Apparent Saturation of Branched-Chain Amino Acid Catabolism After High Dietary Milk Protein Intake in Healthy Adults.

CONTEXT: Milk protein contains high concentrations of branched-chain amino acids (BCAA) that play a critical role in anabolism and are implicated in the onset of obesity and chronic disease. Characterizing BCAA catabolism in the postprandial phase could elucidate the impact of protein intake on obesity risk established in the "early protein hypothesis." OBJECTIVE: To examine the acute effects of protein content of young child formulas as test meals on BCAA catabolism, observing postprandial plasma concentrations of BCAA in relation to their degradation products. METHODS: The TOMI Add-On Study is a randomized, double-blind crossover study in which 27 healthy adults consumed 2 isocaloric young child formulas with alternating higher (HP) and lower (LP) protein and fat content as test meals during separate interventions, while 9 blood samples were obtained over 5 hours. BCAA, branched-chain α-keto acids (BCKA), and acylcarnitines were analyzed using a fully targeted HPLC-ESI-MS/MS approach. RESULTS: Mean concentrations of BCAA, BCKA, and acylcarnitines were significantly higher after HP than LP over the 5 postprandial hours, except for the BCKA α-ketoisovalerate (KIVA). The latter metabolite showed higher postprandial concentrations after LP. With increasing mean concentrations of BCAA, concentrations of corresponding BCKA, acylcarnitines, and urea increased until a breakpoint was reached, after which concentrations of degradation products decreased (for all metabolites except valine and KIVA and Carn C4:0-iso). CONCLUSION: BCAA catabolism is markedly influenced by protein content of the test meal. We present novel evidence for the apparent saturation of the BCAA degradation pathway in the acute postprandial phase up to 5 hours after consumption.

Orphan and paediatric medical devices in Europe: recommendations to support their availability for on-label and off-label clinical indications.

INTRODUCTION: The Medical Device Regulation (EU)745/2017, increased the regulatory requirements and thus the time and the cost associated with marketing medical devices. For a majority of medical device manufacturers, this has lead to reconsiderations of their product portfolio. The risk of important or essential devices being withdrawn is particularly relevant for pediatric patients and other rare disease patients where limited numbers of devices can be sold and hence the investment needed may not be recovered. This generates critical challenges and opportunities from a regulatory and public health perspective. AREAS COVERED: This paper is based upon the experience of the authors who contributed to working groups, guidance development and research related to orphan and pediatric devices. We examine the use of medical devices in orphan and pediatric conditions, the relevant aspects of regulations and associated guidance, and we suggest possible policy and practice interventions to ensure the continued availability of essential devices for children and people with rare diseases. EXPERT OPINION: We recommend a more proactive approach to identifying devices at risk and essential devices, increasing the use of exceptional market approvals, expanding the role of expert panels, engaging with the rare disease communities and supporting registries and standards.

Endothelial epoxyeicosatrienoic acid release is intact in aldosterone excess.

BACKGROUND AND AIMS: Endothelial dysfunction (ED) is considered to be a major driver of the increased incidence of cardiovascular disease in primary aldosteronism (PA). The functionality of the epoxyeicosatrienoic acid (EET) pathway, involving the release of beneficial endothelium-derived lipid mediators, in PA is unknown. Evidence suggests this pathway to be disturbed in various models of experimental hypertension. We therefore assessed EET production in primary human coronary artery endothelial cells exposed to aldosterone excess and measured circulating EET in patients with PA. METHODS: We used qPCR to investigate changes in the expression levels of essential genes for the synthesis and degradation of EET, calcium imaging to address the functional impact on overall endothelial function, as well as mass spectrometry to determine endothelial synthetic capacity to release EET upon stimulation. RNA-seq was performed to gain further mechanistic insights. Eicosanoid concentrations in patient's plasma were also determined by mass spectrometry. RESULTS: Aldosterone, while eliciting proinflammatory VCAM1 expression and disturbed calcium response to acetylcholine, did not negatively affect stimulated release of endothelial EET. Likewise, no differences were observed in eicosanoid concentrations in plasma from patients with PA when compared to essential hypertensive controls. However, an inhibitor of soluble epoxide hydrolase abrogated aldosterone-mediated VCAM1 induction and led to a normalized endothelial calcium response probably by restoring expression of CHRNE. CONCLUSION: EET release appears intact despite aldosterone excess. Epoxide hydrolase inhibition may revert aldosterone-induced functional changes in endothelial cells. These findings indicate a potential new therapeutic principle to address ED, which should be explored in future preclinical and clinical trials.

Comparative Analysis of Nutritional Advice and a Combined Approach for Addressing Impending Stunting in Infants: A Clinical Trial.

Weight faltering (WF) has been associated with stunting and with long-term adverse consequences for health and development. Nutritional care for managing WF may consist of giving nutritional advice (NA) and/or provision of oral nutrition supplements (ONSs). In this study, we aimed to evaluate practical management options in the community for infants with WF aged 6-12 months. This nonrandomized clinical trial was conducted in the community of Makassar, South Sulawesi, from March 2022 to March 2023. A total of 1013 infants were enrolled for screening. Anthropometric measures were performed in 913 infants, of which 170 showed WF below the 15th percentile of the WHO weight increment table without stunting. Infants with a weight increment below P5th were assigned to receive NA plus ONS, while infants between P5th and below P15th were assigned to receive only NA. At the second and third months, ONSs were administered to WF infants who were below P15th. One month after the intervention, 87/105 infants in the NA-plus-ONS group (82.8%) and 52/65 infants in the NA-only group (80%) were no longer WF. After 3 months, infants in the NA-plus-ONS group achieved greater weight gain than infants in the NA group (264.1 g vs. 137.4 g, p < 0.001) as well as greater length gain (2.35 cm vs. 2.14 cm, p < 0.001). WF management should be started at below P15th to achieve a better result. Infants with greater nutritional deficits should be assigned to receive the combination of NA plus ONSs to achieve a higher rate of resolution of growth.

Physical activity, sedentary behaviour, and childhood asthma: a European collaborative analysis.

OBJECTIVES: To investigate the associations of physical activity (PA) and sedentary behaviour in early childhood with asthma and reduced lung function in later childhood within a large collaborative study. DESIGN: Pooling of longitudinal data from collaborating birth cohorts using meta-analysis of separate cohort-specific estimates and analysis of individual participant data of all cohorts combined. SETTING: Children aged 0-18 years from 26 European birth cohorts. PARTICIPANTS: 136 071 individual children from 26 cohorts, with information on PA and/or sedentary behaviour in early childhood and asthma assessment in later childhood. MAIN OUTCOME MEASURE: Questionnaire-based current asthma and lung function measured by spirometry (forced expiratory volume in 1 s (FEV1), FEV1/forced vital capacity) at age 6-18 years. RESULTS: Questionnaire-based and accelerometry-based PA and sedentary behaviour at age 3-5 years was not associated with asthma at age 6-18 years (PA in hours/day adjusted OR 1.01, 95% CI 0.98 to 1.04; sedentary behaviour in hours/day adjusted OR 1.03, 95% CI 0.99 to 1.07). PA was not associated with lung function at any age. Analyses of sedentary behaviour and lung function showed inconsistent results. CONCLUSIONS: Reduced PA and increased sedentary behaviour before 6 years of age were not associated with the presence of asthma later in childhood.

European paediatricians need to be more aware of the risks faced by children who swallow button batteries and how to treat them.

AIM: The aim of this study was to assess how aware European paediatricians were of the risks faced by children who swallowed button batteries and the advice for managing such cases. METHODS: An Internet-based survey was conducted among European paediatricians between 1 April 2023 and 31 May 2023. The researchers contacted members of the European Academy of Paediatrics Research in Ambulatory Setting Network and a number of European national paediatric societies. RESULTS: Responses were received from 605 paediatricians (66.0% females) in 41 countries and 64.5% had encountered cases of button battery ingestion. Only 31.2% had received specific training and only 35.7% were familiar with the advice issued by the European Society for Paediatric Gastroenterology, Hepatology and Nutrition and the European Academy of Pediatrics. While 90.8% of respondents correctly recognised the need for hospitalisation of a child after button battery ingestion, only 30.1% of them identified all symptoms and 58.2% could accurately determine the appropriate diagnostic scope. One in ten underestimated the health or life risks. These deficiencies were significantly attributed to a lack of adequate training (p < 0.01). The overwhelming majority of the respondents expressed the need to increase awareness among physicians and childcare providers, mainly through social media campaigns and advertisements. CONCLUSION: European paediatricians were insufficiently aware of button battery ingestion risks and management, with significant gaps in training and familiarity with advice. Respective education for medical practitioners and raising public awareness should be markedly strengthened.

Metabolomic profiling of upper GI malignancies in blood and tissue: a systematic review and meta-analysis.

OBJECTIVE: To conduct a systematic review and meta-analysis of case-control and cohort human studies evaluating metabolite markers identified using high-throughput metabolomics techniques on esophageal cancer (EC), cancer of the gastroesophageal junction (GEJ), and gastric cancer (GC) in blood and tissue. BACKGROUND: Upper gastrointestinal cancers (UGC), predominantly EC, GEJ, and GC, are malignant tumour types with high morbidity and mortality rates. Numerous studies have focused on metabolomic profiling of UGC in recent years. In this systematic review and meta-analysis, we have provided a collective summary of previous findings on metabolites and metabolomic profiling associated with EC, GEJ and GC. METHODS: Following the PRISMA procedure, a systematic search of four databases (Embase, PubMed, MEDLINE, and Web of Science) for molecular epidemiologic studies on the metabolomic profiles of EC, GEJ and GC was conducted and registered at PROSPERO (CRD42023486631). The Newcastle-Ottawa Scale (NOS) was used to benchmark the risk of bias for case-controlled and cohort studies. QUADOMICS, an adaptation of the QUADAS-2 (Quality Assessment of Diagnostic Accuracy) tool, was used to rate diagnostic accuracy studies. Original articles comparing metabolite patterns between patients with and without UGC were included. Two investigators independently completed title and abstract screening, data extraction, and quality evaluation. Meta-analysis was conducted whenever possible. We used a random effects model to investigate the association between metabolite levels and UGC. RESULTS: A total of 66 original studies involving 7267 patients that met the required criteria were included for review. 169 metabolites were differentially distributed in patients with UGC compared to healthy patients among 44 GC, 9 GEJ, and 25 EC studies including metabolites involved in glycolysis, anaerobic respiration, tricarboxylic acid cycle, and lipid metabolism. Phosphatidylcholines, eicosanoids, and adenosine triphosphate were among the most frequently reported lipids and metabolites of cellular respiration, while BCAA, lysine, and asparagine were among the most commonly reported amino acids. Previously identified lipid metabolites included saturated and unsaturated free fatty acids and ketones. However, the key findings across studies have been inconsistent, possibly due to limited sample sizes and the majority being hospital-based case-control analyses lacking an independent replication group. CONCLUSION: Thus far, metabolomic studies have provided new opportunities for screening, etiological factors, and biomarkers for UGC, supporting the potential of applying metabolomic profiling in early cancer diagnosis. According to the results of our meta-analysis especially BCAA and TMAO as well as certain phosphatidylcholines should be implicated into the diagnostic procedure of patients with UGC. We envision that metabolomics will significantly enhance our understanding of the carcinogenesis and progression process of UGC and may eventually facilitate precise oncological and patient-tailored management of UGC.

EAP and ECPCP urge ban on novel nicotine- (NNCPS) and non-nicotine-containing products (NNDS) to youth.

AIM: We want to verify the correlation between the increasing use of novel nicotine-containing products (NNCPs) and non-nicotine delivery products (NNDPs) among young individuals and the escalating negative health consequences, necessitating their prohibition. METHODS: We performed a comprehensive analysis of the most relevant literature about the utilisation of NNCPs and NNDPs among young individuals and their health effects. RESULTS: Despite being initially seen as less harmful alternatives, for smokers aiming to quit, these products have become more popular due to misleading marketing claims. Teenagers using NNCPs and NNDPs, despite having no smoking history, are more likely to transition to tobacco smoking. Consistent use can lead to health issues like pulmonary damage, asthma, and cardiovascular and ocular problems. CONCLUSION: The EAP and the ECPCP endorse the WHO's appeal to outlaw these hazardous products. They urge European governments to forbid the sale of NNCPs and NNDPs to children and adolescents in order to safeguard their well-being. They also propose specific recommendations (box 4) to support this cause.

Correction: Suitability and safety of L-5-methyltetrahydrofolate as a folate source in infant formula: A randomized-controlled trial.

[This corrects the article DOI: 10.1371/journal.pone.0216790.].

Associations of childhood BMI, general and visceral fat mass with metabolite profiles at school-age.

BACKGROUND: Childhood obesity increases metabolic disease risk. Underlying mechanisms remain unknown. We examined associations of body mass index (BMI), total body fat mass, and visceral fat mass with serum metabolites at school-age, and explored whether identified metabolites improved the identification of children at risk of a metabolically unhealthy phenotype. METHODS: We performed a cross-sectional analysis among 497 children with a mean age of 9.8 (95% range 9.1, 10.6) years, participating in a population-based cohort study. We measured BMI, total body fat mass using DXA, and visceral fat mass using MRI. Serum concentrations of amino-acids, non-esterified-fatty-acids, phospholipids, and carnitines were determined using LC-MS/MS. Children were categorized as metabolically healthy or metabolically unhealthy, according to BMI, blood pressure, lipids, glucose, and insulin levels. RESULTS: Higher BMI and total body fat mass were associated with altered concentrations of branched-chain amino-acids, essential amino-acids, and free carnitines. Higher BMI was also associated with higher concentrations of aromatic amino-acids and alkyl-lysophosphatidylcholines (FDR-corrected p-values < 0.05). The strongest associations were present for Lyso.PC.a.C14.0 and SM.a.C32.2 (FDR-corrected p-values < 0.01). Higher visceral fat mass was only associated with higher concentrations of 6 individual metabolites, particularly Lyso.PC.a.C14.0, PC.aa.C32.1, and SM.a.C32.2. We selected 15 metabolites that improved the prediction of a metabolically unhealthy phenotype, compared to BMI only (AUC: BMI: 0.59 [95% CI 0.47,0.71], BMI + Metabolites: 0.91 [95% CI 0.85,0.97]). CONCLUSIONS: An adverse childhood body fat profile, characterized by higher BMI and total body fat mass, is associated with metabolic alterations, particularly in amino acids, phospholipids, and carnitines. Fewer associations were present for visceral fat mass. We identified a metabolite profile that improved the identification of impaired cardiometabolic health in children, compared to BMI only.

Evaluation of ImpENSA technology-enabled behaviour change module delivered to healthcare professionals in South Africa to improve micronutrient nutrition during the first 1000 days.

Healthcare professionals (HCPs) have vital roles in providing evidence-based care to promote healthy micronutrient nutrition in early life. Providing such care requires scalable training to strengthen knowledge and confident application of effective behaviour change skills. Among 33 public and private HCPs (primarily dietitians) in South Africa, we evaluated the behaviour change aspects of a technology-enabled National Qualification Sub-Framework level 6 programme, Improving Early Nutrition and Health in South Africa ('ImpENSA'). This programme comprises two self-directed micronutrient and behaviour change knowledge-based eLearning and one facilitated online practical skills modules to improve maternal and infant micronutrient nutrition. Using assessments, questionnaires and interviews, we collected data at baseline, after module completion and at 3-month follow-up after programme completion. Questionnaire and interview data showed major improvements in understanding of and attitudes towards person-centred behaviour change support immediately following the eLearning module on behaviour change. The assessment pass rate increased from 38% at baseline to 88% postmodule, demonstrating significant knowledge gain in behaviour change support. Intention to change practice towards a person-centred approach was high and many had already started implementing changes. Three months postprogramme, support was centred around patients' needs. Open relationships with patients, improved patient outcomes and increased job satisfaction were among reported outcomes. Many reported becoming better change facilitators and reflective practitioners. Additional improvements in understanding and attitudes to behaviour change support were evident, reinforced by making changes and experiencing positive outcomes. The findings suggest that technology-enabled learning can equip HCPs with knowledge and skills to effectively support behaviour change for healthy micronutrient nutrition during pregnancy and infancy.

Longitudinal associations between food parenting practices and dietary intake in preschool children: The ToyBox Study.

INTRODUCTION: Food Parenting Practices (FPPs) include the practices parents use in the act of feeding their children, which may further influence their health. OBJECTIVES: To assess associations between changes in FPPs (permissiveness, food availability, guided choices, water encouragement, rules and limits and the use of food as reward) over 1 year and dietary intake (water, energy-dense/nutrient-poor and nutrient-dense foods) at follow-up in 4- to 6-year-old preschool-aged children. METHODS: Longitudinal data from the control group of the ToyBox study, a cluster-randomized controlled intervention study, was used (NCT02116296). Multilevel ordinal logistic regression analyses including FPP as the independent variables and dietary intake as outcome. RESULTS: Nine hundred sixty-four parent-child dyads (50.5% boys and 95.0% mothers) were included. Limited changes on the use of FPPs were observed over time. Nevertheless, in boys, often having F&V at home was associated with higher F&V consumption (OR = 6.92 [1.58; 30.38]), and increasing home availability of F&V was directly associated with higher water consumption (OR = 7.62 [1.63; 35.62]). Also, not having sweets or salty snacks available at home was associated with lower consumption of desserts (OR = 4.34 [1.75; 10.75]). In girls, having F&V availability was associated with higher F&V consumption (OR = 6.72 [1.52; 29.70]) and lower salty snack consumption (OR = 3.26 [1.50; 7.10]) and never having soft drinks at home was associated with lower consumption of sweets (OR = 7.89 [6.32; 9.86]). Also, never being permissive about soft drink consumption was associated with lower soft drink consumption (OR = 4.09 [2.44; 6.85]). CONCLUSION: Using favorable FPPs and avoiding the negative ones is prospectively associated with healthier dietary intake, especially of F&V, and less intake of soft drinks, desserts, and salty snacks.

Plasma Sphingomyelins and Carnitine Esters of Infants Consuming Whole Goat or Cow Milk-Based Infant Formulas or Human Milk.

BACKGROUND: Infant formulas are typically manufactured using skimmed milk, whey proteins, and vegetable oils, which excludes milk fat globule membranes (MFGM). MFGM contains polar lipids, including sphingomyelin (SM). OBJECTIVE: The objective of this study was comparison of infant plasma SM and acylcarnitine species between infants who are breastfed or receiving infant formulas with different fat sources. METHODS: In this explorative study, we focused on SM and acylcarnitine species concentrations measured in plasma samples from the TIGGA study (ACTRN12608000047392), where infants were randomly assigned to receive either a cow milk-based infant formula (CIF) with vegetable oils only or a goat milk-based infant formula (GIF) with a goat milk fat (including MFGM) and vegetable oil mixture to the age ≥4 mo. Breastfed infants were followed as a reference group. Using tandem mass spectrometry, SM species in the study formulas and SM and acylcarnitine species in plasma samples collected at the age of 4 mo were analyzed. RESULTS: Total SM concentrations (∼42 µmol/L) and patterns of SM species were similar in both formulas. The total plasma SM concentrations were not different between the formula groups but were 15 % (CIF) and 21% (GIF) lower in the formula groups than in the breastfed group. Between the formula groups, differences in SM species were statistically significant but small. Total carnitine and major (acyl) carnitine species were not different between the groups. CONCLUSIONS: The higher total SM concentration in breastfed than in formula-fed infants might be related to a higher SM content in human milk, differences in cholesterol metabolism, dietary fatty acid intake, or other factors not yet identified. SM and acylcarnitine species composition in plasma is not closely related to the formula fatty acid composition. This trial was registered at Australian New Zealand Clinical Trials Registry as ACTRN12608000047392.

Maternal and Offspring Fatty Acid Desaturase Variants, Prenatal DHA Supplementation, and Dietary n-6:n-3 Fatty Acid Ratio in Relation to Cardiometabolic Health in Mexican Children.

BACKGROUND: Single-nucleotide polymorphisms (SNPs) in fatty acid desaturase (FADS) genes may modify dietary fatty acid requirements and influence cardiometabolic health (CMH). OBJECTIVES: We evaluated the role of selected variants in maternal and offspring FADS genes on offspring CMH at the age of 11 y and assessed interactions of genotype with diet quality and prenatal docosahexaenoic acid (DHA) supplementation. METHODS: We used data from offspring (n = 203) born to females who participated in a randomized controlled trial of DHA supplementation (400 mg/d) from midgestation to delivery. We generated a metabolic syndrome (MetS) score from body mass index, high-density lipoprotein cholesterol, triglycerides, systolic blood pressure, and fasting glucose and identified 6 distinct haplotypes from 5 offspring FADS SNPs. Dietary n-6 (ω-6):n-3 fatty acid ratios were derived from 24-h recall data (n = 141). We used generalized linear models to test associations of offspring diet and FADS haplotypes with MetS score and interactions of maternal and offspring FADS SNP rs174602 with prenatal treatment group and dietary n-6:n-3 ratio on MetS score. RESULTS: Associations between FADS haplotypes and MetS score were null. Offspring SNP rs174602 did not modify the association of prenatal DHA supplementation with MetS score. Among children with TT or TC genotype for SNP rs174602 (n = 88), those in the highest n-6:n-3 ratio tertile (>8.61) had higher MetS score relative to the lowest tertile [<6.67) (Δ= 0.36; 95% confidence interval (CI): 0.03, 0.69]. Among children with CC genotype (n = 53), those in the highest n-6:n-3 ratio tertile had a lower MetS score relative to the lowest tertile (Δ= -0.23; 95% CI: -0.61, 0.16). CONCLUSIONS: There was evidence of an interaction of offspring FADS SNP rs174602 with current dietary polyunsaturated fatty acid intake, but not with prenatal DHA supplementation, on MetS score. Further studies may help to determine the utility of targeted supplementation strategies and dietary recommendations based on genetic profile.

European Training Requirements in Neonatology 2021: The ESPR, EAP, and UEMS Accredited European Syllabus for Neonatal Training.

INTRODUCTION: The European Union stipulates transnational recognition of professional qualifications for several sectoral professions, including medical doctors. The Union of European Medical Specialists (UEMS), in its "Charter on Training of Medical Specialists," defines the principles for high-level medical training. These principles are manifested in the framework for European Training Requirements (ETR), ensuring medical training reflects modern medical practice and current scientific findings. In 1998, the European Society for Paediatric Research developed the first ETR for Neonatology. We present the ETR Neonatology in its third iteration (ETR III), ratified by the European Academy of Paediatrics (EAP), and approved by UEMS in 2021. METHODS: In generating the ETR III, existing European policy documents on training requirements, including national syllabi and the European Standards of Care for Newborn Health were considered. To ensure the ETR III meets a pan-European standard of expertise in Neonatology, input from representatives from 27 European national paediatric/neonatal societies, and a European parent organisation, was sought. RESULTS: The ETR III summarises the requirements of contemporary training programs in Neonatology and offers a system for accrediting trainers and training centres. We describe the content of the ETR III training syllabus and means of gaining and assessing competency as a medical care provider in Neonatology. CONCLUSION: Graduates of courses following the ETR III Neonatology will obtain a certificate of satisfactory training completion which should be accepted by all European member states as a baseline qualification to practice as a specialist in neonatal medicine, enabling mutual recognition of status throughout Europe.