Utilising surface-level data to explore surface, tooth, individual and family influence on the aetiology of hypomineralised second primary molars.

OBJECTIVES: Hypomineralised second primary molars (HSPM) are common developmental enamel defects. The aims of this study were to use surface-level data to explore the clustering of HSPM at four levels (family, child, tooth, surface). METHODS: This study of 172 twin pairs was nested within the Peri/postnatal Epigenetic Twin Study. HSPM was measured by standardised oral examinations at age 6 years. Multilevel logistic regression models were fitted to assess the correlation structure of surface level data and variation in HSPM. The associations between surface level risk factors and HSPM were then explored using the multilevel logistic regression model using the best fitting correlation structure. RESULTS: The prevalence of HSPM was 68 (19.8%) children, with a total of 141 (10.3%) teeth and 264 tooth surfaces (6.3%) affected. Multilevel models revealed that a hierarchical structure accounting for correlation at the family, child and tooth level best accounted for the variation in HSPM. The estimated variances from the best fitting model (Model 3) were largest at the family level (12.27, 95% CI 6.68, 22.51) compared with 5.23 at the child level and 1.93 at the tooth level. Application of regression analysis utilising this three-level correlation structure identified tooth/surface level factors in addition to the previously identified familial and individual risk factors for HSPM. CONCLUSION: In addition to familial (environmental and genetic) and unique child-level factors, the aetiology of HSPM is likely to be influenced by local tooth-level factors.

Population pharmacokinetics of intravenous artesunate: a pooled analysis of individual data from patients with severe malaria.

There are ~660,000 deaths from severe malaria each year. Intravenous artesunate (i.v. ARS) is the first-line treatment in adults and children. To optimize the dosing regimen of i.v. ARS, the largest pooled population pharmacokinetic study to date of the active metabolite dihydroartemisinin (DHA) was performed. The pooled dataset consisted of 71 adults and 195 children with severe malaria, with a mixture of sparse and rich sampling within the first 12 h after drug administration. A one-compartment model described the population pharmacokinetics of DHA adequately. Body weight had the greatest impact on DHA pharmacokinetics, resulting in lower DHA exposure for smaller children (6-10 kg) than adults. Post hoc estimates of DHA exposure were not significantly associated with parasitological outcomes. Comparable DHA exposure in smaller children and adults after i.v. ARS was achieved under a dose modification for intramuscular ARS proposed in a separate analysis of children.

Gene-wide association study between the aromatase gene (CYP19A1) and female pattern hair loss.

BACKGROUND: Female pattern hair loss (FPHL) is a common trait in which androgens and oestrogens may have a pathogenic role. The aromatase enzyme converts androgens to oestrogens in scalp hair follicles and is differentially expressed in balding and nonbalding scalps of women. Sequence variation in the gene encoding aromatase, CYP19A1, might influence the risk of developing FPHL. OBJECTIVES: To examine the role of CYP19A1 genetic variation in the heritability of FPHL. METHODS: We investigated associations between FPHL and 61 tag single nucleotide polymorphisms (SNPs) representing variation in and around CYP19A1 in 484 caucasian women with grades 3-5 FPHL on the Sinclair scale, and 471 caucasian women with no evidence of hair loss. RESULTS: For the tag SNP rs4646 (overall genotype frequencies: CC, 53.6%; AC, 39.3%; AA, 7.1%), the genotype CC was more frequent in women with FPHL (58.1%) than controls (48.9%) (P = 0.006). Although this result did not achieve experiment-wide significance (P < 0.001 by permutation testing), subanalyses according to sources of recruitment and ages at presentation revealed consistent patterns of association. In particular, young cases (< 40 years) had the highest frequency of the CC genotype (68.2%) among all subgroups. CONCLUSIONS: These findings suggest that the common rs4646 C allele, which has been associated previously with higher circulating oestrogen levels, might be associated with predisposition to FPHL.