Paediatrics (RCH) - Research Publications
Now showing items 1-12 of 1077
Malaysian Females With Congenital Adrenal Hyperplasia: Surgical Outcomes and Attitudes
(FRONTIERS MEDIA SA, 2019-04-17)
Background: Girls born with congenital adrenal hyperplasia have virilized external genitalia. There is considerable debate regarding both the outcomes of feminizing genitoplasty and timing of the surgery in this population. Objective: To investigate outcomes of females 46,XX individuals with CAH in Malaysia, the surgical outcomes of feminizing genitoplasty (FG) and their attitudes toward surgery. Study Design: This is a cross-sectional study involving the two main tertiary centers in Malaysia. All 46,XX patients with CAH and raised female, who had undergone FG were identified and invited to participate. Data on socio-demographic, medical profiles, and attitudes toward surgery were collected. A standardized evaluation of the external genitalia was undertaken including the anatomic and cosmetic evaluation by independent gynecologists. Results: Of 61 individuals identified, 59 participated-consisting of children (n = 12), adolescents (n = 29) and adults (n = 18). All but one had classical CAH (98.3%) and had undergone FG (n = 55, 93.2%) with surgery mostly undertaken by pediatric surgeons trained in DSD work (n = 44, 74.6%). Complications overall were low (20.3%), with repeat surgery rate of 9.1%. External genital examination was performed in 38 participants. Overall 36.8% had absent clitoral glands and 39.5% had a persistent urogenital sinus and in 10.5%, no vaginal orifices were seen. Poor cosmetic outcomes were present in 42.1% with 55.3% recommended for further assessment under general anesthetic. Almost half participants did not venture an opinion on FG, those who did varied from having a positive attitude toward it (18 participants) to 3 opining that it should not be done, or avoided or delayed. From the participants, 35.5% preferred FG to be done early in life compared to 44.0% of the parents. Conclusions: The reoperation rates of the feminizing genitoplasty surgeries were low however due to the anatomic and cosmetic outcomes, reassessment of the external genitalia of these CAH patients may be required once they consider becoming sexually active as they may require further treatment. Many factors such as cultural sensitivities and access to medical treatment and late diagnoses have an impact on attitudes toward FG.
Reducing inequities in early childhood mental health: How might the neighborhood built environment help close the gap? a systematic search and critical review
(MDPI AG, 2019-05-01)
Background: Optimal mental health in early childhood is key to later mental health, physical health, education, and social outcomes; yet, children facing disadvantage tend to have worse mental health and fewer opportunities to develop this foundation. An emerging body of research shows that neighborhoods provide important opportunities for the development of children’s mental health. Synthesizing this evidence can advance understandings of the features of the neighborhood built environment (e.g., housing, parks) that (1) promote optimal mental health in childhood and (2) reduce mental health inequities. Methods: We systematically searched and critically reviewed the international quantitative literature investigating associations between the neighborhood built environment and young children’s mental health. Results: 14 articles met inclusion criteria; most examined nature or public open space. Studies tended to find greater access to or quantity of neighborhood nature or public open space were associated with better mental health. Significant gaps included a lack of studies investigating social infrastructure, and few studies examined how the built environment related to positive mental health (i.e., functioning, rather than problems). Conclusions: Current evidence suggests there is some relationship, but additional research is needed that addresses these gaps and examines differences in associations between child subgroups (e.g., diverse socioeconomic backgrounds).
Investigation of Genetic Variation Underlying Central Obesity amongst South Asians
(PUBLIC LIBRARY SCIENCE, 2016-05-19)
South Asians are 1/4 of the world's population and have increased susceptibility to central obesity and related cardiometabolic disease. Knowledge of genetic variants affecting risk of central obesity is largely based on genome-wide association studies of common SNPs in Europeans. To evaluate the contribution of DNA sequence variation to the higher levels of central obesity (defined as waist hip ratio adjusted for body mass index, WHR) among South Asians compared to Europeans we carried out: i) a genome-wide association analysis of >6M genetic variants in 10,318 South Asians with focused analysis of population-specific SNPs; ii) an exome-wide association analysis of ~250K SNPs in protein-coding regions in 2,637 South Asians; iii) a comparison of risk allele frequencies and effect sizes of 48 known WHR SNPs in 12,240 South Asians compared to Europeans. In genome-wide analyses, we found no novel associations between common genetic variants and WHR in South Asians at P<5x10-8; variants showing equivocal association with WHR (P<1x10-5) did not replicate at P<0.05 in an independent cohort of South Asians (N = 1,922) or in published, predominantly European meta-analysis data. In the targeted analyses of 122,391 population-specific SNPs we also found no associations with WHR in South Asians at P<0.05 after multiple testing correction. Exome-wide analyses showed no new associations between genetic variants and WHR in South Asians, either individually at P<1.5x10-6 or grouped by gene locus at P<2.5x10-6. At known WHR loci, risk allele frequencies were not higher in South Asians compared to Europeans (P = 0.77), while effect sizes were unexpectedly smaller in South Asians than Europeans (P<5.0x10-8). Our findings argue against an important contribution for population-specific or cosmopolitan genetic variants underlying the increased risk of central obesity in South Asians compared to Europeans.
Analysis of variants in GATA4 and FOG2/ZFPM2 demonstrates benign contribution to 46,XY disorders of sex development
BACKGROUND: GATA-binding protein 4 (GATA4) and Friend of GATA 2 protein (FOG2, also known as ZFPM2) form a heterodimer complex that has been shown to influence transcription of genes in a number of developmental systems. Recent evidence has also shown these genes play a role in gonadal sexual differentiation in humans. Previously we identified four variants in GATA4 and an unexpectedly large number of variants in ZFPM2 in a cohort of individuals with 46,XY Differences/Disorders of Sex Development (DSD) (Eggers et al, Genome Biology, 2016; 17: 243). METHOD: Here, we review variant curation and test the functional activity of GATA4 and ZFPM2 variants. We assess variant transcriptional activity on gonadal specific promoters (Sox9 and AMH) and variant protein-protein interactions. RESULTS: Our findings support that the majority of GATA4 and ZFPM2 variants we identified are benign in their contribution to 46,XY DSD. Indeed, only one variant, in the conserved N-terminal zinc finger of GATA4, was considered pathogenic, with functional analysis confirming differences in its ability to regulate Sox9 and AMH and in protein interaction with ZFPM2. CONCLUSIONS: Our study helps define the genetic factors contributing to 46,XY DSD and suggests that the majority of variants we identified in GATA4 and ZFPM2/FOG2 are not causative.
Maternal Obesity Alters Placental Cell Cycle Regulators in the First Trimester of Human Pregnancy: New Insights for BRCA1
In the first trimester of pregnancy, placental development involves a wide range of cellular processes. These include trophoblast proliferation, fusion, and differentiation, which are dependent on tight cell cycle control. The intrauterine environment affects placental development, which also includes the trophoblast cell cycle. In this work, we focus on maternal obesity to assess whether an altered intrauterine milieu modulates expression and protein levels of placental cell cycle regulators in early human pregnancy. For this purpose, we use first trimester placental tissue from lean and obese women (gestational week 5+0-11+6, n = 58). Using a PCR panel, a cell cycle protein array, and STRING database analysis, we identify a network of cell cycle regulators increased by maternal obesity in which breast cancer 1 (BRCA1) is a central player. Immunostaining localizes BRCA1 predominantly to the villous and the extravillous cytotrophoblast. Obesity-driven BRCA1 upregulation is not able to be explained by DNA methylation (EPIC array) or by short-term treatment of chorionic villous explants at 2.5% oxygen with tumor necrosis factor α (TNF-α) (50 mg/mL), leptin (100 mg/mL), interleukin 6 (IL-6) (100 mg/mL), or high glucose (25 nM). Oxygen tension rises during the first trimester, but this change in vitro has no effect on BRCA1 (2.5% and 6.5% O2). We conclude that maternal obesity affects placental cell cycle regulation and speculate this may alter placental development.
The impact of physician migration on mortality in low and middle-income countries: an economic modelling study
(BMJ PUBLISHING GROUP, 2020-01-01)
Background: The WHO estimates a global shortage of 2.8 million physicians, with severe deficiencies especially in low and middle-income countries (LMIC). The unequitable distribution of physicians worldwide is further exacerbated by the migration of physicians from LMICs to high-income countries (HIC). This large-scale migration has numerous economic consequences which include increased mortality associated with inadequate physician supply in LMICs. Methods: We estimate the economic cost for LMICs due to excess mortality associated with physician migration. To do so, we use the concept of a value of statistical life and marginal mortality benefit provided by physicians. Uncertainty of our estimates is evaluated with Monte Carlo analysis. Results: We estimate that LMICs lose US$15.86 billion (95% CI $3.4 to $38.2) annually due to physician migration to HICs. The greatest total costs are incurred by India, Nigeria, Pakistan and South Africa. When these costs are considered as a per cent of gross national income, the cost is greatest in the WHO African region and in low-income countries. Conclusion: The movement of physicians from lower to higher income settings has substantial economic consequences. These are not simply the result of the movement of human capital, but also due to excess mortality associated with loss of physicians. Valuing these costs can inform international and domestic policy discussions that are meant to address this issue.
The associations of economic growth and anaemia for school-aged children in China
Economic growth has brought improvements in many areas of child health, but its effects on anaemia among school-aged children remain unknown. However, this is important because iron deficiency anaemia is common and is the main cause of disability-adjusted life years for school-aged children. In this study, we included 429,222 Chinese children aged 7-17 years from five consecutive national cross-sectional surveys during 1995-2014. Using altitude-adjusted haemoglobin concentration measured from capillary blood samples, we defined anaemia status according to World Health Organization's recommendation. We used logistic regressions weighted by provincial population to examine the association between provincial gross domestic product (GDP) per capita and anaemia, adjusting for sex, age, urban-rural location, regional socio-economic status (SES), fixed effect of province, and clustering of schools. We used generalised additive mixed models to evaluate a potentially non-linear relationship. For each 100% growth in GDP per capita, there was a 40% (odds ratio [OR] = 0.60; 95% confidence interval [CI; 0.56, 0.65]) reduction in anaemia. However, the association was weaker for girls and in cities with a lower SES. The association was weaker across 2005-2014 (OR = 0.75, 95% CI [0.62, 0.90]) compared with 1995-2005 (OR = 0.52; 95% CI [0.44, 0.61]), reflecting a weaker association when GDP per capita reaches around $2,000. The results were similar for moderate-to-severe anaemia. We concluded that economic growth has been associated with reductions in anaemia among school-aged children in China but with fewer benefits for girls and those in poorer settings. Further economic development in China is unlikely to bring similar reductions in anaemia, suggesting that additional population level and targeted interventions will be needed.
Functional analysis of novel desert hedgehog gene variants improves the clinical interpretation of genomic data and provides a more accurate diagnosis for patients with 46,XY differences of sex development
(BMJ PUBLISHING GROUP, 2019-07-01)
BACKGROUND: Desert hedgehog (DHH) gene variants are known to cause 46,XY differences/disorders of sex development (DSD). We have identified six patients with 46,XY DSD with seven novel DHH gene variants. Many of these variants were classified as variants of uncertain significance due to their heterozygosity or associated milder phenotype. To assess variant pathogenicity and to refine the spectrum of DSDs associated with this gene, we have carried out the first reported functional testing of DHH gene variant activity. METHODS: A cell co-culture method was used to assess DHH variant induction of Hedgehog signalling in cultured Leydig cells. Protein expression and subcellular localisation were also assessed for DHH variants using western blot and immunofluorescence. RESULTS: Our co-culture method provided a robust read-out of DHH gene variant activity, which correlated closely with patient phenotype severity. While biallelic DHH variants from patients with gonadal dysgenesis showed significant loss of activity, variants found as heterozygous in patients with milder phenotypes had no loss of activity when tested with a wild type allele. Taking these functional results into account improved clinical interpretation. CONCLUSION: Our findings suggest heterozygous DHH gene variants are unlikely to cause DSD, reaffirming that DHH is an autosomal recessive cause of 46,XY gonadal dysgenesis. Functional characterisation of novel DHH variants improves variant interpretation, leading to greater confidence in patient reporting and clinical management.
The epigenetic clock as a predictor of disease and mortality risk: a systematic review and meta-analysis
BACKGROUND: Ageing is one of the principal risk factors for many chronic diseases. However, there is considerable between-person variation in the rate of ageing and individual differences in their susceptibility to disease and death. Epigenetic mechanisms may play a role in human ageing, and DNA methylation age biomarkers may be good predictors of age-related diseases and mortality risk. The aims of this systematic review were to identify and synthesise the evidence for an association between peripherally measured DNA methylation age and longevity, age-related disease, and mortality risk. METHODS: A systematic search was conducted in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Using relevant search terms, MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and PsychINFO databases were searched to identify articles meeting the inclusion criteria. Studies were assessed for bias using Joanna Briggs Institute critical appraisal checklists. Data was extracted from studies measuring age acceleration as a predictor of age-related diseases, mortality or longevity, and the findings for similar outcomes compared. Using Review Manager 5.3 software, two meta-analyses (one per epigenetic clock) were conducted on studies measuring all-cause mortality. RESULTS: Twenty-three relevant articles were identified, including a total of 41,607 participants. Four studies focused on ageing and longevity, 11 on age-related disease (cancer, cardiovascular disease, and dementia), and 11 on mortality. There was some, although inconsistent, evidence for an association between increased DNA methylation age and risk of disease. Meta-analyses indicated that each 5-year increase in DNA methylation age was associated an 8 to 15% increased risk of mortality. CONCLUSION: Due to the small number of studies and heterogeneity in study design and outcomes, the association between DNA methylation age and age-related disease and longevity is inconclusive. Increased epigenetic age was associated with mortality risk, but positive publication bias needs to be considered. Further research is needed to determine the extent to which DNA methylation age can be used as a clinical biomarker.
The current consensus on the clinical management of intracranial ependymoma and its distinct molecular variants
Multiple independent genomic profiling efforts have recently identified clinically and molecularly distinct subgroups of ependymoma arising from all three anatomic compartments of the central nervous system (supratentorial brain, posterior fossa, and spinal cord). These advances motivated a consensus meeting to discuss: (1) the utility of current histologic grading criteria, (2) the integration of molecular-based stratification schemes in future clinical trials for patients with ependymoma and (3) current therapy in the context of molecular subgroups. Discussion at the meeting generated a series of consensus statements and recommendations from the attendees, which comment on the prognostic evaluation and treatment decisions of patients with intracranial ependymoma (WHO Grade II/III) based on the knowledge of its molecular subgroups. The major consensus among attendees was reached that treatment decisions for ependymoma (outside of clinical trials) should not be based on grading (II vs III). Supratentorial and posterior fossa ependymomas are distinct diseases, although the impact on therapy is still evolving. Molecular subgrouping should be part of all clinical trials henceforth.
Internal state dynamics shape brainwide activity and foraging behaviour
(NATURE RESEARCH, 2020-01-09)
Childhood malnutrition is associated with high morbidity and mortality globally1. Undernourished children are more likely to experience cognitive, physical, and metabolic developmental impairments that can lead to later cardiovascular disease, reduced intellectual ability and school attainment, and reduced economic productivity in adulthood2. Child growth failure (CGF), expressed as stunting, wasting, and underweight in children under five years of age (0-59 months), is a specific subset of undernutrition characterized by insufficient height or weight against age-specific growth reference standards3-5. The prevalence of stunting, wasting, or underweight in children under five is the proportion of children with a height-for-age, weight-for-height, or weight-for-age z-score, respectively, that is more than two standard deviations below the World Health Organization's median growth reference standards for a healthy population6. Subnational estimates of CGF report substantial heterogeneity within countries, but are available primarily at the first administrative level (for example, states or provinces)7; the uneven geographical distribution of CGF has motivated further calls for assessments that can match the local scale of many public health programmes8. Building from our previous work mapping CGF in Africa9, here we provide the first, to our knowledge, mapped high-spatial-resolution estimates of CGF indicators from 2000 to 2017 across 105 low- and middle-income countries (LMICs), where 99% of affected children live1, aggregated to policy-relevant first and second (for example, districts or counties) administrative-level units and national levels. Despite remarkable declines over the study period, many LMICs remain far from the ambitious World Health Organization Global Nutrition Targets to reduce stunting by 40% and wasting to less than 5% by 2025. Large disparities in prevalence and progress exist across and within countries; our maps identify high-prevalence areas even within nations otherwise succeeding in reducing overall CGF prevalence. By highlighting where the highest-need populations reside, these geospatial estimates can support policy-makers in planning interventions that are adapted locally and in efficiently directing resources towards reducing CGF and its health implications.