Is growth in early childhood a window of opportunity for programming long-term health?

Background: Rapid growth characterises early childhood, with the highest weight gain in early infancy and continued relatively high gains during preschool years. Summary: Subnormal weight and length gain from birth to about 2 years of age predict increased childhood wasting and stunting, whereas excessive weight gain in infancy and early childhood is associated with increased later obesity. Breastfeeding attenuates the risk of high early weight gain and later obesity, adding another reason for promoting, protecting and supporting breastfeeding. Avoiding high infant protein intakes from infant formula and complementary foods is strongly recommended since it markedly reduces later obesity and adiposity. This can be achieved by avoiding cows’ and other animal milks as a drink in infancy and choosing infant formula with a low protein content, more similar to breastmilk, for infants not (fully) breastfed. High weight gain in toddlers is also associated with increased later obesity, predicted by overfeeding, high intakes of sugary foods and beverages, and high intakes of protein, particularly animal protein. In an ongoing controlled trial in Germany and Spain, we randomised 1,618 toddlers to milk drinks in the second year of life providing protein contents either similar to cows’ milk or more similar to human milk. First results show high protein milk inducing high weight and length gains deviating from normal growth trajectories, whereas reduced protein intakes support weight and length growth matching WHO growth standards. Follow-up until early school age is ongoing to explore a potential impact on later growth and overweight risk. Key messages: Avoiding rapid weight gain in infancy and toddlerhood can reduce later obesity risk. Promoting, protecting and supporting breastfeeding and avoidance of high animal protein intakes in early childhood can contribute to reaching this goal

Maternal exposure to polychlorinated biphenyls in indoor air and asthma, allergic rhinitis, atopic eczema, and respiratory tract infections in childhood

Polychlorinated biphenyls (PCBs) are industrial chemicals commonly found in food and building materials. PCBs are immunotoxic and may disturb the fetal programming of the immune and respiratory systems. We evaluated the association between maternal PCB exposure in indoor air and asthma, allergic rhinitis, atopic eczema, and respiratory infections in the offspring in the Health Effects of PCBs in Indoor Air (HESPAIR) cohort. This register-based study examined 7982 children born to mothers residing in two partially PCB contaminated residential areas in Greater Copenhagen before and/or during pregnancy. Children were included if their mothers at any point had lived in a contaminated or uncontaminated apartment in the period from 3.6 years prior to conception until the date of birth. PCB exposure was defined as mothers’ number of years in an apartment prior to birth of the child multiplied with the PCB concentration in indoor air based on air measurements. Information on the outcomes was retrieved from the Danish health registers from 1977 to 2018. We estimated adjusted hazard ratios using Cox regression. Our main analyses revealed no association between maternal exposure to PCBs in indoor air and any of the studied allergic and respiratory outcomes. Findings of sensitivity analyses were consistent with main analyses. While these findings may appear reassuring for the considerable number of people living or working in PCB contaminated indoor environments, they should be interpreted with caution due to the indirect measure of exposure, incomplete registration of diagnoses, and lack of supporting evidence from comparable studies

Prevalence of Taylorella equigenitalis in Icelandic mares and geldings in Southern Germany and Austria

Contagious Equine Metritis (CEM) caused by the bacterium Taylorella equigenitalis (T. equigenitalis), is a venereal infection of equids which is of international concern to the equine breeding industry. A recent study showed a high prevalence of T. equigenitalis in Icelandic stallions when compared to stallions of other breeds also using for natural breeding. Consequently, the objectives of the present study were to investigate the prevalence of T. equigenitalis in Icelandic mares and geldings and to determine factors associated with a T. equigenitalis-positive qPCR result. In total, 361 Icelandic horses located in Southern Germany and Austria were tested for T. equigenitalis using a qPCR assay. An overall prevalence of 14.4 % was detected. Positive qPCR results were found in 2.2 % (3/134) of brood mares, 9.0 % (11/122) of maiden mares and in 36.2 % (38/105) of geldings. The odds for a T. equigenitalis-positive qPCR result were significantly lower in both brood (OR = 40.1, 95 % CI: 8.38-192, P < 0.001) and maiden mares (OR = 9.51, 95 % CI: 3.26-25.7, P < 0.001) when compared to geldings. Advancing age was not associated with higher odds for a T. equigenitalis-positive qPCR result (OR = 0.98, 95 % CI: 0.94-1.03, P = 0.51). However, horses of the younger age group showed significantly lower Ct values compared to horses of the older age group (P = 0.04). Furthermore, geldings showed significantly lower Ct values than brood (P < 0.03) and maiden mares (P < 0.001). This study showed a significantly higher prevalence of T. equigenitalis in Icelandic geldings compared to Icelandic mares. Icelandic geldings might therefore represent a reservoir for T. equigenitalis

Analyzing dialect (morpho)syntax in Austria: a non-aggregative dialectometric approach

This paper aims to identify and analyze geographical patterns of (morpho)syntactic variation in traditional Austrian dialects using non-aggregative dialectometric methods (factor analysis). Based on a comprehensive dialect corpus obtained by direct dialect interviews including 163 speakers from 40 locations throughout Austria, our analyses of 79 variants of 30 (morpho)syntactic variables not only show geographical patterns in Austria’s dialects, but also address the linguistic basis of the geographical structures revealed. In particular, the results show that variables at the morphology–syntax interface contribute most to geographical structuring. We argue that this finding is related to structural conditions of these variables and the historical development of the respective variants

RORγt-expressing dendritic cells are functionally versatile and evolutionarily conserved antigen-presenting cells

Conventional dendritic cells (cDCs) are potent antigen-presenting cells (APCs) that integrate signals from their environment allowing them to direct situation-adapted immunity. Thereby they harbor great potential for being targeted in vaccination, autoimmunity, and cancer. Here, we use fate mapping, functional analyses, and comparative cross-species transcriptomics to show that RORγt+ DCs are a conserved, functionally versatile, and transcriptionally distinct type of DCs. RORγt+ DCs entail various populations described in different contexts including Janus cells/RORγt-expressing extrathymic Aire-expressing cells (eTACs), subtypes of Thetis cells, RORγt+-DC (R-DC) like cells, cDC2C and ACY3+ DCs. We show that in response to inflammatory triggers, RORγt+ DCs can migrate to lymph nodes and in the spleen can activate naïve CD4+ T cells. These findings expand the functional repertoire of RORγt+ DCs beyond the known role of eTACs and Thetis cells in inducing T cell tolerance to self-antigens and intestinal microbes in mice. We further show that RORγt+ DCs with proinflammatory features accumulate in autoimmune neuroinflammation in mice and men. Thus, our work establishes RORγt+ DCs as immune sentinel cells that exhibit a broad functional spectrum ranging from inducing peripheral T cell tolerance to T cell activation depending on signals they integrate from their environment

Regulation of nc886 (vtRNA2-1) RNAs is associated with cardiometabolic risk factors and diseases

Non-coding 886 (nc886, vtRNA2-1) is a polymorphically imprinted gene. The methylation status of this locus has been shown to be associated with periconceptional conditions, and both the methylation status and the levels of nc886 RNAs have been shown to associate with later-life health traits. We have previously shown that nc886 RNA levels are associated not only with the methylation status of the locus, but also with a genetic polymorphism upstream from the locus. In this study, we describe the genetic and epigenetic regulators that predict lifelong nc886 RNA levels, as well as their association with cardiometabolic disease (CMD) risk factors and events. We utilised six population cohorts and one CMD cohort comprising 9058 individuals in total. The association of nc886 RNA levels, as predicted by epigenetic and genetic regulators, with CMD phenotypes was analysed using regression models, with a meta-analysis of the results. The meta-analysis showed that individuals with upregulated nc886 RNA levels have higher diastolic blood pressure (β = 0.07, p = 0.008), lower HDL levels (β =  − 0.07, p = 0.006) and an increased incidence of type 2 diabetes (OR = 1.260, p = 0.013). Moreover, CMD patients with upregulated nc886 RNA levels have an increased incidence of stroke (OR = 1.581, p = 0.006) and death (OR = 1.290, p = 0.046). In conclusion, we show that individuals who are predicted to present elevated nc886 RNA levels have poorer cardiovascular health and are at an elevated risk of complications in secondary prevention. This unique mechanism yields metabolic variation in human populations, constituting a CMD risk factor that cannot be modified through lifestyle choices

Optimized monitoring for immune checkpoint inhibitor induced myocarditis using high-sensitivity troponin-T

Background Immune checkpoint inhibitor (ICI)-induced Myocarditis (irMyocarditis) is a rare adverse event with a high mortality rate of 40–50 % and which is mostly not diagnosed until clinical symptoms emerge. Objectives This study aims to screen patients for irMyocarditis using high-sensitivity cardiac troponin-T (hs-TnT) before and regularly during therapy with ICI. Methods A cohort of 280 cancer patients were prospectively screened for levels of hs-TnT at baseline and prior to every ICI infusion. In case of elevation of hs-TnT, patients were referred for further work-up. Results In total, 196 patients exhibited a baseline hs-TnT ≤ 14 ng/l (99th percentile concentration for general population; group A) and 84 patients a hs-TnT > 14 ng/l at baseline (group B). An increase of hs-TnT during ICI-treatment was observed in 56 out of 196 (27.6 %) and 56 out of 84 patients (66.7 %) in group A and B. Cardiovascular assessment was performed in 11.2 % and 27.4 % of patients, respectively, and 4.1 % and 9.5 % of patients were diagnosed with irMyocarditis and treated with corticosteroids. No fatalities occurred in any of the 16 irMyocarditis patients. Defining a threshold with the highest sensitivity and maximum specificity in receiver-operating characteristics curves, identified a limit of 22 ng/l (group A) and 60 ng/l (group B) hs-TnT, associated with a sensitivity of 100 % in both and a specificity of 91.0 % and 89.6 %, respectively, to detect irMyocarditis. Conclusion Screening of hs-TnT can identify irMyocarditis early and lead to reduction of MACE and mortality risk through interruption of ICI-treatment and prompt therapy with corticosteroids

Combination of Ambient and High‐Temperature Beryllium Nitride Motifs in W2Be4N5 and W4Be8N9

Compounds of transition metals and beryllium have a wide range of applications, from everyday tools to high tech applications. Remarkably, no single ternary beryllium nitride with a transition metal is known. Here, we report on the synthesis and properties of the first transition metal nitridoberyllates, namely W2Be4N5 and W4Be8N9. Both compounds were synthesized in a high-temperature high-pressure approach from Be3N2 and W, using azide generated N2 as an oxidizing agent. The crystal structures, consisting of alternating layers of WN6 trigonal prisms and BeN4 tetrahedra, were elucidated by single-crystal X-ray diffraction (sc-XRD). The separating nitridoberyllate layers show either ambient temperature (α-Be3N2 type) or high temperature (β-Be3N2 type) motifs. W2Be4N5 was further corroborated by infrared (IR), nuclear magnetic resonance (NMR) and UV/Vis spectroscopy and vibrating sample magnetometry (VSM) measurements. The latter revealed a mixed valence with an intermediate oxidation state of 3.5 for the W atoms. Both, the synthesis of the first transition metal nitridoberyllates and the synthesis approach using elemental W pave the way to a new field of nitride chemistry