Case report of an infant with congenital mesoblastic nephroma leading to pulmonary metastasis.

Congenital mesoblastic nephroma is considered a tumour with favourable clinical behaviour with only few reported cases of metastases. We report an infant who underwent complete resection and later developed pulmonary metastasis. Ten-month-old baby girl initially presented at 3 weeks of age with macroscopic haematuria, hypertension and a lumbar mass. Contrast-enhanced computed tomography revealed a tumour arising from the left kidney without local invasion or metastasis. She underwent left nephrectomy. Immunohistochemistry confirmed a cellular type of congenital mesoblastic nephroma. At 10 months, she presented with difficulty in breathing. Contrast-enhanced computed tomography revealed an opacity in the right hemi-thorax. Histology of lung mass was suggestive of deposits from the previously excised mesoblastic nephroma. She developed a right-sided haemothorax and succumbed. This case report highlights the fact that even though congenital mesoblastic nephromas are considered tumours with favourable clinical behaviour, they can present later with distant metastasis. Therefore, clinicians need to be aware of this rare malignant potential and adhere to meticulous follow-up protocols.

Prediction Equation for Physical Activity Energy Expenditure in 11-13-Year-Old Sri Lankan Children.

This study aimed to develop a regression equation to predict physical activity energy expenditure (PAEE) using accelerometry. Children aged 11-13 years were recruited and randomly assigned to validation (n = 54) and cross-validation (n = 25) groups. The doubly labelled water (DLW) technique was used to assess energy expenditure and accelerometers were worn by participants across the same period. A preliminary equation was developed using stepwise multiple regression analysis with sex, height, weight, body mass index, fat-free mass, fat mass and counts per minute (CPM) as independent variables. Goodness-of-fit statistics were used to select the best prediction variables. The PRESS (predicted residual error sum of squares) statistical method was used to validate the final prediction equation. The preliminary equation was cross-validated on an independent group and no significant (p > 0.05) difference was observed in the PAEE estimated from the two methods. Independent variables of the final prediction equation (PAEE = [0.001CPM] - 0.112) accounted for 70.6% of the variance. The new equation developed to predict PAEE from accelerometry was found to be valid for use in Sri Lankan children.

Asia-Pacific consensus statement on integrated 24-hour activity guidelines for the early years.

Background: Early childhood is a vital period for development and growth. Promoting beneficial lifestyle behaviours in early childhood can help optimise children's health, development and learning, shape their behaviours in adulthood and offer the best protection against future non-communicable diseases (NCDs). In the Asia-Pacific region, NCDs are significant causes of healthcare burden and mortality. Furthermore, there is also a high prevalence of adverse metabolic risk factors and unhealthy lifestyle behaviours among these children. Method: Representatives from 19 Asia-Pacific nations and/or jurisdictions developed a consensus statement on integrated 24-hour activity guidelines for the early years using the GRADE-ADOLOPMENT framework. Findings: These guidelines apply to all infants, toddlers and pre-schoolers below 5 years of age. The guidelines aim to provide a holistic and practical approach to lifestyle activities by framing physical activity, sedentary behaviour and sleep within a 24-hour period. Dietary patterns were included as they play an integral role in metabolic health and energy balance. Interpretation: Aligned with the World Health Organization's Global Action Plan for the Prevention and Control of NCDs through health promotion interventions in early life, through cultivating healthy lifestyle behaviours in the children's early years, we aim to provide children with the best start in life and reduce the burden of future NCDs in the Asia-Pacific region. Funding: Funded by Integrated platform for research in advancing metabolic health outcomes of women and children.

Assessment of iron overload in a cohort of Sri Lankan patients with transfusion dependent beta thalassaemia and its correlation with pathogenic variants in HBB, HFE, SLC40A1, and TFR2 genes.

BACKGROUND: Iron overload (IO) is a complication in transfusion dependent beta thalassaemia (TDT). Pathogenic variants in genes involving iron metabolism may confer increased risk of IO. The objective of this study was to determine the magnitude of the cardiac and hepatic IO and determine whether pathogenic variants in HFE, SLC40A1 and TFR2 genes increase the risk of IO in a cohort of TDT patients in Sri Lanka. MATERIALS AND METHODS: Fifty-seven (57) patients with TDT were recruited for this study. Serum ferritin was done once in 3 months for a period of one year in all. Those who were ≥ 8 years of age (40 patients) underwent T2* MRI of the liver and heart. Fifty-two (52) patients underwent next generation sequencing (NGS) to identify pathogenic variants in HBB, HFE, SLC40A1 and TFR2 genes. RESULTS: The median age of the patients of this cohort was 10 years. It comprised of 30 (52.6%) boys and 27 (47.4%) girls. The median level of serum ferritin was 2452 ng/dl. Hepatic IO was seen in 37 (92.5%) patients and cardiac IO was seen in 17 (42.5%) patients. There was no statistically significant correlation between serum ferritin and hepatic or cardiac IO. Thirty-two (61.5%), 18 (34.6%), 2 (3.8%) of patients were homozygotes, compound heterozygotes and heterozygotes for pathogenic variants in the HBB gene. Eight (15.4%) and 1 (1.9%) patients were heterozygotes for pathogenic and likely pathogenic variants of HFE genes respectively. There were no pathogenic variants for the TfR2 and SLC40A1 genes. The heterozygotes of the pathogenic variants of the HFE were not at increased risk of IO. CONCLUSIONS: Cardiac T2* MRI helps to detect cardiac IO in asymptomatic patients. It is important to perform hepatic and cardiac T2* MRI to detect IO in patients with TDT. There was no statistically significant correlation between pathogenic variants of HBB and HFE genes with hepatic and cardiac IO in this cohort of patients.

Efficacy of a Dengue Vaccine Candidate (TAK-003) in Healthy Children and Adolescents 2 Years after Vaccination.

BACKGROUND: Takeda's dengue vaccine is under evaluation in an ongoing phase 3 efficacy study; we present a 2-year update. METHODS: Children (20 099, 4-16 years old) were randomized to receive 2 doses of TAK-003 or placebo 3 months apart and are under surveillance to detect dengue by serotype-specific RT-PCR. RESULTS: Cumulative efficacy against dengue approximately 27 months since first dose was 72.7% (95% confidence interval [CI], 67.1%-77.3%), including 67.0% (95% CI, 53.6%-76.5%) in dengue-naive and 89.2% (95% CI, 82.4%-93.3%) against hospitalized dengue. In the second year, decline in efficacy was observed (56.2%; 95% CI, 42.3%-66.8%) with the largest decline in 4-5 year olds (24.5%; 95% CI, -34.2% to 57.5%); efficacy was 60.6% (95% CI, 43.8%-72.4%) in 6-11 year and 71.2% (95% CI, 41.0%-85.9%) in 12-16 year age groups. As TAK-003 efficacy varies by serotype, changes in serotype dominance partially contributed to efficacy differences in year-by-year analysis. No related serious adverse events occurred during the second year. CONCLUSIONS: TAK-003 demonstrated continued benefit independent of baseline serostatus in reducing dengue with some decline in efficacy during the second year. Three-year data will be important to see if efficacy stabilizes or declines further.Clinical Trials Registration. NCT02747927.Takeda's tetravalent dengue vaccine (TAK-003) continued to demonstrate benefit in reducing dengue independent of baseline serostatus up to 2 years after completing vaccination with some decline in efficacy during the second year in 4-16 year olds in dengue-endemic countries.

Three-year Efficacy and Safety of Takeda's Dengue Vaccine Candidate (TAK-003).

BACKGROUND: Takeda's live attenuated tetravalent dengue vaccine candidate (TAK-003) is under evaluation in a long-term clinical trial across 8 dengue-endemic countries. Previously, we have reported its efficacy and safety in both seronegative and seropositive participants and that its performance varies by serotype, with some decline in efficacy from first to second year postvaccination. This exploratory analysis provides an update with cumulative and third-year data. METHODS: Healthy 4-16 year olds (n = 20099) were randomized 2:1 to receive TAK-003 or placebo (0, 3 month schedule). The protocol included baseline serostatus testing of all participants and detection of all symptomatic dengue throughout the trial with a serotype specific reverse transcriptase-polymerase chain reaction. RESULTS: Cumulative efficacy after 3 years was 62.0% (95% confidence interval, 56.6-66.7) against virologically confirmed dengue (VCD) and 83.6% (76.8-88.4) against hospitalized VCD. Efficacy was 54.3% (41.9-64.1) against VCD and 77.1% (58.6-87.3) against hospitalized VCD in baseline seronegatives, and 65.0% (58.9-70.1) against VCD and 86.0% (78.4-91.0) against hospitalized VCD in baseline seropositives. Efficacy against VCD during the third year declined to 44.7% (32.5-54.7), whereas efficacy against hospitalized VCD was sustained at 70.8% (49.6-83.0). Rates of serious adverse events were 2.9% in TAK-003 group and 3.5% in placebo group during the ongoing long-term follow-up (ie, second half of the 3 years following vaccination), but none were related. No important safety risks were identified. CONCLUSIONS: TAK-003 was efficacious against symptomatic dengue over 3 years. Efficacy declined over time but remained robust against hospitalized dengue. A booster dose evaluation is planned.

Effect of Prior Symptomatic Dengue Infection on Dengue Haemorrhagic Fever (DHF) in Children.

Pathogenesis of dengue haemorrhagic fever is not fully understood, but it is thought that there is antibody enhancement during the secondary infection, which causes severe dengue haemorrhagic fever (DHF). Therefore, patients who have DHF should have a documented history of symptomatic dengue infection in the past. A retrospective descriptive-analytical study was conducted at the University Paediatric Unit at Lady Ridgeway Hospital for Children, Colombo, Sri Lanka. All children who had fulfilled the criteria for DHF admitted to the unit from April 2018 to September 2018 were recruited into the study. Relevant data were collected from bed head tickets. One hundred and eighty-four children were included in the final analysis. Thirty-three (17.9%) had a past history of documented symptomatic dengue infection, while 82.1% did not have a documented dengue infection. Twelve patients had dengue shock syndrome, and none of them had previously documented symptomatic dengue fever. Dextran was used in 96 patients in the critical phase. Twelve (42%) patients with past documented symptomatic dengue fever needed dextran while 84 (54.9%) patients without a documented past history of dengue fever needed dextran. In our clinical observation, we noticed that children with DHF mostly did not have a documented symptomatic prior dengue infection, while those with a documented symptomatic prior infection had a milder subsequent illness. In fact, the majority (82.1%) of patients with DHF did not have documented previous symptomatic dengue infection. It was also observed that the clinical course of subsequent dengue infection was less severe in patients with previously documented symptomatic dengue fever. This finding should be further evaluated in a larger scale study minimizing the all-confounding factors. This fact is more important in selecting recipients for vaccines against the dengue virus, which are supposed to produce immunity against the virus without causing the severe disease.

Micronutrient status and associated factors of adiposity in primary school children with normal and high body fat in Colombo municipal area, Sri Lanka.

BACKGROUND: The prevalence of obesity and associated risk of chronic diseases are increasing among the paediatric population. The effectiveness of preventive measures and interventions are likely to improve when all factors which associate with obesity in a specific target group are considered. Currently such comprehensive data is unavailable for Sri Lankan children aged 8-9 years. METHODS: This paper pertains to the data collected from August-2015 to November-2016 for a case-control study which included cases (high body fat) (N = 160; males-81) and controls (normal body fat) (N = 164; males-80) recruited from primary schools in the Colombo Municipal area. Anthropometry and body composition (Bioelectrical impedance analysis-BIA) were measured. Diet, physical activity and socio-demographic data were collected using validated interviewer administered questionnaires. Serum concentrations of vitamins A, D [25(OH)D], E, folate (serum and red blood cell-RBC), zinc (Zn), selenium (Se), copper (Cu), iron (Fe), magnesium (Mg), calcium (Ca), chromium (Cr), manganese (Mn), cobalt (Co), ferritin, leptin and high sensitivity C-reactive protein (hs-CRP) were assessed using fasting blood samples. RESULTS: Cases were from higher socio-economic strata and spent significantly less time on physical activities, more time on sedentary behaviours and consumed higher energy compared to the controls. Cases from both genders had significantly lower levels of vitamin D [25 (OH)D], Fe and Mg (all p < 0.05) and higher levels of Cu and Ca (all p < 0.01) compared to controls. Higher levels of ferritin and Cr were seen among male (p < 0.001) and female (p > 0.05) cases compared to the controls. However, total serum folate levels were lower in male (p < 0.01) and female (p > 0.05) cases while the RBC folate levels were higher among male (p < 0.01) and female (p > 0.05) cases compared with controls. Vitamins A, E, Se, Mn and Co (p > 0.05) were not significantly different between groups. The inflammatory markers, both hs-CRP and leptin levels were higher among cases (p < 0.001) compared to the controls. CONCLUSIONS: This study highlights higher socio-economic status, lower physical activity, more sedentary behaviours, higher energy intake and inconsistent distribution of micronutrients among the children with high body fat when compared with the control group. Increased levels of inflammatory markers indicate the presence of the risk of chronic inflammation in children with high body fat.

Differences in serum markers of oxidative stress in well controlled and poorly controlled asthma in Sri Lankan children: a pilot study.

BACKGROUND: Asthma is a disease characterised by hyper responsiveness and bronchoconstriction of airways, and is a major health burden globally. A dysfunction of the oxidant-antioxidant balance, termed oxidative stress, has been implicated in the pathophysiology of asthma. The present study aims to assess the changes in oxidative stress markers, namely nitric oxide metabolites and antioxidant capacity, in children with poorly controlled and well controlled asthma, in comparison to healthy controls. METHODS: The present study enrolled 72 children (ages 5-15 years) classified into three groups: (1) poorly controlled asthma (n = 20), (2) well controlled asthma (n = 24) and (3) healthy controls (n = 27). An interviewer-administered questionnaire was used to record socio-demographic data of the participants. The serum concentrations of the oxidant markers (nitrite, nitrate and total nitric oxide metabolites [NOx]) were determined using the Griess test, and the total antioxidant capacity (TAOC) was determined using the ABTS decolorisation method. The concentrations of these markers were compared across the three groups. RESULTS: The three study groups were similar in terms of socio-demographic data. The differences across the three groups were statistically significant for serum concentrations of nitrate and NOx (but not nitrite) and serum TAOC. Further analyses showed that the disparity for nitrate and NOx concentrations was greatest between poorly controlled asthma and healthy controls (p = 0.001 and p < 0.001) compared to the well-controlled asthmatics and healthy controls (p = 0.036 and p = 0.049). A significant difference in serum nitrate and NOx concentrations was not observed between the two asthma groups (p = 0.311 and 0.203). The TAOC were significantly lower in poorly controlled asthmatics as compared to well-controlled asthmatics (p = 0.003) and healthy controls (p < 0.001). However, there was no significant difference in the serum TAOC between healthy controls and well-controlled asthmatics (p = 0.496). These findings may indicate that it is perhaps the higher TAOC that contributes to the well controlled state of asthma. CONCLUSIONS: The present study indicated that an imbalance of oxidants and antioxidants in the serum may have an underlying role in asthma pathophysiology, and how these markers may be effective in asthma management.

Association of Serum Uric acid and Gamma-glutamyltransferase with Obesity Related Metabolic Derangements in a Cohort of Children with Obesity in Sri Lanka

Introduction: Gamma-glutamyltransferase (GGT) and serum uric acid (UA) are known to be associated with cardiovascular disease in obese children Objectives: To determine the association of serum UA and GGT with components of metabolic syndrome (MetS) in a group of obese children and determine the validity of UA and GGT in predicting MetS. Methods: Cross sectional analytical study was conducted among 205, 5-15 year old obese children. After a 12- hour overnight fast, blood was drawn for glucose, lipid profile, alanine aminotransferase (ALT), aspartate aminotransferase (AST), insulin, UA and GGT. Oral glucose tolerance test (OGTT) was done with 2 hour plasma glucose. Height, weight, waist circumference, blood pressure and fat mass were measured. USS of abdomen was performed to assess hepatic steatosis. Results: Chi square test showed statistically significant associations between GGT and UA with triglyceride, insulin resistance (HOMA-IR), AST, ALT, AST/ALT ratio and fatty liver. Additionally UA showed a significant association with the OGTT. With existing cut offs (GGT >30 U/L and UA >330 µmol/L) the sensitivity and specificity of GGT in predicting MetS was 19% (95% CI, 13.63-24.37) and 88.4% (95% CI, 84.02-92.78) respectively while for UA was 28.6% (95% CI, 22.42-34.78) and 80.2% (95% CI, 74.75-85.65) respectively. A new cut off value of 19.5 U/L (sensitivity 56% and specificity 55%) for GGT and 275.5 µmol/L (sensitivity 61% and specificity 54%) for UA predicted MetS with greater accuracy. Conclusion: GGT and UA are strongly associated with metabolic derangements and these biomarkers are rather weak in predicting MetS.

Correction to: Dubin-Johnson syndrome and intrahepatic cholestasis of pregnancy in a Sri Lankan family: a case report.

Following publication of the original article [1], the authors requested the following corrections: 1. Author 2-given name should be Dilanthi and family name Warawitage. 2. Author 6-given name should be Nalika and family name de Silva.

Dubin-Johnson syndrome and intrahepatic cholestasis of pregnancy in a Sri Lankan family: a case report.

BACKGROUND: Dubin-Johnson syndrome and intrahepatic cholestasis of pregnancy are rare chronic liver disorders. Dubin-Johnson syndrome may manifest as conjugated hyperbilirubinemia, darkly pigmented liver, presence of abnormal pigment in the parenchyma of hepatocytes and abnormal distribution of the coproporphyrin isomers I and III in the urine. Intrahepatic cholestatic jaundice of pregnancy presents as pruritus, abnormal liver biochemistry and increased serum bile acids. CASE PRESENTATION: A Sri Lankan girl presented with recurrent episodes of jaundice. She had conjugated hyperbilirubinaemia with diffuse, coarse brown pigments in the hepatocytes. Urine coproporphyrin examination suggested Dubin-Johnson syndrome. Genetic studies confirmed missense homozygous variant p.Trp709Arg in the ATP-binding cassette sub-family C member 2 gene ABCC2 that encodes the Multidrug resistance-associated protein 2 that causes Dubin-Johnson syndrome. The gene study of the mother revealed the same missense variant in ABCC2/MRP2 but with a heterozygous status, and in addition a homozygous missense variant p.Val444Ala in the ATP-binding cassette, sub-family B member 11 gene ABCB11 that encodes the bile salt export pump. CONCLUSION: Dubin-Johnson syndrome should be considered when the common causes for conjugated hyperbilirubinaemia have been excluded, and patient has an increased percentage of direct bilirubin relative to total bilirubin concentration. Its early diagnosis prevents repeated hospital admissions and investigations. Knowledge of a well known homozygous variant in ABCB11 gene could help in the management of pregnancy.

Toxocara seropositivity in Sri Lankan children with asthma.

BACKGROUND: Toxocariasis occurs in humans due to infection with Toxocara canis or T. cati, the nematode parasites of dogs and cats, respectively. The relationship between toxocariasis and asthma is complex, with some studies demonstrating that children with asthma were more likely to be Toxocara seropositive as compared to non-asthmatic children, and other studies indicating no such significant relationship. The aim of the present study was to investigate Toxocara seropositivity and its association with asthma in a selected group of Sri Lankan children. METHODS: Two groups of children were studied: group 1 included 100 children with confirmed bronchial asthma who were on regular inhaler steroid treatment for asthma; group 2 included 96 children who did not have physician-diagnosed asthma or upper respiratory tract infections, attending the same hospital. Diagnosis of Toxocara seropositivity was based on IgG Toxocara Microwell Serum Elisa Kits. Enzyme-linked immunosorbent assay was regarded as positive for a reading of 0.3 optical density units. Stool samples were examined for helminth ova. RESULTS: Toxocara seropositivity in children with asthma was 29% and this was significantly more than Toxocara seropositivity among non-asthmatic children (P < 0.001). Toxocara seropositivity was identified as a significant risk factor of asthma in a univariate model. Eosinophilia was seen in a significantly higher proportion of non-asthmatic and asthmatic children who were Toxocara seropositive. Toxocara seropositivity, however, was not identified as a significant risk factor in a multivariate model. CONCLUSIONS: The analysis confirmed previously identified risk factors for asthma but there was no association between the helminth parasitic infection, toxocariasis and bronchial asthma in children.