Pharmacogenetics in the Management of Coumarin Anticoagulant Therapy: The Way Forward or an Expensive Diversion?

Greaves discusses a new study in PLoS Medicine that takes us closer to being able to adopt a pharmacogenetic approach to reduce bleeding risk from coumarin therapy

Clopidogrel has no effect on D-dimer and thrombin-antithrombin III levels in patients with peripheral arterial disease undergoing peripheral percutaneous transluminal angioplasty

Objective: Coagulation activation markers are significantly elevated in patients with peripheral arterial disease compared with healthy controls. The more severe the disease, the higher the markers. Increased coagulation activation may contribute to the disease process and the risk of complications in patients with peripheral arterial disease, particularly after endovascular intervention. Animal studies have shown that clopidogrel significantly inhibits coagulation activation. The aim of this study was to determine whether combination of aspirin and clopidogrel affects thrombin-antithrombin III and D-dimer in patients with intermittent claudication undergoing angioplasty, compared with aspirin alone. Methods: This was a double blind, randomized placebo-controlled trial conducted in a vascular unit in a tertiary referral center. One hundred thirty-two patients with intermittent claudication were randomized to clopidogrel and aspirin or placebo and aspirin, with a loading dose 12 hours before endovascular intervention. D-dimer and thrombin-antithrom- bin III (TAT) levels were measured using enzyme-linked immunosorbent assay at baseline, 1 hour before, and 1 hour, 24 hours, and 30 days after intervention in 103 patients who underwent endovascular intervention. Results: There was a significant rise in D-dimer levels at 1 hour and 24 hours after angioplasty in both groups (placebo group: 63.69, 141.45, 122.18 ng/mL; clopidogrel group: 103.79, 159.95, 134.69 ng/mL), but no difference between the two groups (P .514). Similarly there was a significant rise in TAT levels at 1 hour after angioplasty in both groups (placebo group: 2.93, 6.16 g/L; clopidogrel group: 3.39, 5.27 g/L), with no significant difference between the two groups (P .746). Conclusion: Endovascular intervention results in a significant increase in TAT and D-dimer. The addition of clopidogrel to aspirin has no effect on TAT and D-dimer before or after endovascular intervention.peer-reviewe

Randomized clinical trial of the antiplatelet effects of aspirin–clopidogrel combination versus aspirin alone after lower limb angioplasty

There is a high risk of reocclusion after successful lower limb angioplasty. Platelets play a central role in this process. The aim of this study was to investigate the antiplatelet effect of a combination of aspirin and clopidogrel compared with aspirin alone in patients with claudication undergoing endovascular revascularization. Methods This was a double-blind randomized placebo-controlled trial. Some 132 patients were randomized to clopidogrel and aspirin or placebo and aspirin, with a loading dose 12 h before endovascular intervention. Flow cytometric measurements of platelet fibrinogen binding and P-selectin expression were taken as measures of platelet function at baseline, 12 h after the loading dose, and 1 h, 24 h and 30 days after intervention. Results Within 12 h of the loading dose, platelet activation in the clopidogrel group had decreased (P-selectin by 27·3 per cent, P = 0·017; fibrinogen binding by 34·7 per cent, P = 0·024; stimulated fibrinogen binding by 49·2 per cent, P < 0·001). No change was observed in the placebo group. Platelet function in the clopidogrel group was significantly suppressed compared with baseline at 1 h, 24 h and 30 days after endovascular intervention (stimulated fibrinogen binding by 53·9, 51·7 and 57·2 per cent respectively; all P < 0·001). Conclusion A combination of clopidogrel and aspirin inhibited platelet function more than aspirin alone in patients with claudication before and after angioplasty.peer-reviewe

Double-blind randomized placebo-controlled trial of the antiplatelet effects of aspirin-clopidogrel combination versus aspirin alone at endovascular intervention for intermittent claudication of the lower limb

Intermittent claudication is a common problem which causes significant impairment of quality of life and increased mortality. Endovascular recanalization, widely used for symptomatic relief, carries a high risk of reocclusion. Platelets play a central role in this process. Aspirin currently used in claudicants reduces the risk, and more potent antiplatelet strategies may reduce this further. The aim of this study was to investigate the antiplatelet effect of aspirin–clopidogrel versus aspirin alone in patients with claudication undergoing endovascular intervention. Methods: This was a double-blind randomized placebo-controlled trial; 132 patients were randomized to clopidogrel and aspirin or to placebo and aspirin with a loading dose 12 h before endovascular intervention. Flow cytometric measurement of platelet fibrinogen binding and P-selectin expression as measures of platelet activation status and of platelet responsiveness to stimulation at baseline, 12 h post-loading dose, 1 h, 24 h and 30 days postintervention. Results: Platelet activation was significantly diminished in the clopidogrel group at 12 h post-loading dose compared to baseline (P-selectin: 27·3 per cent reduction, P = 0·017; bound fibrinogen: 34·7 per cent reduction, P = 0·024; stimulated bound fibrinogen: 49 per cent, P < 0·001). No significant change was observed in the control group. Platelet function was significantly suppressed in the clopidogrel group at 1 h, 24 h and 30 days after endovascular intervention compared to the placebo group (P < 0·001). Conclusion: Clopidogrel–aspirin combination dramatically inhibits platelet function in claudicants before and after intervention. The combination treatment may help reduce reocclusion after endovascular recanalization.peer-reviewe

Lifestyle Intervention with or without Lay Volunteers to Prevent Type 2 Diabetes in People with Impaired Fasting Glucose and/or Nondiabetic Hyperglycemia:A Randomized Clinical Trial

Importance:  Nearly half of the older adult population has diabetes or a high-risk intermediate glycemic category, but we still lack trial evidence for effective type 2 diabetes prevention interventions in most of the current high-risk glycemic categories. Objective:  To determine whether a group-based lifestyle intervention (with or without trained volunteers with type 2 diabetes) reduced the risk of progression to type 2 diabetes in populations with a high-risk glycemic category. Design, Setting, and Participants: The Norfolk Diabetes Prevention Study was a parallel, 3-arm, group-based, randomized clinical trial conducted with up to 46 months of follow-up from August 2011 to January 2019 at 135 primary care practices and 8 intervention sites in the East of England. We identified 141 973 people at increased risk of type 2 diabetes, screened 12 778 (9.0%), and randomized those with a high-risk glycemic category, which was either an elevated fasting plasma glucose level alone (≥110 and <126 mg/dL [to convert to millimoles per liter, multiply by 0.0555]) or an elevated glycated hemoglobin level (≥6.0% to <6.5%; nondiabetic hyperglycemia) with an elevated fasting plasma glucose level (≥100 to <110 mg/dL).Interventions A control arm receiving usual care (CON), a theory-based lifestyle intervention arm of 6 core and up to 15 maintenance sessions (INT), or the same intervention with support from diabetes prevention mentors, trained volunteers with type 2 diabetes (INT-DPM). Main Outcomes and Measures:  Type 2 diabetes incidence between arms.Results:  In this study, 1028 participants were randomized (INT, 424 [41.2%] [166 women (39.2%)]; INT-DPM, 426 [41.4%] [147 women (34.5%)]; CON, 178 [17.3%] [70 women (%39.3)]) between January 1, 2011, and February 24, 2017. The mean (SD) age was 65.3 (10.0) years, mean (SD) body mass index 31.2 (5) (calculated as weight in kilograms divided by height in meters squared), and mean (SD) follow-up 24.7 (13.4) months. A total of 156 participants progressed to type 2 diabetes, which comprised 39 of 171 receiving CON (22.8%), 55 of 403 receiving INT (13.7%), and 62 of 414 receiving INT-DPM (15.0%). There was no significant difference between the intervention arms in the primary outcome (odds ratio [OR], 1.14; 95% CI, 0.77-1.7; P = .51), but each intervention arm had significantly lower odds of type 2 diabetes (INT: OR, 0.54; 95% CI, 0.34-0.85; P = .01; INT-DPM: OR, 0.61; 95% CI, 0.39-0.96; P = .033; combined: OR, 0.57; 95% CI, 0.38-0.87; P = .01). The effect size was similar in all glycemic, age, and social deprivation groups, and intervention costs per participant were low at $153 (£122). Conclusions and Relevance:  The Norfolk Diabetes Prevention lifestyle intervention reduced the risk of type 2 diabetes in current high-risk glycemic categories. Enhancing the intervention with DPM did not further reduce diabetes risk. These translatable results are relevant for current diabetes prevention efforts

Bridging the Gap Between Stars and Planets: The Formation and Early Evolution of Brown Dwarfs

This White Paper, submitted to the National Academy of Sciences' Astro2010 Decadal Review Committee, focuses on 2 central themes in the study of young brown dwarfs -- their formation mechanism and disk characteristics -- which are of direct relevance to fundamental questions of stellar and planetary origins and properties.Comment: 8 pages, 3 figures, Astro2010 Science White Paper (v2 has 2 references corrected/updated, and 3 repeated references in the v1 reference list removed

Metformin in non-diabetic hyperglycaemia: the GLINT feasibility RCT.

BACKGROUND: The treatment of people with diabetes with metformin can reduce cardiovascular disease (CVD) and may reduce the risk of cancer. However, it is unknown whether or not metformin can reduce the risk of these outcomes in people with elevated blood glucose levels below the threshold for diabetes [i.e. non-diabetic hyperglycaemia (NDH)]. OBJECTIVE: To assess the feasibility of the Glucose Lowering In Non-diabetic hyperglycaemia Trial (GLINT) and to estimate the key parameters to inform the design of the full trial. These parameters include the recruitment strategy, randomisation, electronic data capture, postal drug distribution, retention, study medication adherence, safety monitoring and remote collection of outcome data. DESIGN: A multicentre, individually randomised, double-blind, parallel-group, pragmatic, primary prevention trial. Participants were individually randomised on a 1 : 1 basis, blocked within each site. SETTING: General practices and clinical research facilities in Cambridgeshire, Norfolk and Leicestershire. PARTICIPANTS: Males and females aged ≥ 40 years with NDH who had a high risk of CVD. INTERVENTIONS: Prolonged-release metformin (500 mg) (Glucophage® SR, Merck KGaA, Bedfont Cross, Middlesex, UK) or the matched placebo, up to three tablets per day, distributed by post. MAIN OUTCOME MEASURES: Recruitment rates; adherence to study medication; laboratory results at baseline and 3 and 6 months; reliability and acceptability of study drug delivery; questionnaire return rates; and quality of life. RESULTS: We sent 5251 invitations, with 511 individuals consenting to participate. Of these, 249 were eligible and were randomised between March and November 2015 (125 to the metformin group and 124 to the placebo group). Participants were followed up for 0.99 years [standard deviation (SD) 0.30 years]. The use of electronic medical records to identify potentially eligible individuals in individual practices was resource intensive. Participants were generally elderly [mean age 70 years (SD 6.7 years)], overweight [mean body mass index 30.1 kg/m2 (SD 4.5 kg/m2)] and male (88%), and the mean modelled 10-year CVD risk was 28.8% (SD 8.5%). Randomisation, postal delivery of the study drug and outcome assessment using registers/medical records were feasible and acceptable to participants. Most participants were able to take three tablets per day, but premature discontinuation of the study drug was common (≈30% of participants by 6 months), although there were no differences between the groups. All randomised participants returned questionnaires at baseline and 67% of participants returned questionnaires by the end of the study. There was no between-group difference in Short Form questionnaire-8 items or EuroQol-5 Dimensions scores. Compared with placebo, metformin was associated with small improvements in the mean glycated haemoglobin level [-0.82 mmol/mol, 95% confidence interval (CI) -1.39 to -0.24 mmol/mol], mean estimated glomerular filtration rate (2.31 ml/minute/1.73 m2, 95% CI -0.2 to 4.81 ml/minute/1.73 m2) and mean low-density lipoprotein cholesterol level (-0.11 mmol/l, 95% CI -0.25 to 0.02 mmol/l) and a reduction in mean plasma vitamin B12 level (-16.4 ng/l, 95% CI -32.9 to -0.01 ng/l). There were 35 serious adverse events (13 in the placebo group, 22 in the metformin group), with none deemed to be treatment related. LIMITATIONS: Changes to sponsorship reduced the study duration, the limited availability of information in medical records reduced recruitment efficiency and discontinuation of study medication exceeded forecasts. CONCLUSIONS: A large, pragmatic trial comparing the effects of prolonged-release metformin and placebo on the risk of CVD events is potentially feasible. However, changes to the study design and conduct are recommended to enable an efficient scaling up of the trial. Recommendations include changing the inclusion criteria to recruit people with pre-existing CVD to increase the recruitment and event rates, using large primary/secondary care databases to increase recruitment rates, conducting follow-up remotely to improve efficiency and including a run-in period prior to randomisation to optimise trial adherence. TRIAL REGISTRATION: Current Controlled Trials ISRCTN34875079. FUNDING: The project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 18. See the NIHR Journals Library website for further project information. Merck KGaA provided metformin and matching placebo

Cross-National Differences in Victimization : Disentangling the Impact of Composition and Context

Varying rates of criminal victimization across countries are assumed to be the outcome of countrylevel structural constraints that determine the supply ofmotivated o¡enders, as well as the differential composition within countries of suitable targets and capable guardianship. However, previous empirical tests of these ‘compositional’ and ‘contextual’ explanations of cross-national di¡erences have been performed upon macro-level crime data due to the unavailability of comparable individual-level data across countries. This limitation has had two important consequences for cross-national crime research. First, micro-/meso-level mechanisms underlying cross-national differences cannot be truly inferred from macro-level data. Secondly, the e¡ects of contextual measures (e.g. income inequality) on crime are uncontrolled for compositional heterogeneity. In this paper, these limitations are overcome by analysing individual-level victimization data across 18 countries from the International CrimeVictims Survey. Results from multi-level analyses on theft and violent victimization indicate that the national level of income inequality is positively related to risk, independent of compositional (i.e. micro- and meso-level) di¡erences. Furthermore, crossnational variation in victimization rates is not only shaped by di¡erences in national context, but also by varying composition. More speci¢cally, countries had higher crime rates the more they consisted of urban residents and regions with lowaverage social cohesion.

Language for Specific Purposes and Corpus-based Pedagogy

This chapter describes how corpus-based pedagogies are used for teaching and learning language for specific purposes (LSP). Corpus linguistics (CL) refers to the study of large quantities of authentic language using computer-assisted methods, which form the basis for computer-assisted language learning (CALL) that uses corpora for reference, exploration, and interactive learning. The use of corpora as reference resources to create LSP materials is described. Direct student uses of corpora are illustrated by three approaches to data-driven learning (DDL) where students engage in hands-on explorations of texts. A combination of indirect and direct corpus applications is shown in an illustration of interactive CALL technologies, including an example of an inclusive corpus-based tool for genre-based writing pedagogy. The chapter concludes with potential prospects for future developments in LSP