Hamilton General Hospital

BACKGROUND: Although more than 80% of the global burden of cardiovascular disease occurs in low-income and middle-income countries, knowledge of the importance of risk factors is largely derived from developed countries. Therefore, the effect of such factors on risk of coronary heart disease in most regions of the world is unknown. METHODS: We established a standardised case-control study of acute myocardial infarction in 52 countries, representing every inhabited continent. 15152 cases and 14820 controls were enrolled. The relation of smoking, history of hypertension or diabetes, waist/hip ratio, dietary patterns, physical activity, consumption of alcohol, blood apolipoproteins (Apo), and psychosocial factors to myocardial infarction are reported here. Odds ratios and their 99% CIs for the association of risk factors to myocardial infarction and their population attributable risks (PAR) were calculated. FINDINGS: Smoking (odds ratio 2.87 for current vs never, PAR 35.7% for current and former vs never), raised ApoB/ApoA1 ratio (3.25 for top vs lowest quintile, PAR 49.2% for top four quintiles vs lowest quintile), history of hypertension (1.91, PAR 17.9%), diabetes (2.37, PAR 9.9%), abdominal obesity (1.12 for top vs lowest tertile and 1.62 for middle vs lowest tertile, PAR 20.1% for top two tertiles vs lowest tertile), psychosocial factors (2.67, PAR 32.5%), daily consumption of fruits and vegetables (0.70, PAR 13.7% for lack of daily consumption), regular alcohol consumption (0.91, PAR 6.7%), and regular physical activity (0.86, PAR 12.2%), were all significantly related to acute myocardial infarction (p<0.0001 for all risk factors and p=0.03 for alcohol). These associations were noted in men and women, old and young, and in all regions of the world. Collectively, these nine risk factors accounted for 90% of the PAR in men and 94% in women. INTERPRETATION: Abnormal lipids, smoking, hypertension, diabetes, abdominal obesity, psychosocial factors, consumption of fruits, vegetables, and alcohol, and regular physical activity account for most of the risk of myocardial infarction worldwide in both sexes and at all ages in all regions. This finding suggests that approaches to prevention can be based on similar principles worldwide and have the potential to prevent most premature cases of myocardial infarction.

BACKGROUND: Angiotensin-converting-enzyme inhibitors improve the outcome among patients with left ventricular dysfunction, whether or not they have heart failure. We assessed the role of an angiotensin-converting-enzyme inhibitor, ramipril, in patients who were at high risk for cardiovascular events but who did not have left ventricular dysfunction or heart failure. METHODS: A total of 9297 high-risk patients (55 years of age or older) who had evidence of vascular disease or diabetes plus one other cardiovascular risk factor and who were not known to have a low ejection fraction or heart failure were randomly assigned to receive ramipril (10 mg once per day orally) or matching placebo for a mean of five years. The primary outcome was a composite of myocardial infarction, stroke, or death from cardiovascular causes. The trial was a two-by-two factorial study evaluating both ramipril and vitamin E. The effects of vitamin E are reported in a companion paper. RESULTS: A total of 651 patients who were assigned to receive ramipril (14.0 percent) reached the primary end point, as compared with 826 patients who were assigned to receive placebo (17.8 percent) (relative risk, 0.78; 95 percent confidence interval, 0.70 to 0.86; P<0.001). Treatment with ramipril reduced the rates of death from cardiovascular causes (6.1 percent, as compared with 8.1 percent in the placebo group; relative risk, 0.74; P<0.001), myocardial infarction (9.9 percent vs. 12.3 percent; relative risk, 0.80; P<0.001), stroke (3.4 percent vs. 4.9 percent; relative risk, 0.68; P<0.001), death from any cause (10.4 percent vs. 12.2 percent; relative risk, 0.84; P=0.005), revascularization procedures (16.3 percent vs. 18.8 percent; relative risk, 0.85; P<0.001), cardiac arrest (0.8 percent vs. 1.3 percent; relative risk, 0.62; P=0.02), [corrected] heart failure (9.1 percent vs. 11.6 percent; relative risk, 0.77; P<0.001), and complications related to diabetes (6.4 percent vs. 7.6 percent; relative risk, 0.84; P=0.03). CONCLUSIONS: Ramipril significantly reduces the rates of death, myocardial infarction, and stroke in a broad range of high-risk patients who are not known to have a low ejection fraction or heart failure.

BACKGROUND: Despite current treatments, patients who have acute coronary syndromes without ST-segment elevation have high rates of major vascular events. We evaluated the efficacy and safety of the antiplatelet agent clopidogrel when given with aspirin in such patients. METHODS: We randomly assigned 12,562 patients who had presented within 24 hours after the onset of symptoms to receive clopidogrel (300 mg immediately, followed by 75 mg once daily) (6259 patients) or placebo (6303 patients) in addition to aspirin for 3 to 12 months. RESULTS: The first primary outcome--a composite of death from cardiovascular causes, nonfatal myocardial infarction, or stroke--occurred in 9.3 percent of the patients in the clopidogrel group and 11.4 percent of the patients in the placebo group (relative risk with clopidogrel as compared with placebo, 0.80; 95 percent confidence interval, 0.72 to 0.90; P<0.001). The second primary outcome--the first primary outcome or refractory ischemia--occurred in 16.5 percent of the patients in the clopidogrel group and 18.8 percent of the patients in the placebo group (relative risk, 0.86; 95 percent confidence interval, 0.79 to 0.94; P<0.001). The percentages of patients with in-hospital refractory or severe ischemia, heart failure, and revascularization procedures were also significantly lower with clopidogrel. There were significantly more patients with major bleeding in the clopidogrel group than in the placebo group (3.7 percent vs. 2.7 percent; relative risk, 1.38; P=0.001), but there were not significantly more patients with episodes of life-threatening bleeding (2.2 percent [corrected] vs. 1.8 percent; P=0.13) or hemorrhagic strokes (0.1 percent vs. 0.1 percent). CONCLUSIONS: The antiplatelet agent clopidogrel has beneficial effects in patients with acute coronary syndromes without ST-segment elevation. However, the risk of major bleeding is increased among patients treated with clopidogrel.

This two-part article provides an overview of the global burden of atherothrombotic cardiovascular disease. Part I initially discusses the epidemiologic transition which has resulted in a decrease in deaths in childhood due to infections, with a concomitant increase in cardiovascular and other chronic diseases; and then provides estimates of the burden of cardiovascular (CV) diseases with specific focus on the developing countries. Next, we summarize key information on risk factors for cardiovascular disease (CVD) and indicate that their importance may have been underestimated. Then, we describe overarching factors influencing variations in CVD by ethnicity and region and the influence of urbanization. Part II of this article describes the burden of CV disease by specific region or ethnic group, the risk factors of importance, and possible strategies for prevention.

BACKGROUND: People who are prescribed self administered medications typically take only about half their prescribed doses. Efforts to assist patients with adherence to medications might improve the benefits of prescribed medications. OBJECTIVES: The primary objective of this review is to assess the effects of interventions intended to enhance patient adherence to prescribed medications for medical conditions, on both medication adherence and clinical outcomes. SEARCH METHODS: We updated searches of The Cochrane Library, including CENTRAL (via http://onlinelibrary.wiley.com/cochranelibrary/search/), MEDLINE, EMBASE, PsycINFO (all via Ovid), CINAHL (via EBSCO), and Sociological Abstracts (via ProQuest) on 11 January 2013 with no language restriction. We also reviewed bibliographies in articles on patient adherence, and contacted authors of relevant original and review articles. SELECTION CRITERIA: We included unconfounded RCTs of interventions to improve adherence with prescribed medications, measuring both medication adherence and clinical outcome, with at least 80% follow-up of each group studied and, for long-term treatments, at least six months follow-up for studies with positive findings at earlier time points. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted all data and a third author resolved disagreements. The studies differed widely according to medical condition, patient population, intervention, measures of adherence, and clinical outcomes. Pooling results according to one of these characteristics still leaves highly heterogeneous groups, and we could not justify meta-analysis. Instead, we conducted a qualitative analysis with a focus on the RCTs with the lowest risk of bias for study design and the primary clinical outcome. MAIN RESULTS: The present update included 109 new RCTs published since the previous update in January 2007, bringing the total number of RCTs to 182; we found five RCTs from the previous update to be ineligible and excluded them. Studies were heterogeneous for patients, medical problems, treatment regimens, adherence interventions, and adherence and clinical outcome measurements, and most had high risk of bias. The main changes in comparison with the previous update include that we now: 1) report a lack of convincing evidence also specifically among the studies with the lowest risk of bias; 2) do not try to classify studies according to intervention type any more, due to the large heterogeneity; 3) make our database available for collaboration on sub-analyses, in acknowledgement of the need to make collective advancement in this difficult field of research. Of all 182 RCTs, 17 had the lowest risk of bias for study design features and their primary clinical outcome, 11 from the present update and six from the previous update. The RCTs at lowest risk of bias generally involved complex interventions with multiple components, trying to overcome barriers to adherence by means of tailored ongoing support from allied health professionals such as pharmacists, who often delivered intense education, counseling (including motivational interviewing or cognitive behavioral therapy by professionals) or daily treatment support (or both), and sometimes additional support from family or peers. Only five of these RCTs reported improvements in both adherence and clinical outcomes, and no common intervention characteristics were apparent. Even the most effective interventions did not lead to large improvements in adherence or clinical outcomes. AUTHORS' CONCLUSIONS: Across the body of evidence, effects were inconsistent from study to study, and only a minority of lowest risk of bias RCTs improved both adherence and clinical outcomes. Current methods of improving medication adherence for chronic health problems are mostly complex and not very effective, so that the full benefits of treatment cannot be realized. The research in this field needs advances, including improved design of feasible long-term interventions, objective adherence measures, and sufficient study power to detect improvements in patient-important clinical outcomes. By making our comprehensive database available for sharing we hope to contribute to achieving these advances.

Systematic reviews can help practitioners keep abreast of the medical literature by summarizing large bodies of evidence and helping to explain differences among studies on the same question. A systematic review involves the application of scientific strategies, in ways that limit bias, to the assembly, critical appraisal, and synthesis of all relevant studies that address a specific clinical question. A meta-analysis is a type of systematic review that uses statistical methods to combine and summarize the results of several primary studies. Because the review process itself (like any other type of research) is subject to bias, a useful review requires clear reporting of information obtained using rigorous methods. Used increasingly to inform medical decision making, plan future research agendas, and establish clinical policy, systematic reviews may strengthen the link between best research evidence and optimal health care.

BACKGROUND: Observational and experimental studies suggest that the amount of vitamin E ingested in food and in supplements is associated with a lower risk of coronary heart disease and atherosclerosis. METHODS: We enrolled a total of 2545 women and 6996 men 55 years of age or older who were at high risk for cardiovascular events because they had cardiovascular disease or diabetes in addition to one other risk factor. These patients were randomly assigned according to a two-by-two factorial design to receive either 400 IU of vitamin E daily from natural sources or matching placebo and either an angiotensin-converting-enzyme inhibitor (ramipril) or matching placebo for a mean of 4.5 years (the results of the comparison of ramipril and placebo are reported in a companion article). The primary outcome was a composite of myocardial infarction, stroke, and death from cardiovascular causes. The secondary outcomes included unstable angina, congestive heart failure, revascularization or amputation, death from any cause, complications of diabetes, and cancer. RESULTS: A total of 772 of the 4761 patients assigned to vitamin E (16.2 percent) and 739 of the 4780 assigned to placebo (15.5 percent) had a primary outcome event (relative risk, 1.05; 95 percent confidence interval, 0.95 to 1.16; P=0.33). There were no significant differences in the numbers of deaths from cardiovascular causes (342 of those assigned to vitamin E vs. 328 of those assigned to placebo; relative risk, 1.05; 95 percent confidence interval, 0.90 to 1.22), myocardial infarction (532 vs. 524; relative risk, 1.02; 95 percent confidence interval, 0.90 to 1.15), or stroke (209 vs. 180; relative risk, 1.17; 95 percent confidence interval, 0.95 to 1.42). There were also no significant differences in the incidence of secondary cardiovascular outcomes or in death from any cause. There were no significant adverse effects of vitamin E. CONCLUSIONS: In patients at high risk for cardiovascular events, treatment with vitamin E for a mean of 4.5 years had no apparent effect on cardiovascular outcomes.

BACKGROUND: In observational studies, lower homocysteine levels are associated with lower rates of coronary heart disease and stroke. Folic acid and vitamins B6 and B12 lower homocysteine levels. We assessed whether supplementation reduced the risk of major cardiovascular events in patients with vascular disease. METHODS: We randomly assigned 5522 patients 55 years of age or older who had vascular disease or diabetes to daily treatment either with the combination of 2.5 mg of folic acid, 50 mg of vitamin B6, and 1 mg of vitamin B12 or with placebo for an average of five years. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, and stroke. RESULTS: Mean plasma homocysteine levels decreased by 2.4 micromol per liter (0.3 mg per liter) in the active-treatment group and increased by 0.8 micromol per liter (0.1 mg per liter) in the placebo group. Primary outcome events occurred in 519 patients (18.8 percent) assigned to active therapy and 547 (19.8 percent) assigned to placebo (relative risk, 0.95; 95 percent confidence interval, 0.84 to 1.07; P=0.41). As compared with placebo, active treatment did not significantly decrease the risk of death from cardiovascular causes (relative risk, 0.96; 95 percent confidence interval, 0.81 to 1.13), myocardial infarction (relative risk, 0.98; 95 percent confidence interval, 0.85 to 1.14), or any of the secondary outcomes. Fewer patients assigned to active treatment than to placebo had a stroke (relative risk, 0.75; 95 percent confidence interval, 0.59 to 0.97). More patients in the active-treatment group were hospitalized for unstable angina (relative risk, 1.24; 95 percent confidence interval, 1.04 to 1.49). CONCLUSIONS: Supplements combining folic acid and vitamins B6 and B12 did not reduce the risk of major cardiovascular events in patients with vascular disease. (ClinicalTrials.gov number, NCT00106886; Current Controlled Trials number, ISRCTN14017017.).

OBJECTIVE: To assess the relationship between nondiabetic glucose levels and cardio vascular risk. RESEARCH DESIGN AND METHODS: Three independent searches using MEDLINE (1966-1996), followed by a manual search of the references from each retrieved article, were conducted by two physicians and one medical librarian. Data had to be reported in at least three quantiles or intervals so that the nature of the relationship between glucose and cardiovascular events (i.e., linear or nonlinear) could be explored, and to ensure that any incremental cardiovascular risk was consistent across quantiles or intervals. RESULTS: Analyzed studies comprised 95,783 people (94% male) who had 3,707 cardiovascular events over 12.4 years (1,193,231 person-years). Studies reporting fasting glucose levels (n = 6), 2-h glucose levels (n = 7), 1-h glucose levels (n = 5), and casual glucose levels (n = 4) were included. The glucose load used varied from 50 to 100 g. The highest glucose interval for most studies included glucose values in the diabetic range. The relationship between glucose levels and the risk of a cardiovascular event was modeled for each study and the beta-coefficients were combined. Compared with a glucose level of 4.2 mmol/l (75 mg/dl), a fasting and 2-h glucose level of 6.1 mmol/dl (110 mg/dl) and 7.8 mmol/l (140 mg/dl) was associated with a relative cardiovascular event risk of 1.33 (95% CI 1.06-1.67) and 1.58 (95% CI 1.19-2.10), respectively. CONCLUSIONS: The progressive relationship between glucose levels and cardiovascular risk extends below the diabetic threshold.

After almost two decades of intensive research, low-molecular-weight heparins have established their niche as an important class of antithrombotic compounds. The demonstration that these compounds are safe and effective for the prevention and treatment of venous thromboembolism has led to the licensing of several of them in Europe and North America. In addition, danaparoid sodium, which is a mixture of dermatan sulfate, heparan sulfate, and chondroitin sulfate, is often used for the treatment of heparin-induced thrombocytopenia.1 Low-molecular-weight heparins have replaced unfractionated heparin in many parts of Europe but are only now finding their place in North America. Their use is . . .

BACKGROUND: The restoration and maintenance of sinus rhythm is a desirable goal in patients with atrial fibrillation, because the prevention of recurrences can improve cardiac function and relieve symptoms. Uncontrolled studies have suggested that amiodarone in low doses may be more effective and safer than other agents in preventing recurrence, but this agent has not been tested in a large, randomized trial. METHODS: We undertook a prospective, multicenter trial to test the hypothesis that low doses of amiodarone would be more efficacious in preventing recurrent atrial fibrillation than therapy with sotalol or propafenone. We randomly assigned patients who had had at least one episode of atrial fibrillation within the previous six months to amiodarone or to sotalol or propafenone, given in an open-label fashion. The patients in the group assigned to sotalol or propafenone underwent a second randomization to determine whether they would receive sotalol or propafenone first; if the first drug was unsuccessful the second agent was prescribed. Loading doses of the drugs were administered and electrical cardioversion was performed (if necessary) within 21 days after randomization for all patients in both groups. The follow-up period began 21 days after randomization. The primary end point was the length of time to a first recurrence of atrial fibrillation. RESULTS: Of the 403 patients in the study, 201 were assigned to amiodarone and 202 to either sotalol (101 patients) or propafenone (101 patients). After a mean of 16 months of follow-up, 71 of the patients who were assigned to amiodarone (35 percent) and 127 of those who were assigned to sotalol or propafenone (63 percent) had a recurrence of atrial fibrillation (P<0.001). Adverse events requiring the discontinuation of drug therapy occurred in 18 percent of the patients receiving amiodarone, as compared with 11 percent of those treated with sotalol or propafenone (P=0.06). CONCLUSIONS: Amiodarone is more effective than sotalol or propafenone for the prevention of recurrences of atrial fibrillation.

AIMS: The objectives of this study were to determine the association of waist circumference (WC) and waist-to-hip ratio (WHR) with the risk of incident cardiovascular disease (CVD) events and to determine whether the strength of association of WC and WHR with CVD risk is different. METHODS AND RESULTS: This meta-regression analysis used a search strategy of keywords and MeSH terms to identify prospective cohort studies and randomized clinical trials of CVD risk and abdominal obesity from the Medline, Embase, and Cochrane databases. Fifteen articles (n = 258 114 participants, 4355 CVD events) reporting CVD risk by categorical and continuous measures of WC and WHR were included. For a 1 cm increase in WC, the relative risk (RR) of a CVD event increased by 2% (95% CI: 1-3%) overall after adjusting for age, cohort year, or treatment. For a 0.01 U increase in WHR, the RR increased by 5% (95% CI: 4-7%). These results were consistent in men and women. Overall risk estimates comparing the extreme quantiles of each measure suggested that WHR was more strongly associated with CVD than that for WC (WHR: RR = 1.95, 95% CI: 1.55-2.44; WC: RR = 1.63, 95% CI: 1.31-2.04), although this difference was not significant. The strength of association for each measure was similar in men and women. CONCLUSION: WHR and WC are significantly associated with the risk of incident CVD events. These simple measures of abdominal obesity should be incorporated into CVD risk assessments.

BACKGROUND: We studied whether aspirin resistance, defined as failure of suppression of thromboxane generation, increases the risk of cardiovascular events in a high-risk population. METHODS AND RESULTS: Baseline urine samples were obtained from 5529 Canadian patients enrolled in the Heart Outcomes Prevention Evaluation (HOPE) Study. Using a nested case-control design, we measured urinary 11-dehydro thromboxane B2 levels, a marker of in vivo thromboxane generation, in 488 cases treated with aspirin who had myocardial infarction, stroke, or cardiovascular death during 5 years of follow-up and in 488 sex- and age-matched control subjects also receiving aspirin who did not have an event. After adjustment for baseline differences, the odds for the composite outcome of myocardial infarction, stroke, or cardiovascular death increased with each increasing quartile of 11-dehydro thromboxane B2, with patients in the upper quartile having a 1.8-times-higher risk than those in the lower quartile (OR, 1.8; 95% CI, 1.2 to 2.7; P=0.009). Those in the upper quartile had a 2-times-higher risk of myocardial infarction (OR, 2.0; 95% CI, 1.2 to 3.4; P=0.006) and a 3.5-times-higher risk of cardiovascular death (OR, 3.5; 95% CI, 1.7 to 7.4; P<0.001) than those in the lower quartile. CONCLUSIONS: In aspirin-treated patients, urinary concentrations of 11-dehydro thromboxane B2 predict the future risk of myocardial infarction or cardiovascular death. These findings raise the possibility that elevated urinary 11-dehydro thromboxane B2 levels identify patients who are relatively resistant to aspirin and who may benefit from additional antiplatelet therapies or treatments that more effectively block in vivo thromboxane production or activity.

BACKGROUND: More than 80% of deaths from cardiovascular disease are estimated to occur in low-income and middle-income countries, but the reasons are unknown. METHODS: We enrolled 156,424 persons from 628 urban and rural communities in 17 countries (3 high-income, 10 middle-income, and 4 low-income countries) and assessed their cardiovascular risk using the INTERHEART Risk Score, a validated score for quantifying risk-factor burden without the use of laboratory testing (with higher scores indicating greater risk-factor burden). Participants were followed for incident cardiovascular disease and death for a mean of 4.1 years. RESULTS: The mean INTERHEART Risk Score was highest in high-income countries, intermediate in middle-income countries, and lowest in low-income countries (P<0.001). However, the rates of major cardiovascular events (death from cardiovascular causes, myocardial infarction, stroke, or heart failure) were lower in high-income countries than in middle- and low-income countries (3.99 events per 1000 person-years vs. 5.38 and 6.43 events per 1000 person-years, respectively; P<0.001). Case fatality rates were also lowest in high-income countries (6.5%, 15.9%, and 17.3% in high-, middle-, and low-income countries, respectively; P=0.01). Urban communities had a higher risk-factor burden than rural communities but lower rates of cardiovascular events (4.83 vs. 6.25 events per 1000 person-years, P<0.001) and case fatality rates (13.52% vs. 17.25%, P<0.001). The use of preventive medications and revascularization procedures was significantly more common in high-income countries than in middle- or low-income countries (P<0.001). CONCLUSIONS: Although the risk-factor burden was lowest in low-income countries, the rates of major cardiovascular disease and death were substantially higher in low-income countries than in high-income countries. The high burden of risk factors in high-income countries may have been mitigated by better control of risk factors and more frequent use of proven pharmacologic therapies and revascularization. (Funded by the Population Health Research Institute and others.).

BACKGROUND: Considerable variability exists in the use of pharmacological thromboprophylaxis among acutely ill medical patients, partly because clinically relevant end points have not been fully assessed in this population. We undertook an international, multicenter, randomized, double-blind, placebo-controlled trial using clinically important outcomes to assess the efficacy and safety of dalteparin in the prevention of venous thromboembolism in such patients. METHODS AND RESULTS: Patients (n=3706) were randomly assigned to receive either subcutaneous dalteparin 5000 IU daily or placebo for 14 days and were followed up for 90 days. The primary end point was venous thromboembolism, defined as the combination of symptomatic deep vein thrombosis, symptomatic pulmonary embolism, and asymptomatic proximal deep vein thrombosis detected by compression ultrasound at day 21 and sudden death by day 21. The incidence of venous thromboembolism was reduced from 4.96% (73 of 1473 patients) in the placebo group to 2.77% (42 of 1518 patients) in the dalteparin group, an absolute risk reduction of 2.19% or a relative risk reduction of 45% (relative risk, 0.55; 95% CI, 0.38 to 0.80; P=0.0015). The observed benefit was maintained at 90 days. The overall incidence of major bleeding was low but higher in the dalteparin group (9 patients; 0.49%) compared with the placebo group (3 patients; 0.16%). CONCLUSIONS: Dalteparin 5000 IU once daily halved the rate of venous thromboembolism with a low risk of bleeding.

Medulloblastoma, the most common malignant paediatric brain tumour, is currently treated with nonspecific cytotoxic therapies including surgery, whole-brain radiation, and aggressive chemotherapy. As medulloblastoma exhibits marked intertumoural heterogeneity, with at least four distinct molecular variants, previous attempts to identify targets for therapy have been underpowered because of small samples sizes. Here we report somatic copy number aberrations (SCNAs) in 1,087 unique medulloblastomas. SCNAs are common in medulloblastoma, and are predominantly subgroup-enriched. The most common region of focal copy number gain is a tandem duplication of SNCAIP, a gene associated with Parkinson’s disease, which is exquisitely restricted to Group 4α. Recurrent translocations of PVT1, including PVT1-MYC and PVT1-NDRG1, that arise through chromothripsis are restricted to Group 3. Numerous targetable SCNAs, including recurrent events targeting TGF-β signalling in Group 3, and NF-κB signalling in Group 4, suggest future avenues for rational, targeted therapy. Medulloblastoma is the most common malignant brain tumour in children; having assembled over 1,000 samples the authors report that somatic copy number aberrations are common in medulloblastoma, in particular a tandem duplication of SNCAIP, a gene associated with Parkinson’s disease, which is restricted to subgroup 4α, and translocations of PVT1, which are restricted to Group 3. Medulloblastoma is the most common malignant brain tumour in children. Four papers published in the 2 August 2012 issue of Nature use whole-genome and other sequencing techniques to produce a detailed picture of the genetics and genomics of this condition. Notable findings include the identification of recurrent mutations in genes not previously implicated in medulloblastoma, with significant genetic differences associated with the four biologically distinct subgroups and clinical outcomes in each. Potential avenues for therapy are suggested by the identification of targetable somatic copy-number alterations, including recurrent events targeting TGFβ signalling in Group 3, and NF-κB signalling in Group 4 medulloblastomas.

AIMS: Coronary heart disease (CHD) is a leading cause of death among men and women globally. Women develop CHD about 10 years later than men, yet the reasons for this are unclear. The purpose of this report is to determine if differences in risk factor distributions exist between women and men across various age categories to help explain why women develop acute MI later than men. METHODS AND RESULTS: We used the INTERHEART global case-control study including 27 098 participants from 52 countries, 6787 of whom were women. The median age of first acute MI was higher in women than men (65 vs. 56 years; P < 0.0001). Nine modifiable risk factors were associated with MI in women and men. Hypertension [2.95(2.66 -3.28) vs. 2.32(2.16-2.48)], diabetes [4.26(3.68-4.94) vs. 2.67(2.43-2.94), physical activity [0.48(0.41-0.57) vs. 0.77(0.71-0.83)], and moderate alcohol use [0.41(0.34-0.50) vs. 0.88(0.82-0.94)] were more strongly associated with MI among women than men. The association of abnormal lipids, current smoking, abdominal obesity, high risk diet, and psychosocial stress factors with MI was similar in women and men. Risk factors associations were generally stronger among younger individuals compared to older women and men. The population attributable risk (PAR) of all nine risk factors exceeded 94%, and was similar among women and men (96 vs. 93%). Men were significantly more likely to suffer a MI prior to 60 years of age than were women, however, after adjusting for levels of risk factors, the sex difference in the probability of MI cases occurring before the age of 60 years was reduced by more than 80%. CONCLUSION: Women experience their first acute MI on average 9 years later than men. Nine modifiable risk factors are significantly associated with acute MI in both men and women and explain greater than 90% of the PAR. The difference in age of first MI is largely explained by the higher risk factor levels at younger ages in men compared to women.

BACKGROUND: Efforts to assist patients with adherence to prescribed, self-administered medications might improve the benefits and efficiency of health care. OBJECTIVE: To update an ongoing review summarising the results of randomised controlled trials (RCTs) of interventions to help patients follow prescriptions for medications, focusing on trials that measured both adherence and clinical outcomes. SEARCH STRATEGY: Computerised searches to July 1998 in MEDLINE, CINAHL, The Cochrane Library, International Pharmaceutical Abstracts (IPA), PsychInfo, Sociofile, and HSTAR; bibliographies in articles on patient adherence; articles in the reviewers' personal collections; and contact with authors. SELECTION CRITERIA: Articles were selected if they reported an unconfounded RCT of an intervention to improve adherence with prescribed medications, measuring both medication adherence and treatment outcome, with at least 80% follow-up of each group studied and, for long-term treatments, at least six months follow-up for studies with positive initial findings. DATA COLLECTION AND ANALYSIS: Information on study design features, interventions and controls, and findings were extracted by one reviewer (PM) and a research assistant and confirmed by two of the other reviewers. The studies were too disparate to warrant meta-analysis. MAIN RESULTS: For short-term treatments, one study, of counselling and written information, showed an effect on adherence and clinical outcome. Ten of 19 interventions for long-term treatments reported in 17 RCTs were associated with improvements in adherence, but only nine interventions led to improvements in treatment outcomes. Almost all of the interventions that were effective for long-term care were complex, including combinations of more convenient care, information, counselling, reminders, self-monitoring, reinforcement, family therapy, and other forms of additional supervision or attention. Even the most effective interventions did not lead to large improvements in adherence and treatment outcomes. Two studies showed that telling patients about adverse effects of treatment did not affect their adherence. REVIEWER'S CONCLUSIONS: The full benefits of medications cannot be realised at currently achievable levels of adherence. Current methods of improving adherence for chronic health problems are mostly complex and not very effective. More studies of innovative approaches to assist patients to follow medication prescriptions are needed.

CONTEXT: Despite many therapeutic advances, mortality in patients with acute ST-segment elevation myocardial infarction (STEMI) remains high. The role of additional antithrombotic agents is unclear, especially among patients not receiving reperfusion therapy. OBJECTIVE: To evaluate the effect of fondaparinux, a factor Xa inhibitor, when initiated early and given for up to 8 days vs usual care (placebo in those in whom unfractionated heparin [UFH] is not indicated [stratum 1] or unfractionated heparin for up to 48 hours followed by placebo for up to 8 days [stratum 2]) in patients with STEMI. DESIGN, SETTING, AND PARTICIPANTS: Randomized double-blind comparison of fondaparinux 2.5 mg once daily or control for up to 8 days in 12,092 patients with STEMI from 447 hospitals in 41 countries (September 2003-January 2006). From day 3 through day 9, all patients received either fondaparinux or placebo according to the original randomized assignment. MAIN OUTCOME MEASURES: Composite of death or reinfarction at 30 days (primary) with secondary assessments at 9 days and at final follow-up (3 or 6 months). RESULTS: Death or reinfarction at 30 days was significantly reduced from 677 (11.2%) of 6056 patients in the control group to 585 (9.7%) of 6036 patients in the fondaparinux group (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.77-0.96; P = .008); absolute risk reduction, 1.5%; 95% CI, 0.4%-2.6%). These benefits were observed at 9 days (537 [8.9%] placebo vs 444 [7.4%] fondaparinux; HR, 0.83; 95% CI, 0.73-0.94; P = .003, and at study end (857 [14.8%] placebo vs 756 [13.4%] fondaparinux; HR, 0.88; 95% CI, 0.79-0.97; P = .008). Mortality was significantly reduced throughout the study. There was no heterogeneity of the effects of fondaparinux in the 2 strata by planned heparin use. However, there was no benefit in those undergoing primary percutaneous coronary intervention. In other patients in stratum 2, fondaparinux was superior to unfractionated heparin in preventing death or reinfarction at 30 days (HR, 0.82; 95% CI, 0.66-1.02; P = .08) and at study end (HR, 0.77; 95% CI, 0.64-0.93; P = .008). Significant benefits were observed in those receiving thrombolytic therapy (HR, 0.79; P = .003) and those not receiving any reperfusion therapy (HR, 0.80; P = .03). There was a tendency to fewer severe bleeds (79 for placebo vs 61 for fondaparinux; P = .13), with significantly fewer cardiac tamponade (48 vs 28; P = .02) with fondaparinux at 9 days. CONCLUSION: In patients with STEMI, particularly those not undergoing primary percutaneous coronary intervention, fondaparinux significantly reduces mortality and reinfarction without increasing bleeding and strokes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT00064428.

As a result of the rising epidemic of obesity, understanding body fat distribution and its clinical implications is critical to timely treatment. Visceral adipose tissue is a hormonally active component of total body fat, which possesses unique biochemical characteristics that influence several normal and pathological processes in the human body. Abnormally high deposition of visceral adipose tissue is known as visceral obesity. This body composition phenotype is associated with medical disorders such as metabolic syndrome, cardiovascular disease and several malignancies including prostate, breast and colorectal cancers. Quantitative assessment of visceral obesity is important for evaluating the potential risk of development of these pathologies, as well as providing an accurate prognosis. This review aims to compare different methods of measuring visceral adiposity with emphasis on their advantages and drawbacks in clinical practice.