Indian Academy of Pediatrics Revised Guidelines on Evaluation, Prevention and Management of Childhood Obesity.

JUSTIFICATION: The last guidelines for pediatric obesity were released in 2004 by Indian Academy of Pediatrics (IAP). Since then, there has been an alarming increase in prevalence and a significant shift in our understanding in the pathogenesis, risk factors, evaluation, and management of pediatric obesity and its complications. Thus, it was decided to revise and update the previous recommendations. OBJECTIVES: To review the existing literature on the burden of childhood obesity and its underlying etiology and risk factors. To recommend evaluation of childhood obesity and suggest optimum prevention and management strategies of childhood obesity. PROCESS: The following IAP chapters (Pediatric and Adolescent Endocrinology, Infant and Young Child feeding, Nutrition, Non-Communicable Disease and Adolescent Health Academy) were invited to nominate members to become part of the writing committee. The Committee held discussions on various aspects of childhood obesity through online meetings between February and August, 2023. Recommendations were then formulated, which were analyzed, revised and approved by all members of the Committee. RECOMMENDATIONS: Exogenous or primary obesity accounts for the majority of cases of childhood obesity. It is important to differentiate it from endogenous or secondary obesity as evaluation and management changes depending on the cause. In Indian, in children under 5 years of age, weight for length/height using WHO charts, and in children 5-18 years, BMI using IAP 2015 charts is used to diagnose overweight and obesity. Waist circumference should be routinely measured in all overweight and obese children and plotted on India specific charts, as it is a key measure of cardio-metabolic risk. Routine evaluation for endocrine causes is not recommended, except in short and obese children with additional diagnostic clues. All obese children more than ten years old should be evaluated for comorbidities like hypertension, dyslipidemia, hyperglycemia and non-alcoholic fatty liver disease/metabolic dysfunction associated steatotic liver disease (NAFLD/ MASLD). Prevention and management of childhood obesity mainly involves healthy diet practices, daily moderate to vigorous physical activity and reduced screen time. Pharmacotherapy may be offered as an addition to lifestyle interventions only in cases of class 3 obesity or if there are any life-threatening comorbidities. Finally, surgical management may be offered in children older than 12 years of age with class 2 obesity and associated comorbidities or class 3 obesity with/without comorbidities, only after failure of a proper trial of intense lifestyle modifications and pharmacotherapy for at least 6 months.

Utility of Subjective Global Nutritional Assessment Tool for the Assessment of Malnutrition in Pediatric Patients with Chronic Liver Disease.

Purpose: Approximately 30% of children with chronic liver disease (CLD) are malnourished. However, proper assessment of their nutritional status is difficult. The subjective global nutritional assessment (SGNA) is a comprehensive approach that uses nutrition-focused history and examination, followed by grading of malnourishment. We aimed to study the prevalence of malnutrition in children with CLD using the SGNA tool. Methods: This cross-sectional observational study included patients aged <18 years with CLD. Nutritional assessments were recorded using SGNA tool. Conventional anthropometric measurements were performed and corroborated with nutritional status using SGNA tool. Results: A total of 85 children with CLD and mean age of 62 months were enrolled in this study. The prevalence of malnourished children according to SGNA was 34%; 22% were moderately malnourished and 12% were severely malnourished. We found statistically significant differences in anthropometric parameters among the three groups. A moderate degree of agreement was found between SGNA and weight-for-age (W/A) (p=0.020), mid-upper arm circumference (MUAC) (p<0.001), and triceps skin-fold thickness (TSF)-for-age (p=0.029). Furthermore, a fair degree of agreement was found between height-for-age (H/A) (p=0.001) and weight-for-height (W/H) (p<0.001). The sensitivity of W/A for detecting malnutrition was 93%, H/A was 90%, MUAC was 86%, and TSF was 88%. The sensitivity was much lower for W/H and body mass index for age (55% for both). Conclusion: In our study, more than one-third of children with CLD were malnourished. Nutritional assessment using SGNA is a reliable method for evaluating nutritional status and is significantly correlated with common anthropometric measurements.

Surfaceome analysis of extracellular vesicles from senescent cells uncovers uptake repressor DPP4.

Senescent cells are beneficial for repairing acute tissue damage, but they are harmful when they accumulate in tissues, as occurs with advancing age. Senescence-associated extracellular vesicles (S-EVs) can mediate cell-to-cell communication and export intracellular content to the microenvironment of aging tissues. Here, we studied the uptake of EVs from senescent cells (S-EVs) and proliferating cells (P-EVs) and found that P-EVs were readily taken up by proliferating cells (fibroblasts and cervical cancer cells) while S-EVs were not. We thus investigated the surface proteome (surfaceome) of P-EVs relative to S-EVs derived from cells that had reached senescence via replicative exhaustion, exposure to ionizing radiation, or treatment with etoposide. We found that relative to P-EVs, S-EVs from all senescence models were enriched in proteins DPP4, ANXA1, ANXA6, S10AB, AT1A1, and EPHB2. Among them, DPP4 was found to selectively prevent uptake by proliferating cells, as ectopic overexpression of DPP4 in HeLa cells rendered DPP4-expressing EVs that were no longer taken up by other proliferating cells. We propose that DPP4 on the surface of S-EVs makes these EVs refractory to internalization by proliferating cells, advancing our knowledge of the impact of senescent cells in aging-associated processes.

ΔNp63 overexpression promotes oral cancer cell migration through hyperactivated Activin A signaling.

Oral cancer is a common malignant tumor of the oral cavity that affects many countries with a prevalent distribution in the Indian subcontinent, with poor prognosis rate on account of locoregional metastases. Gain-of-function mutations in p53 and overexpression of its related transcription factor, p63 are both widely reported events in oral cancers. However, targeting these alterations remains a far-achieved aim due to lack of knowledge on their downstream signaling pathways. In the present study, we characterize the isoforms of p63 and using knockdown strategy, decipher the functions and oncogenic signaling of p63 in oral cancers. Using Microarray and Chromatin Immunoprecipitation experiments, we decipher a novel transcriptional regulatory axis between p63 and Activin A and establish its functional significance in migration of oral cancer cells. Using an orally bioavailable inhibitor of the Activin A pathway to attenuate oral cancer cell migration and invasion, we further demonstrate the targetability of this signaling axis. Our study highlights the oncogenic role of ΔNp63 - Activin A - SMAD2/3 signaling and provides a basis for targeting this oncogenic pathway in oral cancers.

Comparison of clinical and laboratory profile of survivors and non-survivors of SARS-CoV-2-related multisystem inflammatory syndrome of childhood in India: An observational study.

AIM: The SARS-CoV-2 pandemic is characterised by multiple reports of paediatric multisystem inflammatory disease or multisystem inflammatory syndrome in children (MIS-C) with Kawasaki disease-like features often complicated by myocarditis, shock and macrophage activation syndrome. Certain clinical and laboratory markers may be used to identify high risk cases. METHODS: All sequentially admitted patients hospitalised between April 2020 and October 2020, who met the WHO case definition for MIS-C were included. Data included patient demographic information, presenting symptoms, organ dysfunction and laboratory parameters. SARS-CoV-2 infection was diagnosed by nasopharyngeal swab real-time reverse transcription-polymerase chain reaction and/or rapid antibody test for SARS-CoV-2 as recommended. The clinical and laboratory criteria were compared in the survival and non-survival groups. RESULTS: A total of 29 patients with MIS-C were treated during the study period. There were 21 survivors and 8 non-survivors. The non-survivors had more neurocognitive and respiratory symptoms along with increased incidence of myocarditis compared with survivors. The serum levels of CPK-MB, D-dimer, ferritin and triglyceride were significantly raised in non-survivors as compared to survivors. CONCLUSION: The non-survivor group had higher CPK and greater proportion of children with troponin-T elevation indicating higher incidence of myocardial injury and necrosis. The D-dimer, ferritin and triglyceride were also higher in the mortality group, indicating the greater extent of inflammatory damage in this group.

Lipocalin 2 expression promotes tumor progression and therapy resistance by inhibiting ferroptosis in colorectal cancer.

Lipocalin 2 is a siderophore-binding protein that regulates iron homeostasis. Lipocalin 2 expression is elevated in multiple tumor types; however, the mechanisms that drive tumor progression upon Lipocalin 2 expression remain unclear. When Lipocalin 2 is over-expressed, it leads to resistance to 5-fluorouracil in colon cancer cell lines in vitro and in vivo by inhibiting ferroptosis. Lipocalin 2 inhibits ferroptosis by decreasing intracellular iron levels and stimulating the expression of glutathione peroxidase4 and a component of the cysteine glutamate antiporter, xCT. The increase in xCT levels is dependent on increased levels of ETS1 in Lipocalin 2 over-expressing cells. Inhibiting Lipocalin 2 function with a monoclonal antibody leads to a decrease in chemo-resistance and transformation in vitro, and a decrease in tumor progression and chemo-resistance in xenograft mouse models. Lipocalin 2 and xCT levels exhibit a positive correlation in human tumor samples suggesting that the pathway we have identified in cell lines is operative in human tumor samples. These results indicate that Lipocalin 2 is a potential therapeutic target and that the monoclonal antibody described in our study can serve as the basis for a potential therapeutic in patients who do not respond to chemotherapy.

Vitamin D-dependent rickets (VDDR) type 1: case series of two siblings with a CYP27B1 mutation and review of the literature / Raquitismo dependente de vitamina D: tipo 1: série de casos de dois irmãos com mutação CYP27B1 e revisão da literatura

Abstract Two siblings presented with clinical and biochemical features of rickets, initially suspected as hypophosphatemic rickets. There was no improvement initially, hence the siblings were reinvestigated and later diagnosed as having vitamin D-dependent rickets (VDDR) type 1 due to a rare mutation in the CYP27B1 gene encoding the 1α-hydroxylase enzyme. Both siblings improved with calcitriol supplementation. The initial presentation of VDDR is often confusing and algorithmic evaluation helps in diagnosis. We also present a brief review of the literature, including genetics.

Resumo Dois irmãos apresentaram características clínicas e bioquímicas do raquitismo, com suspeita clínica inicial de raquitismo hipofosfatêmico. Não houve melhora no início, portanto os irmãos foram reavaliados e, posteriormente, diagnosticados com raquitismo dependente de vitamina D (VDDR) tipo 1 devido a uma rara mutação no gene CYP27B1, que codifica a enzima 1a-hidroxilase. Ambos os irmãos melhoraram com a suplementação de calcitriol. A apresentação inicial do VDDR geralmente é confusa e a avaliação algorítmica ajuda no diagnóstico. Também apresentamos uma breve revisão da literatura, incluindo genética.

Vitamin D-dependent rickets (VDDR) type 1: case series of two siblings with a CYP27B1 mutation and review of the literature.

Two siblings presented with clinical and biochemical features of rickets, initially suspected as hypophosphatemic rickets. There was no improvement initially, hence the siblings were reinvestigated and later diagnosed as having vitamin D-dependent rickets (VDDR) type 1 due to a rare mutation in the CYP27B1 gene encoding the 1α-hydroxylase enzyme. Both siblings improved with calcitriol supplementation. The initial presentation of VDDR is often confusing and algorithmic evaluation helps in diagnosis. We also present a brief review of the literature, including genetics.

Outcomes of Hospitalized Infants Aged One to Six Months in Relation to Different Anthropometric Indices - An Observational Cohort Study.

OBJECTIVES: Malnutrition in infants less than six months is increasingly recognized. However, the WHO criteria for identifying malnutrition have not been fully evaluated against the risk of in-patient mortality. The observational study was conducted to evaluate the predictability of in-patient mortality of different anthropometric criteria and combination of criteria in order to understand which diagnostic criteria or combination of criteria most accurately predict in-patient mortality. METHODS: Data from a cohort of infants aged one to six months, admitted to Kalawati Saran Children's Hospital, New Delhi between February and December 2018 was analyzed. The discriminatory ability of different anthropometric indexes [weight-for-age Z score (WAZ), weight-for-length Z score (WLZ) and mid-upper arm circumference (MUAC)] and their combinations to predict in-patient mortality was assessed using Receiver operating characteristic (ROC) curves. RESULTS: A total of 1813 infants aged one to six months were admitted during the 11 mo period, of which 107 (5.9%) died in the hospital. Of all admissions, 39.9%, 26% and 23.4% were severely underweight, severely wasted and severely stunted, respectively. WAZ < -3 was the most sensitive predictor of mortality [sensitivity: 74.8%; specificity: 62.3%; area under the curve (AUC): 0.69, 95% CI: 0.64-0.74]. CONCLUSIONS: WAZ < -3 was the most sensitive predictor out of all individual and combined parameters/indexes in identifying infants less than six months at high risk of mortality which suggests that, it should be used to identify at-risk infants between one to six months on admission to in-patient care. Children identified as falling into this category should be properly evaluated and treated during their in-patient stay.

Indian Academy of Pediatrics Guidelines on the Fast and Junk Foods, Sugar Sweetened Beverages, Fruit Juices, and Energy Drinks.

JUSTIFICATION: In view of easy availability and increasing trend of consumption of fast foods and sugar sweetened beverages (fruit juices and drinks, carbonated drinks, energy drinks) in Indian children, and their association with increasing obesity and related non-communicable diseases, there is a need to develop guidelines related to consumption of foods and drinks that have the potential to increase this problem in children and adolescents. OBJECTIVES: To review the evidence and formulate consensus statements related to terminology, magnitude of problem and possible ill effects of junk foods, fast foods, sugar-sweetened beverages and carbonated drinks; and to formulate recommendations for limiting consumption of these foods and beverages in Indian children and adolescents. PROCESS: A National Consultative group constituted by the Nutrition Chapter of the Indian Academy of Pediatrics (IAP), consisting of various stakeholders in private and public sector, reviewed the literature and existing guidelines and policy regulations. Detailed review of literature was circulated to the members, and the Group met on 11th March 2019 at New Delhi for a day-long deliberation on framing the guidelines. The consensus statements and recommendations formulated by the Group were circulated to the participants and a consensus document was finalized. CONCLUSIONS: The Group suggests a new acronym 'JUNCS' foods, to cover a wide variety of concepts related to unhealthy foods (Junk foods, Ultra-processed foods, Nutritionally inappropriate foods, Caffeinated/colored/carbonated foods/beverages, and Sugar-sweetened beverages). The Group concludes that consumption of these foods and beverages is associated with higher free sugar and energy intake; and is associated with higher body mass index (and possibly with adverse cardiometabolic consequences) in children and adolescents. Intake of caffeinated drinks may be associated with cardiac and sleep disturbances. The Group recommends avoiding consumption of the JUNCS by all children and adolescents as far as possible and limit their consumption to not more than one serving per week. The Group recommends intake of regional and seasonal whole fruits over fruit juices in children and adolescents, and advises no fruit juices/drinks to infants and young children (age <2y), whereas for children aged 2-5 y and >5-18 y, their intake should be limited to 125 mL/day and 250mL/day, respectively. The Group recommends that caffeinated energy drinks should not be consumed by children and adolescents. The Group supports recommendations of ban on sale of JUNCS foods in school canteens and in near vicinity, and suggests efforts to ensure availability and affordability of healthy snacks and foods. The Group supports traffic light coding of food available in school canteens and recommends legal ban of screen/print/digital advertisements of all the JUNCS foods for channels/magazines/websites/social media catering to children and adolescents. The Group further suggests communication, marketing and policy/taxation strategies to promote consumption of healthy foods, and limit availability and consumption of the JUNCS foods.

Outcome of Children with Severe Acute Malnutrition and Diarrhea: a Cohort Study.

PURPOSE: Severe acute malnutrition (SAM) is an important public health problem which contributes to significant number of under five deaths. Protocol based management significantly decreases risk of deaths in children with medical complications. METHODS: Outcome of children aged 2 months-5 years admitted and fulfilling definition of SAM having diarrhea (group A) was compared to children with SAM having medical complications other than diarrhea (group B). Both groups were managed according to standard recommended protocols and monitored and followed up for 12 weeks after discharge. RESULTS: The average weight gain, defaulter rate, primary failure, secondary relapse rate and readmission rate were similar in both groups. Length of stay in group A was three days longer (p-value=0.039). Discharge rate was comparable with overall 68% of children successfully discharged and 50% of children reaching weight/height >-2 standard deviation at follow-up of 12 weeks. CONCLUSION: The current management protocol is equally effective for managing children with SAM having diarrhea. Good adherence to management protocol of dehydration and timely modification of therapeutic feeds in children with persistent diarrhea results in satisfactory weight gain.

Reliability of coeliac serology in monitoring dietary adherence in children with coeliac disease on a gluten-free diet.

This study aimed to determine the utility of coeliac serology for monitoring dietary adherence in coeliac disease. Serum anti-tTg IgA and anti-DGP IgG levels of 42 newly diagnosed patients were measured at diagnosis and at intervals of three, six and 12 months after starting a gluten-free diet. Both anti-tTg and anti-DGP antibodies decreased in all patients. The decline in the former was significantly greater at 3-12 months throughout, while in the latter the decline was seen only at three months but not subsequently. Serial measurement of coeliac serology may help in monitoring adherence to a gluten-free diet.

Relationship of physical activity with body image, self esteem sedentary lifestyle, body mass index and eating attitude in adolescents: A cross-sectional observational study.

AIM: To Study Relationship of physical activity (PA) with body image, self-esteem, body mass index (BMI), sedentary lifestyle and eating attitude in adolescents. METHODS: An observational cross-sectional study done at the Centre for Adolescent Health, Kalawati Saran Children Hospital, Lady Hardinge Medical College, New Delhi, India. Volunteering adolescents between the age group of 13 and 18 years were included and assessed using PA questionnaire for adolescents Score, Body Shape Questionnaire-34 Score, Rosenberg self esteem Score, adolescent sedentary activity questionnaire score, eating attitude test (EAT-26) and BMI Z-score. Relationship of these scales to various parameters was assessed using correlation and regression. RESULTS: A total of 191 boys and girls were included in the study; 25% had underweight, 75% were normal (only 1 child had overweight and none had obesity). Three fourth (77%) of the children had low PA. The girls were relatively more inactive (83.9% girls vs. 72.1%boys). Most (90.05%) subjects did not have any concerns related to body image. Almost all the subjects had normal or high self esteem. Nearly one quarter of the subjects (23.56%) had disordered eating behaviours. Multiple regression found the PA is positively dependent on EAT 26 score and adolescent sedentary activity questionnaire (ASAQ) score (sedentary score) in girls, whereas in males ASAQ (sedentary score) score was only variable related to physical activity questionnaire for adolescents score (PAQ-A). CONCLUSION: Normal weight and underweight adolescents had minimal PA and despite this, almost all had normal self-esteem and body image. PA was significantly related to eating and sedentary behaviours.

Plakophilin3 loss leads to an increase in lipocalin2 expression, which is required for tumour formation.

An increase in tumour formation and metastasis are observed upon plakophilin3 (PKP3) loss. To identify pathways downstream of PKP3 loss that are required for increased tumour formation, a gene expression analysis was performed, which demonstrated that the expression of lipocalin2 (LCN2) was elevated upon PKP3 loss and this is consistent with expression data from human tumour samples suggesting that PKP3 loss correlates with an increase in LCN2 expression. PKP3 loss leads to an increase in invasion, tumour formation and metastasis and these phenotypes were dependent on the increase in LCN2 expression. The increased LCN2 expression was due to an increase in the activation of p38 MAPK in the HCT116 derived PKP3 knockdown clones as LCN2 expression decreased upon inhibition of p38 MAPK. The phosphorylated active form of p38 MAPK is translocated to the nucleus upon PKP3 loss and is dependent on complex formation between p38 MAPK and PKP3. WT PKP3 inhibits LCN2 reporter activity in PKP3 knockdown cells but a PKP3 mutant that fails to form a complex with p38 MAPK cannot suppress LCN2 promoter activity. Further, LCN2 expression is decreased upon loss of p38ß, but not p38α, in the PKP3 knockdown cells. These results suggest that PKP3 loss leads to an increase in the nuclear translocation of p38 MAPK and p38ß MAPK is required for the increase in LCN2 expression.

Stevens-Johnson syndrome and toxic epidermal necrolysis-like cutaneous presentation of chikungunya fever: A case series.

Chikungunya fever is a benign, self-limiting, acute viral illness. An epidemic occurred in New Delhi, India, in August and September 2016. We observed many cases with atypical cutaneous features mimicking Stevens-Johnson syndrome and toxic epidermal necrolysis during this epidemic, especially in infants and children. Twenty-one children (13 [61.9%] boys, 8 [38%] girls) presenting with vesico-bullous and necrotic lesions were reviewed. Cutaneous presentation included vesicles and bullae with purpuric macules and necrosis, seen in 16 (76%) patients. Skin lesions resolved in 5-7 days, leaving behind hyperpigmentation in seven (33.3%) patients and hypopigmentation in three (14.2%). Minor oral erosions were observed in three (14.2%) patients, and palmoplantar erythema was seen in four (19.04%). It is essential for dermatologists to understand the Stevens-Johnson syndrome and toxic epidermal necrolysis-like presentation of chikungunya and not to misinterpret it as true Stevens-Johnson syndrome and toxic epidermal necrolysis, which will lead to unnecessary intervention and management.

Oncogenic RAS-Induced Perinuclear Signaling Complexes Requiring KSR1 Regulate Signal Transmission to Downstream Targets.

The precise characteristics that distinguish normal and oncogenic RAS signaling remain obscure. Here, we show that oncogenic RAS and BRAF induce perinuclear relocalization of several RAS pathway proteins, including the kinases CK2 and p-ERK1/2 and the signaling scaffold KSR1. This spatial reorganization requires endocytosis, the kinase activities of MEK-ERK and CK2, and the presence of KSR1. CK2α colocalizes with KSR1 and Rab11, a marker of recycling endosomes, whereas p-ERK associates predominantly with a distinct KSR1-positive endosomal population. Notably, these perinuclear signaling complexes (PSC) are present in tumor cell lines, mouse lung tumors, and mouse embryonic fibroblasts undergoing RAS-induced senescence. PSCs are also transiently induced by growth factors (GF) in nontransformed cells with delayed kinetics (4-6 hours), establishing a novel late phase of GF signaling that appears to be constitutively activated in tumor cells. PSCs provide an essential platform for RAS-induced phosphorylation and activation of the prosenescence transcription factor C/EBPß in primary MEFs undergoing senescence. Conversely, in tumor cells, C/EBPß activation is suppressed by 3'UTR-mediated localization of Cebpb transcripts to a peripheral cytoplasmic domain distinct from the PSC region. Collectively, our findings indicate that sustained PSC formation is a critical feature of oncogenic RAS/BRAF signaling in cancer cells that controls signal transmission to downstream targets by regulating selective access of effector kinases to substrates such as C/EBPß.Significance: In addressing the long-standing question of the difference between normal and oncogenic RAS pathway signaling, this study shows that oncogenic RAS specifically triggers constitutive endocytosis-dependent movement of effector kinases to a perinuclear region, thereby creating connections to unique downstream targets such as the core prosenescence and the inflammatory regulatory transcription factor C/EBPß. Cancer Res; 78(4); 891-908. ©2017 AACR.