{"id":56637,"date":"2024-03-20T11:52:37","date_gmt":"2024-03-20T11:52:37","guid":{"rendered":"https:\/\/biomedpharmajournal.org\/?p=56637"},"modified":"2024-04-01T18:56:33","modified_gmt":"2024-04-01T18:56:33","slug":"childhood-obesity-and-metabolic-syndrome-a-review","status":"publish","type":"post","link":"https:\/\/biomedpharmajournal.org\/staging\/vol17no1\/childhood-obesity-and-metabolic-syndrome-a-review\/","title":{"rendered":"Childhood Obesity and Metabolic Syndrome: A Review"},"content":{"rendered":"\n

Introduction<\/strong><\/p>\n\n\n\n

Obesity is a chronic condition that is defined by the World\nHealth Organisation (WHO) as excessive body weight caused by the accumulation\nof fatty tissue, which has a negative impact on health. It has a multifactorial\netiology and is accompanied by an increased risk of morbidity and mortality.1\n<\/sup>Although the definition of Obesity refers to excess fat2<\/sup>, in\nclinical practice this is difficult to measure directly. Obesity is therefore\nassessed by measuring BMI<\/em> (Body Mass Index), which expresses the ratio\nbetween weight (kg) and height (m2<\/sup>). It is the most widely used\nmethod clinically, thus representing a good screening tool and an indicator of\nexcess adipose tissue, albeit with some limitations in the clinical setting\n(BMI may be high in athletes due to the weight of muscle mass and\nunderestimated in those with low muscle mass).1,3<\/sup><\/p>\n\n\n\n

The World Health Organization (WHO) has categorized\ndifferent classes of obesity based on BMI. However, this classification is not\nvery useful for children and adolescents, as age and gender-specific BMI\nreference curves are more applicable in this age group.4-6<\/sup> The\nInternational Obesity Task Forcehas defined the different clinical\nweight-related conditions by the following percentile ranges, using age- and\ngender-specific reference values (Table 1).<\/p>\n\n\n\n

Table 1: Percentiles and status<\/strong>.<\/p>\n\n\n\n\n\n\n\n\n\n
\n

(5-95)<\/em><\/strong><\/p>\n<\/td>\n

\n

Status<\/em><\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

BMI <5<\/strong><\/p>\n<\/td>\n

\n

Underweight<\/p>\n<\/td>\n<\/tr>\n

\n

5 \u2264 BMI < 85<\/strong><\/p>\n<\/td>\n

\n

Normal weight<\/p>\n<\/td>\n<\/tr>\n

\n

85 \u2264 BMI < 95<\/strong><\/p>\n<\/td>\n

\n

Overweight<\/p>\n<\/td>\n<\/tr>\n

\n

BMI \u2265 95<\/strong><\/p>\n<\/td>\n

\n

Obesity<\/p>\n

(if above 99, severe)<\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

 <\/p>\n\n\n

The BMI z-score (SDS=Standard Deviation Score)\nrepresents the degree of deviation of an individual’s current BMI value from\nthe mean value of the reference population for a given age and sex.7<\/sup>\nIn addition, BMI changes with age, ethnicity, and lifestyle. To determine age-\nand sex-specific thresholds for normal weight, overweight, and obesity in\nchildhood, the International Obesity Task Force has gathered BMI data from\nindividuals of both genders, aged 2 to 18 years, from different populations. These\nvalues intersect the BMI values of 25 and 30 kg\/m2 which, in adults, identify\nthe cut-offs for overweight and Obesity. This aspect is important because, at a\ndevelopmental age, the cardiometabolic complications of Obesity are generally\nnot clinically evident, so knowing that the subject’s BMI is at or above the\nline intersecting the BMI value of 25 or 30 kg\/m2 indicates that, although the\nsubject is at a developmental age, he or she is on the BMI line that may lead\nto cardiometabolic complications as an adult.<\/p>\n\n\n\n

Other methods1,3<\/sup> to assess Obesity aim at\nmeasuring body composition: fat mass <\/em>and its distribution between\nsubcutaneous and visceral fat: fat mass is an indicator for nutritional\nassessment, since adipose tissue represents the largest energy reserve; lean\nmass<\/em>: indicates the amount of water and protein; bone mass<\/em>: indicates\nthe amount of calcium and mineral deposits.<\/p>\n\n\n\n

Methods that can be used to assess Obesity status\ninclude: Plicometry<\/em>: measures the thickness of skin folds. It is a\nsimple but not very accurate method and has its value in patient follow-up,\nincluding pediatric patients. Bioimpedance analysis<\/em>: indirect method of\nmeasuring fat mass, taking advantage of the fact that it is a worse conductor\nthan lean mass (which is rich in electrolytes). DEXA<\/em> (Dual Photon X ray\nAbsorptiometry): evaluates lean, fat and skeletal mass, but is little used in\nclinical practice. It takes advantage of the different absorption of X-rays. In\nchildren, the scan takes about 10 minutes. CT or MRI<\/em>: allow abdominal\nquantification of adipose tissue, but cannot be used clinically. Waist circumference<\/em>:\nis a measurement, taken with a flexible tape placed circumferentially on a\nhorizontal plane passing through the iliac crest, which gives information about\nfat distribution, i.e. about android, visceral, central Obesity,8<\/sup>\nwhich is in fact related to cardiovascular risk, risk of Diabetes,\ndyslipidaemia and non-alcoholic steatosis. Percentile curves have been\ndeveloped for this circumference. The ratio of waist circumference to height is\na further estimate of central adiposity. Analyses of data from the NHANES III\n(National Health and Nutrition Examination Survey) indicate this ratio as one\nof the best predictors of increased LDL-cholesterol, total cholesterol and\ntriglycerides.9<\/sup> If greater than 0.5, it is indicative of Obesity\nwith elevated cardio-metabolic risk.<\/p>\n\n\n\n

Aetiology<\/strong><\/p>\n\n\n\n

Regarding the role of the environment, it is of\nparticular importance that Obesity is a real social disease. Camallero defined\n‘Global Epidemic of Obesity’ as a condition influenced by environmental, social,\nand economic factors that have shaped eating habits and lifestyles, primarily\nsince the 2000s.10<\/sup><\/p>\n\n\n\n

The term ‘obesogenic environment’ encompasses the\nvarious factors contributing to obesity such as urbanization, automation,\nreliance on cars, sedentary lifestyle due to limited public spaces for physical\nactivity, and unhealthy diets.2 <\/sup><\/p>\n\n\n\n

A correlation between time spent watching television\nand Obesity has been demonstrated.2<\/sup> Such a lifestyle leads to less\nphysical activity, resulting in lower energy expenditure, effects on diet and\nsleep.  Sleep deprivation\/fragmentation\nhas also been associated with Obesity (in 13-year-olds, sleep duration is\ninversely proportional to BMI z-score;11<\/sup> in another cohort study,\nevaluating patients for 15 years, sleep deprivation was found to be associated\nwith the risk of being overweight),12<\/sup> alterations in glucose\nhomeostasis and increased insulin resistance;13<\/sup> an unbalanced diet,\nwith high glycemic index foods, sugary drinks, precooked foods, fast food;\ncertain drugs such as psychoactives, antiepileptics and glucocorticoids;\nmicrobiome: some studies have also shown this role in humans, not only in\nanimals. A study found a link between antibiotic use in the first six months of\nlife and higher BMI between 10 and 38 months.14 <\/sup>Another study\nrevealed that prenatal exposure to DDT was associated with obesity in males at\n9 years old, but not in females.15<\/sup><\/p>\n\n\n\n

Meta-analyses in the scientific literature conclude\nthat interventions aimed at Obesity prevention are effective. For example, among\nthem, a Cochrane review16 of 37 studies with 27,946 children found a\nstandardized mean difference in adiposity (measured as BMI or zBMI) of -0.15\nkg\/m2 in BMI . In addition, the importance of incentivized dietary programs in\nschools as a cornerstone of prevention and treatment emerges. Hereditary\nfactors play a significant role in the variations seen in adipose tissue,\naccording to several studies. These genetic factors are estimated to be\nresponsible for anywhere between 40 to 85% of the variation observed.2<\/sup><\/p>\n\n\n\n

Obesity is therefore a heritable trait,17<\/sup>\nbut the genes that contribute to it present a challenge in their\nidentification. A combined meta-analysis of the GWAS and the Metabochip in\nalmost 340,000 patients showed 97 loci associated with BMI18. It is on this\ngenetic substrate that external factors and the obesogenic environment act. Among\nthe genes, the one most associated with Obesity is the Fat mass and obesity\nassociated protein( FTO) gene that maps onto chromosome 16, a common variant in\nthis gene predisposes to type 2 Diabetes mellitus (DM2) and Obesity in\nchildhood and adulthood.19<\/sup> The connection to this association may\nnot be immediately clear, but it seems to be linked to issues involving how\nadipocytes use and store energy resources, as well as problems with\nmitochondrial thermogenesis.20 <\/sup>In addition, certain syndromes and\ndefects in individual genes are linked to Obesity. Among the syndromes,\nPrader-Willi syndrome (chromosome 15, q11-13) is among the most common. It is a\nhypermethylation syndrome, thus representing an example of epigenetic\nmodification. It is characterized by Hypotonia, eating disorders such as\ndysphagia and Obesity, and fertility disorders (hypogonadotropic hypogonadism).\nBardet-Biedl syndrome is an example of another autosomal recessive syndrome.\nThis syndrome can be attributed to mutations in 15 distinct genes, namely BBS1\nto BBS14, as well as SDCCAG8. These genes play a crucial role in the\ndevelopment and functioning of the primary hairpin.21 <\/sup>Affected\nindividuals are characterized not only by Obesity, but also by Microorchidism\nin males, Mental retardation, Renal dystrophies, Polydactyly, Renal\nmalformations especially at the level of the calyces, polyuria and polydipsia.<\/p>\n\n\n\n

Monogenic forms of Obesity are rare and are\nrepresented by: Melanocortin receptor 4 mutation: evidence from patients with a\nhomozygous mutation suggests that the receptor may mediate the anorectic\neffects of leptin, whereas patients with heterozygosity may present with severe\nObesity. Pro-opiomelanocortin mutation (POMC): MSH, via its receptor 4,\nmediates the effects of leptin. Patients with such mutations show hyperphagia\nand Obesity. Leptin gene mutation: obese (ob) mice lacking this gene exhibit\nhyperphagia, insulin resistance, hyperinsulinaemia, infertility, all of which\nare reversible with leptin administration. Leptin receptor mutation.\nPro-hormone convertase type 1 (PCSK1) deficiency, associated with severe\nhormonal disorders and early onset of Obesity. Other genes include BDNF\n(Brain-Derived Neurotrophic Factor) and TrkB (Tropomyosin Receptor Kinase B),\nwhose mutations are associated with hyperphagia, Obesity, impaired short-term\nmemory, hyperactivity and learning difficulties.<\/p>\n\n\n\n

Endocrine disorders2<\/sup> can also cause\nObesity: excess cortisol (Cushing’s syndrome), hypothyroidism, growth hormone\ndeficiency and pseudo-hypoparathyroidism type 1A (hereditary Albright’s\nosteodystrophy). Certain hypothalamic lesions2<\/sup> may also be\nassociated with Obesity. In paediatric age, such lesions may occur following\nsurgery, or they may be traumatic, neoplastic or inflammatory in nature. 22-25<\/sup>\nThere is a rare cause that includes a rapid onset of Obesity, hypothalamic\ndysfunction and autonomic dysregulation (ROHHAD: Rapid-onset Obesity with\nHypothalamic dysfunction, Hypoventilation, and Autonomic Dysregulation),\nsometimes associated with neuroendocrine tumours (ROHHADNET: Rapid-onset\nObesity with Hypothalamic dysfunction, Hypoventilation, Autonomic Dysregulation\nand Neuroendocrine Tumour).<\/p>\n\n\n\n

In addition, there is an essential role played by\n‘metabolic programming’.2,26<\/sup> This concept highlights the significant\nimpact of environmental and nutritional factors on an individual’s\npredisposition to obesity and metabolic diseases. Specifically, these factors\nact at the epigenetic level during critical moments in development, leading to\npermanent effects. Epigenetic changes include methylation, histone\nmodifications, chromatin remodeling and micro-RNA arrangements. These\nmechanisms could explain the link between external factors, such as\nnutrition\/stress\/drugs\/hypoxia\/hormone levels, and phenotypic changes in gene\nexpression.27-37<\/sup><\/p>\n\n\n\n

The most important evidence concerns the gestation\nperiod. Individuals who are born small for gestational age (SGA), large for\ngestational age (LGA), or prematurely are more likely to develop insulin resistance\nand obesity during their developmental years.38-40<\/sup><\/p>\n\n\n\n

Other studies also show an association between birth\nweight and Diabetes, cardiovascular disease, insulin resistance and Obesity.41,42\n<\/sup>The mother’s own weight, gestational Diabetes43<\/sup> and\npre-eclampsia44,45 <\/sup>are factors that correlate with the child’s\nweight and cardiovascular disease. Early childhood is another critical period\nthat has been the subject of several studies highlighting the connection\nbetween weight during this time and the potential risk of developing metabolic\nsyndrome in adulthood.46<\/sup> This relationship is not limited to\nchildhood alone.47 <\/sup>In particular, some studies have shown that\nprotein intake in the first two years of life is associated with a higher BMI\nat school age.48<\/sup><\/p>\n\n\n\n

Pathophysiology\n<\/strong><\/p>\n\n\n\n

With economic, social and lifestyle changes, there has\nbeen an imbalance between energy inputs and outputs, with energy inputs\nincreasing. This excess energy, stored in the chemical form of triglycerides in\nadipose tissue, lays the foundation for Obesity and the accompanying\ndysmetabolism.17<\/sup> The energy balance control system is essential for\nsurvival and is designed to conserve and make the best use of the energy\nrequired for the organism’s life, but it is not regulated to guard against\nexcess, also for evolutionary reasons.49<\/sup> Energy homeostasis concerns\nevery single cell, but certain components of our organism play a primary role,\nsuch as adipose tissue. Adipocytes, which together with vessels, extracellular\nmatrix, macrophages and fibroblasts make up adipose tissue, are very\nheterogeneous. For example, those in visceral fat are more active than those in\nsubcutaneous fat (this explains the greater negative effects of visceral\nadiposity). However, the increase in body fat can be either due to an increase\nin the volume of adipocytes incorporating more triglycerides (hypertrophic Obesity)\nor to an increase in their number, typical of the pediatric age group\n(hyperplastic Obesity). The two components often coexist.49<\/sup><\/p>\n\n\n\n

Among the functions of adipose tissue is the central\nrole it plays in controlling and storing energy in the form of triglycerides.\nIn this task, the key enzyme is the insulin-sensitive lipoprotein lipase<\/em>, which breaks down triglycerides when energy is\nneeded, so that fatty acids are available for oxidation in various tissues.49<\/sup>\nIn addition to this storage function, adipose tissue also plays a role at the\nendocrine level (with production of adipokines), at the metabolic level, in the\nregulation of blood pressure and coagulation (with production of PAI-1 Plasminogen Activator Inhibitor-1<\/em>,\nTF Tissue Factor<\/em>, angiotensinogen,\nangiotensin II), in inflammation (by the production of pro-inflammatory\ncytokines PAF Platelet Activating Factor<\/em>,\nInterleukin-6, 8, 10, 18, 1Beta). The adipocyte also produces complement factor\nD or adipsin.50<\/sup><\/p>\n\n\n\n

Among the adipokines produced by adipose tissue, leptin <\/em>plays an important role. It is a\npeptide hormone capable of crossing the blood-brain barrier and reaching nerve\ncenters (the arcuate nucleus above all), where it has an inhibitory action on\nhunger. It also acts at a peripheral level by stimulating energy consumption.\nIt is therefore increased in obese subjects to counterbalance excessive calorie\nintake, but this compensation is not sufficient or, in any case, not efficient:\nmost obese people are resistant to leptin.49<\/sup> On the contrary, adiponectin<\/em> exhibits plasma levels that are inversely\nproportional to the mass of adipose tissue. <\/em>Its action is mainly at hepatic and muscular level, where, in\nsynergy with insulin stimulation, it optimises the utilisation of energy\nsubstrates.49<\/sup> More recently, another adipokine, adrenomedullin <\/em>(ADM), has been characterised.51<\/sup> It is a\nvasoactive peptide expressed and secreted by a range of tissues, including the\nadrenal medulla, heart, lung, liver, kidney, pancreatic islets, vessel smooth\nmuscle cells and immune cells. ADM levels are elevated in hypertension, renal\nfailure, shock and Diabetes mellitus. Moreover, it is increased in obese\nindividuals, both in plasma and in adipose tissue. Its transcription is\nstimulated by insulin, hypoxia and inflammatory stimuli. ADM has a short\nhalf-life, so in the above-mentioned study, the level of the central region of\nproADM (MR-proADM) was assessed: in obese adolescents, the levels were higher\nthan in their healthy counterparts. It was hypothesized that this represents an\nadaptive mechanism by which the peptide, with its antioxidant and vasodilator\neffect, antagonises the increased blood pressure and inflammatory state typical\nof Obesity. Other hormones that regulate hunger\/satiety are produced at the\ngastrointestinal level:49<\/sup> Cholecystokinin<\/em>:\nreleased from the gastrointestinal tract during a meal, stimulates gallbladder\nmotility, pancreatic secretion and intestinal motility and contributes to a\ncentral sense of satiety. Ghrelin<\/em>:\npeptide of 28 amino acids, produced mainly in the stomach, but also in the\nintestine, placenta and hypothalamus. Gastric production occurs on an empty\nstomach, so it contributes to increased hunger. It is immediately reduced at\nthe end of a meal. Pancreatic polypeptide<\/em>:\ninduces satiety. GLP-1<\/em> (Glucagon Like Peptide 1): inhibits appetite with\na direct central effect, while peripherally it acts by slowing down gastric\nemptying. Glucocorticoids<\/em>, which\ninhibit lipoprotein lipase, also contribute to this regulation, while adrenalin, GH and sex hormones <\/em>promote\nlipolysis. Moreover, sex hormones also play a role in the distribution of body\nfat: in the male, at puberty, there is a decrease in fat mass and an increase\nin lean mass, while in the female, there is an increase in fat compared to\nmuscle mass49<\/sup>. Thyroid\nhormones <\/em>also promote lipolysis because they increase energy consumption\nthrough the inefficient utilization of energy substrates.49<\/sup> Cortisol and insulin<\/em>, on the other hand,\npromote liposynthesis.49<\/sup><\/p>\n\n\n\n

Body weight and fat accumulation are also regulated by\nthe nervous system.49<\/sup> As far as the autonomic nervous system <\/em>is\nconcerned, the sympathetic system has a lipolytic function and promotes\nthermogenesis by acting on beta3 receptors in the adipocytes of the brown\nadipose tissue, while the parasympathetic promotes satiety by slowing down\ngastro-intestinal emptying. It is the central\nnervous system, <\/em>however, that receives various signals from the periphery\nabout nutrient deficit\/excess and, based on their integration, modifies the\nmetabolic and cognitive structures. The main center is the hypothalamus, in\nparticular the arcuate nucleus<\/em>. On\nthis act: Neurotransmitters of the autonomic nervous system; Hormones and\nmetabolites (glucose and fatty acids).<\/p>\n\n\n\n

The arcuate nucleus17,52<\/sup> is capable of\nintegrating and responding by modifying the energy balance. In fact, it\nintegrates leptin signals by modifying the production and release of peptides,\nsuch as neuropeptide Y (NPY), which stimulates appetite, and such as\nproopiomelanocortin (POMC), which decreases it.<\/p>\n\n\n\n

POMC-containing neurons are stimulated by leptin and\nare connected to the paraventricular nucleus, which is responsible for the\ncleavage of POMC into the active peptide \u03b1-MSH, which binds to melanocortin receptor 4 (MC4R)\nleading to satiety, increased metabolic rate, and decreased basal insulin\nlevels. NPY-containing neurons, on the other hand, are inhibited by leptin, so\na reduction in leptin stimulates the activity of these neurons, causing the\nfeeling of hunger (this contributes, for example, to the feeling of hunger\nduring a period of restrictive dieting in which weight is lost, and body fat is\nreduced, and thus leptin). Mutations that can involve and alter this leptin\nsignaling system can lead to an obese phenotype, which underlines the\nimportance of this pathway in weight regulation.<\/p>\n\n\n\n

Regarding energy\nexpenditure,<\/em>49,50<\/sup> we consider: the thermic effect of\nexercise (20-30%), so that a sedentary lifestyle is a risk factor for Obesity. The\nenergy cost for metabolism and nutrient storage (10%): a low thermic effect of\nfood is associated with the development of Obesity. A randomized trial set out\nto determine which level of dietary protein affected body composition, weight\ngain and energy expenditure. It was seen that a low-protein diet was associated\nwith weight gain in general, but the accumulation of adipose tissue was similar\nbetween this type of diet, a high-protein diet and a normal diet.53<\/sup> Obligatory\nthermogenesis, i.e. the basal metabolic rate (energy expenditure required for\nthe chemical processes that take place in the body’s cells under basal\nconditions, i.e. at rest, fasting and at a comfortable temperature). This\naccounts for 60-70% of energy expenditure and decreases with age. Basal\nmetabolism includes maintaining body temperature, the ionic gradient between\ncell membranes, gastrointestinal motility, cardiac and respiratory function. If\nchemical processes are reduced, more energy is dissipated as heat. Thermogenin\n1, UCP-1 (uncoupling protein 1), which is located in the mitochondria, reduces\nthe electrochemical gradient and ATP formation, favoring the dissipation of\nenergy in the form of heat. This not only maintains an appropriate body\ntemperature, but also burns excess calories. UCP-1 is found in brown adipose\ntissue, muscle, viscera and the CNS and thus contributes to basal\nthermogenesis. Initially, however, it was only identified within brown adipose\ntissue, which decreases in the individual with advancing age, while it is\nhighest around 13 years (in the pediatric age group, brown adipose tissue, in\nfact, correlates inversely with Obesity, suggesting its prominent metabolic\nrole).54<\/sup> However, imaging studies (PET-CT) have also identified such\nadipose tissue in adults, especially in women.55<\/sup> It is essentially\nlocated in the supraclavicular and nuchal area. The activation of brown adipose\ntissue is, therefore, an important component of energy expenditure, also in\nadults.56<\/sup> There is, however, a non-exercise-related thermogenesis (NEAT:\nNon-Exercise Activity Thermogenesis), which varies in response to caloric\nintake (increases with overeating). It has been linked to Obesity and is due to\nthe non-exercise physical activity performed during the day (moving,\nmaintaining posture, and spontaneous muscle contractions). The large variation\nin fat deposition observed in overfed individuals can be estimated on the basis\nof the extent of NEAT induction. The molecular basis and regulation, however,\nare still unclear.50<\/sup> Recent information suggests the role of\nhypothalamic nuclei and various neuromediators that together form a complex\nneural network.57<\/sup> It seems that just as physical activity\ncontributes to the prevention of weight gain, an increase in this activity is\nalso a way of controlling it.58<\/sup><\/p>\n\n\n\n

However, the energy expenditure of an obese patient is\nactually similar to that of a normal-weight subject, as weight gain leads to an\nincrease in metabolically active lean mass as well. This expenditure is reduced\nwhen weight loss begins, if there is a loss of lean mass, and due to a\nreduction in sympathetic system activity. There is a tendency to keep this\nexpenditure low at rest, compared to normal-weight subjects, if excess weight\nstarts at a developmental age.50,59<\/sup><\/p>\n\n\n\n

Clinical\nmanifestations<\/strong><\/p>\n\n\n\n

The term ‘morbid Obesity’2<\/sup> refers to\npatients with Obesity-related comorbidities. Such comorbidities may also affect\npediatric patients, especially those with severe Obesity,60<\/sup> who have\na higher risk of early onset of typical adult diseases. They include\nendocrine-metabolic, psychosocial, respiratory, osteomuscular, neurological,\ndermatological, gastrointestinal, neoplastic, and cardiovascular disorders:<\/p>\n\n\n\n

endocrinological-metabolic:<\/em>60-62<\/sup><\/p>\n\n\n\n

Hyper-insulinaemia and insulin resistance are closely correlated with intra-abdominal fat deposits. The molecular link has been well studied, and the various contributing factors include both the fact that insulin itself reduces the expression of its receptor and interference with insulin action by free fatty acids, which are increased in the serum of overweight subjects. Adipokines and hormones produced by adipose tissue also play a role.<\/p>\n\n\n\n

Prediabetes, with increased risk of Diabetes mellitus, characterized by:<\/p>\n\n\n\n

Impaired fasting blood glucose (between 100 and 125 mg\/dL, normal values <100 mg\/dL);<\/p>\n\n\n\n

Impaired glucose tolerance (blood glucose after OGTT between 140 mg\/dL and 199 mg\/dL, normal values <140 mg\/dL);<\/p>\n\n\n\n

Increased glycated haemoglobin (between 5.7% and 6.4%).<\/p>\n\n\n\n

DM-2, with increased risk, given the onset at an early age, of complications.<\/p>\n\n\n\n

Metabolic syndrome48<\/sup>, according to the ATPIII criteria, three of the criteria mentioned below are required, for the International Diabetes Federation (IDF) the first criterion and two of the following, to define this syndrome:<\/p>\n\n\n\n

Obesity, assessed as waist circumference with values > 90\u00b0 percentile,3<\/sup> according to age- and gender-specific cut-offs (for adults, according to ATPIII, the cut-offs are 88 cm for women, 102 cm for men; whereas according to the IDF, the cut-offs are different according to ethnicity and for Europe, e.g. 80 cm for women, 94 cm for men);<\/p>\n\n\n\n

Triglycerides \u2265 150 mg\/dL;<\/p>\n\n\n\n

HDL < 40 mg\/dL;<\/p>\n\n\n\n

Increased blood pressure, according to the National High Blood Pressure Education Program Working Group;<\/p>\n\n\n\n

Impaired fasting blood glucose (\u2265 100 mg\/dL).<\/p>\n\n\n\n

Actually, for the pediatric group there is no\nconsensus on the definition. However, the IDF specifies that for children\nbetween 10 and 16 years of age, the criteria are similar to adults except for\nwaist circumference, as we have specified, while for children over 16, those of\nadults are fine. For children under 10, on the other hand, one cannot properly\nspeak of metabolic syndrome, but an increase in waist circumference must still\nbe monitored.<\/p>\n\n\n\n

Metabolic syndrome is linked to an increased pro-inflammatory and pro-thrombotic state, which increases the risk of cardiovascular disease.<\/p>\n\n\n\n

Hyper-androgenism: adolescent girls have an increased risk of PCOS (Poly-Cystic Ovary Syndrome), which includes hirsutism, menstrual irregularities, acanthosis nigricans, acne, seborrhoea.<\/p>\n\n\n\n

In males there may be hypogonadism, with reduced circulating levels of testosterone and SHBG (Sex Hormone-Binding Globulin) and a relative increase in oestrogen, with gynaecomastia.<\/p>\n\n\n\n

Growth and development: accelerated growth is observed in the obese patient, with a tendency to anticipate pubertal development.<\/p>\n\n\n\n

Psychosocial<\/em>: isolation, discrimination, dysfunctional social and\nschool environments. The issue may also be linked to eating disorders\n(binge-eating disorder and loss of control in relation to food intake).60-62<\/sup><\/p>\n\n\n\n

Respiratory<\/em>: sleep apnoea (severe condition characterized by\nepisodes of respiratory obstruction with awakenings, fragmented sleep and\nconsequent daytime sleepiness, hypoxaemia and hypercapnia) and hypoventilation,\nwith reduced distensibility of the rib cage.60-62<\/sup><\/p>\n\n\n\n

Musculoskeletal<\/em>: discomfort of various kinds, such as knee pain,\nflexible flat feet, valgus knees, increased risk of fractures, but also\nincreased risk of Blount’s disease (characterized by progressive bowing of the\nlegs and torsion of the tibia, caused by growth inhibition of its medial and\nproximal parts), Slipped Capital Femoral Epiphysis (SCFE) and rheumatoid\narthritis (increased pro-inflammatory cytokines, such as IL6, IL1, TNF-alpha).6,60-64<\/sup><\/p>\n\n\n\n

Neurological<\/em>: idiopathic intra-cranial hypertension, which can\nlead to vision disorders.61<\/sup><\/p>\n\n\n\n

Dermatological<\/em>: intertrigo, furunculosis, hydrosadenitis suppurativa\n(characterised by inflammatory nodules and\/or deep cysts), acanthosis\nnigricans, (linked to insulin resistance and manifested by hyperpigmentation\nand thickening of the skin folds of the neck, elbow, dorsal interphalangeal\nspaces).60,61<\/sup><\/p>\n\n\n\n

Gastrointestinal<\/em>: NAFLD (Non-Alcoholic Fatty Liver Disease),\ncharacterized by steatosis up to steato-hepatitis. The cause of this alteration\nseems to be related to insulin resistance. The presence of NAFLD is associated\nwith elements of the metabolic syndrome, such as dyslipidaemia, hypertension,\nand Obesity (the prevalence of this disease in paediatric age has increased\nwith the rise in Obesity in this age group, in fact). Most patients are\nasymptomatic, others have pain in the upper quadrants of the abdomen, fatigue,\nasthenia and malaise. In addition to liver disease, Obesity is the main cause\nof cholelithiasis in pediatric age, as there is an increased secretion of\ncholesterol into the bile in the obese subjects with supersaturation. Signs and\nsymptoms are non-specific and include epigastric and right hypochondrium pain,\njaundice, nausea and vomiting.60,61<\/sup><\/p>\n\n\n\n

Neoplastic<\/em>: Obesity is associated with increased mortality from\ncancer (of the oesophagus, colon, rectum, pancreas, liver, prostate; in women,\nalso of the gallbladder, cervix, endometrium, ovary) in adulthood. There is\nevidence in the literature50<\/sup> of a higher frequency of genomic damage\nin the lymphocytes of obese adolescents and lower efficiency in the DNA repair\nsystem.58<\/sup><\/p>\n\n\n\n

Cardiovascular<\/em>: the subject of this thesis and better described\nlater, it concerns the presence of arterial hypertension, dyslipidaemia,\nincreased levels of AGEs (Advanced Glycation End-Products), changes in cardiac\nmorphology (left ventricular dilatation, cardiac hypertrophy), changes in\nvessel structure and function, including endothelial dysfunction and\nmicrocirculation alterations, early indicators of cardiovascular disease.60-62<\/sup><\/p>\n\n\n\n

It emerges from this that even in the pediatric\npopulation, early recognition of weight gain is important, since Obesity in\nchildhood is predictive of Obesity in adulthood and the risks associated with\nit. Thus, excess weight, especially if it is part of so-called ‘severe Obesity’,\nleads to long-term consequences that alter the quality of life throughout\nchildhood, but certainly in adulthood.2,65-73<\/sup><\/p>\n\n\n\n

This impact justifies the need for urgent and incisive\ninterventions also at the territorial level: the WHO set up the Commission on\nEnding Childhood Obesity (EChO) to identify the best strategies to tackle the\n‘obesogenic environment:74,75<\/sup> promote healthy eating (also through\nmarketing strategies); promote physical activity; implement care during\npre-conception, pregnancy, prenatal care (in order to reduce the risk of\nchildhood Obesity, preventing too low or too high birth weight, prematurity and\nother complications); early attention to childhood diet and physical activity,\nso that children can grow up with healthy habits; implementing programs that\npromote healthy school environments (e.g. through health education in the\nschool curriculum, eliminating the sale of unhealthy food and drinks,\nstandardizing diets in canteens); management of services, to develop and\nsupport the care of the obese child and adolescent.76-80<\/sup> All these\ninitiatives are fully in line with the vision offered by the Action Plan on\nChildhood Obesity 2014-2020, with which the member states, including Italy,\nwanted to respond to the need to help halt the increase in overweight and Obesity\nin children and young people (0-18 years) by 2020. The action plan provides a\nbasis on which to work to develop national policies to combat Obesity based on\neight priority areas of intervention: support a healthy start in life; promote\nhealthy environments (especially in schools and kindergartens); make the\nhealthy option the easy choice; limit marketing and advertising aimed at\nchildren; inform and empower families; encourage physical activity; monitor and\nevaluate the phenomenon; enhance research.<\/p>\n\n\n\n

Patient Assessment and Management <\/strong><\/p>\n\n\n\n

Managing pediatric obesity requires a comprehensive\napproach that includes preventive strategies, as well as proper management\ntechniques. The important steps include:7,62,81<\/sup><\/p>\n\n\n\n

1) Conducting an initial assessment, which involves\ncollecting detailed information such as a food diary, physical activity levels\n(both planned and unplanned), medical history, and family history.<\/p>\n\n\n\n

2) Gathering anthropometric data, such as age, height,\nweight, waist and hip circumference, BMI, and waist circumference to height\nratio. These measurements provide important objective data about the child’s\nphysical health.<\/p>\n\n\n\n

3) Performing a thorough physical examination to\nsearch for signs of potential comorbidities and genetic syndromes. This\nexamination should cover various areas, including the skin (checking for conditions\nlike acanthosis nigricans and hirsutism), abdomen (looking for hepatomegaly),\nmusculoskeletal system (identifying any abnormalities or dysmorphisms), and\ngenito-urinary apparatus (assessing hypogonadism and pubertal status).\nAdditionally, measuring blood pressure is essential, and pediatric hypertension\nis defined when blood pressure values exceed the 95th percentile for sex, age,\nand height in three separate assessments.<\/p>\n\n\n\n

4) Conducting laboratory tests to evaluate the child’s\nlipid profile, glycemic profile, liver function, and thyroid function. Further\nassessments may be necessary based on the child’s history and objective\nexamination, such as measuring sexual and adrenal hormones.<\/p>\n\n\n\n

5) Recommending imaging examinations when needed. For\ninstance, an abdominal ultrasound may be performed if there are suspicions of\nsteatosis or vague abdominal pain. Radiography may be useful to examine the\nskeletal system and identify any associated comorbidities.82-109<\/sup><\/p>\n\n\n\n

These comprehensive steps provide a detailed and\nholistic approach to managing pediatric obesity, enabling healthcare\nprofessionals to tailor interventions and treatments based on each child’s\nindividual needs. As far as the therapeutic aspects are concerned, educational\ntherapy<\/em>aimed at the child\/adolescent and their family members is\nfundamental and must be individualized. Modifying behaviors that promote\novereating and reducing energy expenditure are crucial. It is essential to\nguide individuals and their families towards adopting healthy lifestyles.60,62,110,111<\/sup><\/p>\n\n\n\n

For optimal diet, it is not recommended to follow a\ndetailed day-to-day list, but instead, focus on dietary advice that promotes\nhealthy eating habits.112,113<\/sup><\/p>\n\n\n\n

In fact, the therapeutic objective is the modification\nof lifestyles that, consequently, will lead to weight control. First, it is\nimportant to engage in physical activity, both planned and unplanned, for at\nleast 60 minutes a day.6<\/sup><\/p>\n\n\n\n

To maintain a healthy diet, it is crucial to follow\nthese dietary guidelines: regularly consume five well-balanced meals throughout\nthe day, refraining from snacking in between; steer clear of restrictive diets\nand instead focus on achieving a proper balance of protein, carbohydrates, and\nfat in your main meals; significantly reduce, or better yet eliminate, the\nintake of sugary beverages from your diet; make it a habit to include a\ngenerous amount of vegetables in every meal; opt for cooking methods like\nsteaming, baking, or grilling instead of frying; and finally, avoid indulging\nin energy-dense but nutrient-poor foods commonly found in fast-food\nestablishments. By adhering to these guidelines, you can pave the way to a\nhealthier and more fulfilling lifestyle.6,62<\/sup><\/p>\n\n\n\n

According to the guidelines of the National Heart Lung\nand Blood Institute, the diet for adults is recommended to be hypocaloric, with\na reduction of 500-1000 Kcal\/day from the usual diet.In paediatrics, on the\nother hand, the diet should be normo-caloric (1000 Calories +100 x child’s\nage), balanced and age-appropriate. To ensure optimal nutrition, it is\nrecommended to consume approximately 1 gram of protein per kilogram of body\nweight per day. Additionally, carbohydrates should constitute 45-60% of your\ntotal calorie intake, with simple sugars accounting for less than 15%. Lipids,\non the other hand, should represent 20-35% of total calories, and saturated\nfats should make up less than 10% of that.6<\/sup><\/p>\n\n\n\n

About the timing of intervention, the data in the\nliterature is not unambiguous, but several studies suggest that early treatment\nis more efficient.114-116<\/sup> The choice of treatment approach should be\ndetermined by factors such as age, level of excess weight, family history, the\npresence of other medical conditions, and the support of one’s\nfamily.Strategies more typical of adulthood, such as low-calorie diets, drugs\nand surgery, are reserved for very selected and serious cases. Interventions\nfocused on lifestyle modifications can lead to remarkable improvements in BMI\nand cardiovascular health in the short to medium term. However, it’s worth\nnoting that these benefits may not always be sustained in the long term.62<\/sup><\/p>\n\n\n\n

Conclusions<\/strong><\/p>\n\n\n\n

Obesity is becoming a global epidemic, and it is\ncrucial to diagnose and prevent it at an early stage. The main risk factors are\npoor diet and a sedentary lifestyle, but socio-environmental factors may also\nbe associated.  The environmental factors\nthus include potentially modifiable targets, such as excessive time spent on\nscreens. Over the years, the economic factor has also been added, which over\ntime, becomes an increasingly important risk factor.<\/p>\n\n\n\n

 To promote the\nhealth and healthy growth of children, collaboration between schools, health professionals\nand the family is important. By adopting healthy lifestyles, these patients can\neffectively prevent the development of irreversible vascular complications\nassociated with obesity.<\/p>\n\n\n\n

Acknowledgments<\/strong><\/p>\n\n\n\n

The authors thank \u201cFondazione per l\u2019Oncologia Pediatrica ONLUS\u201d for their dedicated patient care and scientific support.<\/p>\n\n\n\n

Conflict of\ninterest<\/strong><\/p>\n\n\n\n

The authors certify that they have NO affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.<\/p>\n\n\n\n

Funding\nsupport<\/strong><\/p>\n\n\n\n

The authors received no specific funding for this work.<\/p>\n\n\n\n

Authors\u2019 contributions<\/strong> <\/p>\n\n\n\n

All authors participated in the research design, data analysis, and the writing of the manuscript. All authors approved the final version of the manuscript. <\/p>\n\n\n\n

References<\/strong><\/p>\n\n\n\n

  1. Kansra AR, Lakkunarajah S, Jay MS. Childhood and Adolescent Obesity: A Review. Front Pediatr<\/em>. 2021;8:581461.
    CrossRef<\/a><\/li>
  2. Park M, Budisavljevi\u0107 S, Alem\u00e1n-D\u00edaz AY, et al. Child and adolescent health in Europe: Towards meeting the 2030 agenda. J Glob Health<\/em>. 2023 Jan 20;13:04011. doi: 10.7189\/jogh.13.04011..
    CrossRef <\/a><\/li>
  3. Alem\u00e1n-D\u00edaz AY, Backhaus S, Siebers LL, Chukwujama O, Fenski F, Henking CN, Kaminska K, Kuttumuratova A, Weber MW. Child and adolescent health in Europe: monitoring implementation of policies and provision of services. Lancet Child Adolesc Health. 2018<\/em>;2(12):891-904.
    CrossRef <\/a><\/li>
  4. Cole TJ, Bellizzi MC, Flegal KM, Dietz WH. Establishing a standard definition for child overweight and obesity worldwide: international survey. BMJ.<\/em> 2000; 320(7244): 1240-3.
     CrossRef <\/a><\/li>
  5. Cacciari E, Milani S, Balsamo A, et al. Italian cross-sectional growth charts for height, weight and BMI (2 to 20 yr). J Endocrinol Investigat<\/em>. 2006; 29(7): 581-93.
     CrossRef <\/a><\/li>
  6. Leopold S, Zachariah JP. Pediatric Obesity, Hypertension, Lipids. Curr Treat Options Pediatr<\/em>. 2020;6(2):62-77.
    CrossRef <\/a><\/li>
  7. Bashir A, Doreswamy S, Narra LR, et al. Childhood Obesity as a Predictor of Coronary Artery Disease in Adults: A Literature Review. Cureus<\/em>. 2020 ;12(11):e11473.
    CrossRef <\/a><\/li>
  8. Nittari G, Scuri S, Petrelli F, Pirillo I, di Luca NM, Grappasonni I. Fighting obesity in children from European World Health Organization member states. Epidemiological data, medical-social aspects, and prevention programs. Clin Ter<\/em>. 2019;170(3):e223-e230.<\/li>
  9. Kahn HS, Imperatore G, Cheng YJ. A population-based comparison of BMI percentiles and waist-to-height ratio for identifying cardiovascular risk in youth. J Pediatr<\/em>. 2005; 146(4): 482-8.
     CrossRef <\/a><\/li>
  10. Caballero B. The global epidemic of obesity: an overview. Epidemiol Rev<\/em>. 2007; 29: 1-5.
    CrossRef <\/a><\/li>
  11. Araujo J, Severo M, Ramos E. Sleep duration and adiposity during adolescence. Pediatrics<\/em>. 2012; 130(5): e1146-54.
     CrossRef <\/a><\/li>
  12. Bonuck K, Chervin RD, Howe LD. Sleep-disordered breathing, sleep duration, and childhood overweight: a longitudinal cohort study. J Pediatr<\/em>. 2015; 166(3): 632-9.
     CrossRef <\/a><\/li>
  13. Koren D, Levitt Katz LE, Brar PC, Gallagher PR, Berkowitz RI, Brooks LJ. Sleep architecture and glucose and insulin homeostasis in obese adolescents. Diabetes Care<\/em>. 2011; 34(11): 2442-7.
     CrossRef <\/a><\/li>
  14. Trasande L, Blustein J, Liu M, Corwin E, Cox LM, Blaser MJ. Infant antibiotic exposures and early-life body mass. Intern J Obesity<\/em>. 2013; 37(1): 16-23.
     CrossRef <\/a><\/li>
  15. Warner M, Wesselink A, Harley KG, Bradman A, Kogut K, Eskenazi B. Prenatal exposure to dichlorodiphenyltrichloroethane and obesity at 9 years of age in the CHAMACOS study cohort. Am J Epidemiol<\/em>. 2014; 179(11): 1312-22.
    CrossRef <\/a><\/li>
  16. Waters E, de Silva-Sanigorski A, Hall BJ, et al. Interventions for preventing obesity in children. Cochrane Database System Rev<\/em>. 2011; (12): CD001871.
     CrossRef <\/a><\/li>
  17. Al-Jawaldeh A, Hammerich A, Doggui R, Engesveen K, Lang K, McColl K. Implementation of WHO Recommended Policies and Interventions on Healthy Diet in the Countries of the Eastern Mediterranean Region: From Policy to Action. Nutrients<\/em>. 2020;12(12):3700.
    CrossRef <\/a><\/li>
  18. Locke AE, Kahali B, Berndt SI, et al. Genetic studies of body mass index yield new insights for obesity biology. Nature.<\/em> 2015; 518(7538): 197-206.
     CrossRef <\/a><\/li>
  19. Frayling TM, Timpson NJ, Weedon MN, et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science<\/em>. 2007; 316(5826): 889-94.
    CrossRef <\/a><\/li>
  20. Claussnitzer M, Dankel SN, Kim KH, et al. FTO Obesity Variant Circuitry and Adipocyte Browning in Humans. NEJM.<\/em> 2015; 373(10): 895-907.
     CrossRef <\/a><\/li>
  21. Janssen S, Ramaswami G, Davis EE, et al. Mutation analysis in Bardet-Biedl syndrome by DNA pooling and massively parallel resequencing in 105 individuals. Human Gen<\/em>. 2011; 129(1): 79-90.
     CrossRef <\/a><\/li>
  22. Cefalo MG, Maurizi P, Arlotta A, et al. Hepatic veno-occlusive disease: a chemotherapy-related toxicity in children with malignancies. Paediatr Drugs<\/em>. 2010;12(5):277-84.
    CrossRef <\/a><\/li>
  23.  Lindblad A, Samkange-Zeeb F, de Henauw S, et al. Cardiometabolic risk profile among children with migrant parents and role of parental education: the IDEFICS\/I.Family cohort. Int J Obes (Lond)<\/em>. 2023 Sep 1. doi: 10.1038\/s41366-023-01359-5.
    CrossRef <\/a><\/li>
  24. Muskens JB, Ester WA, Klip H, Zinkstok J, van Dongen-Boomsma M, Staal WG. Novel Insights into Somatic Comorbidities in Children and Adolescents Across Psychiatric Diagnoses: An Explorative Study. Child Psychiatry Hum Dev<\/em>. 2023 Sep 1. doi: 10.1007\/s10578-023-01587-w.
    CrossRef <\/a><\/li>
  25. Perrone MG, Ruggiero A, Centonze A, Carrieri A, Ferorelli S, Scilimati A. Diffuse Intrinsic Pontine Glioma (DIPG): Breakthrough and Clinical Perspective. Curr Med Chem<\/em>. 2021;28(17):3287-3317.
    CrossRef <\/a><\/li>
  26. Agosti M, Tandoi F, Morlacchi L, Bossi A. Nutritional and metabolic programming during the first thousand days of life. Med Surg Pediatr<\/em>. 2017; 39(2): 157.
     CrossRef <\/a><\/li>
  27. Ruggiero A, Barone G, Liotti L, Chiaretti A, Lazzareschi I, Riccardi R. Safety and efficacy of fentanyl administered by patient controlled analgesia in children with cancer pain. Support Care Cancer<\/em>. 2007;15(5):569-73.
    CrossRef <\/a><\/li>
  28. Peng L, Hu R, Feng Y, Shi W, Zhao L, Jiang L. The relationship betweefamily diet consumption, family environment, parent anxiety and nutrition status in children during the COVID-19 pandemic: a longitudinal study. Front Public Health<\/em>. 2023 Aug 10;11:1228626. doi: 10.3389\/fpubh.2023.1228626.
    CrossRef <\/a><\/li>
  29. Matuszak O, Banach W, Pogorza\u0142y B, et al. The long-term effect of maternal obesity on the cardiovascular health of the offspring – systematic review. Curr Probl Cardiol<\/em>. 2023 Aug 29:102062. doi: 10.1016\/j.cpcardiol.2023.102062.
    CrossRef <\/a><\/li>
  30. Andargie TE, Roznik K, Redekar NR, et al. Cell-free DNA reveals distinct pathology of multisystem inflammatory syndrome in children (MIS-C). J Clin Invest<\/em>. 2023 Aug 31:e171729. doi: 10.1172\/JCI171729.
    CrossRef <\/a><\/li>
  31. Zvenyach T, Dietz WH. Quality Measurement Gaps and Future Directions in the Assessment of Obesity. Curr Obes Rep<\/em>. 2023 Aug 31. doi:10.1007\/s13679-023-00525-0.
    CrossRef <\/a><\/li>
  32.  Kazeminasab F, Sharafifard F, Miraghajani M, Behzadnejad N, Rosenkranz SK. The effects of exercise training on insulin resistance in children andadolescents with overweight or obesity: a systematic review and meta-analysis. Front Endocrinol (Lausanne)<\/em>. 2023 Aug 10;14:1178376. doi:10.3389\/fendo.2023.1178376.
    CrossRef <\/a><\/li>
  33. Ruggiero A, Maurizi P, Larocca LM, Arlotta A, Riccardi R. Childhood CD4+\/CD56+ hematodermic neoplasm: case report and review of the literature. Haematologica<\/em>. 2006;91(12 Suppl):ECR48.
     CrossRef <\/a><\/li>
  34. Mier-Mota J, Ponce-Gonz\u00e1lez JG, Perez-Bey A, et al. Longitudinal effects of FTO gene polymorphism on body composition, cardiorespiratory fitness, physical activity, inflammatory markers, and cardiovascular risk in children and adolescents. “The UP & DOWN study”. Scand J Med Sci Sports<\/em>. 2023 Aug 30. doi:10.1111\/sms.14469.
     CrossRef <\/a><\/li>
  35. Jiang Q, Risica PM, Tovar A, et al. Mediation of the Association between Social Environmental Characteristics of Family Childcare Home and Weight Status in Children by Diet Quality. Res Sq<\/em> [Preprint]. 2023 Aug 16:rs.3.rs-3147729. doi: 10.21203\/rs.3.rs-3147729\/v1.
    CrossRef <\/a><\/li>
  36. Hager K, Du M, Li Z, et al. Impact of Produce Prescriptions on Diet, Food Security, and Cardiometabolic Health Outcomes: A Multisite Evaluation of 9 Produce Prescription Programs in the United States. Circ Cardiovasc Qual Outcomes<\/em>. 2023 Aug 29:e009520. doi: 10.1161\/CIRCOUTCOMES.122.009520.
    CrossRef <\/a><\/li>
  37. Posteraro B, Bruno S, Boccia S, et al. Candida parapsilosis bloodstream infection in pediatric oncology patients: results of an epidemiologic investigation. Infect Control Hosp Epidemiol<\/em>. 2004;25(8):641-5.
    CrossRef <\/a><\/li>
  38. Chiavaroli V, Giannini C, D’Adamo E, de Giorgis T, Chiarelli F, Mohn A. Insulin resistance and oxidative stress in children born small and large for gestational age. Pediatrics<\/em>. 2009; 124(2): 695-702.
     CrossRef <\/a><\/li>
  39. Renom Espineira A, Fernandes-Rosa FL, Bueno AC, et al. Postnatal growth and cardiometabolic profile in young adults born large for gestational age. Clin Endocrinol<\/em>. 2011; 75(3): 335-41.
     CrossRef <\/a><\/li>
  40. Efstathiou SP, Skeva, II, Zorbala E, Georgiou E, Mountokalakis TD. Metabolic syndrome in adolescence: can it be predicted from natal and parental profile? The Prediction of Metabolic Syndrome in Adolescence (PREMA) study. Circulation<\/em>. 2012; 125(7): 902-10.
     CrossRef <\/a><\/li>
  41. Sridhar SB, Darbinian J, Ehrlich SF, et al. Maternal gestational weight gain and offspring risk for childhood overweight or obesity. Am J Obstet Gynecol<\/em>. 2014; 211(3): 259 e1-8.
     CrossRef <\/a><\/li>
  42. Deierlein AL, Siega-Riz AM, Adair LS, Herring AH. Effects of pre-pregnancy body mass index and gestational weight gain on infant anthropometric outcomes. J Pediatr<\/em>. 2011; 158(2): 221-6.
     CrossRef <\/a><\/li>
  43. Lawlor DA, Lichtenstein P, Langstrom N. Association of maternal diabetes mellitus in pregnancy with offspring adiposity into early adulthood: sibling study in a prospective cohort of 280,866 men from 248,293 families. Circulation<\/em>. 2011; 123(3): 258-65.
     CrossRef <\/a><\/li>
  44. Washburn L, Nixon P, Russell G, Snively BM, O’Shea TM. Adiposity in adolescent offspring born prematurely to mothers with preeclampsia. J Pediatr<\/em>. 2013; 162(5): 912-7 e1.
    CrossRef <\/a><\/li>
  45. Davis EF, Lazdam M, Lewandowski AJ, et al. Cardiovascular risk factors in children and young adults born to preeclamptic pregnancies: a systematic review. Pediatrics<\/em>. 2012; 129(6): e1552-61.
     CrossRef <\/a><\/li>
  46. Leunissen RW, Kerkhof GF, Stijnen T, Hokken-Koelega A. Timing and tempo of first-year rapid growth in relation to cardiovascular and metabolic risk profile in early adulthood. JAMA<\/em>. 2009; 301(21): 2234-42.
    CrossRef <\/a><\/li>
  47. Taveras EM, Rifas-Shiman SL, Sherry B, et al. Crossing growth percentiles in infancy and risk of obesity in childhood. Arch Pediatr Adolesc Med<\/em>. 2011; 165(11): 993-8.
    CrossRef <\/a><\/li>
  48. Weber M, Grote V, Closa-Monasterolo R, et al. Lower protein content in infant formula reduces BMI and obesity risk at school age: follow-up of a randomized trial. Am J Clin Nutr<\/em>. 2014; 99(5): 1041-51.
     CrossRef <\/a><\/li>
  49. Vigneri R, Sava L, Scacca L. Note di fisiopatologia dei disordini del peso e del comportamento alimentare. In: Lenzi A, Lombardi G, Martino E, Vigneri R, eds. Endocrinologia Clinica. Torino: Minerva Medica<\/em>; 2011: 347-52.<\/li>
  50. Alem\u00e1n-D\u00edaz AY, Backhaus S, Siebers LL, Chukwujama O, Fenski F, Henking CN, et al. Child and adolescent health in Europe: monitoring implementation of policies and provision of services. Lancet Child Adolesc Health<\/em>. 2018;2:891-904.
     CrossRef <\/a><\/li>
  51. Del Ry S, Cabiati M, Bianchi V, Federico G, et al. Mid-regional-pro- adrenomedullin plasma levels are increased in obese adolescents. Eur J Nutr<\/em>. 2016; 55(3): 1255-60.
     CrossRef <\/a><\/li>
  52. Barness LA, Opitz JM, Gilbert-Barness E. Obesity: genetic, molecular, and environmental aspects. Am J Med Genet<\/em>. (Part A) 2007; 143A(24): 3016-34.
     CrossRef <\/a><\/li>
  53. Bray GA, Smith SR, de Jonge L, et al. Effect of dietary protein content on weight gain, energy expenditure, and body composition during overeating: a randomized controlled trial. JAMA<\/em>. 2012; 307(1): 47-55.
     CrossRef <\/a><\/li>
  54. Drubach LA, Palmer EL, 3rd, Connolly LP, Baker A, Zurakowski D, Cypess AM. Pediatric brown adipose tissue: detection, epidemiology, and differences from adults. J Pediatr<\/em>. 2011; 159(6): 939-44.
     CrossRef <\/a><\/li>
  55. Cypess AM, Lehman S, Williams G, et al. Identification and importance of brown adipose tissue in adult humans. NEJM<\/em>. 2009; 360(15): 1509-17.
     CrossRef <\/a><\/li>
  56. Ouellet V, Labbe SM, Blondin DP, et al. Brown adipose tissue oxidative metabolism contributes to energy expenditure during acute cold exposure in humans. J Clin Invest<\/em>. 2012; 122(2): 545-52.
     CrossRef <\/a><\/li>
  57. Villablanca PA, Alegria JR, Mookadam F, Holmes DR, Jr., Wright RS, Levine JA. Nonexercise activity thermogenesis in obesity management. Mayo Clinic Proceedings<\/em>. 2015; 90(4): 509-19.
     CrossRef <\/a><\/li>
  58. von Loeffelholz C. The Role of Non-exercise Activity Thermogenesis in Human Obesity. In: De Groot LJ, Chrousos G, Dungan K, et al., eds. Endotext. South Dartmouth (MA); 2000.<\/li>
  59. Taghizadeh S, Farhangi MA. The effectiveness of pediatric obesity prevention policies: a comprehensive systematic review and dose-response meta-analysis of controlled clinical trials. J Transl Med<\/em>. 2020;18(1):480.
    CrossRef<\/a><\/li>
  60. Kelly AS, Barlow SE, Rao G, et al. Severe obesity in children and adolescents: identification, associated health risks, and treatment approaches: a scientific statement from the American Heart Association. Circulation<\/em>. 2013; 128(15): 1689-712.
     CrossRef <\/a><\/li>
  61. Linardon J, Wade TD, de la Piedad Garcia X, Brennan L. The efficacy of cognitive-behavioral therapy for eating disorders: A systematic review and meta-analysis. J Consult Clin Psychol<\/em>. 2017;85(11):1080-1094.
     CrossRef <\/a><\/li>
  62. Liberali R, Del Castanhel F, Kupek E, Assis MAA. Latent Class Analysis of Lifestyle Risk Factors and Association with Overweight and\/or Obesity in Children and Adolescents: Systematic Review. Child Obes<\/em>. 2021;17(1):2-15.
    CrossRef <\/a><\/li>
  63. Thompson SV, Hannon BA, An R, Holscher HD. Effects of isolated soluble fiber supplementation on body weight, glycemia, and insulinemia in adults with overweight and obesity: a systematic review and meta-analysis of randomized controlled trials. Am J Clin Nutr<\/em>. 2017;106(6):1514-1528.
     CrossRef <\/a><\/li>
  64. Singer G, Granger DN. Inflammatory responses underlying the microvascular dysfunction associated with obesity and insulin resistance. Microcirculation<\/em>. 2007; 14(4-5): 375-87.
     CrossRef <\/a><\/li>
  65. Triarico S, Agresti P, Rinninella E, et al. Oral Microbiota during Childhood and Its Role in Chemotherapy-Induced Oral Mucositis in Children with Cancer. Pathogens<\/em>. 2022;11(4):448.
    CrossRef <\/a><\/li>
  66.  Ara\u00fajo D, Morgado C, Correia-Pinto J, Antunes H. Predicting insulin resistance in a paediatric population with obesity. J Pediatr Gastroenterol Nutr<\/em>. 2023 Aug 23. doi: 10.1097\/MPG.0000000000003910.
     CrossRef <\/a><\/li>
  67. Song Y, Kong Y, Xie X, Wang Y, Wang N. Association between precocious puberty and obesity risk in children: a systematic review and meta-analysis. Front Pediatr<\/em>. 2023 Aug 11;11:1226933. doi: 10.3389\/fped.2023.1226933.
    CrossRef <\/a><\/li>
  68. Tom\u00e1\u0161 S, Terezie \u0160, Stella S. Masked Hypertension in Healthy Children and Adolescents: Who Should Be Screened? Curr Hypertens Rep<\/em>. 2023 Aug 28. doi: 10.1007\/s11906-023-01260-6.
    CrossRef <\/a><\/li>
  69. Palacios-Marin I, Serra D, Jim\u00e9nez-Chillar\u00f3n JC, Herrero L, Todor\u010devi\u0107 M. Childhood obesity: Implications on adipose tissue dynamics and metabolic health. Obes Rev<\/em>. 2023 Aug 22:e13627. doi: 10.1111\/obr.13627.
    CrossRef <\/a><\/li>
  70. Kiyak U, Urganci N, Usta M. Assesment of functional gastrointestinal diseases in obese children. Eur J Pediatr<\/em>. 2023 Aug 22. doi:10.1007\/s00431-023-05165-z.
    CrossRef <\/a><\/li>
  71. Romano A, Triarico S, Rinninella E, et al. Clinical Impact of Nutritional Status and Sarcopenia in Pediatric Patients with Bone and Soft Tissue Sarcomas: A Pilot Retrospective Study (SarcoPed). Nutrients<\/em>. 2022;14(2):383.
    CrossRef <\/a><\/li>
  72. Yan W, Wu S, Liu Q, Zheng Q, Gu W, Li X. The link between obesity and insulin resistance among children: Effects of key metabolites. J Diabetes<\/em>. 2023 Aug 25. doi: 10.1111\/1753-0407.13460.
    CrossRef <\/a><\/li>
  73. Piester TL, Jagtap N, Kalapala R. Review of paediatric obesity and non- alcoholic fatty liver disease-A focus on emerging non-pharmacologic treatment strategies. Pediatr Obes<\/em>. 2023 Aug 21:e13067. doi: 10.1111\/ijpo.13067.
    CrossRef <\/a><\/li>
  74. Azzara A, Pirillo C, Giovannini C, Federico G, Scarpato R. Different repair kinetic of DSBs induced by mitomycin C in peripheral lymphocytes of obese and normal weight adolescents. Mutation Res<\/em>. 2016; 789: 9-14.
     CrossRef <\/a><\/li>
  75. Nishtar S, Gluckman P, Armstrong T. Ending childhood obesity: a time for action. Lancet<\/em>. 2016; 387(10021): 825-7.
     CrossRef <\/a><\/li>
  76. Handjieva-Darlenska T, \u0141uszczki E, Torbahn G, et al. After 32 Years of Action and Engagement, the European Childhood Obesity Group Keeps Fighting for the Best Prevention and Treatment of Pediatric Obesity. Ann Nutr Metab<\/em>. 2023 Aug 25;79(4):343-344. doi: 10.1159\/000533575.
    CrossRef <\/a><\/li>
  77. Ruggiero A, Ariano A, Triarico S, et al. Cisplatin-induced nephrotoxicity in children: what is the best protective strategy? J Oncol Pharm Pract<\/em>. 2021;27(1):180-186.
    CrossRef <\/a><\/li>
  78. Bondyra-Wi\u015bniewska B, Harton A. Effect of the Nutritional Intervention Program on Body Weight and Selected Cardiometabolic Factors in Children and Adolescents with Excess Body Weight and Dyslipidemia: Study Protocol and Baseline Data. Nutrients<\/em>. 2023 Aug 19;15(16):3646. doi: 10.3390\/nu15163646.
     CrossRef <\/a><\/li>
  79. Sofia R, Melita V, De Vita A, et al. Cardiac Surveillance for Early Detection of Late Subclinical Cardiac Dysfunction in Childhood Cancer Survivors After Anthracycline Therapy. Front Oncol<\/em>. 2021;11:624057.
    CrossRef <\/a><\/li>
  80. Xing Y, Zhang P, Li X, et al. New predictive models and indices for screening MAFLD in school-aged overweight\/obese children. Eur J Pediatr<\/em>. 2023 Aug 30. doi:10.1007\/s00431-023-05175-x.
     CrossRef <\/a> <\/li>
  81. Valdes DS, So D, Gill PA, Kellow NJ. Effect of Dietary Acetic Acid Supplementation on Plasma Glucose, Lipid Profiles, and Body Mass Index in Human Adults: A Systematic Review and Meta-analysis. J Acad Nutr Diet<\/em>. 2021;121(5):895-914.
     CrossRef <\/a><\/li>
  82. Chiaretti A, Ruggiero A, Barbi E, et al. Comparison of propofol versus propofol-ketamine combination in pediatric oncologic procedures performed by non-anesthesiologists. Pediatr Blood Cancer<\/em>. 2011;57(7):1163-1167
    CrossRef <\/a><\/li>
  83. Gao XF, Wu BB, Pan YL, et al. Gut microbiome biomarkers in adolescent obesity: a regional study. Health Inf Sci Syst<\/em>. 2023 Aug 17;11(1):37. doi: 10.1007\/s13755-023-00236-9.
    CrossRef <\/a><\/li>
  84. Zemel BS, Shepherd JA, Grant SFA, et al. Reference Ranges for Body Composition Indices by Dual Energy X-ray Absorptiometry from the Bone Mineral Density in Childhood Study Cohort. Am J Clin Nutr<\/em>. 2023 Aug 18:S0002-9165(23)66076-9. doi:10.1016\/j.ajcnut.2023.08.006.
    CrossRef <\/a><\/li>
  85. Tong X, Liu C, Liang M, Ye X, Deng Z, Zhang X. Screening and validation of differentially expressed genes in adipose tissue of patients with obesity and type 2 diabetes mellitus. Biomol Biomed<\/em>. 2023 Aug 17. doi: 10.17305\/bb.2023.9498.
    CrossRef <\/a><\/li>
  86. Gavela-P\u00e9rez T, Parra-Rodr\u00edguez A, Vales-Villamar\u00edn C, et al. Relationship between eating habits, sleep patterns and physical activity and the degree of obesity in children and adolescents. Endocrinol Diabetes Nutr (Engl Ed)<\/em>. 2023 Sep;70 Suppl 3:10-17. doi: 10.1016\/j.endien.2023.08.001.
    CrossRef <\/a><\/li>
  87. Falsini B, Chiaretti A, Barone G, et al. Topical nerve growth factor as a visual rescue strategy in pediatric optic gliomas: a pilot study including electrophysiology. Neurorehabil Neural Repair<\/em>. 2011; 25: 512-520
     CrossRef <\/a><\/li>
  88. Yoong SL, Lum M, Wolfenden L, et al. Healthy eating interventions delivered in early childhood education and care settings for improving the diet of children aged six months to six years. Cochrane Database Syst Rev<\/em>. 2023 Aug 22;8(8):CD013862. doi:10.1002\/14651858.CD013862.pub3.
    CrossRef <\/a><\/li>
  89. Grey E, Griffin T, Jolly K, et al. Extended brief interventions for weight management and obesity prevention in children: A rapid evidence review. Obes Rev<\/em>. 2023 Aug 21:e13633. doi: 10.1111\/obr.13633.
    CrossRef <\/a><\/li>
  90. Ruggiero A, Rizzo D, Trombatore G, Maurizi P, Riccardi R. The ability of mannitol to decrease cisplatin-induced nephrotoxicity in children: real or not?. Cancer Chemother Pharmacol<\/em>. 2016;77(1):19-26.
     CrossRef <\/a><\/li>
  91. Mainieri F, La Bella S, Rinaldi M, Chiarelli F. Rare genetic forms of obesity in childhood and adolescence, a comprehensive review of their molecular mechanisms and diagnostic approach. Eur J Pediatr<\/em>. 2023 Aug 23. doi:10.1007\/s00431-023-05159-x.
    CrossRef <\/a><\/li>
  92. Vandevijvere S, De Pauw R, Djojosoeparto S, et al. Upstream Determinants of Overweight and Obesity in Europe. Curr Obes Rep<\/em>. 2023 Aug 18. doi:10.1007\/s13679-023-00524-1.
    CrossRef <\/a><\/li>
  93. Ruggiero A, Rizzo D, Mastrangelo S, Battaglia D, Attin\u00e0 G, Riccardi R. Interactions between antiepileptic and chemotherapeutic drugs in children with brain tumors: is it time to change treatment?. Pediatr Blood Cancer<\/em>. 2010;54(2):193-198
     CrossRef <\/a><\/li>
  94. Aronsson CA, Tamura R, Vehik K, et al. Dietary Intake and Body Mass Index Influence the Risk of Islet Autoimmunity in Genetically At-Risk Children: A Mediation Analysis Using the TEDDY Cohort. Pediatr Diabetes<\/em>. 2023;2023:3945064. doi:10.1155\/2023\/3945064.
    CrossRef <\/a><\/li>
  95. Ahern S, Marshall S, Wallbank G, et al. Communication strategies and effectiveness of early childhood obesity-related prevention programs for linguistically diverse communities: A rapid review. Obes Rev<\/em>. 2023 Aug 22:e13634. doi: 10.1111\/obr.13634.
    CrossRef <\/a><\/li>
  96. Falsini B, Ziccardi L, Lazzareschi I, et al. Longitudinal assessment of childhood optic gliomas: relationship between flicker visual evoked potentials and magnetic resonance imaging findings. J Neurooncol<\/em>. 2008; 88: 87-96.
    CrossRef<\/a><\/li>
  97. Romano A, Capozza MA, Mastrangelo S, et al. Assessment and Management of Platinum-Related Ototoxicity in Children Treated for Cancer. Cancers (Basel)<\/em>. 2020;12(5):1266.
    CrossRef <\/a><\/li>
  98. Alfraidi A, Alafif N, Alsukait R. The Impact of Mandatory Food-Marketing Regulations on Purchase and Exposure: A Narrative Review. Children (Basel)<\/em>. 2023 Jul 25;10(8):1277. doi: 10.3390\/children10081277.
    CrossRef <\/a><\/li>
  99. Pulungan AB, Puteri HA, Ratnasari AF, et al. Childhood Obesity as a Global Problem: A Cross-sectional Survey on Global Awareness and National Program Implementation. J Clin Res Pediatr Endocrinol<\/em>. 2023 Aug 25. doi: 10.4274\/jcrpe.galenos.2023.2023-7-5.
     CrossRef <\/a><\/li>
  100. Russo P, Lauria F, Sirangelo I, Siani A, Iacomino G. Association between Urinary AGEs and Circulating miRNAs in Children and Adolescents with Overweight and Obesity from the Italian I.Family Cohort: A Pilot Study. J Clin Med<\/em>. 2023 Aug 18;12(16):5362. doi: 10.3390\/jcm12165362.
    CrossRef <\/a><\/li>
  101. Fetoni AR, Ruggiero A, Lucidi D, et al. Audiological Monitoring in Children Treated with Platinum Chemotherapy. Audiol Neurootol<\/em>. 2016;21(4):203-211.
    CrossRef <\/a><\/li>
  102. Peng L, Hu R, Feng Y, Shi W, Zhao L, Jiang L. The relationship between family diet consumption, family environment, parent anxiety and nutrition status children during the COVID-19 pandemic: a longitudinal study. Front Public Health<\/em>. 2023 Aug 10;11:1228626. doi: 10.3389\/fpubh.2023.1228626.<\/li>
  103. Kazeminasab F, Sharafifard F, Miraghajani M, Behzadnejad N, Rosenkranz SK. The effects of exercise training on insulin resistance in children and adolescents with overweight or obesity: a systematic review and meta-analysis. Front Endocrinol<\/em> (Lausanne). 2023 Aug 10;14:1178376. doi:10.3389\/fendo.2023.1178376.
    CrossRef <\/a><\/li>
  104. Giordano P, Lassandro G, Barone A, et al. Use of Eltrombopag in Children With Chronic Immune Thrombocytopenia (ITP): A Real Life Retrospective Multicenter Experience of the Italian Association of Pediatric Hematology and Oncology (AIEOP). Front Med<\/em> (Lausanne). 2020 Feb 28;7:66. doi: 10.3389\/fmed.2020.00066.
     CrossRef <\/a><\/li>
  105. Trisciuzzi MT, Riccardi R,  Piccardi M, et al. A fast visual evoked potential method for functional assessment and follow-up of childhood optic gliomas. Clin Neurophysiol<\/em>. 2004; 115: 217-226.
     CrossRef <\/a><\/li>
  106. Riccardi A, Mazzarella G, Cefalo G, et al. Pharmacokinetics of Temozolomide given three times a day in pediatric and adult patients. Cancer Chemother Pharmacol<\/em>. 2003; 52: 459-464
     CrossRef <\/a><\/li>
  107. Wilson OWA, Thai M, Williams L, Nutter S, Myre M, Russell-Mayhew S. A scoping review of school-based anthropometric measurement. Obes Rev<\/em>. 2023 Aug 31:e13610. doi: 10.1111\/obr.13610.
    CrossRef <\/a><\/li>
  108. Lazzareschi I, Ruggiero A, Riccardi R, Attin\u00e0 G, Colosimo C, Lasorella A. Hypersensitivity reactions to carboplatin in children. J Neurooncol<\/em>. 2002; 58:33-37
    CrossRef <\/a><\/li>
  109. Ribeiro SM, Basso MB, Massignan C, Leal SC. Playful educational interventions in children and adolescents’ health literacy: a systematic review. Health Promot Int<\/em>. 2023 Aug 1;38(4):daad089. doi: 10.1093\/heapro\/daad089.
    CrossRef <\/a><\/li>
  110. Flynn AC, Suleiman F, Windsor-Aubrey H, Wolfe I, O’Keeffe M, Poston L, Dalrymple KV. Preventing and treating childhood overweight and obesity in children up to 5 years old: A systematic review by intervention setting. Matern Child Nutr<\/em>. 2022;18(3):e13354.
     CrossRef <\/a><\/li>
  111. Lioret S, Harrar F, Boccia D, et al. The effectiveness of interventions during the first 1,000\u2009days to improve energy balance-related behaviors or prevent overweight\/obesity in children from socio-economically disadvantaged families of high-income countries: a systematic review. Obes Rev<\/em>. 2023 Jan;24(1):e13524. doi: 10.1111\/obr.13524.
    CrossRef <\/a><\/li>
  112. Denstel KD, Beyl RA, Danos DM, et al. An examination of the relationships between the neighborhood social environment, adiposity, and cardiometabolic disease risk in adolescence: a cross-sectional study. BMC Public Health<\/em>. 2023 Sep 1;23(1):1692. doi:10.1186\/s12889-023-16580-0.
    CrossRef <\/a><\/li>
  113. Demirhan I, Oner E, Kurutas EB. Evaluation of the relationship between insulin resistance and 8-iso prostaglandin levels in obesity children. Folia Med<\/em> (Plovdiv). 2023 Aug 31;65(4):589-596. doi: 10.3897\/folmed.65.e81316.
    CrossRef <\/a><\/li>
  114. Danielsson P, Svensson V, Kowalski J, Nyberg G, Ekblom O, Marcus C. Importance of age for 3-year continuous behavioral obesity treatment success and dropout rate. Obesity Facts<\/em>. 2012; 5(1): 34-44.
     CrossRef <\/a><\/li>
  115. Danielsson P, Kowalski J, Ekblom O, Marcus C. Response of severely obese children and adolescents to behavioral treatment. Arch Pediatr Adolesc Med<\/em>. 2012; 166(12): 1103-8.
     CrossRef <\/a><\/li>
  116. Davoli AM, Broccoli S, Bonvicini L, et al. Pediatrician-led motivational interviewing to treat overweight children: an RCT. Pediatrics<\/em>. 2013; 132(5): e1236-46.
     CrossRef <\/a><\/li><\/ol>\n","protected":false},"excerpt":{"rendered":"

    Introduction Obesity is a chronic condition that is defined by […]<\/p>\n","protected":false},"author":15,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[113],"tags":[],"class_list":["post-56637","post","type-post","status-publish","format-standard","hentry","category-vol17no1"],"_links":{"self":[{"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/posts\/56637","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/users\/15"}],"replies":[{"embeddable":true,"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/comments?post=56637"}],"version-history":[{"count":5,"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/posts\/56637\/revisions"}],"predecessor-version":[{"id":57383,"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/posts\/56637\/revisions\/57383"}],"wp:attachment":[{"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/media?parent=56637"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/categories?post=56637"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/tags?post=56637"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}