Determinants of the urinary and serum metabolome in children from six European populations

Background Environment and diet in early life can affect development and health throughout the life course. Metabolic phenotyping of urine and serum represents a complementary systems-wide approach to elucidate environment–health interactions. However, large-scale metabolome studies in children combining analyses of these biological fluids are lacking. Here, we sought to characterise the major determinants of the child metabolome and to define metabolite associations with age, sex, BMI and dietary habits in European children, by exploiting a unique biobank established as part of the Human Early-Life Exposome project (http://www.projecthelix.eu). Methods Metabolic phenotypes of matched urine and serum samples from 1192 children (aged 6–11) recruited from birth cohorts in six European countries were measured using high-throughput 1H nuclear magnetic resonance (NMR) spectroscopy and a targeted LC-MS/MS metabolomic assay (Biocrates AbsoluteIDQ p180 kit). Results We identified both urinary and serum creatinine to be positively associated with age. Metabolic associations to BMI z-score included a novel association with urinary 4-deoxyerythronic acid in addition to valine, serum carnitine, short-chain acylcarnitines (C3, C5), glutamate, BCAAs, lysophosphatidylcholines (lysoPC a C14:0, lysoPC a C16:1, lysoPC a C18:1, lysoPC a C18:2) and sphingolipids (SM C16:0, SM C16:1, SM C18:1). Dietary-metabolite associations included urinary creatine and serum phosphatidylcholines (4) with meat intake, serum phosphatidylcholines (12) with fish, urinary hippurate with vegetables, and urinary proline betaine and hippurate with fruit intake. Population-specific variance (age, sex, BMI, ethnicity, dietary and country of origin) was better captured in the serum than in the urine profile; these factors explained a median of 9.0% variance amongst serum metabolites versus a median of 5.1% amongst urinary metabolites. Metabolic pathway correlations were identified, and concentrations of corresponding metabolites were significantly correlated (r > 0.18) between urine and serum. Conclusions We have established a pan-European reference metabolome for urine and serum of healthy children and gathered critical resources not previously available for future investigations into the influence of the metabolome on child health. The six European cohort populations studied share common metabolic associations with age, sex, BMI z-score and main dietary habits. Furthermore, we have identified a novel metabolic association between threonine catabolism and BMI of children

Human rights dimensions of food, health and care in children’s homes in Kampala, Uganda – a qualitative study

Background More than 14 % of Ugandan children are orphaned and many live in children’s homes. Ugandan authorities have targeted adolescent girls as a priority group for nutrition interventions as safeguarding nutritional health before pregnancy can reduce the chance of passing on malnutrition to the offspring and thus future generations. Ugandan authorities have obligations under international human rights law to progressively realise the rights to adequate food, health and care for all Ugandan children. Two objectives guided this study in children’s homes: (a) To examine female adolescent residents’ experiences, attitudes and views regarding: (i) eating patterns and food, (ii) health conditions, and (iii) care practices; and (b) to consider if the conditions in the homes comply with human rights standards and principles for the promotion of the rights to adequate food, health and care. Methods A human rights-based approach guided the planning and conduct of this study. Five children’s homes in Kampala were included where focus group discussions were held with girls aged 12-14 and 15-17 years. These discussions were analysed through a phenomenological approach. The conditions of food, health and care as experienced by the girls, were compared with international standards for the realisation of the human rights to adequate food, health and care. Results Food, health and care conditions varied greatly across the five homes. In some of these the girls consumed only one meal per day and had no access to clean drinking water, soap, toilet paper and sanitary napkins. The realisation of the right to adequate food for the girls was not met in three homes, the realisation of the right to health was not met in two homes, and the realisation of the right to care was not met in one home. Conclusions In three of the selected children’s homes human rights standards for food, health or care were not met. Care in the children’s homes was an important contributing factor for whether standards for the rights to adequate food and health were met

Early Oligocene initiation of North Atlantic Deep Water formation

Dating the onset of deep-water flow between the Arctic and North Atlantic oceans is critical for modelling climate change in the Northern Hemisphere1, 2 and for explaining changes in global ocean circulation throughout the Cenozoic era3 (from about 65 million years ago to the present). In the early Cenozoic era, exchange between these two ocean basins was inhibited by the Greenland–Scotland ridge3, 4, but a gateway through the Faeroe–Shetland basin has been hypothesized3, 5. Previous estimates of the date marking the onset of deep-water circulation through this basin—on the basis of circumstantial evidence from neighbouring basins—have been contradictory5, 6, 7, 8, 9, ranging from about 35 to 15 million years ago. Here we describe the newly discovered Southeast Faeroes drift, which extends for 120 km parallel to the basin axis. The onset of deposition in this drift has been dated to the early Oligocene epoch (35 million years ago) from a petroleum exploration borehole. We show that the drift was deposited under a southerly flow regime, and conclude that the initiation of deep-water circulation from the Norwegian Sea into the North Atlantic Ocean took place much earlier than is currently assumed in most numerical models of ancient ocean circulation

Expanding the phenotype of ASXL3-related syndrome: A comprehensive description of 45 unpublished individuals with inherited and de novo pathogenic variants in ASXL3

The study aimed at widening the clinical and genetic spectrum of ASXL3-related syndrome, a neurodevelopmental disorder, caused by truncating variants in the ASXL3 gene. In this international collaborative study, we have undertaken a detailed clinical and molecular analysis of 45 previously unpublished individuals with ASXL3-related syndrome, as well as a review of all previously published individuals. We have reviewed the rather limited functional characterization of pathogenic variants in ASXL3 and discuss current understanding of the consequences of the different ASXL3 variants. In this comprehensive analysis of ASXL3-related syndrome, we define its natural history and clinical evolution occurring with age. We report familial ASXL3 pathogenic variants, characterize the phenotype in mildly affected individuals and discuss nonpenetrance. We also discuss the role of missense variants in ASXL3. We delineate a variable but consistent phenotype. The most characteristic features are neurodevelopmental delay with consistently limited speech, significant neuro-behavioral issues, hypotonia, and feeding difficulties. Distinctive features include downslanting palpebral fissures, hypertelorism, tubular nose with a prominent nasal bridge, and low-hanging columella. The presented data will inform clinical management of individuals with ASXL3-related syndrome and improve interpretation of new ASXL3 sequence variants

Expanding the phenotype of ASXL3-related syndrome: A comprehensive description of 45 unpublished individuals with inherited and de novo pathogenic variants in ASXL3

Purpose. The study aimed at widening the clinical and genetic spectrum of ASXL3-related syndrome, a neurodevelopmental disorder, caused by truncating variants in the ASXL3 gene. Methods. In this international collaborative study, we have undertaken a detailed clinical and molecular analysis of 45 previously unpublished individuals with ASXL3-related syndrome, as well as a review of all previously published individuals. We have reviewed the rather limited functional characterisation of pathogenic variants in ASXL3 and discuss current understanding of the consequences of the different ASXL3 variants. Results. In this comprehensive analysis of ASXL3-related syndrome, we define its natural history and clinical evolution occurring with age. We report familial ASXL3 pathogenic variants, characterise the phenotype in mildly affected individuals and discuss non-penetrance. We also discuss the role of missense variants in ASXL3. We delineate a variable but consistent phenotype. The most characteristic features are neurodevelopmental delay with consistently limited speech, significant neuro-behavioural issues, hypotonia and feeding difficulties. Distinctive features include down-slanting palpebral fissures, hypertelorism, tubular nose with a prominent nasal bridge and low-hanging columella. Conclusion. The presented data will inform clinical management of individuals with ASXL3-related syndrome and improve interpretation of new ASXL3 sequence variants.