New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

A genome-wide association search for type 2 diabetes genes in African Americans.

African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations

Variability in antifungal utilization among neonatal, pediatric, and adult inpatients in academic medical centers throughout the United States of America

Abstract Background Identification of factors associated with antifungal utilization in neonatal, pediatric, and adult patient groups is needed to guide antifungal stewardship initiatives in academic medical centers. Methods For this hospital-level analysis, we analyzed antifungal use in hospitals across the United States of America, excluding centers only providing care for hematology/oncology patients. Analysis of variance was used to compare antifungal use between patient groups. Three multivariable linear regression models were used to determine independent factors associated with antifungal use in the neonatal, pediatric, and adult patient groups. Results For the neonatal, pediatric, and adult patient groups, 54, 44, and 60 hospitals were included, respectively. Total antifungal use was significantly lower in the neonatal patient group (14 days of therapy (DOT)/1000 patient days (PDs) versus 76 in pediatrics and 74 in adults, p < 0.05). There were no significant associations identified with total antifungal DOT/1000 PDs in the neonatal patient group (model R2 = 0.11). In the pediatric patient group (model R2 = 0.55), admission to immunosuppressed service lines and total broad-spectrum antibiotic use were positively associated with total antifungal use (coefficients of 1.95 and 0.41, both p < 0.05). In the adult patient group (model R2 = 0.79), admission to immunosuppressed service lines, total invasive fungal infections, and total broad-spectrum antibiotic use were positively associated with total antifungal use (coefficients of 5.08, 5.17, and 0.137, all p < 0.05). Conclusions Variability in antifungal use in the neonatal group could not be explained well, whereas factors were associated with antifungal use in the adult and pediatric patient groups. These data can help guide antifungal stewardship initiatives

Relationship of Carbapenem Restriction in 22 University Teaching Hospitals to Carbapenem Use and Carbapenem-Resistant Pseudomonas aeruginosa▿

Many hospital antimicrobial stewardship programs restrict the availability of selected drugs by requiring prior approval. Carbapenems may be among the restricted drugs, but it is unclear if hospitals that restrict availability actually use fewer carbapenems than hospitals that do not restrict use. Nor is it clear if restriction is related to resistance. We evaluated the relationship between carbapenem restriction and the volume of carbapenem use and both the incidence rate and proportion of carbapenem-resistant Pseudomonas aeruginosa isolates from 2002 through 2006 in a retrospective, longitudinal, multicenter analysis among a consortium of academic health centers. Carbapenem use was measured from billing records as days of therapy per 1,000 patient days. Hospital antibiograms were used to determine both the incidence rate and proportion of carbapenem-resistant P. aeruginosa isolates. A survey inquired about restriction policies for antibiotics, including carbapenems. General linear mixed models were used to examine study outcomes. Among 22 hospitals with sufficient data for analysis, overall carbapenem use increased significantly over the 5 years of study (P < 0.0001), although overall carbapenem resistance in P. aeruginosa did not change. Hospitals that restricted carbapenems (n = 8; 36%) used significantly fewer carbapenems (P = 0.04) and reported lower incidence rates of carbapenem-resistant P. aeruginosa (P = 0.01) for all study years. Fluoroquinolone use was a potential confounder of these relationships, but hospitals that restricted carbapenems actually used fewer fluoroquinolones than those that did not. Restriction of carbapenems is associated with both lower use and lower incidence rates of carbapenem resistance in P. aeruginosa

Identifying hospital antimicrobial resistance targets via robust ranking

<p>We develop a robust ranking procedure to uncover trends in variation in antibiotic resistance (AR) rates across hospitals for some antibiotic-bacterium pairs over several years. We illustrate how the method can be used to detect potentially dangerous trends and to direct attention to hospitals’ management practices. A robust method is indicated because some unusual reported resistance rates may be due to measurement protocol differences and not any real difference in AR rates. Our proposed method is less sensitive to outlier observations than other robust methods. The application on real AR data shows how a dangerous trend in a particular AR rate would be detected. Our results indicate the potential benefits of systematic AR rate collection and AR reporting systems across hospitals.</p