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Conduit dilatation above 110% and TPVI in conduits16 mm is not recommended. However, if we want to reach normal values for RVOT diameters and diminish reintervention rates, pushing these boundaries is essential.Analysis of subsequent patients who underwent TPVI with Edwards Sapien valves in conduits ≤16 mm between 2010 and 2020.In n = 33 cases median age was 13 years (5-20 y) and median weight 47 kg (15-91 kg). Preexisting RVOT grafts were n = 28 Contegra® conduits and n = 5 homografts (12 mm n = 15; 14 mm n = 11; 16 mm n = 7). Implanted were the Sapien (n = 8), Sapien XT (n = 10) and Sapien 3 valve (n = 15) with 20 mm (n = 4), 23 mm (n = 19), 26 mm (n = 9) and 29 mm (n = 1). Mean minimal RVOT diameter after TPVI was 22,7 ± 2,3 mm (18-30 mm) which is 150% of the mean minimal RVOT diameter before TPVI (15,1 ± 4,3 mm). Covered stents were used in n = 10 cases. Contained conduit rupture occurred in n = 7 cases (21%). Residual RVOT gradients of 5,7 ± 4,9 mmHg (0-18 mmHg) showed adequate RV unloading.TPVI could be performed successfully in all patients. Dilatation above 150% and a valve/conduit diameter ratio up to 2,4 were well tolerated. There was a considerable amount of conduit rupture but all were confined without further need for intervention or surgery.

The breast milk microbiota has been described as a source of bacteria for infant gut colonisation. We studied the effect of Lactobacillus fermentum CECT5716 (Lc40) on growth and infection incidence of the infants, when the probiotic is administrated to the mothers. Moreover, whether such effects might depend on the interaction between the mother or infant microbiota and the probiotic administration. A total of 291 mother-infant pairs were studied for 16 weeks in a randomised double-blinded placebo-controlled multicentre trial. The Lc40 group (n=139) received 1 capsule/day containing 3×109cfu Lc40; the control group (n=152) received 1 placebo (maltodextrin) capsule/day. A positive and significant correlation of the Staphylococcus load between breast milk and infant faeces was only observed in control group. Additionally, the weight z-score of the infants whose mothers had higher values of Lactobacillus in their breast milk were significantly higher for the Lc40 group. We observed a significant lower incidence of conjunctivitis in the infants whose mothers received Lc40. A higher load of Staphylococcus in infant faeces significantly increased the risk of respiratory infections. Such incidence, under an absent or low Staphylococcus load in the faeces, was significantly 36 times higher in the infants in the control group than in the infants in the Lc40 group. However, the protective effect of Lc40 was gradually reduced as the Staphylococcus load of the milk increased. The administration of Lc40 to nursing women might influence infant growth and health but it seems to depend on its interactions with mother or infant microbiota. Registered in the US Library of Medicine ( www.clinicaltrials.gov ): NCT02203877.

Aims Kawasaki disease (KD) is an acute systemic vasculitis with possible long-term impact of general cardio-vascular health. An endothelial glycocalyx disorder during the disease's acute phase might predispose to long-term vascular anomalies leading to endothelial dysfunction and atherosclerosis. To investigate any association between increased cardiovascular risk and endothelial glycocalyx, we assessed circulating glycocalyx components in patients with a KD history, and analysed their association with acute-phase clinical features and more importantly, with patients' current cardiovascular risk factors. Methods This prospective observational cohort study included 51 subjects: 31 patients with a history of KD, and 20 healthy subjects matched for age and sex. We analysed serum syndecan-1 and hyaluronan via ELISA. We assessed features reported during the acute phase of KD such as blood counts, C-reactive protein (CRP) levels and coronary artery aneurysms (CAA), and their current blood pressure and lipid markers in relation to measured glycocalyx components. Results Our multivariate analysis revealed that hyaluronan and syndecan-1 levels were not associated with KD. However, the latter exhibited a significant association with acute-phase blood count alterations in patients with KD. Furthermore, significant interactions of hyaluronan and syndecan-1 with certain cardiovascular risk factors like blood lipids and blood pressure were only present in KD patients. Conclusion Vasculitis during KD's acute phase might predispose to a long-term endothelial glycocalyx alteration, influenced by other factors having a vascular impact such as blood pressure and circulating lipids. Clinical trial registration German Clinical Trials Register on 25th February 2016, DRKS00010071 https://www.drks.de/drks_web/ .

Reducing the incidence of gastrointestinal infections (GIs) that occur at early stages to mitigate hospitalizations and treatments with adverse effects is a promising strategy for providing well-being to infants and their families. This systematic review and meta-analysis explores whether the early administration of Limosilactobacillus fermentum CECT5716 might be effective as a preventive therapy for GIs. We reviewed the literature to identify randomized controlled trials (RCTs) investigating the effectiveness of milk formulas supplemented with L. fermentum CECT5716 administered to infants at early stages to reduce the incidence of GIs. The MEDLINE (via PubMed), Web of Science (WoS), and Cochrane Central Register of Controlled Trials (via CENTRAL) databases were searched up to 15 June 2021. GI data from the included studies were synthesized in a random-effects model. Three RCTs were finally selected including 435 infants. There was a significant reduction in the incidence rate of GIs for those receiving L. fermentum CECT5716 compared with those receiving placebo (IRR: 0.52, 95% CI: 0.36–0.74, p = 0.0004). Heterogeneity between studies was moderate (I2 = 54.5%). Based on the present systematic review and meta-analysis, the administration of L. fermentum CECT5716 at doses from 1 × 109 to 8.4 × 108 cfu/day in milk formulas may prevent GIs in infants up to 12 months old. Longer-term studies including a higher number of infants are needed to determine whether the use of this probiotic during the early stages of life is an efficient way to reduce the incidence of GIs.

Background: Metformin, a first-line oral antidiabetic agent that has shown promising results in terms of treating childhood and adolescent obesity, might influence the composition of the gut microbiota. We aimed to evaluate whether the gut microbiota of non-diabetic children with obesity changes after a metformin intervention. Methods: The study was a multicenter and double-blind randomized controlled trial in 160 children with obesity. Children were randomly assigned to receive either metformin (1 g/day) or placebo for 6 months in combination with healthy lifestyle recommendations in both groups. Then, we conducted a metagenomic analysis in a subsample obtained from 33 children (15 metformin, 18 placebo). A linear mixed-effects model (LMM) was used to determine the abundance changes from baseline to six months according to treatment. To analyze the data by clusters, a principal component analysis was performed to understand whether lifestyle habits have a different influence on the microbiota depending on the treatment group. Results: Actinobacteria abundance was higher after placebo treatment compared with metformin. However, the interaction time x treatment just showed a trend to be significant (4.6% to 8.1% after placebo vs. 3.8 % to 2.6 % after metformin treatment, p = 0.055). At genus level, only the abundance of Bacillus was significantly higher after the placebo intervention compared with metformin (2.5% to 5.7% after placebo vs. 1.5 % to 0.8 % after metformin treatment, p = 0.044). Furthermore, different ensembles formed by Firmicutes, Bacteroidetes, and Verrucomicrobia were found according to the interventions under a similar food consumption, Spanish Ministry of Health, Social and Equality, General Department for Pharmacy and Health Products, Instituto de Salud Carlos III-Fondo de Investigación Sanitaria (FONDOS FEDER), Redes temáticas de investigación cooperativa RETIC Red SAMID RD12/0026/0015

Julio Plaza-Díaz is part of the “UGR Plan Propio de Investigación 2016” and the “Excellence actions: Unit of Excellence on Exercise and Health (UCEES), University of Granada”. Francisco J. Ruiz-Ojeda and Belén Pastor-Villaescusa are supported by a grant to postdoctoral researchers at foreign universities and research centers from the “Fundación Alfonso Martín-Escudero”, Madrid, Spain. We are grateful to Belen Vazquez-Gonzalez for assistance with the illustration service., Sweeteners that are a hundred thousand times sweeter than sucrose are being consumed as sugar substitutes. The effects of sweeteners on gut microbiota composition have not been completely elucidated yet, and numerous gaps related to the effects of nonnutritive sweeteners (NNS) on health still remain. The NNS aspartame and acesulfame-K do not interact with the colonic microbiota, and, as a result, potentially expected shifts in the gut microbiota are relatively limited, although acesulfame-K intake increases Firmicutes and depletes Akkermansia muciniphila populations. On the other hand, saccharin and sucralose provoke changes in the gut microbiota populations, while no health effects, either positive or negative, have been described; hence, further studies are needed to clarify these observations. Steviol glycosides might directly interact with the intestinal microbiota and need bacteria for their metabolization, thus they could potentially alter the bacterial population. Finally, the effects of polyols, which are sugar alcohols that can reach the colonic microbiota, are not completely understood; polyols have some prebiotics properties, with laxative effects, especially in patients with inflammatory bowel syndrome. In this review, we aimed to update the current evidence about sweeteners’ effects on and their plausible biological interactions with the gut microbiota.

The authors would like to thank the Spanish children and parents who participated in the study., Polygenetic risk scores (pGRSs) consisting of adult body mass index (BMI) genetic variants have been widely associated with obesity in children populations. The implication of such obesity pGRSs in the development of cardio-metabolic alterations during childhood as well as their utility for the clinical prediction of pubertal obesity outcomes has been barely investigated otherwise. In the present study, we evaluated the utility of an adult BMI predisposing pGRS for the prediction and pharmacological management of obesity in Spanish children, further investigating its implication in the appearance of cardio-metabolic alterations. For that purpose, we counted on genetics data from three well-characterized children populations (composed of 574, 96 and 124 individuals), following both cross-sectional and longitudinal designs, expanding childhood and puberty. As a result, we demonstrated that the pGRS is strongly associated with childhood BMI Z-Score (B = 1.56, SE = 0.27 and p-value = 1.90 × 10−8 ), and that could be used as a good predictor of obesity longitudinal trajectories during puberty. On the other hand, we showed that the pGRS is not associated with cardio-metabolic comorbidities in children and that certain environmental factors interact with the genetic predisposition to the disease. Finally, according to the results derived from a weight-reduction metformin intervention in children with obesity, we discarded the utility of the pGRS as a pharmacogenetics marker of metformin response., Plan Nacional de Investigacion Cientifica, Desarrollo e Innovacion Tecnologica (I + D + I), Instituto de Salud Carlos III-Health Research Funding (FONDOS FEDER) PI1102042 PI1102059 PI1601301 PI1600871, Spanish Ministry of Health, Social and Equality, General Department for Pharmacy and Health Products EC10-243 EC10-056 EC10-281 EC10-227, Regional Government of Andalusia ("Plan Andaluz de investigacion, desarrollo e innovacion (2018)") P18-RT-2248, Mapfre Foundation ("Research grants by Ignacio H. de Larramendi 2017"), Instituto de Salud Carlos III IFI17/00048

Background: Kawasaki Disease (KD) is a generalized vasculitis in childhood with possible long-term impact on cardiovascular health besides the presence of coronary artery lesions. Standard vascular parameters such as carotid intima–media thickness (cIMT) have not been established as reliable markers of vascular anomalies after KD. The carotid intima–media roughness (cIMR) representing carotid intimal surface structure is considered a promising surrogate marker for predicting cardiovascular risk even beyond cIMT. We therefore measured cIMR in patients with a history of KD in comparison to healthy controls to investigate whether KD itself and/or KD key clinical aspects are associated with cIMR alterations in the long-term. Methods: We assessed cIMR in this case-control study (44 KD, mean age in years (SD); 13.4 (7.5); 36 controls, mean age 12.1 (5.3)) approximately matched by sex and age. Different clinical outcomes such as the coronary artery status and acute phase inflammation data were analyzed in association with cIMR values. Results: When comparing all patients with KD to healthy controls, we detected no significant difference in cIMR. None of the clinical parameters indicating the disease severity, such as the persistence of coronary artery aneurysm, were significantly associated with our cIMR values. However, according to our marginally significant findings (p = 0.044), we postulate that the end-diastolic cIMR may be rougher than the end-systolic values in KD patients. Conclusions: We detected no significant differences in cIMR between KD patients and controls that could confirm any evidence that KD predisposes patients to a subsequent general arteriopathy. Our results, however, need to be interpreted in the light of the low number of study participants.

Metformin is a first-line oral antidiabetic agent that has shown additional effects in treating obesity and metabolic syndrome. Inter-individual variability in metformin response could be partially explained by the genetic component. Here, we aimed to test whether common genetic variants can predict the response to metformin intervention in obese children. The study was a multicenter and double-blind randomized controlled trial that was stratified according to sex and pubertal status in 160 children with obesity. Children were randomly assigned to receive either metformin (1g/d) or placebo for six months after meeting the defined inclusion criteria. We conducted a post hoc genotyping study in 124 individuals (59 placebo, 65 treated) comprising finally 231 genetic variants in candidate genes. We provide evidence for 28 common variants as promising pharmacogenetics regulators of metformin response in terms of a wide range of anthropometric and biochemical outcomes, including body mass index (BMI) Z-score, and glucose, lipid, and inflammatory traits. Although no association remained statistically significant after multiple-test correction, our findings support previously reported variants in metformin transporters or targets as well as identify novel and promising loci, such as the ADYC3 and the BDNF genes, with plausible biological relation to the metformin’s action mechanism. Trial Registration: Registered on the European Clinical Trials Database (EudraCT, ID: 2010-023061-21) on 14 November 2011 (URL: https://www.clinicaltrialsregister.eu/ctr-search/trial/2010-023061-21/ES)., This research was funded by the Spanish Ministry of Health, Social and Equality, General Department for Pharmacy and Health Products (codes and beneficiaries: EC10-243, Ramón Cañete, Reina Sofía Hospital, Córdoba; EC10-056, Ángel Gil, University of Granada and Virgen de las Nieves University Hospital, Granada; EC10-281, Rosaura Leis, Clinic University Hospital of Santiago, Santiago de Compostela; and EC10-227, Gloria Bueno, Lozano Blesa University Clinical Hospital, Zaragoza)

BPV is supported by a grant to postdoctoral researchers at foreign universities and research centers from the Alfonso Martín Escudero Foundation, Spain., Introduction Obesity is a disorder characterized by a disproportionate increase in body weight in relation to height, mainly due to the accumulation of fat, and is considered a pandemic of the present century by many international health institutions. It is associated with several non-communicable chronic diseases, namely, metabolic syndrome, type 2 diabetes mellitus (T2DM), cardiovascular diseases (CVD), and cancer. Metabolomics is a useful tool to evaluate changes in metabolites due to being overweight and obesity at the body fluid and cellular levels and to ascertain metabolic changes in metabolically unhealthy overweight and obese individuals (MUHO) compared to metabolically healthy individuals (MHO). Objectives We aimed to conduct a systematic review (SR) of human studies focused on identifying metabolomic signatures in obese individuals and obesity-related metabolic alterations, such as inflammation or oxidative stress. Methods We reviewed the literature to identify studies investigating the metabolomics profile of human obesity and that were published up to May 7th, 2019 in SCOPUS and PubMed through an SR. The quality of reporting was evaluated using an adapted of QUADOMICS. Results Thirty-three articles were included and classified according to four types of approaches. (i) studying the metabolic signature of obesity, (ii) studying the differential responses of obese and non-obese subjects to dietary challenges (iii) studies that used metabolomics to predict weight loss and aimed to assess the effects of weight loss interventions on the metabolomics profiles of overweight or obese human subjects (iv) articles that studied the effects of specific dietary patterns or dietary compounds on obesity-related metabolic alterations in humans. Conclusion The present SR provides state-of-the-art information about the use of metabolomics as an approach to understanding the dynamics of metabolic processes involved in human obesity and emphasizes metabolic signatures related to obesity phenotypes., ODRH has received funding from the European Union Seventh Framework Programme (FP7-PEOPLE-2013-COFUND) under grant agreement n° 609020 - Scientia Fellows.

Overweight and obesity are considered a world pandemic of the 21st century. Obesity is a complex multifactorial disease influenced by lifestyle, behavioral, environmental, and genetic factors. Metabolic syndrome (MetS) is a cluster of associated metabolic disturbances which tend to coexist, commonly represented by the combination of obesity (especially abdominal obesity), hyperglycemia, dyslipidemia, and hypertension. MetS is associated with an increased risk of cardiovascular diseases (CVDs), characterized by abnormal cytokine production that leads to endothelial dysfunction. Oxidative stress is associated with CVDs and their related risk factors, such as obesity and type 2 diabetes, and with other chronic degenerative processes such as cancer and other aging-related diseases. Epidemiological evidence indicates that polyphenol-rich diets, such as the Mediterranean diet, are associated with antioxidant, antiinflammatory, and antiobesity effects and with the reduction of risk factors for MetS and CVDs. Polyphenols can be found in nature, mainly in plants and vegetables. Probably the best known beneficial effect of polyphenols is their antioxidant capacity, which is capable of reducing reactive oxygen species and various organic substrates and minerals. In this chapter we explain the nature of polyphenols and their classification, and elucidate their potential mechanism of action and the current evidence in regard to obesity and MetS.

The prevalence of cardiovascular diseases (CVD) is rising and is the prime cause of death in all developed countries. Bioactive compounds (BAC) can have a role in CVD prevention and treatment. The aim of this work was to examine the scientific evidence supporting phenolic BAC efficacy in CVD prevention and treatment by a systematic review. Databases utilized were Medline, LILACS and EMBASE, and all randomized controlled trials (RCTs) with prospective, parallel or crossover designs in humans in which the effects of BAC were compared with that of placebo/control were included. Vascular homeostasis, blood pressure, endothelial function, oxidative stress and inflammatory biomarkers were considered as primary outcomes. Cohort, ecological or case-control studies were not included. We selected 72 articles and verified their quality based on the Scottish Intercollegiate Guidelines Network, establishing diverse quality levels of scientific evidence according to two features: the design and bias risk of a study. Moreover, a grade of recommendation was included, depending on evidence strength of antecedents. Evidence shows that certain polyphenols, such as flavonols can be helpful in decreasing CVD risk factors. However, further rigorous evidence is necessary to support the BAC effect on CVD prevention and treatment.

OBJECTIVES: Metformin has shown its effectiveness in treating obesity in adults. However, little research has been conducted in children, with a lack of attention on pubertal status. The objectives were to determine whether oral metformin treatment reduces BMI z score, cardiovascular risk, and inflammation biomarkers in children who are obese depending on pubertal stage and sex. METHODS: This was a randomized, prospective, double-blind, placebo-controlled, multicenter trial, stratified according to pubertal stage and sex, conducted at 4 Spanish clinical hospitals. Eighty prepubertal and 80 pubertal nondiabetic children who were obese aged 7 to 14 years with a BMI >95th percentiles were recruited. The intervention included 1 g/d of metformin versus placebo for 6 months. The primary outcome was a reduction in BMI z score. Secondary outcomes comprised insulin resistance, cardiovascular risk, and inflammation biomarkers. RESULTS: A total of 140 children completed the study (72 boys). Metformin decreased the BMI z score versus placebo in the prepubertal group (−0.8 and −0.6, respectively; difference, 0.2; P = .04). Significant increments were observed in prepubertal children treated with metformin versus placebo recipients in the quantitative insulin sensitivity check index (0.010 and −0.007; difference, 0.017; P = .01) and the adiponectin–leptin ratio (0.96 and 0.15; difference, 0.81; P = .01) and declines in interferon-γ (−5.6 and 0; difference, 5.6; P = .02) and total plasminogen activator inhibitor-1 (−1.7 and 2.4; difference, 4.1; P = .04). No serious adverse effects were reported. CONCLUSIONS: Metformin decreased the BMI z score and improved inflammatory and cardiovascular-related obesity parameters in prepubertal children but not in pubertal children. Hence, the differential response according to puberty might be related to the dose of metformin per kilogram of weight. Further investigations are necessary.

Background Overweight and obesity are considered to be serious public health problems. In pediatric populations, insulin resistance, dyslipidemia, and hypertension associated with obesity occur with increased frequencies. Metformin is an oral anti-hyperglycemic agent that has been demonstrated to be efficacious in the treatment of diabetic and non-diabetic obese adults. A considerable amount of pharmacogenetic research has demonstrated that genetic variation is one of the major factors affecting metformin response. Additionally, potential microbiota-mediated mechanisms of metformin effect have been recently described. However, scant work has been conducted in children, with no attention being paid to the potential effects of pubertal development. Thus, the main objective of the present study is to evaluate the effect of metformin treatment together with lifestyle recommendations in a randomized control trial (RCT) of obese children according to pubertal stage, genetic variants and signature of gut microbiota. Methods/design This is a randomized, prospective, double-blind, placebo-controlled, multicenter trial, which is stratified by puberty and sex. Eighty pre-pubertal (40 boys and 40 girls) and 80 pubertal non-diabetic obese children (40 boys and 40 girls) are being recruited in four Spanish Clinical Hospitals. The inclusion criteria to participate in the RCT include a Body Mass Index (BMI) above the 95th percentile and age 7–14 years. The pubertal stage is determined based on the Tanner criteria. Participants are assigned to two groups in accordance with a randomization schedule and receive 1 g of metformin or placebo for six months in combination with healthy lifestyle recommendations in both groups. The primary outcomes include changes in the BMI Z score and the biomarkers associated with the early appearance of insulin resistance syndrome, inflammation, cardiovascular risk according of the presence of genetic determinants of metformin response, as well as possible modifications in microbiota. Discussion This study will assess the differential response of metformin treatment at six months in pre-pubertal and pubertal obese children. Trial registration Registered by European Clinical Trials Database (EudraCT, ID: 2010-023061-21) on 14 November 2011. Electronic supplementary material The online version of this article (doi:10.1186/s13063-016-1403-4) contains supplementary material, which is available to authorized users.

The new and recent advances in neuroelectric and neuroimaging technologies provide a new era for further exploring and understanding how brain and cognition function can be stimulated by environmental factors, such as exercise, and particularly to study whether physical exercise influences brain development in early ages. The present study, namely the ActiveBrains project, aims to examine the effects of a physical exercise programme on brain and cognition, as well as on selected physical and mental health outcomes in overweight/obese children. A total of 100 participants aged 8 to 11 years are randomized into an exercise group (N=50) or a control group (N=50). The intervention lasts 20-weeks, with 3-5 sessions per week of 90 min each, and is mainly focused on high-intensity aerobic exercise yet also includes muscle-strengthening exercises. The extent to what the intervention effect remains 8-months after the exercise programme finishes is also studied in a subsample. Brain structure and function and cognitive performance are assessed using structural and functional magnetic resonance imaging and electroencephalographic recordings. Secondary outcomes include physical health outcomes (e.g. physical fitness, body fatness, bone mass and lipid-metabolic factors) and mental health outcomes (e.g. chronic stress indicators and overall behavioural and personality measurements such as anxiety or depression). This project will substantially contribute to the existing knowledge and will have an impact on societies, since early stimulation of brain development might have long lasting consequences on cognitive performance, academic achievement and in the prevention of behavioural problems and the promotion of psychological adjustment and mental health. Clinical trials. Gov identifier: NCT02295072.

Background/Aims: The prevalence of cardiovascular diseases (CVD) is rising and it is the prime cause of death in all developed countries. Bioactive compounds (BACs) can play a role in CVD prevention and treatment. To examine the scientific evidence supporting BACs groups' efficacy in CVD prevention and treatment, we conducted a systematized review. Methods: All available information on Medline, LILACS and EMBASE; all randomized controlled trials (RCTs) with prospective, parallel or crossover designs in humans in which the BACs effect was compared with that of placebo/control. Vascular homeostasis, blood pressure, endothelial function, oxidative stress and inflammatory biomarkers were considered primary outcomes. Results: We selected 26 articles, verifying their quality based on the Scottish Intercollegiate Guidelines Network, establishing diverse quality levels of scientific evidence according to the design and bias risk of a study. Grades of recommendation were included, depending on the evidence strength of antecedents. Conclusions: Evidence shows that certain BACs' derivative from active lipids and nitrogen compounds, mainly from horse chestnut seed extract, sterol plants, allium derivatives, and certain doses of beta-glucans, can be helpful in decreasing the prevalence of CVD risk factors. However, further rigorous evidence is necessary to support and prove BACs' effect on CVD prevention and treatment.