Investigating the effect of farm milk consumption on childhood asthma and allergies in the context of farming, early life nutrition and innate immunity

Background In the past 20 years, investigations in affluent countries repeatedly found that an exposure to farming environments was associated with lowered risks for atopic disease in childhood. Subsequently, consumption of cow’s milk from farms that was not commercially processed was consistently identified as one specific protective farm related factor. Microorganisms, fatty acids and proteins in milk were speculated to possibly underlie these inverse associations of farm milk with atopic outcomes. The pathways mediating this potential protection remain unclear. Recent research findings indicated an involvement of the innate immune system. Objectives To elucidate the previously observed inverse associations of farm milk consumption with childhood asthma and allergic disease by identifying underlying milk components, by putting these results in the context of similar associations of farm related and dietary exposures and by assessing the role of the innate immune system. Methods The cross-sectional GABRIEL study was conducted in rural areas of Germany, Switzerland, Austria and Poland. The initial study population comprised 103’219 6-12 year old children. Atopic health outcomes and farming and lifestyle exposures were assessed by comprehensive questionnaires. Cow’s milk was collected as it was consumed at the participants’ homes from about 800 children. The prospective birth cohort study PASTURE was conducted in rural areas of Germany, Austria, Switzerland and Finland. Initially, 1’133 pregnant women were recruited in the third trimester. Environmental exposures and self reports about atopic disease were assessed by extensive questionnaires during pregnancy and yearly up to age 6. A detailed food frequency diary during year 1 provided information on introduction of complementary foods. Blood samples were used to measure gene expression of innate immunity receptors at birth and age 1. Results A traditional type of farming namely with cows and cultivation was protective for childhood asthma, hay fever and atopy. The inverse association of general farm exposure with asthma could be explained by early life consumption of farm milk, contact with cows and contact with straw. The association with atopy, hay fever and atopic dermatitis could not be fully explained by these factors. Reported consumption of unboiled farm milk was significantly associated with reduced risk for asthma, atopic sensitization, hay fever and atopic dermatitis. Whey proteins (bovine serum albumin, α-lactalbumin, β-lactoglobulin) were identified as milk constituents possibly explaining the epidemiologically observed protective farm milk association with asthma whereas reduced risk for atopic sensitization could not be associated with any investigated milk constituent. Microorganisms and fat content of milk showed no associations with allergic health outcomes. Increasing diversity of introduced complementary food items was inversely associated with the risk to develop atopic dermatitis after age 1, independently of other farming exposures. An inverse association was also found with the introduction of yogurt during the first year of life. Maternal farming during pregnancy was associated with a significant up-regulation of Toll-like receptors (TLR) 7 and 8 gene expressions. Child’s farm milk consumption during first year of life was associated with up-regulation of TLR4, 5 and 6 gene expression. Conclusions and outlook The variations between associations of specific farming and dietary exposures in early life with specific atopic diseases suggest that different pathways may be involved in the protection against the development of these outcomes. Several factors explained the decreased risk for asthma in children living on farms but specific factors explaining decreased risks for atopy, hay fever and atopic dermatitis are yet to be identified. Our findings add to the evidence that early life exposures may have an effect on the development of the innate immune system. We could further demonstrate that relevant exposures differed between in utero and child’s direct exposure during first year of life. Results generated with cross-sectional data need to be confirmed in prospective studies to establish temporal relationships and future studies need to employ more advanced methods to assess microbial diversity in environmental exposures. An important research question for further investigations will be whether and how the innate immune system mediates the inverse associations of farm related and dietary exposure with the development of atopic disease in early life. Raw milk consumption has the potential to be used as preventive measure for the development of atopic disease in early life but pathogens pose a health risk and make an implementation unlikely. A native milk product that is safe and can still exert “protective effects” on atopic diseases could be facilitated by modern non-thermal pasteurization techniques

Spin injection across magnetic/non-magnetic interfaces with finite magnetic layers

We have reconsidered the problem of spin injection across ferromagnet/non-magnetic-semiconductor (FM/NMS) and dilute-magnetic-semiconductor/non-magnetic-semiconductor interfaces, for structures with \textit{finite} magnetic layers (FM or DMS). By using appropriate physical boundary conditions, we find expressions for the resistances of these structures which are in general different from previous results in the literature. When the magnetoresistance of the contacts is negligible, we find that the spin-accumulation effect alone cannot account for the $d$ dependence observed in recent magnetoresistance data. In a limited parameter range, our formulas predict a strong $d$ dependence arising from the magnetic contacts in systems where their magnetoresistances are sizable.Comment: 6 pages, 3 eps figs. (extended version- new title + two new figures added

Health-related quality of life in rural children living in four European countries: the GABRIEL study

Objective: Measuring children's health-related quality of life (HRQOL) is of growing importance given increasing chronic diseases. By integrating HRQOL questions into the European GABRIEL study, we assessed differences in HRQOL between rural farm and non-farm children from Germany, Austria, Switzerland and Poland to relate it to common childhood health problems and to compare it to a representative, mostly urban German population sample (KIGGS). Methods: The parents of 10,400 school-aged children answered comprehensive questionnaires including health-related questions and the KINDL-R questions assessing HRQOL. Results: Austrian children reported highest KINDL-R scores (mean: 80.9; 95% CI [80.4, 81.4]) and Polish children the lowest (74.5; [73.9, 75.0]). Farm children reported higher KINDL-R scores than non-farm children (p=0.002). Significantly lower scores were observed in children with allergic diseases (p<0.001), with sleeping difficulties (p<0.001) and in overweight children (p=0.04). The German GABRIEL sample reported higher mean scores (age 7-10years: 80.1, [79.9, 80.4]; age 11-13years: 77.1, [74.9, 79.2]) compared to the urban KIGGS study (age 7-10years: 79.0, [78.7-79.3]; age 11-13years: 75.1 [74.6-75.6]). Socio-demographic or health-related factors could not explain differences in HRQOL between countries. Conclusions: Future increases in chronic diseases may negatively impact children's HRQO

Spin interactions and switching in vertically tunnel-coupled quantum dots

We determine the spin exchange coupling J between two electrons located in two vertically tunnel-coupled quantum dots, and its variation when magnetic (B) and electric (E) fields (both in-plane and perpendicular) are applied. We predict a strong decrease of J as the in-plane B field is increased, mainly due to orbital compression. Combined with the Zeeman splitting, this leads to a singlet-triplet crossing, which can be observed as a pronounced jump in the magnetization at in-plane fields of a few Tesla, and perpendicular fields of the order of 10 Tesla for typical self-assembled dots. We use harmonic potentials to model the confining of electrons, and calculate the exchange J using the Heitler-London and Hund-Mulliken technique, including the long-range Coulomb interaction. With our results we provide experimental criteria for the distinction of singlet and triplet states and therefore for microscopic spin measurements. In the case where dots of different sizes are coupled, we present a simple method to switch on and off the spin coupling with exponential sensitivity using an in-plane electric field. Switching the spin coupling is essential for quantum computation using electronic spins as qubits.Comment: 13 pages, 9 figure

omega-3 fatty acids contribute to the asthma-protective effect of unprocessed cow's milk

Background: Living on a farm has repeatedly been shown to protect children from asthma and allergies. A major factor involved in this effect is consumption of unprocessed cow's milk obtained directly from a farm. However, this phenomenon has never been shown in a longitudinal design, and the responsible milk components are still unknown. Objectives: We sought to assess the asthma-protective effect of unprocessed cow's milk consumption in a birth cohort and to determine whether the differences in the fatty acid (FA) composition of unprocessed farm milk and industrially processed milk contributed to this effect. Methods: The Protection Against Allergy-Study in Rural Environments (PASTURE) study followed 1133 children living in rural areas in 5 European countries from birth to age 6 years. In 934 children milk consumption was assessed by using yearly questionnaires, and samples of the ``usually'' consumed milk and serum samples of the children were collected at age 4 years. Doctor-diagnosed asthma was parent reported at age 6 years. In a nested case-control study of 35 asthmatic and 49 nonasthmatic children, 42 FAs were quantified in milk samples. Results: The risk of asthma at 6 years of age was reduced by previous consumption of unprocessed farm milk compared with shop milk (adjusted odds ratio for consumption at 4 years, 0.26; 95% CI,0.10-0.67). Part of the effect was explained by the higher fat content of farm milk, particularly the higher levels of omega-3 polyunsaturated FAs (adjusted odds ratio, 0.29; 95% CI,0.11-0.81). Conclusion: Continuous farm milk consumption in childhood protects against asthma at school age partially by means of higher intake of omega-3 polyunsaturated FAs, which are precursors of anti-inflammatory mediators.Peer reviewe

Assessment of pesticide safety knowledge and practices in Vietnam: A cross-sectional study of smallholder farmers in the Mekong Delta

Over the past three decades, the Vietnamese Mekong Delta has experienced a significant increase in agricultural productivity, partly achieved through increased agrochemical use. To abate negative effects on human and environmental health, several national programs were launched to enhance safer pesticide use. This study aimed to assess the patterns and relationships of official sustainable agriculture educational programs, pesticide safety knowledge, and practices of smallholder farmers in the Mekong Delta. A cross-sectional survey was conducted with 400 smallholder farmers from three communes in Thoi Lai district (Can Tho province) from March to May 2020. Twenty-four questions on pesticide safety knowledge and practices were used to identify traits using latent class analysis. Adjusted generalized linear regression was used to assess determinants of pesticide safety knowledge and estimate associations of pesticide safety knowledge with pesticide practices. 96.2% of participants have used at least one WHO class II pesticide during the past year while the use of specific personal protective equipment was limited mainly due to unavailability (37.0%) or discomfort (83.0%). High education (Odds Ratio (OR), 95% Confidence Interval; 3.84, 1.70–9.45), exposure to official educational programs (1.87, 1.13–3.12), peer-to-peer knowledge exchange (3.58, 2.18–6.00), and learning from governmental extension services (2.31, 1.14–4.98) were positively associated with increased pesticide safety knowledge. Compared to poor practices, pesticide safety knowledge was increasingly positively associated with intermediate (1.65, 1.02–2.66) and good pesticide practices (8.96, 2.58–31.12). These findings highlight the importance of school education and educational programs, access to PPE, and addressing discomforts of PPE to improve the protection of farmers from pesticide exposures. Simultaneously, pesticide market authorization processes should be reconsidered to promote the authorization of less toxic products. Further indepth studies on the nature of pesticides used, nonuse of personal protective equipment, and effectiveness of educational programs will further define leverage points for safer pesticide use

Farm-like indoor microbiota in non-farm homes protects children from asthma development

Asthma prevalence has increased in epidemic proportions with urbanization, but growing up on traditional farms offers protection even today(1). The asthma-protective effect of farms appears to be associated with rich home dust microbiota(2,3), which could be used to model a health-promoting indoor microbiome. Here we show by modeling differences in house dust microbiota composition between farm and non-farm homes of Finnish birth cohorts(4) that in children who grow up in non-farm homes, asthma risk decreases as the similarity of their home bacterial microbiota composition to that of farm homes increases. The protective microbiota had a low abundance of Streptococcaceae relative to outdoor-associated bacterial taxa. The protective effect was independent of richness and total bacterial load and was associated with reduced proinflammatory cytokine responses against bacterial cell wall components ex vivo. We were able to reproduce these findings in a study among rural German children(2) and showed that children living in German non-farm homes with an indoor microbiota more similar to Finnish farm homes have decreased asthma risk. The indoor dust microbiota composition appears to be a definable, reproducible predictor of asthma risk and a potential modifiable target for asthma prevention.Peer reviewe

Latent class analysis reveals clinically relevant atopy phenotypes in 2 birth cohorts

Background: Phenotypes of childhood-onset asthma are characterized by distinct trajectories and functional features. For atopy, definition of phenotypes during childhood is less clear. Objective: We sought to define phenotypes of atopic sensitization over the first 6 years of life using a latent class analysis (LCA) integrating 3 dimensions of atopy: allergen specificity, time course, and levels of specific IgE (sIgE). Methods: Phenotypes were defined by means of LCA in 680 children of the Multizentrische Allergiestudie (MAS) and 766 children of the Protection against allergy: Study in Rural Environments (PASTURE) birth cohorts and compared with classical nondisjunctive definitions of seasonal, perennial, and food sensitization with respect to atopic diseases and lung function. Cytokine levels were measured in the PASTURE cohort. Results: The LCA classified predominantly by type and multiplicity of sensitization (food vs inhalant), allergen combinations, and sIgE levels. Latent classes were related to atopic disease manifestations with higher sensitivity and specificity than the classical definitions. LCA detected consistently in both cohorts a distinct group of children with severe atopy characterized by high seasonal sIgE levels and a strong propensity for asthma; hay fever; eczema; and impaired lung function, also in children without an established asthma diagnosis. Severe atopy was associated with an increased IL-5/IFN-gamma ratio. A path analysis among sensitized children revealed that among all features of severe atopy, only excessive sIgE production early in life affected asthma risk. Conclusions: LCA revealed a set of benign, symptomatic, and severe atopy phenotypes. The severe phenotype emerged as a latent condition with signs of a dysbalanced immune response. It determined high asthma risk through excessive sIgE production and directly affected impaired lung function.Peer reviewe

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to &lt;90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], &gt;300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of &lt;15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P&lt;0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P&lt;0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Treatment patterns in children with autism in the United States

Children with autism receive different types of non-drug treatments. We aimed to describe caregiver-reported pattern of care and its variability by geography and healthcare coverage in a US-wide sample of children aged 3-17 years. We recruited caregivers from the Simons Foundation Powering Autism Research for Knowledge (SPARK) cohort. Two online questionnaires (non-drug treatment, Autism Impact Measure) were completed in September/October 2017. Primary outcome measures were caregiver-reported types and intensities of treatments (behavioral, developmental/relationship, speech and language (SLT), occupational, psychological, other; parent/caregiver training) in the previous 12 months. Main explanatory variables were geography and type of healthcare coverage. We investigated associations between the type/intensity of treatments and geography (metropolitan/nonmetropolitan) or coverage (Medicaid vs privately insured by employer) using regression analysis. Caregivers (n = 5,122) were mainly mothers (92.1%) with mean (SD) age of 39.0 (7.3) years. Mean child age was 9.1 (3.9) years; mostly males (80.0%). Almost all children received at least one intervention (96.0%). Eighty percent received SLT or occupational therapy, while 52.0% received both. Behavioral therapy and SLT were significantly more frequent and more intense in metropolitan than in nonmetropolitan areas. No consistently significant associations were seen between healthcare coverage and frequency or intensity of interventions. At least one barrier such as waiting list and no coverage was reported by 44.8%. In conclusion, in children sampled from SPARK, we observed differences between metropolitan and nonmetropolitan areas, while we did not find significant differences between those privately insured versus Medicaid. Autism Res 2019, 12: 517-526 (c) 2019 The Authors. Autism Research published by International Society for Autism Research published by Wiley Periodicals, Inc.Lay SummaryThe American Academy of Child and Adolescent Psychiatry recommends the use of multiple treatment modalities in autism spectrum disorder (ASD). We wanted to understand what types of treatment children (aged 3-17 years) with ASD receive in the United States, how and where the treatments take place and for how long. We invited caregivers from Simons Foundation Powering Autism Research for Knowledge (SPARK , ) to complete the study questions online. Participants reported on utilization of conventional, non-drug treatments for ASD, including behavioral interventions, developmental/relationship interventions, speech and language therapy (SLT), occupational therapy, psychological therapy, and parent/caregiver training. People that completed the study (n = 5,122) were primarily mothers of the child with ASD (92%); most of the children were boys (80%). The ASD care for the child was mostly coordinating by the mother. Almost all children received at least some type of non-drug therapies (96%), most often SLT and/or occupational therapy, mainly provided in school. Behavioral therapy was most often received in public school in rural areas, while at home in urban areas. We saw less use of behavioral therapy and SLT in rural areas, but overall comparable use between children covered by Medicaid and those covered by private insurance. Almost half the caregivers reported at least one barrier to treatment, such as waiting list and no coverage. More than half said that their child benefited much or very much from the therapies received. While overall non-drug treatment rates for children with ASD were high in the United States in our study, differences existed depending on where the family lives; not only regarding the type of therapy, but also where it takes place.</p