Calculation of the Hadronic Vacuum Polarization Disconnected Contribution to the Muon Anomalous Magnetic Moment

We report the first lattice QCD calculation of the hadronic vacuum polarization disconnected contribution to the muon anomalous magnetic moment at physical pion mass. The calculation uses a refined noise-reduction technique which enabled the control of statistical uncertainties at the desired level with modest computational effort. Measurements were performed on the $48^3 \times 96$ physical-pion-mass lattice generated by the RBC and UKQCD collaborations. We find $a_\mu^{\rm HVP~(LO)~DISC} = -9.6(3.3)(2.3)\times 10^{-10}$, where the first error is statistical and the second systematic.Comment: 8 pages, 13 figure

Variation at the NFATC2 Locus Increases the Risk of Thiazolidinedione-Induced Edema in the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) Study

Objective: Thiazolidinediones are used to treat type 2 diabetes. Their use has been associated with peripheral edema and congestive heart failure - outcomes that may have a genetic etiology. Research Design and Methods: We genotyped 4,197 participants of the multiethnic DREAM (Diabetes Reduction Assessment with ramipril and rosiglitazone Medication) trial with a 50k single nucleotide polymorphisms (SNP) array, which captures ∼2000 cardiovascular, inflammatory, and metabolic genes. We tested 32,088 SNPs for an association with edema among Europeans who received rosiglitazone (n = 965). Results: One SNP, rs6123045, in NFATC2 was significantly associated with edema (odds ratio 1.89 [95% CI 1.47-2.42]; P = 5.32 × 10-7, corrected P = 0.017). Homozygous individuals had the highest edema rate (hazard ratio 2.89, P = 4.22 × 10-4) when compared with individuals homozygous for the protective allele, with heterozygous individuals having an intermediate risk. The interaction between the SNP and rosiglitazone for edema was significant (P = 7.68 × 10-3). Six SNPs in NFATC2 were significant in both Europeans and Latin Americans (P < 0.05). Conclusions: Genetic variation at the NFATC2 locus contributes to edema among individuals who receive rosiglitazone

IL8 polymorphisms and overall survival in pazopanib- or sunitinib-treated patients with renal cell carcinoma.

BACKGROUND: We evaluated germline single nucleotide polymorphisms (SNPs) for association with overall survival (OS) in pazopanib- or sunitinib-treated patients with advanced renal cell carcinoma (aRCC). METHODS: The discovery analysis tested 27 SNPs within 13 genes from a phase III pazopanib trial (N=241, study 1). Suggestive associations were then pursued in two independent datasets: a phase III trial (COMPARZ) comparing pazopanib vs sunitinib (N=729, study 2) and an observational study of sunitinib-treated patients (N=89, study 3). RESULTS: In study 1, four SNPs showed nominally significant association (P≤0.05) with OS; two of these SNPs (rs1126647, rs4073) in IL8 were associated (P≤0.05) with OS in study 2. Because rs1126647 and rs4073 were highly correlated, only rs1126647 was evaluated in study 3, which also showed association (P≤0.05). In the combined data, rs1126647 was associated with OS after conservative multiple-test adjustment (P=8.8 × 10(-5); variant vs reference allele hazard ratio 1.32, 95% confidence interval: 1.15-1.52), without evidence for heterogeneity of effects between studies or between pazopanib- and sunitinib-treated patients. CONCLUSIONS: Variant alleles of IL8 polymorphisms are associated with poorer survival outcomes in pazopanib- or sunitinib-treated patients with aRCC. These findings provide insight in aRCC prognosis and may advance our thinking in development of new therapies

Physiogenomic analysis of weight loss induced by dietary carbohydrate restriction

BACKGROUND: Diets that restrict carbohydrate (CHO) have proven to be a successful dietary treatment of obesity for many people, but the degree of weight loss varies across individuals. The extent to which genetic factors associate with the magnitude of weight loss induced by CHO restriction is unknown. We examined associations among polymorphisms in candidate genes and weight loss in order to understand the physiological factors influencing body weight responses to CHO restriction. METHODS: We screened for genetic associations with weight loss in 86 healthy adults who were instructed to restrict CHO to a level that induced a small level of ketosis (CHO ~10% of total energy). A total of 27 single nucleotide polymorphisms (SNPs) were selected from 15 candidate genes involved in fat digestion/metabolism, intracellular glucose metabolism, lipoprotein remodeling, and appetite regulation. Multiple linear regression was used to rank the SNPs according to probability of association, and the most significant associations were analyzed in greater detail. RESULTS: Mean weight loss was 6.4 kg. SNPs in the gastric lipase (LIPF), hepatic glycogen synthase (GYS2), cholesteryl ester transfer protein (CETP) and galanin (GAL) genes were significantly associated with weight loss. CONCLUSION: A strong association between weight loss induced by dietary CHO restriction and variability in genes regulating fat digestion, hepatic glucose metabolism, intravascular lipoprotein remodeling, and appetite were detected. These discoveries could provide clues to important physiologic adaptations underlying the body mass response to CHO restriction

Clinical laboratory reference values amongst children aged 4 weeks to 17 months in Kilifi, Kenya: A cross sectional observational study

Reference intervals for clinical laboratory parameters are important for assessing eligibility, toxicity grading and management of adverse events in clinical trials. Nonetheless, haematological and biochemical parameters used for clinical trials in sub-Saharan Africa are typically derived from industrialized countries, or from WHO references that are not region-specific. We set out to establish community reference values for haematological and biochemical parameters amongst children aged 4 weeks to 17 months in Kilifi, Kenya. We conducted a cross sectional study nested within phase II and III trials of RTS, S malaria vaccine candidate. We analysed 10 haematological and 2 biochemical parameters from 1,070 and 423 community children without illness prior to experimental vaccine administration. Statistical analysis followed Clinical and Laboratory Standards Institute EP28-A3c guidelines. 95% reference ranges and their respective 90% confidence intervals were determined using non-parametric methods. Findings were compared with published ranges from Tanzania, Europe and The United States. We determined the reference ranges within the following age partitions: 4 weeks to <6 months, 6 months to less than <12 months, and 12 months to 17 months for the haematological parameters; and 4 weeks to 17 months for the biochemical parameters. There were no gender differences for all haematological and biochemical parameters in all age groups. Hb, MCV and platelets 95% reference ranges in infants largely overlapped with those from United States or Europe, except for the lower limit for Hb, Hct and platelets (lower); and upper limit for platelets (higher) and haematocrit(lower). Community norms for common haematological and biochemical parameters differ from developed countries. This reaffirms the need in clinical trials for locally derived reference values to detect deviation from what is usual in typical children in low and middle income countries