in 3991 entries after removing duplicates, plus 20 other items found via references and conference abstracts; 421 systematic reviews were relevant and included in this overview. The majority contained some evidence on asthma (72.9%). Allergic rhinitis, atopic eczema and food hypersensitivity were covered in 15.7%, 24.5% and 9.0%, respectively. Commonly studied risk factors for atopic eczema included dietary and microbial factors, while for asthma, pollution and genetic factors were often investigated in systematic reviews. There was some indication of differing search characteristics across topics. CONCLUSION: We present a comprehensive overview with an indexed database of published systematic reviews in allergy epidemiology. We believe that this clarifies where most research interest has focussed and which areas could benefit from further research. We propose that this effort is updated every few years to include the most recently published evidence and to extend the search to an even broader list of hypersensitivity/allergic disorders.

BACKGROUND: Epidemiological evidence suggests that routine vaccinations can have nontargeted effects on susceptibility to infections and allergic disease. Such effects may depend on age at vaccination, and a delay in pertussis vaccination has been linked to reduced risk of allergic disease. We aimed to test the hypothesis that delay in vaccines containing diphtheria-tetanus-acellular pertussis (DTaP) is associated with reduced risk of food allergy and other allergic diseases. METHODS: HealthNuts is a population-based cohort in Melbourne, Australia. Twelve-month-old infants were skin prick-tested to common food allergens, and sensitized infants were offered oral food challenges to determine food allergy status. In this data linkage study, vaccination data for children in the HealthNuts cohort were obtained from the Australian Childhood Immunisation Register. Associations were examined between age at the first dose of DTaP and allergic disease. RESULTS: Of 4433 children, 109 (2.5%) received the first dose of DTaP one month late (delayed DTaP). Overall, delayed DTaP was not associated with primary outcomes of food allergy (adjusted odds ratio (aOR) 0.77; 95% CI: 0.36-1.62, P = 0.49) or atopic sensitization (aOR: 0.66; 95% CI: 0.35-1.24, P = 0.19). Amongst secondary outcomes, delayed DTaP was associated with reduced eczema (aOR: 0.57; 95% CI: 0.34-0.97, P = 0.04) and reduced use of eczema medication (aOR: 0.45; 95% CI: 0.24-0.83, P = 0.01). CONCLUSIONS: There was no overall association between delayed DTaP and food allergy; however, children with delayed DTaP had less eczema and less use of eczema medication. Timing of routine infant immunizations may affect susceptibility to allergic disease.