Bi-allelic genetic variants in the translational GTPases GTPBP1 and GTPBP2 cause a distinct identical neurodevelopmental syndrome.

The homologous genes GTPBP1 and GTPBP2 encode GTP-binding proteins 1 and 2, which are involved in ribosomal homeostasis. Pathogenic variants in GTPBP2 were recently shown to be an ultra-rare cause of neurodegenerative or neurodevelopmental disorders (NDDs). Until now, no human phenotype has been linked to GTPBP1. Here, we describe individuals carrying bi-allelic GTPBP1 variants that display an identical phenotype with GTPBP2 and characterize the overall spectrum of GTP-binding protein (1/2)-related disorders. In this study, 20 individuals from 16 families with distinct NDDs and syndromic facial features were investigated by whole-exome (WES) or whole-genome (WGS) sequencing. To assess the functional impact of the identified genetic variants, semi-quantitative PCR, western blot, and ribosome profiling assays were performed in fibroblasts from affected individuals. We also investigated the effect of reducing expression of CG2017, an ortholog of human GTPBP1/2, in the fruit fly Drosophila melanogaster. Individuals with bi-allelic GTPBP1 or GTPBP2 variants presented with microcephaly, profound neurodevelopmental impairment, pathognomonic craniofacial features, and ectodermal defects. Abnormal vision and/or hearing, progressive spasticity, choreoathetoid movements, refractory epilepsy, and brain atrophy were part of the core phenotype of this syndrome. Cell line studies identified a loss-of-function (LoF) impact of the disease-associated variants but no significant abnormalities on ribosome profiling. Reduced expression of CG2017 isoforms was associated with locomotor impairment in Drosophila. In conclusion, bi-allelic GTPBP1 and GTPBP2 LoF variants cause an identical, distinct neurodevelopmental syndrome. Mutant CG2017 knockout flies display motor impairment, highlighting the conserved role for GTP-binding proteins in CNS development across species.

A systematic review and meta-analysis on nutritional and dietary interventions for the treatment of acute respiratory infection in pediatric patients: An EAACI taskforce.

Acute respiratory infections are a major cause of morbidity and mortality in children worldwide. Dietary and nutritional interventions, including minerals and vitamin supplementation, have been explored as potential treatments for these infections. However, the evidence on their efficacy is limited and inconclusive. This systematic review and meta-analysis aim to provide a comprehensive summary of the available evidence on the effectiveness of dietary and nutritional interventions for treating acute respiratory tract infections in children. A systematic review was conducted according to the PRISMA 2020 guidelines in April 2022 and updated in April 2023. Clinical trials focusing on dietary or nutritional interventions, including supplementations, in children with acute respiratory tract infections were included. The selection of interventions and outcomes was based on biological plausibility. Data were extracted using a standardized form, and the risk of bias was assessed using the Cochrane Risk of Bias Tool. Meta-analysis was performed using random-effect models. A total of 50 studies were included in the review. Four trials were conducted in low, 32 in lower-middle, 12 in upper-middle, and only two in high-income countries. The studies evaluated various dietary interventions, including zinc, vitamin A, vitamin E, vitamin D, and probiotics. The results of individual studies on the efficacy of these interventions were mixed, with some showing positive effects on clinical outcomes such as duration of symptoms, while others showed no significant impact. Meta-analysis was conducted for zinc supplementation in children with pneumonia, and the pooled results suggested a potential limited benefit in terms of reduced hospital length of stay but not time to recovery. Meta-analyses on vitamin D did not show any effect in children with pneumonia. This systematic review fills a critical gap in the literature by synthesizing the available evidence on the efficacy and safety of nutritional or dietary interventions for acute respiratory tract infections in children. The findings indicate no dietary or nutritional intervention can currently be recommended for the routine treatment of respiratory tract infections in children based on single supplement studies. The metanalysis suggests that zinc supplementation might have a beneficial effect on length of hospitalization in children with pneumonia. New studies are needed to establish more conclusive evidence for pediatric acute respiratory diseases especially for children living in a context of high-income countries.

A systematic review and meta-analysis of nutritional and dietary interventions in randomized controlled trials for skin symptoms in children with atopic dermatitis and without food allergy: An EAACI task force report.

This systematic review and meta-analysis aimed to consolidate evidence on dietary interventions for atopic eczema/dermatitis (AD) skin symptoms in children without food allergies, following PRISMA 2020 guidelines. Systematic review updates were conducted in May 2022 and June 2023, focusing on randomized placebo-controlled trials (RCTs) involving children with AD but without food allergies. Specific diets or supplements, such as vitamins, minerals, probiotics, prebiotics, symbiotics, or postbiotics, were explored in these trials. Exclusions comprised descriptive studies, systematic reviews, meta-analyses, letters, case reports, studies involving elimination diets, and those reporting on food allergens in children and adolescents. Additionally, studies assessing exacerbation of AD due to food allergy/sensitization and those evaluating elimination diets' effects on AD were excluded. Nutritional supplementation studies were eligible regardless of sensitization profile. Evaluation of their impact on AD clinical expression was performed using SCORAD scores, and a meta-analysis of SCORAD outcomes was conducted using random-effect models (CRD42022328702). The review encompassed 27 RCTs examining prebiotics, Vitamin D, evening primrose oil, and substituting cow's milk formula with partially hydrolyzed whey milk formula. A meta-analysis of 20 RCTs assessing probiotics, alone or combined with prebiotics, revealed a significant reduction in SCORAD scores, suggesting a consistent trend in alleviating AD symptoms in children without food allergies. Nonetheless, evidence for other dietary interventions remains limited, underscoring the necessity for well-designed intervention studies targeting multiple factors to understand etiological interactions and propose reliable manipulation strategies.

Malnutrition management in children with chronic kidney disease.

Chronic kidney disease (CKD) encompasses diverse conditions such as congenital anomalies, glomerulonephritis, and hereditary nephropathies, necessitating individualized nutritional interventions. Early detection is pivotal due to the heightened risk of adverse outcomes, including compromised growth and increased healthcare costs. The nutritional assessment in pediatric CKD employs a comprehensive, multidisciplinary approach, considering disease-specific factors, growth metrics, and dietary habits. The prevalence of malnutrition, as identified through diverse tools and guidelines, underscores the necessity for regular and vigilant monitoring. Nutritional management strategies seek equilibrium in calorie intake, protein requirements, and electrolyte considerations. Maintaining a well-balanced nutritional intake is crucial for preventing systemic complications and preserving the remaining kidney function. The nuanced landscape of enteral nutrition, inclusive of gastrostomy placement, warrants consideration in scenarios requiring prolonged support, with an emphasis on minimizing risks for optimized outcomes. In conclusion, the ongoing challenge of managing nutrition in pediatric CKD necessitates continuous assessment and adaptation. This review underscores the significance of tailored dietary approaches, not only to foster growth and prevent complications but also to enhance the overall quality of life for children grappling with CKD.

Over-the-scope clip for closure of persistent gastrocutaneous fistula after gastrostomy tube removal: a multicenter pediatric experience.

BACKGROUND: Percutaneous endoscopic gastrostomy is commonly used for enteral nutritional access, but gastrocutaneous fistulae (GCF) may persist after tube removal, posing clinical challenges. The use of endoscopic closure devices, including over-the-scope clips (OTSC), has shown promise in managing non-healing fistulae, although data in the pediatric population are limited. METHODS: A retrospective multicenter study analyzed pediatric patients who underwent GCF closure following gastrostomy tube removal. Data from seven centers across multiple countries were collected, including patient demographics, procedural details, complications, and outcomes. Closure techniques were compared between OTSC and surgical closure. RESULTS: Of 67 pediatric patients included, 21 underwent OTSC closure and 46 had surgical closure. Surgical closure demonstrated a higher success rate (100%) compared to OTSC closure (61.9%, P < 0.001). While procedural duration was shorter for OTSC closure (25 vs. 40 min, P = 0.002), complications, and scar quality were comparable between techniques. A subsequent sub-analysis did not reveal differences based on center experience. CONCLUSION: OTSC closure is feasible and safe in pediatric patients, but surgical closure remains superior in achieving sustained GCF closure, although OTSC offers benefits, such as shorter procedural duration, potentially reducing the duration of general anesthesia exposure. Non-operative approaches, including OTSC, may be a valuable alternative to surgical closure.

Definition and assessment of fever-related discomfort in pediatric literature: a systematic review.

Guidelines advocate that the symptomatic management of fever should prioritize alleviating the child's discomfort. We investigated the definition and assessment of discomfort in febrile children within the scientific pediatric literature. A systematic review was conducted in accordance with PRISMA 2020 guidelines and preregistered on the Prospero database (CRD42023471590). Databases including PubMed, Embase, and Cochrane were searched. Studies addressing discomfort in febrile children were eligible. Out of 794 initially identified articles, 27 original studies and seven guidelines specifically used the term 'discomfort'. Only 14 original articles provided a definition of discomfort, revealing substantial heterogeneity and no clear-cut definition. Discomfort was often assessed subjectively, predominantly through parent or self-report, and only two studies used a scoring system for assessment. The definitions varied widely, with terms such as crying, irritability, shivering and chills, pain and distress, goosebumps commonly used and evaluation of observable modifications such as facial modifications. Overall, no consensus on a single, standardized definition was available. CONCLUSIONS: This systematic review shows the absence of a standardized definition and assessment of discomfort in febrile children. The findings of the present analysis might be the basis for building a consensus and developing a new tool to evaluate discomfort. WHAT IS KNOWN: • Discomfort is currently considered the main criterion to guide antipyretic administration in children with fever. • Despite this clear-cut recommendation, it has been questioned whether a commonly accepted understanding and assessment of this condition exists. WHAT IS NEW: • This systematic review identifies a significant heterogeneity in definitions and assessment of discomfort in children with fever. • Both subjective parameters and observable modifications in physiological parameters should be included in a new and shared characterization of discomfort.

The debate continues on the best age to stop breastfeeding.

The ongoing debate on the optimal duration of breastfeeding in high-income countries is challenging. The decision to continue breastfeeding beyond the introduction of solids according to WHO indications involves multifaceted considerations, such as nutritional needs, psychological factors and cultural influences, given the growing number of immigrants. The impact on maternal health, sleep routines and family dynamics should be carefully weighed too. CONCLUSION: Next studies should investigate associations of different modalities and periods of breastfeeding with physical and neurodevelopmental outcomes, including psychological aspects. A personalised and gradual approach is suggested, guided by informed decisions and a supportive network.

Ketogenic diet in children and adolescents: The effects on growth and nutritional status.

The ketogenic diet is known to be a possible adjuvant treatment in several medical conditions, such as in patients with severe or drug-resistant forms of epilepsy. Its use has recently been increasing among adolescents and young adults due to its supposed weight-loss effect, mediated by lipolysis and lowered insulin levels. However, there are still no precise indications on the possible use of ketogenic diets in pediatric age for weight loss. This approach has also recently been proposed for other types of disorder such as inherited metabolic disorders, Prader-Willi syndrome, and some specific types of cancers. Due to its unbalanced ratio of lipids, carbohydrates and proteins, a clinical evaluation of possible side effects with a strict evaluation of growth and nutritional status is essential in all patients following a long-term restrictive diet such as the ketogenic one. The prophylactic use of micronutrients supplementation should be considered before starting any ketogenic diet. Lastly, while there is sufficient literature on possible short-term side effects of ketogenic diets, their possible long-term impact on growth and nutritional status is not yet fully understood, especially when started in pediatric age.

Effects of vitamin D supplementation in obese and overweight children and adolescents: A systematic review and meta-analysis.

Due to the lipophilic nature of vitamin D, overweight and obese patients have an increased risk of inadequate circulating 25-hydroxy-vitamin D (25(OH)D) concentrations. Vitamin D deficiency has in turn several consequences especially among children and adolescents. Therefore, a few supplementation strategies of vitamin D for pediatric subjects with an excessive body weight have been proposed, but their efficacy remains controversial. The aim of this systematic review and meta-analysis was to evaluate the effect of vitamin D supplementation in overweight and obese children and adolescents. Three databases (PubMed, Embase and Web of Science) were searched to collect trials on the effect of vitamin D supplementation in the pediatric overweight or obese population. Twenty-three studies were included in the systematic review. Results on modification of metabolic or cardiovascular outcomes were controversial. On the other hand, the meta-analysis showed a mean difference by 1.6 ng/ml in subjects supplemented with vitamin D as compared to placebo. In conclusion, vitamin D supplementation slightly increases 25(OH)D levels in pediatric subjects with overweight and obesity. However, the effects on metabolic and cardiovascular outcomes remain controversial. New efforts should be devoted to promoting effective interventions to improve the health of children and adolescents with overweight and obesity.

Bioactive compounds in childhood obesity and associated metabolic complications: Current evidence, controversies and perspectives.

Obesity represents the most frequent chronic disease among children worldwide, with a significant global burden on society. Metabolically unhealthy obesity (MUO) can affect children since their first years of life, and novel therapeutic strategies to tackle metabolic complications are under investigation. This review focuses on bioactive compounds and their possible beneficial effects on obesity, particularly omega-3, docosahexaenoic acid, vitamin D, biotics, polysaccharide macromolecules, polyphenols, inositols, alpha lipoic acid, and bromelaine. Our aim is to summarize current evidence about bioactive compounds in the treatment of obesity, highlighting recent findings on their use in children and adolescents. Most studied molecules are omega-3 and vitamin D, despite the heterogeneity between the studies. Moreover, given the emerging interest in the gut-brain axis in the link between metabolic health and microbiota, various studies on prebiotics, probiotics, synbiotics, postbiotics and polysaccharide macromolecules have been considered. Some preclinical studies seem to highlight a possible role of the polyphenols, even if their clinical evidence is still discussed. Lastly, we describe possible effects of inositols and alpha-lipoic acid. Despite some dietary supplements seem to be promising in overweight subjects, only in a few of them a dose/response efficacy has been found in the pediatric age. Innovative, well-designed and targeted clinical trials are then needed to prove the beneficial effects of these compounds that could support the standard behavioral therapy for obesity.

Perception, knowledge and attitude towards childhood fever: A survey among final-year medical students.

AIMS: Undue concerns about the consequences of fever and its inappropriate management have been documented worldwide among physicians. However, no data exist on medical students. We investigated the perception, knowledge and attitude towards childhood fever among final-year medical students. METHODS: Between June and September 2021, final-year medical students of six Italian universities were invited to complete an online survey on their conceptions and attitude towards pharmacological and non-pharmacological management of childhood fever. History of relevant personal or second-hand experience with childhood fever was also addressed. Both quantitative and qualitative approaches were used. RESULTS: Of 1095 (69%) final-year medical students, 756 completed the survey. Many students believe that high fever might cause brain damage, would recommend physical methods and alternate two drugs for fever. Most students do not think that fever has mainly beneficial effects. In Northern Italy, students are less likely to believe that fever might lead to brain damage (OR 0.55, 95% CI 0.33-0.94), and in Southern Italy students are more likely to advise physical methods (OR 1.77, 95% CI 1.22-2.57) and less likely to believe that fever has mainly beneficial effects (OR 0.55, 95% CI 0.39-0.77). History of a relevant personal episode of fever during childhood was not associated with these outcomes. CONCLUSIONS: Misconceptions about fever are common among final-year medical students in Italy. Cultural factors rather than individually learned traits might underlie these beliefs. Medical students are a promising target for educational interventions to improve childhood fever management.

Refeeding Syndrome in Pediatric Age, An Unknown Disease: A Narrative Review.

Refeeding syndrome (RS) is characterized by electrolyte imbalances that can occur in malnourished and abruptly refed patients. Typical features of RS are hypophosphatemia, hypokalemia, hypomagnesemia, and thiamine deficiency. It is a potentially life-threatening condition that can affect both adults and children, although there is scarce evidence in the pediatric literature. The sudden increase in food intake causes a shift in the body's metabolism and electrolyte balance, leading to symptoms such as weakness, seizures, and even heart failure. A proper management with progressive increase in nutrients is essential to prevent the onset of this condition and ensure the best possible outcomes. Moreover, an estimated incidence of up to 7.4% has been observed in pediatric intensive care unit patients receiving nutritional support, alone or as an adjunct. To prevent RS, it is important to carefully monitor feeding resumption, particularly in severely malnourished individuals. A proper strategy should start with small amounts of low-calorie fluids and gradually increasing the calorie content and amount of food over several days. Close monitoring of electrolyte levels is critical and prophylactic use of dietary supplements such as thiamine may be required to correct any imbalances that may occur. In this narrative review, we aim to provide a comprehensive understanding of RS in pediatric clinical practice and provide a possible management algorithm.

Childhood fever and medical students: A multicentre, educational intervention.

AIM: Misconceptions and non-evidence-based practices toward childhood fever are reported worldwide. Medical students might be ideal candidates to introduce long-lasting changes in clinical practice. However, no study has gauged the effectiveness of an educational intervention to improve fever management in this population. We conducted an educational, interventional study on childhood fever among final-year medical students. METHODS: We conducted a prospective, multicentre interventional study employing a pre/post-test design. Participants from three Italian Universities filled in a questionnaire just before the intervention (T0), immediately after (T1) and 6 months later (T2) in 2022. The intervention was a two-hour lecture focused on the pathophysiology of fever, recommendations for its treatment and risks associated with improper management. RESULTS: 188 final-year medical students (median age of 26 years, 67% females) were enrolled. Relevant improvements in the criterion for treating fever and conceptions about the beneficial effects of fever were observed at T1 and T2. Similar data were found for the reduction of physical methods advice to decrease body temperature and concerns for brain damage from fever. CONCLUSION: This study shows for the first time that an educational intervention is effective in changing students' conceptions and attitudes toward fever both in the short and medium term.

Approach to fever in children among final-year nursing students: a multicenter survey.

BACKGROUND: Unfounded concerns regarding fever are increasingly observed among nurses worldwide. However, no study has so far explored the preferred approach towards pediatric fever among nursing students. Therefore, we aimed to investigate the attitude towards pediatric fever among final-year nursing students. METHODS: Between February and June 2022, final-year nursing students of 5 Italian university hospitals were asked to answer an online survey on their approach to fever in children. Both quantitative and qualitative methods were utilized. Multiple regression models were employed to explore the existence of moderators on fever conceptions. RESULTS: The survey was filled in by 121 nursing students (response rate 50%). Although most students (98%) do not consider discomfort to treat fever in children, only a minority would administer a second dose of the same antipyretic in nonresponsive cases (5.8%) or would alternate antipyretic drugs (13%). Most students would use physical methods to decrease fever (84%) and do not think that fever has mainly beneficial effects in children (72%). The own know-how adequacy on fever was inversely associated (OR 0.33, 95% CI 0.13-0.81) with the beliefs that high fever might lead to brain damage. No further predictive variable was significantly associated with the concern that fever might be associated with brain damage, the advice of physical methods use, and the assumption that fever has mostly positive effects. DISCUSSION: This study shows for the first time that misconceptions and inappropriate attitudes towards fever in children are common among final-year nursing students. Nursing students could potentially be ideal candidates for improving fever management within clinical practice and amongst caregivers.

Sodium assessment in neonates, infants, and children: a systematic review.

Hyponatremia is a common disorder in childhood. The indirect and the direct potentiometry are currently the most popular techniques employed for sodium assessment, although discrepancies between the two techniques may be > 10 mmol/L. It is known that < 20% of the recently published articles report information about the technique used for sodium analysis, but no data are available on pediatric studies. This study aimed at investigating the laboratory technique employed for sodium measurement in studies conducted in childhood. A systematic literature search in PubMed, Embase, and Web of Science was undertaken to identify articles containing the word "hyponatremia" in the title between 2013 and 2020. Papers with < 10 subjects were excluded. A total of 565 articles were included. Information on the laboratory technique used for sodium analysis was more commonly (p = 0.035) reported in pediatric (n = 15, 28%) than in non-pediatric (n = 81, 16%) reports. The frequency of reports with and without information on the technique for sodium assessment was not different with respect to the study characteristics, the quartile of the journal where the paper was published, the country income setting, and the inclusion of neonates among the 54 pediatric studies.   Conclusion: Most pediatric papers do not report any information on the technique used for sodium analysis. Although international authorities have recommended the implementation of direct potentiometry, a low awareness on this issue is still widespread in pediatric research. What is Known: • Direct potentiometry and indirect potentiometry are currently employed for sodium analysis in blood. • Direct potentiometry is more accurate. What is New: • Less than 30% of pediatric articles provide information on the technique employed for sodium analysis in blood. • Indirect potentiometry is more frequently employed than direct potentiometry in pediatric studies.

Sharenting: hidden pitfalls of a new increasing trend- suggestions on an appropriate use of social media.

BACKGROUND: The term "sharenting", defining the practice of sharing children's photos on social media, has become widespread globally. This phenomenon introduces new risks for children, often overlooked by parents lacking experience or caution in protecting their children from potential harms. MAIN BODY: Parents share multimedia contents with positive intentions, but the lack of immediate risk perception prevails. An Italian study revealed that a significant percentage of parents (68%) frequently share their children's photos on social platforms, often without considering potential risks. Pediatricians play a crucial role in raising awareness among parents regarding the dangers associated with online sharing and must empower families with defensive strategies to safeguard children's privacy. CONCLUSIONS: The commentary emphasizes the need for increased parental assistance in comprehending the risks of sharenting and using social media prudently. Pediatricians are pivotal in guiding parents, striking a balance between the natural urge to share children's progress and an awareness of associated risks. Immediate action by scientific societies involves training and informing parents through various digital and print resources. A concrete regulation of this phenomenon is needed to protect children's rights, but prioritizing digital awareness and education seems pivotal in mitigating sharenting-related risks.

The non-clinical burden of febrile seizures: a systematic review.

Febrile seizures (FS) can be frightening for parents, even though they are usually harmless. Various questionnaires have been used to assess parental reactions and awareness about FS, revealing insufficient knowledge. Studies have shown that educational interventions significantly reduce parental concerns, improve knowledge, and promote better first-aid measures. Providing clear information and emotional support to parents is important to reduce their concerns and improve FS management. Healthcare providers should give comprehensive information about FS, including the risk of recurrence, and provide clear instructions on their management. The economic impact of FS includes direct and indirect costs. Studies have shown a decrease of hospitalizations and associated costs due to improved clinical adherence to guidelines, which also reduces the inappropriate use of healthcare resources. This systematic review provides a comprehensive overview of the existing literature on parental anxiety and education about FS, as well as their economic impact, aiming at identifying areas for improvement in the management of FS and providing valuable insights for healthcare providers and policymakers to better address the non-clinical burden of this condition.

Febrile Seizures: A Systematic Review of Different Guidelines.

BACKGROUND: Febrile seizures (FS) are the most common neurological disorder in pediatric age. FS affect 2% to 12% of children and result from a complex interplay of genetic and environmental factors. Effective management and unambiguous recommendations are crucial for allocating health care resources efficiently and ensuring cost-effectiveness in treating FS. METHODS: This systematic review compares existing guidelines to provide insights into FS management. Seven guidelines published between 1991 and 2021, from Japan, United Kingdom, United States, Mexico, India, and Italy, were included. Data extraction covered definitions, diagnostic criteria, hospital admission criteria, diagnostic tests, management, and prophylaxis recommendations. RESULTS: Hospital admission criteria varied but typically included age <18 months and complex FS. Neuroimaging and lumbar puncture recommendations varied, with most guidelines suggesting limited use. Pharmacologic prophylaxis was generally discouraged for simple FS but considered only for high-risk cases, due to the benign nature of FS and the potential side effects of antiseizure medications. CONCLUSIONS: Guidelines on FS exhibit similarities and differences, highlighting the need for standardized management and improved parental education to enhance clinical outcomes and reduce economic and social costs associated with FS. Future research should focus on creating updated international guidelines and ensuring their practical implementation.