Genetic polymorphisms associated with carotid artery intima-media thickness and coronary artery calcification in women of the Kronos Early Estrogen Prevention Study.

Menopausal hormone treatment (MHT) may limit progression of cardiovascular disease (CVD) but poses a thrombosis risk. To test targeted candidate gene variation for association with subclinical CVD defined by carotid artery intima-media thickness (CIMT) and coronary artery calcification (CAC), 610 women participating in the Kronos Early Estrogen Prevention Study (KEEPS), a clinical trial of MHT to prevent progression of CVD, were genotyped for 13,229 single nucleotide polymorphisms (SNPs) within 764 genes from anticoagulant, procoagulant, fibrinolytic, or innate immunity pathways. According to linear regression, proportion of European ancestry correlated negatively, but age at enrollment and pulse pressure correlated positively with CIMT. Adjusting for these variables, two SNPs, one on chromosome 2 for MAP4K4 gene (rs2236935, ß = 0.037, P value = 2.36 × 10(-06)) and one on chromosome 5 for IL5 gene (rs739318, ß = 0.051, P value = 5.02 × 10(-05)), associated positively with CIMT; two SNPs on chromosome 17 for CCL5 (rs4796119, ß = -0.043, P value = 3.59 × 10(-05); rs2291299, ß = -0.032, P value = 5.59 × 10(-05)) correlated negatively with CIMT; only rs2236935 remained significant after correcting for multiple testing. Using logistic regression, when we adjusted for waist circumference, two SNPs (rs11465886, IRAK2, chromosome 3, OR = 3.91, P value = 1.10 × 10(-04); and rs17751769, SERPINA1, chromosome 14, OR = 1.96, P value = 2.42 × 10(-04)) associated positively with a CAC score of >0 Agatston unit; one SNP (rs630014, ABO, OR = 0.51, P value = 2.51 × 10(-04)) associated negatively; none remained significant after correcting for multiple testing. Whether these SNPs associate with CIMT and CAC in women randomized to MHT remains to be determined.

High-BMI at diagnosis is associated with inferior survival in patients with osteosarcoma: a report from the Children's Oncology Group.

BACKGROUND: Body mass index (BMI), at diagnosis has been associated with lower survival and increased toxicity in cancer patients. We analyzed the effect of BMI at diagnosis on therapy related toxicities and outcome in pediatric osteosarcoma patients treated on Children's Oncology Group (COG) trial INT0133. PROCEDURES: All patients enrolled on COG-INT0133 with height, weight and toxicity information were eligible. BMI was expressed as age and gender specific percentiles using height and weight at diagnosis. Patients were classified into high, normal and low BMI groups. Logistic regression models were used to analyze toxicities; Kaplan-Meier curves were created to assess event free (EFS) and overall survival (OAS). RESULTS: Seven hundred and ten patients met eligibility criteria. BMI distribution was: 447 normal BMI, 74 low BMI, and 189 high BMI. Renal toxicity was higher in the high BMI group (OR = 2.7, 95% CI 1.2-6.4, P = = 0.01) only during one of the courses of therapy. Compared to the normal BMI group, patients with high BMI had significantly worse OAS at 5 years compared to those with normal BMI, 69.7% versus 80.5% (HR = 1.6, 95% CI 1.1-2.2, P = 0.005) and a trend towards worse event-free survival at 3 years 66.2% versus 75.5% (HR = 1.3 95% CI 0.9-1.8, P = 0.05). There was no difference in EFS or OAS in patients with low BMI compared to patients with normal BMI. CONCLUSIONS: High BMI at diagnosis is associated with worse OAS in patients with osteosarcoma. No clinically significant differences in toxicity were observed in the various BMI groups.

Hereditary hemorrhagic telangiectasia and risks for adverse pregnancy outcomes.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular dysplasia characterized by epistaxis, mucocutaneous telangiectasias, and arteriovenous malformations (AVM) in the brain, lung, liver, gastrointestinal tract, or spine. While pregnant women with HHT are known to have increased risks due to pulmonary AVMs, little is known about any increased risk for fetal birth defects or other adverse pregnancy outcomes. To investigate potential increased risk, individuals with a clinical diagnosis of HHT were asked to complete a survey composed of four sections: demographics, personal history of HHT, personal history of birth defects (modeled after state registries), and reproductive history. A total of 226 participants reported outcomes of 560 pregnancies, as well as self-reported personal history of birth defects. Of the 560 pregnancies, 450 (80.4%) resulted in 457 live births and 63 (13.8%) were pre-term. Of the 110 pregnancy losses, 80 (72.7%) were first trimester and five were stillborn. Anomalies considered to be medically or cosmetically significant were reported in 17 babies (3.7%). The presence of significant anomalies was not significantly associated with whether the baby had an HHT diagnosis (P=0.55) or the gender of the parent with HHT (P=0.32). Four liveborn babies and one stillborn had a cerebral AVM or hemorrhage in the perinatal period. Prevalence of uterine hemorrhage, pre-eclampsia, placental abnormalities, low-birth weight, and infertility did not appear increased over the general population. These data provide some reassurance that HHT does not lead to an appreciable increased risk for birth defects or other adverse pregnancy outcomes.

Accounting for model uncertainty in estimating global burden of disease.

OBJECTIVE: To illustrate the effects of failing to account for model uncertainty when modelling is used to estimate the global burden of disease, with specific application to childhood deaths from rotavirus infection. METHODS: To estimate the global burden of rotavirus infection, different random-effects meta-analysis and meta-regression models were constructed by varying the stratification criteria and including different combinations of covariates. Bayesian model averaging was used to combine the results across models and to provide a measure of uncertainty that reflects the choice of model and the sampling variability. FINDINGS: In the models examined, the estimated number of child deaths from rotavirus infection varied between 492,000 and 664,000. While averaging over the different models' estimates resulted in a modest increase in the estimated number of deaths (541,000 as compared with the World Health Organization's estimate of 527,000), the width of the 95% confidence interval increased from 105,000 to 198,000 deaths when model uncertainty was taken into account. CONCLUSION: Sampling variability explains only a portion of the overall uncertainty in a modelled estimate. The uncertainty owing to both the sampling variability and the choice of model(s) should be given when disease burden results are presented. Failure to properly account for uncertainty in disease burden estimates may lead to inappropriate uses of the estimates and inaccurate prioritization of global health needs.

Alpha-1-antitrypsin deficiency and smoking as risk factors for mismatch repair deficient colorectal cancer: a study from the colon cancer family registry.

In a previous study, alpha-1-antitrypsin (A1AT) deficiency alleles were found to be over represented among individuals with microsatellite unstable (MSI-high) colorectal cancers, and this was most significant in former or current smokers. We evaluated this association in a larger case-control study, stratified by microsatellite instability phenotypes. Concordant with prior observations, gender (female) and smoking history were positively associated with colorectal cancers having an MSI-high phenotype. No difference in frequency of A1AT deficiency alleles was found between cases and controls, irrespective of the MSI subtype.