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Rationale: Natural variations in the abundance of the stable isotopes of nitrogen (δ 15 N) and carbon (δ 13 C) offer valuable insights into metabolic fluxes. In the wake of strong interest in cancer metabolism, recent research has revealed δ 15 N and δ 13 C variations in cancerous compared to non-cancerous tissues and cell lines. However, our understanding of natural isotopic variations in cultured mammalian cells, particularly in relation to metabolism, remains limited. This study aims to start addressing this gap using metabolic modulations in cells cultured under controlled conditions., Methods: Prostate cancer cells (PC3) were cultured in different conditions and their δ 15 N and δ 13 C were measured using isotope ratio mass spectrometry. Isotopic variations during successive cell culture passages were assessed and two widely used cell culture media (RPMI and DMEM) were compared. Metabolism was modulated through glutamine deprivation and hypoxia., Results: Successive cell culture passages generally resulted in reproducible δ 15 N and δ 13 C values. The impact of culture medium composition on δ 15 N and δ 13 C of the cells highlights the importance of maintaining a consistent medium composition across conditions whenever possible. Glutamine deprivation and hypoxia induced a lower δ 13 C in bulk cell samples, with only the former affecting δ 15 N. Gaps between theory and experiments were bridged and the lessons learned throughout the process are provided., Conclusions: Exposing cultured cancer cells to hypoxia allowed us to further investigate the relation between metabolic modulations and natural isotopic variations, while mitigating the confounding impact of changing culture medium composition. This study highlights the potential of natural δ 13 C variations for studying substrate fluxes and nutrient allocation in reproducible culture conditions. Considering cell yield and culture medium composition is pivotal to the success of this approach., (© 2024 The Author(s). Rapid Communications in Mass Spectrometry published by John Wiley & Sons Ltd.)

The aim of our study was to assess the nutritional status of hospitalized children with cystic fibrosis. We extracted data from the ePINUT surveys. Undernutrition was defined as a body mass index (BMI) of <18.5 according to the International Obesity Task Force cut-off, and the nutritional status goal was defined as a BMI z-score ≥0 SD for children older than 2 years and a weight-for-height z-score ≥0 SD for those younger than 2 years. Undernutrition frequency in the 114 patients with cystic fibrosis was 46% and was higher than in children with other chronic diseases (n = 5863; 30.5%; p = 0.001); 81% of children were below the nutritional status goal. Undernutrition frequency in cystic fibrosis is higher than in other chronic diseases., Competing Interests: Declaration of Competing Interest R.H and A.DL. declare research support from Nutricia, Advanced Medical Nutrition (logistics of the surveys). L.V. and V.R declare that they have no competing interest., (Copyright © 2023 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.)

Setting-up a high quality, compliant and efficient pharmacovigilance (PV) system in multi-country clinical trials can be more challenging for academic sponsors than for companies. To ensure the safety of all participants in academic studies and that the PV system fulfils all regulations, we set up a centralized PV system that allows sponsors to delegate work on PV. This initiative was put in practice by our Inserm-ANRS MIE PV department in two distinct multinational European consortia with 19 participating countries: conect4children (c4c) for paediatrics research and EU-Response for Covid-19 platform trials. The centralized PV system consists of some key procedures to harmonize the complex safety processes, creation of a local safety officer (LSO) network and centralization of all safety activities. The key procedures described the safety management plan for each trial and how tasks were shared and delegated between all stakeholders. Processing of serious adverse events (SAEs) in a unique database guaranteed the full control of the safety data and continuous evaluation of the risk-benefit ratio. The LSO network participated in efficient regulatory compliance across multiple countries. In total, there were 1312 SAEs in EU-Response and 83 SAEs in c4c in the four trials. We present here the lessons learnt from our experience in four clinical trials. We managed heterogeneous European local requirements and implemented efficient communication with all trial teams. Our approach builds capacity for PV that can be used by multiple academic sponsors., (© 2023 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: Animal studies have demonstrated that fetal exposure to high maternal cholesterol levels during pregnancy predisposes to aortic atheroma in the offspring. In humans, little is known about the consequences of this exposure on the development of atherosclerotic cardiovascular disease later in life. We wanted to assess whether maternal/paternal inheritance of familial hypercholesterolemia (FH) gene mutation could be associated with subclinical coronary atherosclerosis., Methods: We retrospectively included 1350 patients, followed in the French registry of FH, with a documented genetic diagnosis. We selected 556 age- and sex-matched pair of patients based on the sex of the parents who transmitted the FH gene mutation, free of coronary cardiovascular event, and with a subclinical coronary atherosclerosis evaluation assessed using coronary artery calcium (CAC) score. We performed univariate and multivariate analysis to assess the individual effect of parental inheritance of the FH gene mutation on the CAC score., Results: In the whole population, patients with maternal inheritance of FH gene mutation (n=639) less frequently had a family history of premature cardiovascular events (27.7% versus 45%, P <0.0001) and were 2 years older (46.9±16.8 versus 44.7±15.9 years old, P =0.02) than those with paternal inheritance (n=711). There was no difference in the prevalence of cardiovascular events between the two groups. In the matched subgroup, maternal inheritance was significantly associated with an increase in CAC score value by 86% (95% CI, 23%-170%; P =0.003), a 1.81-fold risk of having a CAC score ≥100 Agatston units (95% CI, 1.06-3.11; P =0.03), and a 2.72-fold risk of having a CAC score ≥400 Agatston units (95% CI, 1.39-5.51; P =0.004) when compared with paternal inheritance in multivariate analysis., Conclusions: Maternal inheritance of FH gene mutation was associated with more severe subclinical coronary atherosclerosis assessed by CAC score and may be considered as a potential cardiovascular risk factor.

In 2019, the French National Authority for Health (Haute Autorité de Santé, HAS) published guidelines on the diagnosis of undernutrition. The present article focuses on the impact of switching from the 2012 guidelines of the Nutrition Committee of the French Paediatric Society (CNSFP) to the HAS guidelines on the frequency of hospital undernutrition in children. We selected for the period 2010-2019 from the ePINUT database: (1) all children aged more than 2 years with (2) clinically confirmed nutritional status in (3) French sites. The frequency of undernutrition was 15.4% vs. 28.8% using the CNSFP and HAS criteria, respectively (p < 0.01; n = 6304). When compared to non-malnourished children regardless of the criteria used, malnourished children: (1) stayed longer in hospital (CNSFP: 9.0 ± 11.8 vs. 6.5 ± 8.7 days, p < 0.01; HAS: 7.8 ± 10.1 vs. 6.4 ± 8.4 days, p < 0.01), (2) gained more weight during hospitalization (% of weight at admission) (CNSFP: +1.4 ± 4.1 vs. -0.3 ± 3.5%, p < 0.01; HAS: +2.3 ± 4.7 vs. -0.1 ± 3.4%, p < 0.01), and (3) received nutritional support more frequently during hospitalization (CNSFP: 20% vs. 5%, p < 0.01; HAS: 13% vs. 4%, p < 0.01). Switching to the HAS guidelines resulted in an almost twofold higher frequency of undernutrition in hospitalized children. Initiation of nutritional care remained low considering the nutritional status. The present study warrants interventional studies to determine which children may benefit more from nutritional therapy to improve their outcome., (Copyright © 2022 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.)

Despite various international regulatory initiatives over the last 20 years, many challenges remain in the field of paediatric drug development and evaluation. Indeed, drug research and development is still focused essentially on adult indications, thereby excluding many paediatric patients, limiting the feasibility of trials and favouring competing developments. Off-label prescribing persists and the development of age-appropriate dosage forms for children remains limited. Against this background, the members of this panel (TR) recommend the launch of multi-partner exchange forums on specific topics in order to focus new drug research and development on the real, unmet medical needs of children and adolescents, and in keeping with the underlying mechanisms of action. Scientific information sharing and cooperation between stakeholders are also essential for defining reference evaluation methods in each medical field. These forums can be organised through existing paediatric facilities and research networks at the French and European level. The latter are specifically dedicated to paediatric research and can facilitate clinical trial implementation and patient enrolment. Moreover, specific grants and public/private partnerships are still needed to support studies on the repositioning of drugs in paediatric indications, and pharmacokinetic studies aimed at defining appropriate dosages. The development of new pharmaceutical forms, better suited for paediatric use, and the promotion of resulting innovations will stimulate future investments. Initiatives to gather observational safety and efficacy data following off-label and/or derogatory early access should also be encouraged to compensate for the lack of information available in these situations. Finally, the creation of Ethics Committees (EC) with a specific "mother-child" advisory expertise should be promoted to ensure that the current regulation (Jardé law in France) is implemented whilst also taking into account the paediatric specificities in medical trials., (Copyright © 2022. Published by Elsevier Masson SAS.)

While clinical evidence remains limited, an extensive amount of research suggests a beneficial role of n-3 polyunsaturated fatty acid supplementation in cancer treatment. One potential benefit is an improvement of protein homeostasis, but how protein metabolism depends on proinflammatory cytokines in this context remains unclear. Here, using the natural abundance of the stable isotopes of nitrogen as a marker of changes in protein metabolism during a randomized, double-blind, controlled clinical trial, we show that protein homeostasis is affected way faster than proinflammatory cytokines in metastatic breast cancer patients supplemented with n-3 polyunsaturated fatty acids. We provide some evidence that this response is unrelated to major changes in whole-body substrate oxidation. In addition, we demonstrate that more fatty acids were impacted by metabolic regulations than by differences in their intake levels during the supplementation. This study documents that the percentage of patients that complied with the supplementation decreased with time, making compliance assessment crucial for the kinetic analysis of the metabolic and inflammatory responses. Our results highlight the time-dependent nature of metabolic and inflammatory changes during long-chain n-3 fatty acid supplementation.

We have previously advocated that nutritional care be raised to the level of a human right, in close relationship to two well-recognized fundamental rights: the right to food and the right to health. This article aims to analyze the implication of nutritional care as a human right for healthcare practitioners. We will focus on the impact of the Human Rights Basic Approach (HRBA) on healthcare professionals (HCPs), namely how they can translate HRBA into routine clinical practice. Ethics and human rights are guiding values for clinical nutrition practitioners. Together they ensure a patient-centered approach, in which the needs and rights of the patients are of the most significant importance. Human rights are based on the powerful idea of equal dignity for all people while expressing a set of core values, including fairness, respect, equality, dignity, and autonomy (FREDA). Through the analysis of FREDA principles, we have provided the elements to understand human rights and how an HRBA can support clinicians in the decision-making process. Clinical practice guidelines in clinical nutrition should incorporate disease-specific ethical issues and the HRBA. The HRBA should contribute to building conditions for HCPs to provide optimal and timely nutritional care. Nutritional care must be exercised by HCPs with due respect for several fundamental ethical values: attentiveness, responsibility competence, responsiveness, and solidarity., (© 2022 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism and American Society for Parenteral and Enteral Nutrition [Published by Wiley]. All rights reserved.)

Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent chronic liver disease that occurs mostly in the context of insulin resistance and obesity. It has rapidly evolved into the most common cause of liver disease among children. The incidence is high in obese children and a greater risk of disease progression is associated with severe obesity, highlighting the role of nutrition. To date, there is no consensus on NAFLD management. This is a narrative review of clinical studies on the potential benefit of nutritional interventions, including lifestyle modifications, vitamins, docosahexaenoic acid, and probiotics in children with NAFLD. The Comité de nutrition de la Société Française de Pédiatrie (CN-SFP) emphasizes the effect of limiting added sugar intake, i.e., fructose or sucrose-containing beverages, and promoting physical activity in the care of NAFLD., Competing Interests: Conflicts of interests The author and co-authors have no conflicts of interest to declare, (Copyright © 2021. Published by Elsevier Masson SAS.)

Objective: To capture the early effects of the coronavirus disease 2019 (COVID-19) pandemic on pediatric clinical research., Study Design: Pediatric clinical research networks from 20 countries and 50 of their affiliated research sites completed two surveys over one month from early May to early June 2020. Networks liaised with their affiliated sites and contributed to the interpretation of results through pan-European group discussions. Based on first detection dates of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), countries formed 1 early detecting and 1 late detecting cluster. We tested the hypothesis that this clustering influenced clinical research., Results: Research sites were first impacted by the pandemic in mid-March 2020 (March 16 ± 10 days, the same date as lockdown initiation; P = .99). From first impact up until early June, site initiation and feasibility analysis processes were affected for >50% of the sites. Staff were redirected to COVID-19 research for 44% of the sites, and 75.5% of sites were involved in pediatric COVID-19 research (only 6.3% reported COVID-19 cases in their other pediatric trials). Mitigation strategies were used differently between the early and late detecting country clusters and between countries with and without a pediatric COVID-19 research taskforce. Positive effects include the development of teleworking capacities., Conclusions: Through this collaborative effort from pediatric research networks, we found that pediatric trials were affected and conducted with a range of unequally applied mitigations across countries during the pandemic. The global impact might be greater than captured. In a context where clinical research is increasingly multinational, this report reveals the importance of collaboration between national networks., (Copyright © 2021 Elsevier Inc. All rights reserved.)