Quantitative analysis of topical treatments in atopic dermatitis: unexpectedly low use of emollients and strong correlation of topical corticosteroid use both with depression and concurrent asthma.

BACKGROUND: Despite decades of use, the actual amounts of topical corticosteroids (TCS) and emollients used in moderate-to-severe atopic dermatitis (AD) under real-world conditions are unknown. Thus, it remains unclear whether inadequate use is widespread. OBJECTIVES: To quantify the use of TCS and emollients in moderate-to-severe AD. METHODS: Double-blinded drug prescribing was recorded prospectively at the point of drug dispensing within a catchment area of approximately 450 000 people over a 31-year period in a population-based cohort marked by failure of disease control in primary care (n = 844). For each patient, prescribing was recorded over a 12-month period in order to minimize fluctuations. RESULTS: This approach resulted in a near-complete dataset, which was essentially free of reporting bias and recording bias. Atopic comorbidities matched expected frequencies. Median use of TCS was statistically significantly higher in juvenile patients (age < 16 years) compared with adult patients (49·2 vs. 38·1 g per month), in male vs. female patients (46·8 vs. 29·7 g per month) and in patients receiving concurrent asthma treatment (40·4 vs. 26·7 g per month). TCS use was strongly associated with antidepressant treatment. Emollient use was unexpectedly low with a median of 9·6 g per day (range 1·4-30·1). Results were replicated in an independent validation cohort. CONCLUSIONS: Deficient use of emollients may be a factor contributing to AD severity. Our analysis showed that the use of TCS does not exceed current guidelines. Accurate quantification of topical treatments provides a widely accessible strategy to measure the real-world impact of novel AD treatments. What's already known about this topic? Both emollient and topical corticosteroid (TCS) use have been a mainstay of atopic dermatitis (AD) treatment for over 60 years. The actual quantities used by patients under real-world conditions are unknown. What does this study add? The real-world use of emollients is fourfold lower than the amount recommended in current guidelines. Underuse of emollients may be a significant factor in disease exacerbation. The use of TCS is significantly higher in male patients and is higher in patients with AD who also have asthma. The use of TCS is strongly associated with concurrent antidepressant treatment.

Implementation of a new strategy to improve the peri-operative management of neuromuscular blockade and its effects on postoperative pulmonary complications.

Inappropriate dosing of neostigmine for antagonism of neuromuscular blockade has been associated with postoperative pulmonary complications. We evaluated the effects of a quality improvement initiative tailored to optimise the use of neostigmine in antagonising neuromuscular blockade on postoperative pulmonary complications, costs and duration of hospital stay. The quality improvement initiative consisted of: a reduction in available neostigmine aliquot sizes; a cognitive aid; an educational component; and a financial incentive for the intra-operative documentation of train-of-four measurement before administration of neostigmine. We conducted a pre-specified analysis of data obtained in our quality improvement study. Additional analyses were conducted in a propensity-matched cohort. An interrupted time series design was used to discriminate between the intervention and a counterfactual scenario. We analysed 12,025 consecutive surgical cases performed in 2015. Postoperative pulmonary complications occurred in 220 (7.5%) of 2937 cases pre-intervention and 568 (6.3%) of 9088 cases post-intervention. Adjusted regression analyses showed significantly a lower risk of postoperative pulmonary complications (OR 0.73 (95%CI 0.61-0.88); p = 0.001), lower costs (incidence rate ratio 0.95 (95%CI 0.93-0.97); p < 0.001) and shorter duration of hospital stay (incidence rate ratio 0.91 (95%CI 0.87-0.94); p < 0.001) after implementation of the quality improvement initiative. Analyses in a propensity-matched sample (n = 2936 per group) and interrupted time series analysis (n = 27,202 cases) confirmed the findings. Our data show that a local, multifaceted quality improvement initiative can enhance the quality of intra-operative neuromuscular blocking agent utilisation, thereby reducing the incidence of postoperative pulmonary complications.

A genome-wide association study identifies variants in KCNIP4 associated with ACE inhibitor-induced cough.

The most common side effect of angiotensin-converting enzyme inhibitor (ACEi) drugs is cough. We conducted a genome-wide association study (GWAS) of ACEi-induced cough among 7080 subjects of diverse ancestries in the Electronic Medical Records and Genomics (eMERGE) network. Cases were subjects diagnosed with ACEi-induced cough. Controls were subjects with at least 6 months of ACEi use and no cough. A GWAS (1595 cases and 5485 controls) identified associations on chromosome 4 in an intron of KCNIP4. The strongest association was at rs145489027 (minor allele frequency=0.33, odds ratio (OR)=1.3 (95% confidence interval (CI): 1.2-1.4), P=1.0 × 10(-8)). Replication for six single-nucleotide polymorphisms (SNPs) in KCNIP4 was tested in a second eMERGE population (n=926) and in the Genetics of Diabetes Audit and Research in Tayside, Scotland (GoDARTS) cohort (n=4309). Replication was observed at rs7675300 (OR=1.32 (1.01-1.70), P=0.04) in eMERGE and at rs16870989 and rs1495509 (OR=1.15 (1.01-1.30), P=0.03 for both) in GoDARTS. The combined association at rs1495509 was significant (OR=1.23 (1.15-1.32), P=1.9 × 10(-9)). These results indicate that SNPs in KCNIP4 may modulate ACEi-induced cough risk.

Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes.

AIMS/HYPOTHESIS: Human complex metabolic traits are in part regulated by genetic determinants. Here we applied exome sequencing to identify novel associations of coding polymorphisms at minor allele frequencies (MAFs) >1% with common metabolic phenotypes. METHODS: The study comprised three stages. We performed medium-depth (8×) whole exome sequencing in 1,000 cases with type 2 diabetes, BMI >27.5 kg/m(2) and hypertension and in 1,000 controls (stage 1). We selected 16,192 polymorphisms nominally associated (p < 0.05) with case-control status, from four selected annotation categories or from loci reported to associate with metabolic traits. These variants were genotyped in 15,989 Danes to search for association with 12 metabolic phenotypes (stage 2). In stage 3, polymorphisms showing potential associations were genotyped in a further 63,896 Europeans. RESULTS: Exome sequencing identified 70,182 polymorphisms with MAF >1%. In stage 2 we identified 51 potential associations with one or more of eight metabolic phenotypes covered by 45 unique polymorphisms. In meta-analyses of stage 2 and stage 3 results, we demonstrated robust associations for coding polymorphisms in CD300LG (fasting HDL-cholesterol: MAF 3.5%, p = 8.5 × 10(-14)), COBLL1 (type 2 diabetes: MAF 12.5%, OR 0.88, p = 1.2 × 10(-11)) and MACF1 (type 2 diabetes: MAF 23.4%, OR 1.10, p = 8.2 × 10(-10)). CONCLUSIONS/INTERPRETATION: We applied exome sequencing as a basis for finding genetic determinants of metabolic traits and show the existence of low-frequency and common coding polymorphisms with impact on common metabolic traits. Based on our study, coding polymorphisms with MAF above 1% do not seem to have particularly high effect sizes on the measured metabolic traits.

The effect of vitamin D replacement on markers of vascular health in stroke patients - a randomised controlled trial.

BACKGROUND AND AIMS: Low vitamin D levels are associated with increased incidence of future cardiovascular events and are common in stroke patients. We tested whether vitamin D supplementation could reduce blood pressure and improve markers of vascular health in patients who had previously suffered a stroke. METHODS AND RESULTS: Randomised, placebo-controlled, double-blind trial. Community-dwelling patients with a history of stroke and baseline 25-hydroxyvitamin D levels <75 nmol/L received 100,000 units of oral vitamin D2 or placebo at baseline. Office and 24 h blood pressure, endothelial function measured by flow-mediated dilatation of the brachial artery, cholesterol, oxidised low density lipoprotein, B-type natriuretic peptide and heart rate turbulence were measured at baseline, 8 weeks and 16 weeks. 58 patients were randomised. Mean age was 67 years, mean baseline blood pressure 128/72 mmHg, mean baseline 25-hydroxyvitamin D level was 38 nmol/L. Serum 25-hydroxyvitamin D levels were higher in the intervention group at 8 weeks compared to placebo (54 vs 42 nmol/L, P = 0.002) and remained higher at 16 weeks. Office systolic and diastolic blood pressure showed no significant change between groups at 8 weeks (systolic 126.1 vs 131.3 mmHg; adjusted P = 0.97); (diastolic 73.1 vs 74.9 mmHg, adjusted P = 0.15). Flow mediated dilatation was significantly higher in the intervention group at 8 weeks (6.9% vs 3.7%, adjusted P = 0.007) but was not significantly different at 16 weeks. CONCLUSIONS: High dose oral vitamin D supplementation did not improve blood pressure but produced short-term improvement in endothelial function in stroke patients with well-controlled baseline blood pressure. CLINICAL TRIALS REGISTRATION: ISRCTN28737567.

A role for coding functional variants in HNF4A in type 2 diabetes susceptibility.

AIMS/HYPOTHESIS: Rare mutations in the gene HNF4A, encoding the transcription factor hepatocyte nuclear factor 4α (HNF-4A), account for ~5% of cases of MODY and more frequent variants in this gene may be involved in multifactorial forms of diabetes. Two low-frequency, non-synonymous variants in HNF4A (V255M, minor allele frequency [MAF] ~0.1%; T130I, MAF ~3.0%)-known to influence downstream HNF-4A target gene expression-are of interest, but previous type 2 diabetes association reports were inconclusive. We aimed to evaluate the contribution of these variants to type 2 diabetes susceptibility through large-scale association analysis. METHODS: We genotyped both variants in at least 5,745 cases and 14,756 population controls from the UK and Denmark. We also undertook an expanded association analysis that included previously reported and novel genotype data obtained in Danish, Finnish, Canadian and Swedish samples. A meta-analysis incorporating all published association studies of the T130I variant was subsequently carried out in a maximum sample size of 14,279 cases and 26,835 controls. RESULTS: We found no association between V255M and type 2 diabetes in either the initial (p = 0.28) or the expanded analysis (p = 0.44). However, T130I demonstrated a modest association with type 2 diabetes in the UK and Danish samples (additive per allele OR 1.17 [95% CI 1.08-1.28]; p = 1.5 × 10⁻4), which was strengthened in the meta-analysis (OR 1.20 [95% CI 1.10-1.30]; p = 2.1 × 10⁻5). CONCLUSIONS/INTERPRETATION: Our data are consistent with T130I as a low-frequency variant influencing type 2 diabetes risk, but are not conclusive when judged against stringent standards for genome-wide significance. This study exemplifies the difficulties encountered in association testing of low-frequency variants.

Genetic association analysis of LARS2 with type 2 diabetes.

AIMS/HYPOTHESIS: LARS2 has been previously identified as a potential type 2 diabetes susceptibility gene through the low-frequency H324Q (rs71645922) variant (minor allele frequency [MAF] 3.0%). However, this association did not achieve genome-wide levels of significance. The aim of this study was to establish the true contribution of this variant and common variants in LARS2 (MAF > 5%) to type 2 diabetes risk. METHODS: We combined genome-wide association data (n = 10,128) from the DIAGRAM consortium with independent data derived from a tagging single nucleotide polymorphism (SNP) approach in Dutch individuals (n = 999) and took forward two SNPs of interest to replication in up to 11,163 Dutch participants (rs17637703 and rs952621). In addition, because inspection of genome-wide association study data identified a cluster of low-frequency variants with evidence of type 2 diabetes association, we attempted replication of rs9825041 (a proxy for this group) and the previously identified H324Q variant in up to 35,715 participants of European descent. RESULTS: No association between the common SNPs in LARS2 and type 2 diabetes was found. Our replication studies for the two low-frequency variants, rs9825041 and H324Q, failed to confirm an association with type 2 diabetes in Dutch, Scandinavian and UK samples (OR 1.03 [95% CI 0.95-1.12], p = 0.45, n = 31,962 and OR 0.99 [0.90-1.08], p = 0.78, n = 35,715 respectively). CONCLUSIONS/INTERPRETATION: In this study, the largest study examining the role of sequence variants in LARS2 in type 2 diabetes susceptibility, we found no evidence to support previous data indicating a role in type 2 diabetes susceptibility.

The Y402H variant of complement factor H is associated with age-related macular degeneration but not with diabetic retinal disease in the Go-DARTS study.

AIMS: The Y402H variant of complement factor H (CFH) is associated with risk of age-related macular degeneration (ARMD). In common with ARMD, diabetic retinal disease also appears to involve complement activation. The aim was to investigate the impact of Y402H on both retinal pathologies in patients with Type 2 diabetes (T2DM) undergoing systematic eye screening. METHODS: Patients with T2DM (n = 2350) were genotyped for the CFH Y402H variant. The association of genotype with retinal disease was determined in both retrospective and prospective models. RESULTS: The retrospective study demonstrated that the HH genotype was associated with an age-adjusted odds ratio of 7.4 for ARMD (P = 2.9 x 10(-11)). In a longitudinal study in the disease-free cohort, the age-adjusted hazard ratio was 2.8 (P = 2.4 x 10(-7)). The life-time hazard ratio was 3.4 (P = 2.1 x 10(-16)). We found no association of Y402H with development of referable diabetic retinal disease. CONCLUSION: The ARMD-associated Y402H variant in CFH does not appear to be associated with diabetic retinal disease, although complement activation is involved in the pathoaetiology of both conditions.

The cost of cerebral ischaemia.

Cerebral ischaemia is a major cause of disability and death globally and has a profoundly negative impact on the individuals it affects, those that care for them and society as a whole. The most common and familiar manifestation is stroke, 85% of which are ischaemic and which is the second leading cause of death and most common cause of complex chronic disability worldwide. Stroke survivors often suffer from long-term neurological disabilities significantly reducing their ability to integrate effectively in society with all the financial and social consequences that this implies. These difficulties cascade to their next of kin who often become caregivers and are thus indirectly burdened. A more insidious consequence of cerebral ischaemia is progressive cognitive impairment causing dementia which although less abrupt is also associated with a significant long-term disability. Globally cerebrovascular diseases are responsible for 5.4 million deaths every year (1 in 10 of total). Approximately 3% of total healthcare expenditure is attributable to cerebral ischaemia with cerebrovascular diseases costing EU healthcare systems 21 billion euro in 2003. The cost to the wider economy (including informal care and lost productivity) is even greater with stroke costing the UK 7-8 billion pound in 2005 and the US $62.7 billion in 2007. Cerebrovascular disease cost the EU 34 billion euro in 2003. From 2005 to 2050 the anticipated cost of stroke to the US economy is estimated at $2.2 trillion. Given the global scale of the problem and the enormous associated costs it is clear that there is an urgent need for advances in the prevention of cerebral ischaemia and its consequences. Such developments would result in profound benefits for both individuals and their wider societies and address one of the world's most pre-eminent public health issues.

Long-term adherence to statin treatment in diabetes.

AIMS: To determine the patterns and predictors of long-term adherence to statin therapy in all patients with diabetes in the community setting. METHODS: We retrospectively studied patients with diabetes who were resident in Tayside, Scotland from 1 January 1989 to 31 May 2003 and initiated statin treatment during that time. The main outcome measure was percentage of days covered (PDC) by a statin, calculated at regular intervals. Predictors of suboptimal adherence (PDC < 80%) were identified using generalized linear models for repeated measures. RESULTS: Six thousand four hundred and sixty-two patients were included in the study. In the first year, the mean PDC was 87, 61% in the first and second quarter, respectively, and 65% after 13 years. Less than 50% of patients maintained a PDC of > 80% after 13 years. Predictors of poor long-term adherence were younger age, higher HbA(1c), no history of smoking, no cardiovascular morbidity at baseline and occurrence of cardiovascular disease after statin commencement. CONCLUSIONS: This study suggests that barriers to long-term adherence to statins tend to arise early on in the therapeutic course. In general, long-term adherence is poor in patients with diabetes, especially among those with few other cardiovascular risk factors.

PPARG locus haplotype variation and exacerbations in asthma.

The peroxisome proliferator-activated receptor gamma (PPARgamma) regulates inflammation and may play a role in asthma. Using mouthwash-derived DNA and clinical interviews and measurements, we investigated the association of previously characterized single-nucleotide polymorphisms in the PPARG gene (Pro12Ala, C1431T, and C-681G) with asthma exacerbations in patients aged 3-22 years (n=569). The common homozygous haplotype combination of the Pro12 and C1431 alleles was associated with increased risk for asthma exacerbations (ProC, odds ratio (OR) 1.87, 95% confidence interval 1.25-2.79; P=0.002). The ProC genotype was associated with increased school absences (OR 1.82, 95% confidence interval 1.21-2.76; P=0.004) and hospital admissions (OR 2.32, 95% confidence interval 1.18-4.58; P=0.015) over the preceding 6 months. The population-attributable risk of this genotype was 33%. Common genetic variation at the PPARG locus may play an important role in modulating the long-term control of asthma in children and young adults.

Mental health initiatives as peace initiatives in Sri Lankan schoolchildren affected by armed conflict.

The Health Reach Sri Lanka project (1993-96) is described. It was a school-based assessment of children's exposure to war-related events and the presence of psychological distress, undertaken in six communities in parts of Sri Lanka variously affected by armed conflict. Its objectives, methods and results are presented. The research project aimed to raise national awareness of the psychosocial effects of armed conflict on children, using a community-development approach to local capacity building, based on the 'health initiative as peace initiative' model. As a follow-up to the study, a locally run programme, based on creative play and trauma-healing, was established, initially for the children involved in the study. This was later extended to other children in the district affected by armed conflict.

Parental experiences of a paediatric cochlear implant programme.

Although cochlear implantation is a well-established procedure in profoundly deaf children, very little research has investigated whether parents are satisfied with the treatment (including assessment, surgery and rehabilitation) or its outcome, and whether it has met their expectations. In this study, 44 parents of children who had received cochlear implants completed a confidential postal questionnaire. Results indicated that the majority of parents felt that the information they and their child received was both sufficient and appropriate. Many parents experienced more distress than they anticipated, but perceived their child as having experienced less physical discomfort than expected. Some suggestions for improving the service were made, but in general it was felt that little more could be done to inform our 'consumers', or to reduce levels of stress.

VAMPIRE: Vessel assessment and measurement platform for images of the REtina.

We present VAMPIRE, a software application for efficient, semi-automatic quantification of retinal vessel properties with large collections of fundus camera images. VAMPIRE is also an international collaborative project of four image processing groups and five clinical centres. The system provides automatic detection of retinal landmarks (optic disc, vasculature), and quantifies key parameters used frequently in investigative studies: vessel width, vessel branching coefficients, and tortuosity. The ultimate vision is to make VAMPIRE available as a public tool, to support quantification and analysis of large collections of fundus camera images.

Common nonsynonymous substitutions in SLCO1B1 predispose to statin intolerance in routinely treated individuals with type 2 diabetes: a go-DARTS study.

SLCO1B1 gene variants are associated with severe statin-induced myopathy. We examined whether these variants are also associated with general statin intolerance in a large population of patients with type 2 diabetes receiving statins as part of routine clinical care. A total of 4,196 individuals were genotyped for rs4149056 (Val174Ala) and rs2306283 (Asp130Asn). Intolerance was defined by serum biochemistry and also by discontinuation, switching, or reduction in dose of the prescribed statin drug. Ala174 was associated with higher intolerance (odds ratio = 2.05, P = 0.043), whereas Asp130 was associated with lower intolerance (odds ratio = 0.71, P = 0.026). Ala174 was associated with a lower low-density lipoprotein cholesterol (LDLc) response to statins (P = 0.01) whereas 130D was associated with a greater LDLc response to statins (P = 0.048), as previously reported; however, this association was no longer present when data for statin-intolerant individuals were removed from the analysis. This study suggests that common genetic variants selected for an extreme phenotype of statin-induced myopathy also predispose to more common milder statin intolerance and may, for this reason, impact lipid-lowering efficacy.

Loss-of-function CYP2C9 variants improve therapeutic response to sulfonylureas in type 2 diabetes: a Go-DARTS study.

Sulfonylureas are metabolized mainly by the cytochrome p450 2C9 (CYP2C9) enzyme. Two CYP2C9 variants--*2 (Arg144Cys) and *3 (Ile359Leu)--are associated with reduced enzyme activity and impaired substrate metabolism. We identified 1,073 incident users of sulfonylureas in Tayside, Scotland, and assessed the impact of the combined CYP2C9*2 and CYP2C9*3 genotypes on early and sustained sulfonylurea response. We found that patients with two copies of a loss-of-function allele were 3.4 times (P = 0.0009) more likely to achieve a treatment hemoglobin A(1c) (HbA(1c)) level <7% than patients with two wild-type CYP2C9 alleles. This corresponds to a 0.5% (P = 0.003) greater reduction in HbA(1c) concentration. In addition, *2 and *3 allele carriers were less likely to experience treatment failure with sulfonylurea monotherapy (P = 0.04; per-allele hazard ratio 0.79; 95% confidence interval 0.63-0.99). In conclusion, CYP2C9 loss-of-function alleles are associated with greater response to sulfonylureas and decreased failure of therapy consistent with the pharmacokinetic role of CYP2C9.

TCF7L2 in the Go-DARTS study: evidence for a gene dose effect on both diabetes susceptibility and control of glucose levels.

AIMS/HYPOTHESIS: The gene encoding transcription factor 7-like 2 (TCF7L2) has been identified as a type 2 diabetes locus from genome-wide linkage studies and subsequent association analysis. We investigated the role of two common variants in TCF7L2 in a large case-control study recruited from the Tayside region of Scotland, UK. SUBJECTS AND METHODS: We genotyped 6,516 participants for rs12255372 and rs7903146 and analysed the role in type 2 diabetes susceptibility using binary logistic regression. Age, sex and obesity status were examined as covariates. The distribution of the genotypes within different treatment groups of cases was examined. RESULTS: Both variants were associated with type 2 diabetes (p < 10(-13)). The variants were present at very similar frequencies and were in strong linkage disequilibrium (R(2) = 0.88, D' = 0.89). A gene dosage effect of the rare allele of both variants was observed, the heterozygote CT group of rs7903146 having an odds ratio of 1.36 (95% CI 1.2-1.5, p=1.54 x 10(-7)) for type 2 diabetes and the TT homozygote having a greater risk (OR = 2.03, 95% CI 1.7-2.5, p=1.40 x 10(-12)). An interaction with sex was observed, the males displaying a higher degree of genotype-associated risk compared with the females (p = 0.023). The T allele was associated with increased HbA(1c) levels in both cases and controls, and with decreased BMI and waist circumference in case but not controls. The T allele was overrepresented in individuals requiring insulin treatment and underrepresented in the patients being managed by diet alone (p = 0.006). CONCLUSIONS: We have confirmed TCF7L2 to be a diabetes locus in a large case-control study in Tayside, UK. Our data suggest that variants of TCF7L2 may be associated with increased disease severity and therapeutic failure.

The effect of obesity on glycaemic response to metformin or sulphonylureas in Type 2 diabetes.

AIMS: In treating Type 2 diabetes (T2DM), UK guidelines recommend metformin in obese and overweight patients, and either sulphonylureas or metformin in normal weight patients. Although other factors influence prescribing choice, a key objective in treating T2DM is to lower plasma glucose. There is little data on how glycaemic response to oral agents varies with body mass index (BMI). Therefore, we assessed current prescribing practice and effect of BMI on glycaemic response to sulphonylureas and metformin in a large population T2DM cohort. METHODS: BMI was determined in 3856 T2DM patients on sulphonylurea or metformin monotherapy in 2001-2002. Patients were identified from the Diabetes Audit and Research in Tayside, Scotland (DARTS) database. In a linear regression, the effect of BMI and other confounders on drug response was assessed in 2064 treatment-naïve patients commencing sulphonylureas or metformin between 1994 and 2002. RESULTS: In 2001-2002, metformin was more likely to be used in obese than non-obese patients: 13% normal weight, 33.6% overweight and 62.1% obese patients were treated with metformin. Glycaemic response to sulphonylureas was not influenced by BMI (P = 0.81). Metformin was more effective in lowering glucose in those with a lower BMI (r = -0.02, P = 0.02), although the clinical impact of this was small. The HbA(1c) reduction in non-obese patients was similar to that in obese patients (1.46% vs. 1.34%, P = 0.11). CONCLUSIONS: Glycaemic response to metformin in non-obese and obese patients is similar, suggesting that an individual's BMI should not influence the choice of oral agent. Given the non-glycaemia-related benefits of metformin, it should be used in more non-obese patients than is current practice in Tayside, Scotland.

The Pro12Ala and C-681G variants of the PPARG locus are associated with opposing growth phenotypes in young schoolchildren.

AIMS/HYPOTHESIS: Peroxisome proliferator-activated receptor gamma is an important regulator of adiposity in mouse and man, and common variation in the PPARG gene has been associated with birthweight, adult obesity, insulin sensitivity and type 2 diabetes. We hypothesised that these variants may be associated with childhood obesity. METHODS: Height and weight were recorded for 2454 prepubertal children aged between 4 and 10 years, who were then genotyped for three common variants of the PPARG locus: C-681G, Pro12Ala and C1431T. RESULTS: No single variant of PPARG was significantly associated with height, weight or BMI. However, when modelling the variants together we detected an opposing interaction between the -681G and the Ala12 variants in height and weight, but not BMI (p=0.018, 0.013 and 0.119 respectively). The data were consistent with the Ala12 carriers being deficient in energy storage/utilisation, leading to reduced growth. In contrast, the -681G variant, which has been associated with increased adult height, was associated with accelerated growth. The two variants were in strong linkage disequilibrium. However, rare individuals bearing the isolated variants demonstrated the greatest variation from the mean, the most contrasting genotypes being associated with a variation of 7 kg in weight and 6 cm in height, standardised to 7.4-year-olds (p=0.006 and p=0.02 respectively). CONCLUSIONS/INTERPRETATION: This study demonstrates that quantitative trait analysis of energy balance/growth and the PPARG locus is complex and requires the use of multiple genetic markers.

Candida dubliniensis at a cancer center.

Candida dubliniensis, a germ tube-positive yeast first described and identified as a cause of oral candidiasis in patients with acquired immunodeficiency syndrome in Europe in 1995, has an expanding clinical and geographic distribution that appears to be similar to that of the other germ tube-positive yeast, Candida albicans. This study determined the frequency, clinical spectrum, drug susceptibility profile, and suitable methods for identification of this emerging pathogen at a cancer center in 1998 and 1999. Twenty-two isolates were recovered from 16 patients with solid-organ or hematologic malignancies or acquired immunodeficiency syndrome. Two patients with cancer had invasive infection, and 14 were colonized with fungus or had superficial fungal infection. All isolates produced germ tubes and chlamydospores at 37 degrees C, did not grow at 45 degrees C, and gave negative reactions with d-xylose and alpha-methyl-d-glucoside in the API 20 C AUX and ID 32 C yeast identification systems. Phenotypic identification was confirmed by molecular beacon probe technology. All isolates were susceptible to the antifungal drugs amphotericin B, 5-fluorocytosine, fluconazole, itraconazole, and ketoconazole.