Distribution and dynamics of Greenland subglacial lakes.

Few subglacial lakes have been identified beneath the Greenland Ice Sheet (GrIS) despite extensive documentation in Antarctica, where periodic release of water can impact ice flow. Here we present an ice-sheet-wide survey of Greenland subglacial lakes, identifying 54 candidates from airborne radio-echo sounding, and 2 lakes from ice-surface elevation changes. These range from 0.2-5.9 km in length, and are mostly distributed away from ice divides, beneath relatively slow-moving ice. Based on our results and previous observations, we suggest three zones of formation: stable lakes in northern and eastern regions above the Equilibrium Line Altitude (ELA) but away from the interior; hydrologically-active lakes near the ELA recharged by surface meltwater and; small, seasonally-active lakes below the ELA, which form over winter and drain during the melt season. These observations provide important constraints on the GrIS's basal thermal regime and help refine our understanding of the subglacial hydrological system.

Hospitalised hip fracture risk with rosiglitazone and pioglitazone use compared with other glucose-lowering drugs.

AIMS/HYPOTHESIS: Current drug labels for thiazolidinediones (TZDs) warn of increased fractures, predominantly for distal fractures in women. We examined whether exposure to TZDs affects hip fracture in women and men and compared the risk to that found with other drugs used in diabetes. METHODS: Using a nationwide database of prescriptions, hospital admissions and deaths in those with type 2 diabetes in Scotland we calculated TZD exposure among 206,672 individuals. Discrete-time failure analysis was used to model the effect of cumulative drug exposure on hip fracture during 1999-2008. RESULTS: There were 176 hip fractures among 37,479 exposed individuals. Hip fracture risk increased with cumulative exposure to TZD: OR per year of exposure 1.18 (95% CI 1.09, 1.28; p = 3 × 10(-5)), adjusted for age, sex and calendar month. Hip fracture increased with cumulative exposure in both men (OR 1.20; 95% CI 1.03, 1.41) and women (OR 1.18; 95% CI 1.07, 1.29) and risks were similar for pioglitazone (OR 1.18) and rosiglitazone (OR 1.16). The association was similar when adjusted for exposure to other drugs for diabetes and for other potential confounders. There was no association of hip fracture with cumulative exposure to sulfonylureas, metformin or insulin in this analysis. The 90-day mortality associated with hip fractures was similar in ever-users of TZD (15%) and in never-users (13%). CONCLUSIONS/INTERPRETATION: Hip fracture is a severe adverse effect with TZDs, affecting both sexes; labels should be changed to warn of this. The excess mortality is at least as much as expected from the reported association of pioglitazone with bladder cancer.

A gene variant near ATM is significantly associated with metformin treatment response in type 2 diabetes: a replication and meta-analysis of five cohorts.

AIMS/HYPOTHESIS: In this study we aimed to replicate the previously reported association between the glycaemic response to metformin and the SNP rs11212617 at a locus that includes the ataxia telangiectasia mutated (ATM) gene in multiple additional populations. METHODS: Incident users of metformin selected from the Diabetes Care System West-Friesland (DCS, n = 929) and the Rotterdam Study (n = 182) from the Netherlands, and the CARDS Trial (n = 254) from the UK were genotyped for rs11212617 and tested for an association with both HbA(1c) reduction and treatment success, defined as the ability to reach the treatment target of an HbA(1c) ≤ 7 % (53 mmol/mol). Finally, a meta-analysis including data from literature was performed. RESULTS: In the DCS cohort, we observed an association between rs11212617 genotype and treatment success on metformin (OR 1.27, 95% CI 1.03, 1.58, p = 0.028); in the smaller Rotterdam Study cohort, a numerically similar but non-significant trend was observed (OR 1.45, 95% CI 0.87, 2.39, p = 0.15); while in the CARDS cohort there was no significant association. In meta-analyses of these three cohorts separately or combined with the previously published cohorts, rs11212617 genotype is associated with metformin treatment success (OR 1.24, 95% CI 1.04, 1.49, p = 0.016 and OR 1.25, 95% CI 1.33, 1.38, p = 7.8 × 10(-6), respectively). CONCLUSIONS/INTERPRETATION: A gene variant near ATM is significantly associated with metformin treatment response in type 2 diabetic patients from the Netherlands and the UK. This is the first robustly replicated common susceptibility locus found to be associated with metformin treatment response.

Apolipoproteins, cardiovascular risk and statin response in type 2 diabetes: the Collaborative Atorvastatin Diabetes Study (CARDS).

AIMS/HYPOTHESIS: Controversy surrounds whether the ratio of apolipoprotein B (ApoB) to apolipoprotein A-I (ApoA-I) is the best lipoprotein discriminator of CHD risk in non-diabetic populations, but the issue has never been investigated in type 2 diabetes. METHODS: In 2,627 participants without known vascular disease in the Collaborative Atorvastatin Diabetes Study, ApoB, ApoA-I, LDL-cholesterol (LDLC) and HDL-cholesterol (HDLC) were assayed at baseline. RESULTS: There were 108 CHD and 59 stroke endpoints over 3.9 years. The ApoB:A-I ratio at baseline was the lipoprotein variable most closely predicting CHD risk both by comparison of the hazard ratio for a 1 SD change or tertiles of frequency distribution. The areas under the receiver-operator curve for the ApoB:ApoA-I and the LDLC to HDLC [corrected] ratios, although not significantly different from each other, were greater (p = 0.0005 and p = 0.0125 respectively) than that of non-HDLC:HDLC. The 27% decrease in the ApoB:ApoA-I ratio on atorvastatin predicted a 32% (95% CI 5.4-51.2%) risk reduction in CHD, close to the 36% decrease observed. Neither the ApoB:ApoA-I nor any other lipoprotein concentration or ratio predicted the stroke outcome. CONCLUSIONS/INTERPRETATION: Overall, the ApoB:ApoA-I ratio improved on the non-HDLC:HDLC ratio in predicting CHD, but, depending on the assessment chosen, its superiority over LDLC:HDLC may be marginal. The statin-induced decrease in stroke risk may not be lipoprotein mediated. TRIAL REGISTRATION: ClinicalTrials.gov NCT00327418. FUNDING: The study was supported by unrestricted grants from Diabetes UK, the Department of Health and Pfizer to the University of Manchester and to University College, London.

Cost-effectiveness of primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes: results from the Collaborative Atorvastatin Diabetes Study (CARDS).

AIMS/HYPOTHESIS: We estimated the cost-effectiveness of atorvastatin treatment in the primary prevention of cardiovascular disease in patients with type 2 diabetes using data from the Collaborative Atorvastatin Diabetes Study (CARDS). SUBJECTS AND METHODS: A total of 2,838 patients, who were aged 40 to 75 years and had type 2 diabetes without a documented history of cardiovascular disease and without elevated LDL-cholesterol, were recruited from 32 centres in the UK and Ireland and randomly allocated to atorvastatin 10 mg daily (n = 1,428) or placebo (n = 1,410). These subjects were followed-up for a median period of 3.9 years. Direct treatment costs and effectiveness were analysed to provide estimates of cost per endpoint-free year over the trial period for alternative definitions of endpoint, and of cost per life-year gained and cost per quality-adjusted life-year (QALY) gained over a patient's lifetime. RESULTS: Over the trial period, the incremental cost-effectiveness ratio (ICER) was estimated to be 7,608 pounds per year free of any CARDS primary endpoint; the ICER was calculated to be 4,896 pounds per year free of any cardiovascular endpoint and 4,120 pounds per year free of any study endpoint. Over lifetime, the incremental cost per life-year gained was 5,107 pounds and the cost per QALY was 6,471 pounds (costs and benefits both discounted at 3.5%). CONCLUSIONS/INTERPRETATION: Primary prevention of cardiovascular disease with atorvastatin is a cost-effective intervention in patients with type 2 diabetes, with the ICER for this intervention falling within the current acceptance threshold ( 20,000 pounds per QALY) specified by the National Institute for Health and Clinical Excellence (NICE).

Rapid emergence of effect of atorvastatin on cardiovascular outcomes in the Collaborative Atorvastatin Diabetes Study (CARDS).

AIMS/HYPOTHESIS: The aim of this study was to determine the pattern of the effect of the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor atorvastatin on cardiovascular events in patients with type 2 diabetes and no prior history of cardiovascular disease (CVD). MATERIALS AND METHODS: A post hoc analysis of data from the Collaborative Atorvastatin Diabetes Study (CARDS), a randomised, placebo-controlled trial of 2,838 patients with type 2 diabetes, was performed. Patients received atorvastatin (10 mg daily) or placebo and were evaluated for cardiovascular and other outcomes over a median follow-up period of 3.9 years. Cox proportional hazards modelling was carried out, and the hazard ratios calculated for various times after randomisation to treatment were investigated. RESULTS: A reduction in the primary endpoint of major CVD events was apparent and statistically significant as soon as 18 months after treatment initiation. The effect of atorvastatin on CHD events was apparent by 6 months, and at 1 year was similar to the 37% relative risk reduction observed at trial closure. CONCLUSIONS/INTERPRETATION: Atorvastatin alters the pathogenesis of CVD rapidly, such that the effect on cardiovascular events is apparent within months of initiation of therapy.

Baseline characteristics in the Collaborative AtoRvastatin Diabetes Study (CARDS) in patients with Type 2 diabetes.

AIM: To describe baseline characteristics of patients in the Collaborative AtoRvastatin Diabetes Study (CARDS), a randomized, placebo-controlled trial of lipid lowering with atorvastatin 10 mg daily for the primary prevention of major cardiovascular events in patients with Type 2 diabetes. METHODS: The main eligibility criteria were Type 2 diabetes, age 40-75 years, no previous history of coronary heart disease, stroke or other major cardiovascular events, a documented history of at least one of retinopathy, micro- or macroalbuminuria, hypertension or current smoking, LDL-cholesterol < or = 4.14 mmol/l and triglycerides < or = 6.78 mmol/l. RESULTS: Randomization of 2838 persons (909 women) into CARDS was completed in June 2001. At entry, mean age was 62 years, 12% were over 70 years old and median duration of diabetes was 6 years. Median fasting lipid levels were total cholesterol 5.4 mmol/l, LDL-cholesterol 3.1 mmol/l, HDL-cholesterol 1.4 mmol/l and triglyceride 1.7 mmol/l. There was a documented history of retinopathy in 30% of patients, micro/macroalbuminuria in 11% (additionally 17% had micro/macroalbuminuria based on two elevated pretreatment measurements of albumin-creatinine ratios), hypertension in 79% and 23% were current smokers. CONCLUSION: CARDS will contribute importantly to the evidence for the macrovascular and microvascular benefits of lipid lowering with atorvastatin in patients with Type 2 diabetes. The results are likely to have important implications for the management of patients.

Prevalence of HIV, hepatitis B, and hepatitis C antibodies in prisoners in England and Wales: a national survey.

Prisoners in eight of the 135 prisons in England and Wales were surveyed in 1997 and 1998 to study the prevalence of and risk factors for transmission of bloodborne viruses in prison. Subjects voluntarily completed a risk factor questionnaire and provided oral fluid specimens for unlinked anonymous testing for the presence of antibodies to HIV, hepatitis C virus (HCV), and the core antigen of hepatitis B virus (HBc). Almost 8% (4778) of the total of 60,561 prisoners were eligible and four fifths (3942) of those eligible took part. Among all those tested (3930) 0.4% (14) were positive for anti-HIV, 8% (308) for anti-HBc, and 7% (293) for anti-HCV (the anti-HBc and anti-HCV prevalences were not adjusted for assay sensitivities of 82% and 80%, respectively). Twenty-four per cent (777/3176) of adult prisoners reported ever having injected drugs, 30% of whom (224/747) reported having injected in prison. Three quarters of those who injected in prison (167/224) shared needles or syringes. Among adult injecting drug users, 0.5% (4/775) had anti-HIV, 31% (240/775) anti-HCV, and 20% (158/775) anti-HBc. The presence of anti-HCV and anti-HBc was associated with injecting inside prison and number of previous times in prison. The results suggest that hepatitis viruses are probably being transmitted in prisons through sharing non-sterile injecting equipment and that a risk of HIV transmission exists. Harm minimisation measures for the 6% of prisoners who continue to inject while in prison should be strengthened.

CD4 cell counts in adults with newly diagnosed HIV infection: results of surveillance in England and Wales, 1990-1998. CD4 Surveillance Scheme Advisory Group.

OBJECTIVES: To describe the distribution and changes in CD4 cell counts (both initial and subsequent) in HIV-infected persons over time and determine the factors influencing these counts. DESIGN: Reports were requested from laboratories measuring CD4 cell counts in England and Wales. Initial counts were analysed and median counts were followed over time. METHODS: Time trends and the relationship between initial CD4 cell count and age, sex, and HIV risk category were studied using quantile regression methods or chi-square tests. RESULTS: Between 1990 and 1998, 9553 adults were newly diagnosed with HIV infection and had a CD4 cell count within 6 months of HIV diagnosis. Over 50% of initial CD4 cell counts in each major risk category were below 350 cells/mm3. Older age (P < 0.001), male sex (P < 0.013) and heterosexual risk (P < 0.001) were independently associated with lower initial CD4 cell counts. For heterosexually infected adults, the median initial CD4 cell count was significantly negatively associated with the year of diagnosis (P = 0.03) and the median age increased through the time period examined (P < 0.001), whereas for men who have sex with men (MSM), there was no significant change in these values over time. For each year cohort of newly diagnosed individuals, the median CD4 cell count in subsequent years decreased until 1996 and then increased thereafter, consistent with a treatment effect. CONCLUSION: Across all major risk groups, a large proportion of HIV-infected adults are being diagnosed late in the course of HIV disease. For the heterosexually infected, the data suggest an ageing cohort effect, whereas for MSM the data are consistent with continuing transmission.