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1.  Two years of school-based intervention program could improve the physical fitness among Ecuadorian adolescents at health risk: subgroups analysis from a cluster-randomized trial 
BMC Pediatrics  2016;16:51.
Adolescents with overweight and poor physical fitness have an increased likelihood of developing cardiovascular diseases during adulthood. In Ecuador, a health promotion program improved the muscular strength and speed-agility, and reduced the decline of the moderate-to-vigorous physical activity of adolescents after 28 months. We performed a sub-group analysis to assess the differential effect of this intervention in overweight and low-fit adolescents.
We performed a cluster-randomized pair matched trial in schools located in Cuenca–Ecuador. In total 20 schools (clusters) were pair matched, and 1440 adolescents of grade 8 and 9 (mean age of 12.3 and 13.3 years respectively) participated in the trial. For the purposes of the subgroup analysis, the adolescents were classified into groups according to their weight status (body mass index) and aerobic capacity (scores in the 20 m shuttle run and FITNESSGRAM standards) at baseline. Primary outcomes included physical fitness (vertical jump, speed shuttle run) and physical activity (proportion of students achieving over 60 min of moderate–to-vigorous physical activity/day). For these primary outcomes, we stratified analysis by weight (underweight, normal BMI and overweight/obese) and fitness (fit and low fitness) groups. Mixed linear regression models were used to assess the intervention effect.
The prevalence of overweight/obesity, underweight and poor physical fitness was 20.3 %, 5.8 % and 84.8 % respectively. A higher intervention effect was observed for speed shuttle run in overweight (β = −1.85 s, P = 0.04) adolescents compared to underweight (β = −1.66 s, P = 0.5) or normal weight (β = −0.35 s, P = 0.6) peers. The intervention effect on vertical jump was higher in adolescents with poor physical fitness (β = 3.71 cm, P = 0.005) compared to their fit peers (β = 1.28 cm, P = 0.4). The proportion of students achieving over 60 min of moderate-to-vigorous physical activity/day was not significantly different according to weight or fitness status.
Comprehensive school-based interventions that aim to improve diet and physical activity could improve speed and strength aspects of physical fitness in low-fit and overweight/obese adolescents.
Trial registration identifier NCT01004367. Registered October 28, 2009.
Electronic supplementary material
The online version of this article (doi:10.1186/s12887-016-0588-8) contains supplementary material, which is available to authorized users.
PMCID: PMC4840972  PMID: 27102653
Fitness; Physical activity; Adolescents; Randomized control trial; Subgroup analysis; Body mass index
2.  Salivary miRNA profiles identify children with autism spectrum disorder, correlate with adaptive behavior, and implicate ASD candidate genes involved in neurodevelopment 
BMC Pediatrics  2016;16:52.
Autism spectrum disorder (ASD) is a common neurodevelopmental disorder that lacks adequate screening tools, often delaying diagnosis and therapeutic interventions. Despite a substantial genetic component, no single gene variant accounts for >1 % of ASD incidence. Epigenetic mechanisms that include microRNAs (miRNAs) may contribute to the ASD phenotype by altering networks of neurodevelopmental genes. The extracellular availability of miRNAs allows for painless, noninvasive collection from biofluids. In this study, we investigated the potential for saliva-based miRNAs to serve as diagnostic screening tools and evaluated their potential functional importance.
Salivary miRNA was purified from 24 ASD subjects and 21 age- and gender-matched control subjects. The ASD group included individuals with mild ASD (DSM-5 criteria and Autism Diagnostic Observation Schedule) and no history of neurologic disorder, pre-term birth, or known chromosomal abnormality. All subjects completed a thorough neurodevelopmental assessment with the Vineland Adaptive Behavior Scales at the time of saliva collection. A total of 246 miRNAs were detected and quantified in at least half the samples by RNA-Seq and used to perform between-group comparisons with non-parametric testing, multivariate logistic regression and classification analyses, as well as Monte-Carlo Cross-Validation (MCCV). The top miRNAs were examined for correlations with measures of adaptive behavior. Functional enrichment analysis of the highest confidence mRNA targets of the top differentially expressed miRNAs was performed using the Database for Annotation, Visualization, and Integrated Discovery (DAVID), as well as the Simons Foundation Autism Database (AutDB) of ASD candidate genes.
Fourteen miRNAs were differentially expressed in ASD subjects compared to controls (p <0.05; FDR <0.15) and showed more than 95 % accuracy at distinguishing subject groups in the best-fit logistic regression model. MCCV revealed an average ROC-AUC value of 0.92 across 100 simulations, further supporting the robustness of the findings. Most of the 14 miRNAs showed significant correlations with Vineland neurodevelopmental scores. Functional enrichment analysis detected significant over-representation of target gene clusters related to transcriptional activation, neuronal development, and AutDB genes.
Measurement of salivary miRNA in this pilot study of subjects with mild ASD demonstrated differential expression of 14 miRNAs that are expressed in the developing brain, impact mRNAs related to brain development, and correlate with neurodevelopmental measures of adaptive behavior. These miRNAs have high specificity and cross-validated utility as a potential screening tool for ASD.
Electronic supplementary material
The online version of this article (doi:10.1186/s12887-016-0586-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4841962  PMID: 27105825
miRNA; Next generation sequencing; RNA-Seq; Biomarker; Saliva
3.  Childhood asthma and physical activity: a systematic review with meta-analysis and Graphic Appraisal Tool for Epidemiology assessment 
BMC Pediatrics  2016;16:50.
Childhood asthma is a global problem affecting the respiratory health of children. Physical activity (PA) plays a role in the relationship between asthma and respiratory health. We hypothesized that a low level of PA would be associated with asthma in children and adolescents. The objectives of our study were to (1) summarize the evidence available on associations between PA and asthma prevalence in children and adolescents and (2) assess the role of PA in new-onset or incident asthma among children and adolescents.
We searched Medline, the Cochrane Library, and Embase and extracted data from original articles that met the inclusion criteria. Summary odds ratios (ORs) and confidence intervals (CIs) were used to express the results of the meta-analysis (forest plot). We explored heterogeneity using funnel plots and the Graphic Appraisal Tool for Epidemiology (GATE).
We retrieved 1,571 titles and selected 11 articles describing three cohort and eight cross-sectional studies for inclusion. A meta-analysis of the cohort studies revealed a risk of new-onset asthma in children with low PA (OR [95 % CI] 1.32 [0.95; 1.84] [random effects] and 1.35 [1.13; 1.62] [fixed effects]). Three cross-sectional studies identified significant positive associations between childhood asthma or asthma symptoms and low PA.
Children and adolescents with low PA levels had an increased risk of new-onset asthma, and some had a higher risk of current asthma/or wheezing; however, there was some heterogeneity among the studies. This review reveals a critical need for future longitudinal assessments of low PA, its mechanisms, and its implications for incident asthma in children. The systematic review was prospectively registered at PROSPERO (registration number: CRD42014013761; available at: [accessed: 24 March 2016]).
Electronic supplementary material
The online version of this article (doi:10.1186/s12887-016-0571-4) contains supplementary material, which is available to authorized users.
PMCID: PMC4836150  PMID: 27091126
Systematic review; Pediatric; Asthmatic disease; Exercise
4.  Exploring spatial variations and factors associated with childhood stunting in Ethiopia: spatial and multilevel analysis 
BMC Pediatrics  2016;16:49.
Stunting reflects a failure to receive adequate nutrition over a long period of time. Stunting is associated with adverse functional consequences including poor cognition, low educational performance, low adult wages, and poor reproductive outcomes. The objective of the study was to investigate spatial variations and factors associated with childhood stunting in Ethiopia.
This study is a secondary data analysis of the 2011 Ethiopian Demographic and Health Survey (EDHS). A total of 9893 children aged 0–59 months were included in the analysis. The Getis-Ord spatial statistical tool was used to identify high and low hotspots areas of stunting. A multilevel multivariable logistic regression was used to identify factors associated with stunting.
Statistically significant hotspots of stunting were found in northern parts of the country whereas low hotspots where there was less stunting than expected were found in the central, eastern, and western parts of the country. In the final model of multilevel logistic regression analysis, individual and community level factors accounted for 36.6 % of childhood stunting. Short birth interval [AOR = 1.68; 95%CI: (1.46–1.93)], being male [AOR = 1.20; 95%CI: (1.08–1.33)], and being from a male-headed household [AOR = 1.18; 95 % CI: (1.01–1.38)] were the factors that increased the odds of stunting at the individual level. Children in the age group between 24–35 months were more likely to be stunted than children whose age was less than one year [AOR = 6.61; 95 % CI: (5.17–8.44)]. The odds of stunting among children with severe anemia were higher than children with no anemia [AOR = 3.23; 95%CI: (2.35–4.43)]. Children with mothers who had completed higher education had lower odds of being stunted compared to children whose mothers had no formal education [AOR = 0.42; 95%CI: (0.18–0.94)]. The odds of being stunted were lower among children whose fathers completed higher education [AOR = 0.58; 95%CI: (0.38–0.89)] compared to children whose fathers had no formal education. Children whose mothers who had high a Body Mass Index (BMI) (≥25.0 kg/m2) were less likely to be stunted compared with children whose mothers had a normal BMI (18.5 kg/m2-24.9 kg/m2)[AOR = 0.69; 95%CI: (0.52–0.90)]. Children from the poorest wealth quintile had higher odds of being stunted compared to children from the richest wealth quintiles [AOR = 1.43; 95 % CI: (1.08–1.88)]. Unavailability of improved latrine facilities and living in the northern parts of the country (Tigray, Affar, Amhara and Benishangul-Gumuzregions) were factors associated with higher odds of stunting from the community-level factors.
Stunting in children under five years old is not random in Ethiopia, with hotspots of higher stunting in the northern part of Ethiopia. Both individual and community-level factors were significant determinants of childhood stunting. The regions with high hotspots of child stunting should be targeted with additional resources, and the identified factors should be considered for nutritional interventions.
PMCID: PMC4833938  PMID: 27084512
Stunting; Children; Ethiopia
5.  Retinoblastoma in a pediatric oncology reference center in Southern Brazil 
BMC Pediatrics  2016;16:48.
Retinoblastoma (Rb) is the most common intraocular tumor diagnosed in children in Brazil. However, detailed information is lacking regarding patient clinical demographics. This study aimed to determine the clinical profile of patients with Rb who were treated in a public university hospital in southern Brazil from 1983 to 2012. Methods: Patients’ medical records were reviewed to retrospectively identify patients with a principal diagnosis of Rb. Rb was classified as hereditary or non-hereditary. Clinical staging was reviewed by an ophthalmologist. Statistical analysis was performed using SPSS.
Of 165 patients with a diagnosis of Rb during this period, 140 were included in the study. Disease was unilateral in 65.0 % of patients, bilateral in 32.9 %, and trilateral in 2.1 %. The mean age at onset of the first sign/symptom was 18.1 month, and 35.7 % of patients were diagnosed during the first year of life. The most common presenting signs were leukocoria (73.6 %) and strabismus (20.7 %). The mean age at diagnosis was 23.5 months, and time to diagnosis was 5.4 months. In patients with clinical features of hereditary Rb, both onset of the first sign/symptom and diagnosis were at an earlier age than in patients without these features (12.3 vs 21.6 months [P = 0.001] and 15.9 vs 28.0 months [P < 0.001], respectively). However, there was no significant difference in overall survival between the two groups. Ocular stage at diagnosis was advanced in 76.5 % (Reese V) and 78.1 % (International Classification D or E). Of patients with unilateral and bilateral disease, 35.2 % and 34.8 %, respectively, had extraocular disease at diagnosis; 10.7 % had metastatic disease at diagnosis. Enucleation was observed in 88.1 % and exenteration in 11.9 % of patients; 93.6 % patients were followed until 2012, and 22.9 % relapsed. Overall survival was 86.4 %.
Most Rb diagnoses are still diagnosed in advanced stages of the disease, considerably reducing overall survival time and the rate of eye and vision preservation.
Electronic supplementary material
The online version of this article (doi:10.1186/s12887-016-0579-9) contains supplementary material, which is available to authorized users.
PMCID: PMC4818960  PMID: 27038613
Retinoblastoma; Malignant tumors of the retina; Intraocular malignancies; Hereditary retinoblastoma; Pediatric tumors
6.  Association of maternal diabetes/glycosuria and pre-pregnancy body mass index with offspring indicators of non-alcoholic fatty liver disease 
BMC Pediatrics  2016;16:47.
Little is known about early life determinants of non-alcoholic fatty liver disease (NAFLD). We examined associations of maternal pregnancy diabetes/glycosuria and pre-pregnancy body mass index (BMI) with offspring markers of NAFLD and liver pathology and examined mediation by birthweight and concurrent offspring adiposity.
We used data from a UK prospective pregnancy cohort. Offspring underwent abdominal ultrasonography (USS) at mean age 17.8 years. Outcomes included USS-assessed fatty liver, estimated liver volume and shear velocity, a variant of elastography (a marker of liver fibrosis) (N = 1 215) and blood-based markers of liver pathology [alanine amino transferase, aspartate amino transferase, gamma- glutamyltransferase and haptoglobin] (N = 2 359).
2.1 % (N = 25) of participants had USS-assessed fatty liver [maternal diabetes/glycosuria (N = 7) and no diabetes/glycosuria (N = 18)]. Maternal diabetes/glycosuria was associated with greater odds of offspring USS fatty liver in confounder adjusted models [adjusted odds ratio (aOR) 6.74 (95 % confidence interval (CI) 2.47, 18.40)] and higher shear velocity [adjusted ratio of geometric mean (aRGM):1.10 (95 % CI 1.05, 1.15)]. These associations were not mediated by offspring birthweight or concurrent adiposity. Maternal diabetes/glycosuria was not associated with liver volume or blood-based outcomes. Greater maternal pre-pregnancy BMI was associated with greater odds of offspring USS fatty liver [aOR 2.72 (95 % CI: 1.20, 6.15)], higher liver volume [aRGM 1.03 (95 % CI 1.00, 1.07)] and shear velocity [aRGM1.03 (95 % CI: 1.01, 1.06)] in confounder adjusted models. These associations were largely mediated by offspring adiposity. Maternal pre-pregnancy BMI was not consistently associated with blood-based outcomes.
Results suggest that maternal pregnancy diabetes/glycosuria is associated with offspring NAFLD through mechanisms other than offspring’s own adiposity.
Electronic supplementary material
The online version of this article (doi:10.1186/s12887-016-0585-y) contains supplementary material, which is available to authorized users.
PMCID: PMC4818433  PMID: 27036545
Pregnancy diabetes; Glycosuria; Obesity; NAFLD; Fetal overnutrition; ALSPAC
7.  Who is our cohort: recruitment, representativeness, baseline risk and retention in the “Watch Me Grow” study? 
BMC Pediatrics  2016;16:46.
The “Watch Me Grow” (WMG) study examines the current developmental surveillance system in South West Sydney. This paper describes the establishment of the study birth cohort, including the recruitment processes, representativeness, follow-up and participants’ baseline risk for future developmental risk.
Newborn infants and their parents were recruited from two public hospital postnatal wards and through child health nurses during the years 2011–2013. Data was obtained through a detailed participant questionnaire and linked with the participant’s electronic medical record (EMR). Representativeness was determined by Chi-square analyses of the available clinical, psychosocial and sociodemographic EMR data, comparing the WMG participants to eligible non-participants. Reasons for non-participation were also elicited. Participant characteristics were examined in six, 12, and 18-month follow-ups.
The number of infants recruited totalled 2,025, with 50 % of those approached agreeing to participate. Reasons for parents not participating included: lack of interest, being too busy, having plans to relocate, language barriers, participation in other research projects, and privacy concerns. The WMG cohort was broadly representative of the culturally diverse and socially disadvantaged local population from which it was sampled. Of the original 2025 participants enrolled at birth, participants with PEDS outcome data available at follow-up were: 792 (39 %) at six months, 649 (32 %) at 12 months, and 565 (28 %) at 18 months. Participants with greater psychosocial risk were less likely to have follow-up outcome data. Almost 40 % of infants in the baseline cohort were exposed to at least two risk factors known to be associated with developmental risk.
The WMG study birth cohort is a valuable resource for health services due to the inclusion of participants from vulnerable populations, despite there being challenges in being able to actively follow-up this population.
PMCID: PMC4806415  PMID: 27013220
Participation bias; Recruitment; Birth cohort
8.  Simultaneous mutations of LAMB2 and NPHP1genes in a Chinese girl with isolated congenital nephrotic syndrome: a case report 
BMC Pediatrics  2016;16:44.
LAMB2 mutations cause Pierson syndrome (OMIM 609049), an autosomal recessive genetic disease typically characterized by congenital nephrotic syndrome (CNS) and early onset renal failure, as well as bilateral microcoria. NPHP1 mutations cause familial juvenile nephronophthisis type 1 (NPHP1, OMIM 256100), another autosomal recessive renal disease that usually occurs years after birth. Both Pierson syndrome and nephronophthisis cause end-stage renal disease and rare kidney diseases in children. We report an extremely rare case of concurrent mutations of LAMB2 and NPHP1 in a Chinese girl with isolated CNS and the association of the phenotype with novel non-truncating mutations of LAMB2.
Case presentation
A-34-day-old girl presented with CNS but no eye abnormalities, and mild hyperechogenicity of kidneys. A novel c.1176_1178delTCT mutation caused deletion of a glycine in exon 9 of LAMB2, and another mutation c.4923 + 2 T > G led to a splicing error. In addition, compound heterozygous mutations of NPHP1 were identified in this child using next generation sequencing, and confirmed by Sanger sequencing.
Mutations of the LAMB2 and NPHP1 are present in infants with isolated CNS. Next generation sequencing enabled high-throughput screening for mutant genes promptly, with clinically significant outcomes. In addition, our results expand the phenotype spectrum of LAMB2 mutations as the only renal manifestation.
PMCID: PMC4802576  PMID: 27004562
Congenital nephrotic syndrome; Pierson syndrome; Juvenile nephronophthisis; Next generation sequencing; Gene mutation
9.  The HI HOPES data set of deaf children under the age of 6 in South Africa: maternal suspicion, age of identification and newborn hearing screening 
BMC Pediatrics  2016;16:45.
Identification of deafness before 3 months of age substantially improves the socio-linguistic and cognitive development of deaf children. Existing studies demonstrating the feasibility of newborn hearing screening in South Africa have used small samples unrepresentative of general population characteristics. This study establishes the characteristics of the largest data set of deaf infants and their families in South Africa on which there is baseline and longitudinal data (n = 532); explores its representativeness in terms of socio-demographic features and reports on access to and quality of newborn hearing screening within the sample. It examines specifically the relationship between age of maternal suspicion of childhood deafness and age of identification of deafness by cohort characteristics.
Secondary analysis, using descriptive and inferential statistics, of a pre-existing longitudinal data set (n = 532) of deaf infants under 6 years of age, and their families, collected as routine monitoring of the HI HOPES (HH) early intervention programme.
The HH cohort is representative in terms of racial profile and private/public health care use but displays slightly higher level of maternal education and slightly lower socio-economic status than national comparators. 102 out of 532 infants had undergone newborn hearing screening, resulting in 29 true positives, 15 of whom would have met the criteria for targeted screening. Later onset deafness does not account for the 73 false negatives. The median age of maternal suspicion (n = 247) of infant deafness was 18 months; the median age of identification of 28 months. Age of identification was unrelated to private/public health care status. The median delay between age of suspicion and age of identification was significantly longer in the public sector (7 m; IQR 0–15 m) compared to the private sector (2 m; IQR 0–8.5 m) (p = 0.035). Age of suspicion was unrelated to level of maternal education. Earlier age of suspicion did not predict earlier identification.
Targeted screening as timely response to maternal suspicion offers a viable means to reduce substantially the age of identification of deafness in South Africa until implementation of newborn hearing screening on a population-wide basis can be justified.
PMCID: PMC4804475  PMID: 27004530
Newborn hearing screening; Maternal suspicion; Age of identification; Deaf infants; South Africa
10.  Echocardiographic pattern of rheumatic valvular disease in a contemporary sub-Saharan African pediatric population: an audit of a major cardiac ultrasound unit in Yaounde, Cameroon 
BMC Pediatrics  2016;16:43.
Rheumatic Heart Disease (RHD) remains a major cause of childhood acquired heart disease in developing countries. However reported echocardiographic features are limited to a few countries. This report is on the demographic and echocardiographic features of RHD in children using data from the largest referral hospital in Yaounde, the capital city of Cameroon.
The register of the cardiac ultrasound unit of the Yaounde General Hospital for the period 2003–2013 served as basis for data collection. RHD diagnosis was based on the World Heart Federation Criteria for the diagnosis of RHD. Demographic data, pattern of valve lesions and severity were analyzed.
A total of 1130 first echocardiographic examinations were performed in children aged ≤ 18 years. Sixty-five (5.8 %) had a definite echocardiographic diagnosis of RHD with their mean age being 11.8 years (SD 3.6) and 31 (47.1 %) being boys. The commonest primary reasons for requesting an echocardiographic examination were a clinical diagnosis of RHD (24.6 %) without heart failure, a clinical diagnosis of heart failure (24.6 %), and heart murmurs (21.5 %). Isolated mitral regurgitation was the most common valve lesion (49.2 %) and was frequently associated with aortic regurgitation (35.4 %). Severe lesions were found in 63.3 % of participants. No right heart lesion was reported.
A sizable proportion of children undergoing echocardiographic examination at this major referral hospital in Cameroon had RHD, with lesions found only on the left heart. These lesions predominated on the mitral valve, were commonly associated with aortic regurgitation, and more often severe.
PMCID: PMC4800770  PMID: 27000111
Rheumatic heart disease; Children; Cameroon
11.  Evaluation of the revised Nipissing District Developmental Screening (NDDS) tool for use in general population samples of infants and children 
BMC Pediatrics  2016;16:42.
There is widespread interest in identification of developmental delay in the first six years of life. This requires, however, a reliable and valid measure for screening. In Ontario, the 18-month enhanced well-baby visit includes province-wide administration of a parent-reported survey, the Nipissing District Developmental Screening (NDDS) tool, to facilitate early identification of delay. Yet, at present the psychometric properties of the NDDS are largely unknown.
812 children and their families were recruited from the community. Parents (most often mothers) completed the NDDS. A sub-sample (n = 111) of parents completed the NDDS again within a two-week period to assess test-retest reliability. For children 3 or younger, the criterion measure was the Bayley Scales of Infant Development, 3rd edition; for older children, a battery of other measures was used. All criterion measures were administered by trained assessors. Mild and severe delays were identified based on both published cut-points and on the distribution of raw scores. Sensitivity, specificity, positive and negative predictive values were calculated to assess agreement between tests.
Test-retest reliability was modest (Spearman’s rho = .62, p < 001). Regardless of the age of the child, the definition of delay (mild versus severe), or the cut-point used on the NDDS, sensitivities (from 29 to 68 %) and specificities (from 58 to 88 %) were poor to moderate.
The modest test-retest results, coupled with the generally poor observed agreement with criterion measures, suggests the NDDS should not be used on its own for identification of developmental delay in community or population-based settings.
PMCID: PMC4794856  PMID: 26983782
12.  Availability and affordability of essential medicines for children in the Western part of Ethiopia: implication for access 
BMC Pediatrics  2016;16:40.
Essential medicines (EMs) are those medicines which satisfy the priority health care needs of the population. Although it is a fundamental human right, access to essential medicines has been a big challenge in developing countries particularly for children. WHO recommends assessing the current situations on availability and affordability of EMs as the first step towards enhancing access to them. Therefore, the aim of this study was to assess access to EMs for children based on availability, affordability, and price.
We adapted the WHO and Health Action International tools to measure availability, affordability, and prices of EMs. We collected data on 22 EMs for children from 15 public to 40 private sectors’ drug outlets in east Wollega zone. Availability was expressed as percentage of drug outlets per sector that stocked surveyed medicines on the day of data collection, and prices were expressed as median price ratio. Affordability was measured as the number of daily wages required for the lowest-paid government unskilled worker (1.04 US $per day) to purchase one standard treatment of an acute condition or treatment for a chronic condition for a month.
The average availability of essential medicines was 43 % at public and 42.8 % at private sectors. Lowest priced medicines were sold at median of 1.18 and 1.54 times their international reference prices (IRP) in the public and private sectors, respectively. Half of these medicines were priced at 0.90 to 1.3 in the public sector and 1.23 to 2.07 in the private sector times their respective IRP. Patient prices were 36 % times higher in the private sector than in the public sector. Medicines were unaffordable for treatment of common conditions prevalent in the zone at both public and private sectors as they cost a day or more days’ wages for the lowest paid government unskilled worker.
Access to EMs to children is hampered by low availability and high price which is unaffordable. Thus, further study on larger scale is critical to identify acute areas for policy interventions such as price and or supply, and to enhance access to EMs to children.
Electronic supplementary material
The online version of this article (doi:10.1186/s12887-016-0572-3) contains supplementary material, which is available to authorized users.
PMCID: PMC4791837  PMID: 26979737
Access to medicine; Children; Availability; Affordability; Prices of medicine; East wollega zone; Nekemte town; Ethiopia
13.  The large contribution of twins to neonatal and post-neonatal mortality in The Gambia, a 5-year prospective study 
BMC Pediatrics  2016;16:39.
A high twinning rate and an increased risk of mortality among twins contribute to the high burden of infant mortality in Africa. This study examined the contribution of twins to neonatal and post-neonatal mortality in The Gambia, and evaluated factors that contribute to the excess mortality among twins.
We analysed data from the Basse Health and Demographic Surveillance System (BHDSS) collected from January 2009 to December 2013. Demographic and epidemiological variables were assessed for their association with mortality in different age groups.
We included 32,436 singletons and 1083 twins in the analysis (twining rate 16.7/1000 deliveries). Twins represented 11.8 % of all neonatal deaths and 7.8 % of post-neonatal deaths. Mortality among twins was higher than in singletons [adjusted odds ratio (AOR) 4.33 (95 % CI: 3.09, 6.06) in the neonatal period and 2.61 (95 % CI: 1.85, 3.68) in the post-neonatal period]. Post-neonatal mortality among twins increased in girls (P for interaction = 0.064), being born during the dry season (P for interaction = 0.030) and lacking access to clean water (P for interaction = 0.042).
Mortality among twins makes a significant contribution to the high burden of neonatal and post-neonatal mortality in The Gambia and preventive interventions targeting twins should be prioritized.
PMCID: PMC4791939  PMID: 26979832
Twins; HDSS; Mortality; Risk factors; Neonatal; Post-neonatal
14.  An analysis of volumes, prices and pricing trends of the pediatric antiretroviral market in developing countries from 2004 to 2012 
BMC Pediatrics  2016;16:41.
The pediatric antiretroviral (ARV) market is poorly described in the literature, resulting in gaps in understanding treatment access. We analyzed the pediatric ARV market from 2004 to 2012 and assessed pricing trends and associated factors.
Data on donor funded procurements of pediatric ARV formulations reported to the Global Price Reporting Mechanism database from 2004 to 2012 were analyzed.
Outcomes of interest were the volume and mean price per patient-year ARV formulation based on WHO ARV dosing recommendations for a 10 kg child. Factors associated with the price of formulations were assessed using linear regression; potential predictors included: country income classification, geographical region, market segment (originator versus generic ARVs), and number of manufacturers per formulation. All analyses were adjusted for type of formulations (single, dual or triple fixed-dose combinations (FDCs))
Data from 111 countries from 2004 to 2012 were included, with procurement of 33 formulations at a total value of USD 204 million. Use of dual and triple FDC formulations increased substantially over time, but with limited changes in price. Upon multivariate analysis, prices of originator formulations were found to be on average 72 % higher than generics (p < 0.001). A 10 % increase in procurement volume was associated with a 1 % decrease (p < 0.001) in both originator and generic prices. The entry of one additional manufacturer producing a formulation was associated with a decrease in prices of 2 % (p < 0.001) and 8 % (p < 0.001) for originator and generic formulations, respectively. The mean generic ARV price did not differ by country income level. Prices of originator ARVs were 48 % (p < 0.001) and 14 % (p < 0.001) higher in upper-middle income and lower-middle income countries compared to low income countries respectively, with the exception of South Africa, which had lower prices despite being an upper-middle income country.
The donor funded pediatric ARV market as represented by the GPRM database is small, and lacks price competition. It is dominated by generic drugs due to the lower prices offered and the practicality of FDC formulations. This market requires continued donor support and the current initiatives to protect it are important to ensure market viability, especially if new formulations are to be introduced in the future.
PMCID: PMC4793558  PMID: 26979974
Pediatrics antiretroviral market; Pediatric antiretroviral prices; Global Price Reporting Mechanism; Price trends; Pediatric antiretroviral procurement
15.  Fitting the pieces of the puzzle together: a case report of the Dunnigan-type of familial partial lipodystrophy in the adolescent girl 
BMC Pediatrics  2016;16:38.
Familial partial lipodystrophy of the Dunnigan type (FPLD 2) is a rare autosomal dominant disorder caused by the mutations of the lamin A/C gene leading to the defective adipogenesis, premature death of adipocytes and lipotoxicity. FPLD 2 is characterized by a progressive loss of subcutaneous adipose tissue in the limbs and trunk, and accumulation of body fat in the face and neck with accompanying severe metabolic derangements including insulin resistance, glucose intolerance, diabetes, dyslipidemia, steatohepatitis. Clinical presentation of FPLD 2 can often lead to misdiagnosis with metabolic syndrome, type 2 diabetes or Cushing syndrome.
Case presentation
We report a case of a 14-year-old girl admitted to the Department of Paediatrics due to chronic hypertransaminasemia. On physical examination the girl appeared to have athletic posture. She demonstrated the absence of subcutaneous adipose tissue in the extremities, sparing the face, neck and gluteal area, pseudo-hypertrophy of calves, prominent peripheral veins of limbs, massive acanthosis nigricans around the neck, in axillary and inguinal regions and natural skin folds, hepatosplenomegaly. Laboratory results revealed hypertransaminasemia, elevated γ-glutamyltranspeptydase, and dyslipidemia, hyperinsulinaemia with insulin resistance, impaired glucose tolerance, and hyperuricemia. Diffuse steatoheptitis in the liver biopsy was stated. Clinical suspicion of FPLD 2 was confirmed genetically. The pathogenic mutation, R482W (p.Arg482Trp), responsible for the FPLD 2 phenotype was identified in one allele of the LMNA gene.
Presented case highlights the importance of the holistic approach to a patient and the need of accomplished collaboration between paediatricians and geneticists. FPLD 2 should be considered in the differential diagnosis of diabetes, dyslipidemia, steatohepatitis, acanthosis nigricans and polycystic ovary syndrome.
Electronic supplementary material
The online version of this article (doi:10.1186/s12887-016-0581-2) contains supplementary material, which is available to authorized users.
PMCID: PMC4790055  PMID: 26976018
Familial partial lipodystrophy; LMNA gene; steatohepatittis
16.  Constitutional delay of puberty: presentation and inheritance pattern in 48 familial cases 
BMC Pediatrics  2016;16:37.
The mechanism that initiates the onset of puberty is largely unknown but the age of onset is mainly under genetic control and influenced by environmental factors including nutrition. Familial forms of constitutional delay of puberty (CDP) suggest the involvement of genetic factors. The purpose of this study is to describe the presentation and the mode of inheritance of CDP in a series of familial cases.
A retrospective, single center study was carried out over 10 years on 48 probands (14 girls and 34 boys) from 48 families seen for CDP with a familial component.
Of the 48 probands, 46 (96 %) had at least one affected 1st degree relatives and 2 (4 %, 2 boys) had only 2nd degree relatives affected.
In girls, 11 families (79 %) exhibited exclusive maternal inheritance, 1 (7 %) paternal inheritance and 2 (14 %) both maternal and paternal inheritance. In boys, 14 families (41 %) exhibited exclusive maternal inheritance, 12 (35 %) paternal inheritance and 8 (24 %) both maternal and paternal inheritance.
In the boys with bilineal inheritance, the ages at onset of puberty (16 ± 1.41 years) and at evaluation (16.05 ± 2.47 years) were higher than in those with unilineal inheritance (15.25 ± 0.35 and 15.1 ± 0.42 years respectively), but the difference was not significant.
In girls exclusive maternal inheritance seems to be the major mode of inheritance whereas for boys the mode of inheritance was almost equally maternal, paternal or bilineal. Clinical phenotype of boys with bilineal inheritance seems to be more severe, but the difference did not reach statistical significance, perhaps because of the small sample size. This greater severity of the phenotype in boys with bilineal inheritance is likely due to inheriting different puberty timing genes from each parent. Future research should be directed at identifying such genes.
PMCID: PMC4789265  PMID: 26970893
CDP constitutional delay of puberty; GnRH; Hypothalamic-pituitary-gonadal axis; Pubertal delay; Unilineal and bilineal inheritance; Autosomal dominant inheritance
17.  Play interventions to reduce anxiety and negative emotions in hospitalized children 
BMC Pediatrics  2016;16:36.
Hospitalization is a stressful and threatening experience, which can be emotionally devastating to children. Hospital play interventions have been widely used to prepare children for invasive medical procedures and hospitalization. Nevertheless, there is an imperative need for rigorous empirical scrutiny of the effectiveness of hospital play interventions, in particular, using play activities to ease the psychological burden of hospitalized children. This study tested the effectiveness of play interventions to reduce anxiety and negative emotions in hospitalized children.
A non-equivalent control group pre-test and post-test, between subjects design was conducted in the two largest acute-care public hospitals in Hong Kong. A total of 304 Chinese children (ages 3-12) admitted for treatments in these two hospitals were invited to participate in the study. Of the 304 paediatric patients, 154 received hospital play interventions and 150 received usual care.
Children who received the hospital play interventions exhibited fewer negative emotions and experienced lower levels of anxiety than those children who received usual care.
This study addressed a gap in the literature by providing empirical evidence to support the effectiveness of play interventions in reducing anxiety and negative emotions in hospitalized children. Findings from this study emphasize the significance of incorporating hospital play interventions to provide holistic and quality care to ease the psychological burden of hospitalized children.
Trial registration NCT02665403. Registered 22 January 2016.
PMCID: PMC4787017  PMID: 26969158
Anxiety; Children; Emotions; Hospitalization; Paediatrics; Play interventions
18.  Effect of timing of umbilical cord clamping on anaemia at 8 and 12 months and later neurodevelopment in late pre-term and term infants; a facility-based, randomized-controlled trial in Nepal 
BMC Pediatrics  2016;16:35.
Delayed cord clamping at birth has shown to benefit neonates with increased placental transfusion leading to higher haemoglobin concentrations, additional iron stores and less anaemia later in infancy, higher red blood cell flow to vital organs and better cardiopulmonary adaptation. As iron deficiency in infants even without anaemia has been associated with impaired development, delayed cord clamping seems to benefit full term infants also in regions with a relatively low prevalence of iron deficiency anaemia. In Nepal, there is a high anaemia prevalence among children between 6 and 17 months (72–78 %). The objective of the proposed study is to evaluate the effects of delayed and early cord clamping on anaemia (and haemoglobin level) at 8 and 12 months, ferritin at 8 and 12 months, bilirubin at 2–3 days, admission to Neonatal Intensive Care Unit (NICU) or special care nursery, and development at 12 and 18–24 months of age.
A randomized, controlled trial comparing delayed and early cord clamping will be implemented at Paropakar Maternity and Women’s Hospital in Kathmandu, Nepal. Pregnant woman of gestational age 34–41 weeks who deliver vaginally will be included in the study. The interventions will consist of delayed clamping of the umbilical cord (≥180 s after delivery) or early clamping of the umbilical cord (≤60 s). At 8 and 12 months of age, infant’s iron status and developmental milestones will be measured.
This trial is important to perform because, although strong indications for the beneficial effect of delayed cord clamping on anaemia at 8 to 12 months of age exist, it has not yet been evaluated by a randomized trial in this setting. The proposed study will analyse both outcome as well as safety effects. Additionally, the results may not only contribute to practice in Nepal, but also to the global community, in particular to other low-income countries with a high prevalence of iron deficiency anaemia.
Trial registration
Clinical NCT02222805. Registered August 19 2014.
PMCID: PMC4787033  PMID: 26965317
19.  Prevention and care of paediatric HIV infection in Ouagadougou, Burkina Faso: knowledge, attitudes and practices of the caregivers 
BMC Pediatrics  2016;16:33.
The paediatric Human Immunodeficiency Virus (HIV) epidemic still progresses because of operational challenges in implementing prevention of mother-to-child HIV transmission (PMCT) programs. We assessed the knowledge, attitudes and practices (KAP) of children’s caregivers regarding mother-to-child transmission (MTCT) of HIV, paediatric HIV infection, early infant diagnosis (EID), and paediatric antiretroviral treatment in Ouagadougou, Burkina Faso.
We undertook a qualitative survey in the four public hospitals managing HIV exposed or infected children, in Ouagadougou in 2011. A sociologist used a semi-structured questionnaire to interview caregivers of children less than 5 years old attending the paediatrics wards on their KAP. Study participants were divided into four groups as follows:
those who did not yet know their children’s HIV infection status, those who were waiting for their children’s HIV test results, those who were waiting for antiretroviral treatment, and those who were already on antiretroviral treatment.
A total of 37 caregivers were interviewed. The mean age was 32.5 years, and 29 (78 %) were mothers. Twenty seven (73 %) caregivers had primary or higher level of education, and 15 (40 %) described their occupation as “housewife”. Overall, 36 (97 %) of caregivers knew that the main route of HIV transmission for infants was through MTCT and 14 (38 %) specified that it occurred during pregnancy or delivery. Five percent thought that MTCT of HIV occurred during conception. PMTCT interventions could help prevent infant HIV infection according to 32 (87 %) caregivers. Thirty five percent of caregivers stated EID as a prevention strategy. Fifty-four percent of the participants believed that replacement feeding option would prevent MTCT of HIV; 24 (65 %) stated that they would prefer medical practitioners seek caregivers’ consent before carrying out any HIV-test for their child, and that caregivers’ consent was not compulsory before antiretroviral treatment. All caregivers thought that it was necessary to treat HIV-infected children, although they did not know what interventions could be done.
This study highlighted the low level of caregivers’ knowledge on paediatric HIV prevention and care in Ouagadougou. Awareness programs targeting caregivers need to be strengthened in order to improve the uptake of HIV early infant diagnosis and care.
Electronic supplementary material
The online version of this article (doi:10.1186/s12887-016-0569-y) contains supplementary material, which is available to authorized users.
PMCID: PMC4784410  PMID: 26961234
HIV infection; Caregivers; Early infant diagnosis; Paediatrics; Africa
20.  The Linked CENTURY Study: linking three decades of clinical and public health data to examine disparities in childhood obesity 
BMC Pediatrics  2016;16:32.
Despite the need to identify the causes of disparities in childhood obesity, the existing epidemiologic studies of early life risk factors have several limitations. We report on the construction of the Linked CENTURY database, incorporating CENTURY (Collecting Electronic Nutrition Trajectory Data Using Records of Youth) Study data with birth certificates; and discuss the potential implications of combining clinical and public health data sources in examining the etiology of disparities in childhood obesity.
We linked the existing CENTURY Study, a database of 269,959 singleton children from birth to age 18 years with measured heights and weights, with each child’s Massachusetts birth certificate, which captures information on their mothers’ pregnancy history and detailed socio-demographic information of both mothers and fathers.
Overall, 74.2 % were matched, resulting in 200,343 children in the Linked CENTURY Study with 1,580,597 well child visits. Among this cohort, 94.0 % (188,334) of children have some father information available on the birth certificate and 60.9 % (121,917) of children have at least one other sibling in the dataset.
Using maternal race/ethnicity from the birth certificate as an indicator of children’s race/ethnicity, 75.7 % of children were white, 11.6 % black, 4.6 % Hispanic, and 5.7 % Asian. Based on socio-demographic information from the birth certificate, 20.0 % of mothers were non-US born, 5.9 % smoked during pregnancy, 76.3 % initiated breastfeeding, and 11.0 % of mothers had their delivery paid for by public health insurance. Using clinical data from the CENTURY Study, 22.7 % of children had a weight-for-length ≥ 95th percentile between 1 and 24 months and 12.0 % of children had a body mass index ≥ 95th percentile at ages 5 and 17 years.
By linking routinely-collected data sources, it is possible to address research questions that could not be answered with either source alone. Linkage between a clinical database and each child’s birth certificate has created a unique dataset with nearly complete racial/ethnic and socio-demographic information from both parents, which has the potential to examine the etiology of racial/ethnic and socioeconomic disparities in childhood obesity.
PMCID: PMC4784443  PMID: 26961130
Birth certificates; Electronic health records; Health status disparities; Medical record linkage; Pediatric obesity
21.  Multiple anti-epileptic drug use in children with epilepsy in Mulago hospital, Uganda: a cross sectional study 
BMC Pediatrics  2016;16:34.
Seizures in up to one third of children with epilepsy may not be controlled by the first anti-epileptic drug (AED). In this study, we describe multiple AED usage in children attending a referral clinic in Uganda, the factors associated with multiple AED use and seizure control in affected patients.
One hundred thirty nine patients attending Mulago hospital paediatric neurology clinic with epilepsy and who had been on AEDs for ≥6 months were consecutively enrolled from July to December 2013 to reach the calculated sample size. With consent, the history and physical examination were repeated and the neurophysiologic and imaging features obtained from records. Venous blood was also drawn to determine AED drug levels. We determined the proportion of children on multiple AEDs and performed regression analyses to determine factors independently associated with multiple AED use.
Forty five out of 139 (32.4 %) children; 46.7 % female, median age 6 (IQR = 3–9) years were on multiple AEDs. The most common combination was sodium valproate and carbamazepine. We found that 59.7 % of children had sub-therapeutic drug levels including 42.2 % of those on multi-therapy. Sub-optimal seizure control (adjusted odds ratio [ORa] 3.93, 95 % CI 1.66–9.31, p = 0.002) and presence of focal neurological deficits (ORa 3.86, 95 % CI 1.31–11.48, p = 0.014) were independently associated with multiple AED use but not age of seizure onset, duration of epilepsy symptoms, seizure type or history of status epilepticus.
One third of children with epilepsy in Mulago receive multiple AEDs. Multiple AED use is most frequent in symptomatic focal epilepsies but doses are frequently sub-optimal. There is urgent need to improve clinical monitoring in our patients.
PMCID: PMC4785653  PMID: 26961364
Epilepsy; Therapy; Anti-epileptic drugs; Children
22.  Neck circumference as a predictor of metabolic syndrome, insulin resistance and low-grade systemic inflammation in children: the ACFIES study 
BMC Pediatrics  2016;16:31.
The current study aims to evaluate the association between neck circumference (NC) and several cardio-metabolic risk factors, to compare it with well-established anthropometric indices, and to determine the cut-off point value of NC for predicting children at increased risk of metabolic syndrome, insulin resistance and low-grade systemic inflammation.
A total of 669 school children, aged 8–14, were recruited. Demographic, clinical, anthropometric and biochemical data from all patients were collected. Correlations between cardio-metabolic risk factors and NC and other anthropometric variables were evaluated using the Spearman’s correlation coefficient. Multiple linear regression analysis was applied to further examine these associations. We then determined by receiver operating characteristic (ROC) analyses the optimal cut-off for NC for identifying children with elevated cardio-metabolic risk.
NC was positively associated with fasting plasma glucose and triglycerides (p = 0.001 for all), and systolic and diastolic blood pressure, C-reactive protein, insulin and HOMA-IR (p < 0.001 for all), and negatively with HDL-C (p = 0.001). Whereas, other anthropometric indices were associated with fewer risk factors.
NC could be used as clinically relevant and easy to implement indicator of cardio-metabolic risk in children.
PMCID: PMC4782326  PMID: 26956385
Childhood obesity; Anthropometric measurements; Neck circumference; Metabolic syndrome; Low-grade systemic inflammation; Insulin resistance; Cardiometabolic risk; Latin America; Colombia
23.  Early days of life are crucial for child survival in Gamo Gofa Zone, Southern Ethiopia: A community based study 
BMC Pediatrics  2016;16:30.
Though, Ethiopia has shown progress in the reduction of under-five mortality in the last few years, the problem of neonatal and under-five mortality are still among the highest in the world and that warrants continuous investigation of the situation for sustained interventions to maintain the reduction beyond the millennium development goals. Therefore, this study was conducted with the objective of determining the magnitude of childhood mortalities in the designated community.
A census of 11 kebeles (lowest administrative units in Ethiopia) of Arba Minch Town and 11 kebeles of Arba Minch Zuria District, which were not part of Arba Minch Demographic Surveillance System (DSS), had been done in order to identify all children (alive and dead) born between September 01, 2007 and September 30, 2014. Besides, all children born after July 01, 2009 were tracked from the data base of the Arba Minch DSS. Descriptive analyses with frequency and cross tabulation with the corresponding confidence interval and p-value were made using SPSS 16 and STATA 11. Extended Mantel-Haenszel chi-square for linear trend was also performed to assess presence of linear trend through the study period using open-Epi version 2.3.
A total of 20,161 children were included for this analysis. The overall weighted under five, infant and neonatal mortalities with their corresponding 95 % confidence intervals were: 42.76 (39.56-45.97), 33.89 (31.03-36.76) and 18.68 (16.53-20.83) per 1000 live births, respectively. Majority of neonatal deaths occurred within the first 7 days of life. Under-five mortality was found to be significantly higher among non-DSS rural kebeles, overall rural kebeles and females.
Significant number of children died during their early days of life. Strengthening of maternal and child health interventions during pregnancy, during and immediately after birth are recommended in order to avert majorities of neonatal deaths.
PMCID: PMC4779572  PMID: 26946507
Under five; Infant; Neonatal; Child; Mortality; Death; Determinants of mortality; Gamo Gofa; Ethiopia
24.  Validating the Children’s Depression Inventory in the context of Rwanda 
BMC Pediatrics  2016;16:29.
Depression is often co-morbid with chronic conditions, and when combined with HIV it can increase progression and reduce survival. A brief and accurate screening tool for depression among children living with HIV is necessary to increase access to mental health care and improve HIV-related outcomes in the long-term.
A validation study was conducted, comparing the Children’s Depression Inventory (CDI) with a structured clinical assessment as the gold standard among children living with HIV ages 7-14 years in Rwanda. The response rate was 87 % and the analysis was performed among 100 study participants.
Twenty-five percent of children had a diagnosis of depression based on the clinical interview. Sensitivity of the CDI ranged from 44 to 76 % and specificity was 92 to 100 % for cut-off scores from 5 to 9. The area under the curve (AUC) for receiver operating characteristic analysis, an estimate of overall accuracy, was 0.87 (95 % confidence interval: 0.77 – 0.97).
The significant prevalence of depression among children living with HIV in Rwanda reflects a critical need to advance mental health care in this population. Although overall accuracy of the CDI is reasonable in this context, further research needs to be done to develop a more sensitive measure of depression in this vulnerable population. Development of a highly sensitive screening measure will be a fundamental step towards improving access to mental health care among children living with HIV, potentially improving health outcomes and quality of life in the long-term as this vulnerable population transitions into adulthood.
PMCID: PMC4762156  PMID: 26898199
Rwanda; Children; Adolescents; Depression; Screening; HIV; Chronic disease; Validation
25.  Case report: severe asymptomatic hyponatremia in Prader-Willi Syndrome 
BMC Pediatrics  2016;16:28.
Prader-Willi syndrome is a complex neurogenetic, multisystem disorder. Despite the variable endocrine abnormalities and hypothalamic-pituitary axis dysfunction, hyponatremia has been reported in only a few PWS patients. In previously reported PWS individuals, hyponatremia was associated with abnormal fluid intake or during desmopressin treatment.
Case presentation
We describe an infant with Prader-Willi syndrome who had severe, prolonged asymptomatic hyponatremia without a history of excessive fluid intake or desmopressin treatment. We compare the findings with those of the few other reported cases and describe, for the first time, results of a hypertonic saline infusion test and studies of adrenal cortical function.
Hyponatremia should be suspected in children with Prader-Willi syndrome, especially in infants with severe failure to thrive. Further studies are needed to determine the pathophysiology of hyponatremia in this syndrome.
Electronic supplementary material
The online version of this article (doi:10.1186/s12887-016-0563-4) contains supplementary material, which is available to authorized users.
PMCID: PMC4758139  PMID: 26888082
Prader-Willi syndrome (PWS); Hyponatremia; Anti-diuretic hormone (ADH); Adrenocortioctrophic hormone (ACTH) test

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