Showing papers by "Clinical Trial Service Unit published in 2016"

Epidemiology of Atherosclerosis and the Potential to Reduce the Global Burden of Atherothrombotic Disease

Abstract: Atherosclerosis is a leading cause of vascular disease worldwide. Its major clinical manifestations include ischemic heart disease, ischemic stroke, and peripheral arterial disease. In high-income countries, there have been dramatic declines in the incidence and mortality from ischemic heart disease and ischemic stroke since the middle of the 20th century. For example, in the United Kingdom, the probability of death from vascular disease in middle-aged men (35-69 years) has decreased from 22% in 1950 to 6% in 2010. Most low- and middle-income countries have also reported declines in mortality from stroke over the last few decades, but mortality trends from ischemic heart disease have been more varied, with some countries reporting declines and others reporting increases (particularly those in Eastern Europe and Asia). Many major modifiable risk factors for atherosclerosis have been identified, and the causal relevance of several risk factors is now well established (including, but not limited to, smoking, adiposity, blood pressure, blood cholesterol, and diabetes mellitus). Widespread changes in health behaviors and use of treatments for these risk factors are responsible for some of the dramatic declines in vascular mortality in high-income countries. In order that these declines continue and are mirrored in less wealthy nations, increased efforts are needed to tackle these major risk factors, particularly smoking and the emerging obesity epidemic.

Efficacy and Tolerability of Evolocumab vs Ezetimibe in Patients With Muscle-Related Statin Intolerance: The GAUSS-3 Randomized Clinical Trial

Abstract: Importance Muscle-related statin intolerance is reported by 5% to 20% of patients. Objective To identify patients with muscle symptoms confirmed by statin rechallenge and compare lipid-lowering efficacy for 2 nonstatin therapies, ezetimibe and evolocumab. Design, Setting, and Participants Two-stage randomized clinical trial including 511 adult patients with uncontrolled low-density lipoprotein cholesterol (LDL-C) levels and history of intolerance to 2 or more statins enrolled in 2013 and 2014 globally. Phase A used a 24-week crossover procedure with atorvastatin or placebo to identify patients having symptoms only with atorvastatin but not placebo. In phase B, after a 2-week washout, patients were randomized to ezetimibe or evolocumab for 24 weeks. Interventions Phase A: atorvastatin (20 mg) vs placebo. Phase B: randomization 2:1 to subcutaneous evolocumab (420 mg monthly) or oral ezetimibe (10 mg daily). Main Outcome and Measures Coprimary end points were the mean percent change in LDL-C level from baseline to the mean of weeks 22 and 24 levels and from baseline to week 24 levels. Results Of the 491 patients who entered phase A (mean age, 60.7 [SD, 10.2] years; 246 women [50.1%]; 170 with coronary heart disease [34.6%]; entry mean LDL-C level, 212.3 [SD, 67.9] mg/dL), muscle symptoms occurred in 209 of 491 (42.6%) while taking atorvastatin but not while taking placebo. Of these, 199 entered phase B, along with 19 who proceeded directly to phase B for elevated creatine kinase (N = 218, with 73 randomized to ezetimibe and 145 to evolocumab; entry mean LDL-C level, 219.9 [SD, 72] mg/dL). For the mean of weeks 22 and 24, LDL-C level with ezetimibe was 183.0 mg/dL; mean percent LDL-C change, −16.7% (95% CI, −20.5% to −12.9%), absolute change, −31.0 mg/dL and with evolocumab was 103.6 mg/dL; mean percent change, −54.5% (95% CI, −57.2% to −51.8%); absolute change, −106.8 mg/dL ( P P P = .17). Active study drug was stopped for muscle symptoms in 5 of 73 ezetimibe-treated patients (6.8%) and 1 of 145 evolocumab-treated patients (0.7%). Conclusions and Relevance Among patients with statin intolerance related to muscle-related adverse effects, the use of evolocumab compared with ezetimibe resulted in a significantly greater reduction in LDL-C levels after 24 weeks. Further studies are needed to assess long-term efficacy and safety. Trial Registration clinicaltrials.gov Identifier:NCT01984424

The Burden of Hypertension and Associated Risk for Cardiovascular Mortality in China

Abstract: Importance Hypertension is a leading cause of premature death in China, but limited evidence is available on the prevalence and management of hypertension and its effect on mortality from cardiovascular disease (CVD). Objectives To examine the prevalence, diagnosis, treatment, and control of hypertension and to assess the CVD mortality attributable to hypertension in China. Design, Setting and Participants This prospective cohort study (China Kadoorie Biobank Study) recruited 500 223 adults, aged 35 to 74 years, from the general population in China. Blood pressure (BP) measurements were recorded as part of the baseline survey from June 25, 2004, to August 5, 2009, and 7028 deaths due to CVD were recorded before January 1, 2014 (mean duration of follow-up: 7.2 years). Data were analyzed from June 9, 2014, to July 17, 2015. Exposures Prevalence and diagnosis of hypertension (systolic BP ≥140 mm Hg, diastolic BP ≥90 mm Hg, or receiving treatment for hypertension) and treatment and control rates overall and in various population subgroups. Main Outcomes and Measures Cox regression analysis yielded age- and sex-specific rate ratios for deaths due to CVD comparing participants with and without uncontrolled hypertension, which were used to estimate the number of CVD deaths attributable to hypertension. Results The cohort included 205 167 men (41.0%) and 295 056 women (59.0%) with a mean (SD) age of 52 (10) years for both sexes. Overall, 32.5% of participants had hypertension; the prevalence increased with age (from 12.6% at 35-39 years of age to 58.4% at 70-74 years of age) and varied substantially by region (range, 22.7%-40.7%). Of those with hypertension, 30.5% had received a diagnosis from a physician; of those with a diagnosis of hypertension, 46.4% were being treated; and of those treated, 29.6% had their hypertension controlled (ie, systolic BP Conclusions and Relevance About one-third of Chinese adults in this national cohort population had hypertension. The levels of diagnosis, treatment, and control were much lower than in Western populations, and were associated with significant excess mortality.

SGLT2 Inhibition and cardiovascular events: why did EMPA-REG Outcomes surprise and what were the likely mechanisms?

Abstract: While the modest reduction in the primary composite outcome of myocardial infarction, stroke or cardiovascular death in the EMPA-REG Outcomes trial was welcome, the 30–40% reductions in heart failure hospitalisation (HFH) and cardiovascular and all-cause deaths in patients treated with empagliflozin were highly impressive and unexpected. In this review, we discuss briefly why cardiovascular endpoint trials for new diabetes agents are required and describe the results of the first four such trials to have reported, as a precursor to understanding why the EMPA-REG Outcomes results came as a surprise. Thereafter, we discuss potential mechanisms that could explain the EMPA-REG Outcomes results, concentrating on non-atherothrombotic effects. We suggest that the main driver of benefit may derive from the specific effects of sodium-glucose linked transporter-2 (SGLT2) inhibition on renal sodium and glucose handling, leading to both diuresis and improvements in diabetes-related maladaptive renal arteriolar responses. These haemodynamic and renal effects are likely to be beneficial in patients with clinical or subclinical cardiac dysfunction. The net result of these processes, we argue, is an improvement in cardiac systolic and diastolic function and, thereby, a lower risk of HFH and sudden cardiac death. We also discuss whether other drugs in this class are likely to show similar cardiovascular benefits. Finally, areas for future research are suggested to better understand the relevant mechanisms and to identify other groups who may benefit from SGLT2 inhibitor therapy.

Association of Lipid Fractions With Risks for Coronary Artery Disease and Diabetes

Abstract: Importance Low-density lipoprotein cholesterol (LDL-C) is causally related to coronary artery disease (CAD), but the relevance of high-density lipoprotein cholesterol (HDL-C) and triglycerides (TGs) is uncertain. Lowering of LDL-C levels by statin therapy modestly increases the risk of type 2 diabetes, but it is unknown whether this effect is specific to statins. Objective To investigate the associations of 3 routinely measured lipid fractions with CAD and diabetes through mendelian randomization (MR) using conventional MR and making use of newer approaches, such as multivariate MR and MR-Egger, that address the pleiotropy of genetic instruments where relevant. Design, Setting, and Participants Published data from genome-wide association studies were used to construct genetic instruments and then applied to investigate associations between lipid fractions and the risk of CAD and diabetes using MR approaches that took into account pleiotropy of genetic instruments. The study was conducted from March 12 to December 31, 2015. Main Outcomes and Measures Coronary artery disease and diabetes. Results Genetic instruments composed of 130 single-nucleotide polymorphisms (SNPs) were used for LDL-C (explaining 7.9% of its variance), 140 SNPs for HDL-C (6.6% of variance), and 140 SNPs for TGs (5.9% of variance). A 1-SD genetically instrumented elevation in LDL-C levels (equivalent to 38 mg/dL) and TG levels (equivalent to 89 mg/dL) was associated with higher CAD risk; odds ratios (ORs) were 1.68 (95% CI, 1.51-1.87) for LDL-C and 1.28 (95% CI, 1.13-1.45) for TGs. The corresponding OR for HDL-C (equivalent to a 16-mg/dL increase) was 0.95 (95% CI, 0.85-1.06). All 3 lipid traits were associated with a lower risk of type 2 diabetes. The ORs were 0.79 (95% CI, 0.71-0.88) for LDL-C and 0.83 (95% CI, 0.76-0.90) for HDL-C per 1-SD elevation. For TG, the MR estimates for diabetes were inconsistent, with MR-Egger giving an OR of 0.83 (95%CI, 0.72-0.95) per 1-SD elevation. Conclusions and Relevance Routinely measured lipid fractions exhibit contrasting associations with the risk of CAD and diabetes. Increased LDL-C, HDL-C, and possibly TG levels are associated with a lower risk of diabetes. This information will be relevant to the design of clinical trials of lipid-modifying agents, which should carefully monitor participants for dysglycemia and the incidence of diabetes.

Fresh Fruit Consumption and Major Cardiovascular Disease in China.

Abstract: BackgroundIn Western populations, a higher level of fruit consumption has been associated with a lower risk of cardiovascular disease, but little is known about such associations in China, where the consumption level is low and rates of stroke are high. MethodsBetween 2004 and 2008, we recruited 512,891 adults, 30 to 79 years of age, from 10 diverse localities in China. During 3.2 million person-years of follow-up, 5173 deaths from cardiovascular disease, 2551 incident major coronary events (fatal or nonfatal), 14,579 ischemic strokes, and 3523 intracerebral hemorrhages were recorded among the 451,665 participants who did not have a history of cardiovascular disease or antihypertensive treatments at baseline. Cox regression yielded adjusted hazard ratios relating fresh fruit consumption to disease rates. ResultsOverall, 18.0% of participants reported consuming fresh fruit daily. As compared with participants who never or rarely consumed fresh fruit (the “nonconsumption” category), those who ate fresh frui...

Perioperative Rosuvastatin in Cardiac Surgery.

Abstract: BackgroundComplications after cardiac surgery are common and lead to substantial increases in morbidity and mortality. Meta-analyses of small randomized trials have suggested that perioperative statin therapy can prevent some of these complications. MethodsWe randomly assigned 1922 patients in sinus rhythm who were scheduled for elective cardiac surgery to receive perioperative rosuvastatin (at a dose of 20 mg daily) or placebo. The primary outcomes were postoperative atrial fibrillation within 5 days after surgery, as assessed by Holter electrocardiographic monitoring, and myocardial injury within 120 hours after surgery, as assessed by serial measurements of the cardiac troponin I concentration. Secondary outcomes included major in-hospital adverse events, duration of stay in the hospital and intensive care unit, left ventricular and renal function, and blood biomarkers. ResultsThe concentrations of low-density lipoprotein cholesterol and C-reactive protein after surgery were lower in patients assigned ...

Selecting instruments for Mendelian randomization in the wake of genome-wide association studies

Abstract: Mendelian randomization (MR) studies typically assess the pathogenic relevance of environmental exposures or disease biomarkers, using genetic variants that instrument these exposures. The approach is gaining popularity-our systematic review reveals a greater than 10-fold increase in MR studies published between 2004 and 2015. When the MR paradigm was first proposed, few biomarker- or exposure-related genetic variants were known, most having been identified by candidate gene studies. However, genome-wide association studies (GWAS) are now providing a rich source of potential instruments for MR analysis. Many early reviews covering the concept, applications and analytical aspects of the MR technique preceded the surge in GWAS, and thus the question of how best to select instruments for MR studies from the now extensive pool of available variants has received insufficient attention. Here we focus on the most common category of MR studies-those concerning disease biomarkers. We consider how the selection of instruments for MR analysis from GWAS requires consideration of: the assumptions underlying the MR approach; the biology of the biomarker; the genome-wide distribution, frequency and effect size of biomarker-associated variants (the genetic architecture); and the specificity of the genetic associations. Based on this, we develop guidance that may help investigators to plan and readers interpret MR studies.

Effects of Alteplase for Acute Stroke on the Distribution of Functional Outcomes A Pooled Analysis of 9 Trials

Abstract: Background— Thrombolytic therapy with intravenous alteplase within 4.5 hours of ischemic stroke onset increases the overall likelihood of an excellent outcome (no, or nondisabling, symptoms). Any improvement in functional outcome distribution has value, and herein we provide an assessment of the effect of alteplase on the distribution of the functional level by treatment delay, age, and stroke severity. Methods— Prespecified pooled analysis of 6756 patients from 9 randomized trials comparing alteplase versus placebo/open control. Ordinal logistic regression models assessed treatment differences after adjustment for treatment delay, age, stroke severity, and relevant interaction term(s). Results— Treatment with alteplase was beneficial for a delay in treatment extending to 4.5 hours after stroke onset, with a greater benefit with earlier treatment. Neither age nor stroke severity significantly influenced the slope of the relationship between benefit and time to treatment initiation. For the observed case mix of patients treated within 4.5 hours of stroke onset (mean 3 hours and 20 minutes), the net absolute benefit from alteplase (ie, the difference between those who would do better if given alteplase and those who would do worse) was 55 patients per 1000 treated (95% confidence interval, 13–91; P =0.004). Conclusions— Treatment with intravenous alteplase initiated within 4.5 hours of stroke onset increases the chance of achieving an improved level of function for all patients across the age spectrum, including the over 80s and across all severities of stroke studied (top versus bottom fifth means: 22 versus 4); the earlier that treatment is initiated, the greater the benefit.

Diabetes and Cause-Specific Mortality in Mexico City

Abstract: BackgroundMost large, prospective studies of the effects of diabetes on mortality have focused on high-income countries where patients have access to reasonably good medical care and can receive treatments to establish and maintain good glycemic control. In those countries, diabetes less than doubles the rate of death from any cause. Few large, prospective studies have been conducted in middle-income countries where obesity and diabetes have become common and glycemic control may be poor. MethodsFrom 1998 through 2004, we recruited approximately 50,000 men and 100,000 women 35 years of age or older into a prospective study in Mexico City, Mexico. We recorded the presence or absence of previously diagnosed diabetes, obtained and stored blood samples, and tracked 12-year disease-specific deaths through January 1, 2014. We accepted diabetes as the underlying cause of death only for deaths that were due to acute diabetic crises. We estimated rate ratios for death among participants who had diabetes at recruit...

Risk of intracerebral haemorrhage with alteplase after acute ischaemic stroke: a secondary analysis of an individual patient data meta-analysis

Abstract: Summary Background Randomised trials have shown that alteplase improves the odds of a good outcome when delivered within 4·5 h of acute ischaemic stroke However, alteplase also increases the risk of intracerebral haemorrhage; we aimed to determine the proportional and absolute effects of alteplase on the risks of intracerebral haemorrhage, mortality, and functional impairment in different types of patients Methods We used individual patient data from the Stroke Thrombolysis Trialists' (STT) meta-analysis of randomised trials of alteplase versus placebo (or untreated control) in patients with acute ischaemic stroke We prespecified assessment of three classifications of intracerebral haemorrhage: type 2 parenchymal haemorrhage within 7 days; Safe Implementation of Thrombolysis in Stroke Monitoring Study's (SITS-MOST) haemorrhage within 24–36 h (type 2 parenchymal haemorrhage with a deterioration of at least 4 points on National Institutes of Health Stroke Scale [NIHSS]); and fatal intracerebral haemorrhage within 7 days We used logistic regression, stratified by trial, to model the log odds of intracerebral haemorrhage on allocation to alteplase, treatment delay, age, and stroke severity We did exploratory analyses to assess mortality after intracerebral haemorrhage and examine the absolute risks of intracerebral haemorrhage in the context of functional outcome at 90–180 days Findings Data were available from 6756 participants in the nine trials of intravenous alteplase versus control Alteplase increased the odds of type 2 parenchymal haemorrhage (occurring in 231 [6·8%] of 3391 patients allocated alteplase vs 44 [1·3%] of 3365 patients allocated control; odds ratio [OR] 5·55 [95% CI 4·01–7·70]; absolute excess 5·5% [4·6–6·4]); of SITS-MOST haemorrhage (124 [3·7%] of 3391 vs 19 [0·6%] of 3365; OR 6·67 [4·11–10·84]; absolute excess 3·1% [2·4–3·8]); and of fatal intracerebral haemorrhage (91 [2·7%] of 3391 vs 13 [0·4%] of 3365; OR 7·14 [3·98–12·79]; absolute excess 2·3% [1·7–2·9]) However defined, the proportional increase in intracerebral haemorrhage was similar irrespective of treatment delay, age, or baseline stroke severity, but the absolute excess risk of intracerebral haemorrhage increased with increasing stroke severity: for SITS-MOST intracerebral haemorrhage the absolute excess risk ranged from 1·5% (0·8–2·6%) for strokes with NIHSS 0–4 to 3·7% (2·1–6·3%) for NIHSS 22 or more (p=0·0101) For patients treated within 4·5 h, the absolute increase in the proportion (6·8% [4·0% to 9·5%]) achieving a modified Rankin Scale of 0 or 1 (excellent outcome) exceeded the absolute increase in risk of fatal intracerebral haemorrhage (2·2% [1·5% to 3·0%]) and the increased risk of any death within 90 days (0·9% [–1·4% to 3·2%]) Interpretation Among patients given alteplase, the net outcome is predicted both by time to treatment (with faster time increasing the proportion achieving an excellent outcome) and stroke severity (with a more severe stroke increasing the absolute risk of intracerebral haemorrhage) Although, within 4·5 h of stroke, the probability of achieving an excellent outcome with alteplase treatment exceeds the risk of death, early treatment is especially important for patients with severe stroke Funding UK Medical Research Council, British Heart Foundation, University of Glasgow, University of Edinburgh

Night Shift Work and Breast Cancer Incidence: Three Prospective Studies and Meta-analysis of Published Studies.

Abstract: Background: It has been proposed that night shift work could increase breast cancer incidence. A 2007 World Health Organization review concluded, mainly from animal evidence, that shift work involving circadian disruption is probably carcinogenic to humans. We therefore aimed to generate prospective epidemiological evidence on night shift work and breast cancer incidence. Methods: Overall, 522 246 Million Women Study, 22 559 EPIC-Oxford, and 251 045 UK Biobank participants answered questions on shift work and were followed for incident cancer. Cox regression yielded multivariable-adjusted breast cancer incidence rate ratios (RRs) and 95% confidence intervals (CIs) for night shift work vs no night shift work, and likelihood ratio tests for interaction were used to assess heterogeneity. Our meta-analyses combined these and relative risks from the seven previously published prospective studies (1.4 million women in total), using inverse-variance weighted averages of the study-specific log RRs. Results: In the Million Women Study, EPIC-Oxford, and UK Biobank, respectively, 673, 28, and 67 women who reported night shift work developed breast cancer, and the RRs for any vs no night shift work were 1.00 (95% CI = 0.92 to 1.08), 1.07 (95% CI = 0.71 to 1.62), and 0.78 (95% CI = 0.61 to 1.00). In the Million Women Study, the RR for 20 or more years of night shift work was 1.00 (95% CI = 0.81 to 1.23), with no statistically significant heterogeneity by sleep patterns or breast cancer risk factors. Our meta-analysis of all 10 prospective studies included 4660 breast cancers in women reporting night shift work; compared with other women, the combined relative risks were 0.99 (95% CI = 0.95 to 1.03) for any night shift work, 1.01 (95% CI = 0.93 to 1.10) for 20 or more years of night shift work, and 1.00 (95% CI = 0.87 to 1.14) for 30 or more years. Conclusions: The totality of the prospective evidence shows that night shift work, including long-term shift work, has little or no effect on breast cancer incidence.

Effect of mineralocorticoid receptor antagonists on proteinuria and progression of chronic kidney disease: a systematic review and meta-analysis.

Abstract: Hypertension and proteinuria are critically involved in the progression of chronic kidney disease. Despite treatment with renin angiotensin system inhibition, kidney function declines in many patients. Aldosterone excess is a risk factor for progression of kidney disease. Hyperkalaemia is a concern with the use of mineralocorticoid receptor antagonists. We aimed to determine whether the renal protective benefits of mineralocorticoid antagonists outweigh the risk of hyperkalaemia associated with this treatment in patients with chronic kidney disease. We conducted a meta-analysis investigating renoprotective effects and risk of hyperkalaemia in trials of mineralocorticoid receptor antagonists in chronic kidney disease. Trials were identified from MEDLINE (1966–2014), EMBASE (1947–2014) and the Cochrane Clinical Trials Database. Unpublished summary data were obtained from investigators. We included randomised controlled trials, and the first period of randomised cross over trials lasting ≥4 weeks in adults. Nineteen trials (21 study groups, 1 646 patients) were included. In random effects meta-analysis, addition of mineralocorticoid receptor antagonists to renin angiotensin system inhibition resulted in a reduction from baseline in systolic blood pressure (−5.7 [−9.0, −2.3] mmHg), diastolic blood pressure (−1.7 [−3.4, −0.1] mmHg) and glomerular filtration rate (−3.2 [−5.4, −1.0] mL/min/1.73 m2). Mineralocorticoid receptor antagonism reduced weighted mean protein/albumin excretion by 38.7 % but with a threefold higher relative risk of withdrawing from the trial due to hyperkalaemia (3.21, [1.19, 8.71]). Death, cardiovascular events and hard renal end points were not reported in sufficient numbers to analyse. Mineralocorticoid receptor antagonism reduces blood pressure and urinary protein/albumin excretion with a quantifiable risk of hyperkalaemia above predefined study upper limit.

Adult height, coronary heart disease and stroke: a multi-locus Mendelian randomization meta-analysis

Abstract: Background: We investigated causal effect of completed growth, measured by adult height, on coronary heart disease (CHD), stroke and cardiovascular traits, using instrumental variable (IV) Mendelian randomization meta-analysis. Methods: We developed an allele score based on 69 single nucleotide polymorphisms (SNPs) associated with adult height, identified by the IBCCardioChip, and used it for IV analysis against cardiovascular risk factors and events in 21 studies and 60 028 participants. IV analysis on CHD was supplemented by summary data from 180 height-SNPs from the GIANT consortium and their corresponding CHD estimates derived from CARDIoGRAMplusC4D. Results: IV estimates from IBCCardioChip and GIANT-CARDIoGRAMplusC4D showed that a 6.5-cm increase in height reduced the odds of CHD by 10% [odds ratios 0.90; 95% confidence intervals (CIs): 0.78 to 1.03 and 0.85 to 0.95, respectively],which agrees with the estimate from the Emerging Risk Factors Collaboration (hazard ratio 0.93; 95% CI: 0.91 to 0.94). IV analysis revealed no association with stroke (odds ratio 0.97; 95% CI: 0.79 to 1.19). IV analysis showed that a 6.5-cm increase in height resulted in lower levels of body mass index (P < 0.001), triglycerides (P < 0.001), non high-density (non-HDL) cholesterol (P < 0.001), C-reactive protein (P = 0.042), and systolic blood pressure (P = 0.064) and higher levels of forced expiratory volume in 1 s and forced vital capacity (P < 0.001 for both). Conclusions: Taller individuals have a lower risk of CHD with potential explanations being that taller people have a better lung function and lower levels of body mass index, cholesterol and blood pressure.

The acceptability of repeat Internet-based hybrid diet assessment of previous 24-h dietary intake: administration of the Oxford WebQ in UK Biobank

Abstract: Although dietary intake over a single 24-h period may be atypical of an individual's habitual pattern, multiple 24-h dietary assessments can be representative of habitual intake and help in assessing seasonal variation. Web-based questionnaires are convenient for the participant and result in automatic data capture for study investigators. This study reports on the acceptability of repeated web-based administration of the Oxford WebQ--a 24-h recall of frequency from a set food list suitable for self-completion from which energy and nutrient values can be automatically generated. As part of the UK Biobank study, four invitations to complete the Oxford WebQ were sent by email over a 16-month period. Overall, 176 012 (53% of those invited) participants completed the online version of the Oxford WebQ at least once and 66% completed it more than once, although only 16% completed it on all four occasions. The response rate for any one round of invitations varied between 34 and 26%. On most occasions, the Oxford WebQ was completed on the same day that they received the invitation, although this was less likely if sent on a weekend. Participants who completed the Oxford WebQ tended to be white, female, slightly older, less deprived and more educated, which is typical of health-conscious volunteer-based studies. These findings provide preliminary evidence to suggest that repeated 24-h dietary assessment via the Internet is acceptable to the public and a feasible strategy for large population-based studies.

The impact of social disadvantage in moderate-to-severe chronic kidney disease: an equity-focused systematic review

Abstract: It is unclear whether a social gradient in health outcomes exists for people with moderate-to-severe chronic kidney disease (CKD). We critically review the literature for evidence of social gradients in health and investigate the 'suitability' of statistical analyses in the primary studies. In this equity-focused systematic review among adults with moderate-to-severe CKD, factors of disadvantage included gender, race/ethnicity, religion, education, socio-economic status or social capital, occupation and place of residence. Outcomes included access to healthcare, kidney disease progression, cardiovascular events, all-cause mortality and suitability of analyses. Twenty-four studies in the pre-dialysis population and 34 in the dialysis population representing 8.9 million people from 10 countries were included. In methodologically suitable studies among pre-dialysis patients, a significant social gradient was observed in access to healthcare for those with no health insurance and no home ownership. Low income and no home ownership were associated with higher cardiovascular event rates and higher mortality [HR 1.94, 95% confidence interval (CI) 1.27-2.98; HR 1.28, 95% CI 1.04-1.58], respectively. In methodologically suitable studies among dialysis patients, females, ethnic minorities, those with low education, no health insurance, low occupational level or no home ownership were significantly less likely to access cardiovascular healthcare than their more advantaged dialysis counterparts. Low education level and geographic remoteness were associated with higher cardiovascular event rates and higher mortality (HR 1.54, 95% CI 1.01-2.35; HR 1.21, 95% CI 1.08-1.37), respectively. Socially disadvantaged pre-dialysis and dialysis patients experience poorer access to specialist cardiovascular health services, and higher rates of cardiovascular events and mortality than their more advantaged counterparts.

Cardiac Mortality Among 200 000 Five-Year Survivors of Cancer Diagnosed at 15 to 39 Years of Age: The Teenage and Young Adult Cancer Survivor Study.

Abstract: Background: Survivors of teenage and young adult cancer are acknowledged as understudied. Little is known about their long-term adverse health risks, particularly of cardiac disease that is increased in other cancer populations where cardiotoxic treatments have been used. Methods: The Teenage and Young Adult Cancer Survivor Study cohort comprises 200 945 5-year survivors of cancer diagnosed at 15 to 39 years of age in England and Wales from 1971 to 2006, and followed to 2014. Standardized mortality ratios, absolute excess risks, and cumulative risks were calculated. Results: Two thousand sixteen survivors died of cardiac disease. For all cancers combined, the standardized mortality ratios for all cardiac diseases combined was greatest for individuals diagnosed at 15 to 19 years of age (4.2; 95% confidence interval, 3.4–5.2) decreasing to 1.2 (95% confidence interval, 1.1–1.3) for individuals aged 35 to 39 years (2 P for trend <0.0001). Similar patterns were observed for both standardized mortality ratios and absolute excess risks for ischemic heart disease, valvular heart disease, and cardiomyopathy. Survivors of Hodgkin lymphoma, acute myeloid leukaemia, genitourinary cancers other than bladder cancer, non-Hodgkin lymphoma, lung cancer, leukaemia other than acute myeloid, central nervous system tumour, cervical cancer, and breast cancer experienced 3.8, 2.7, 2.0, 1.7, 1.7, 1.6, 1.4, 1.3 and 1.2 times the number of cardiac deaths expected from the general population, respectively. Among survivors of Hodgkin lymphoma aged over 60 years, almost 30% of the total excess number of deaths observed were due to heart disease. Conclusions: This study of over 200 000 cancer survivors shows that age at cancer diagnosis was critical in determining subsequent cardiac mortality risk. For the first time, risk estimates of cardiac death after each cancer diagnosed between the ages of 15 and 39 years have been derived from a large population-based cohort with prolonged follow-up. The evidence here provides an initial basis for developing evidence-based follow-up guidelines. # Clinical Perspective {#article-title-33}

Chronic kidney disease and the risk of cancer: an individual patient data meta-analysis of 32,057 participants from six prospective studies.

Abstract: Chronic kidney disease (CKD) is an established risk factor for cardiovascular disease but the relevance of reduced kidney function to cancer risk is uncertain. Individual patient data were collected from six studies (32,057 participants); including one population-based cohort and five randomized controlled trials. Participants were grouped into one of five CKD categories (estimated glomerular filtration rate [eGFR] ≥75 mL/min/1.73 m2; eGFR ≥60 to <75 mL/min/1.73 m2; eGFR ≥45 to <60 mL/min/1.73 m2; eGFR <45 mL/min/1.73 m2; on dialysis). Stratified Cox regression was used to assess the impact of CKD category on cancer incidence and cancer death. Over a follow-up period of 170,000 person-years (mean follow-up among survivors 5.6 years), 2626 participants developed cancer and 1095 participants died from cancer. Overall, there was no significant association between CKD category and cancer incidence or death. As compared with the reference group with eGFR ≥75 mL/min/1.73 m2, adjusted hazard ratio (HR) estimates for each category of renal function, in descending order, were: 0.98 (95 % CI 0.87–1.10), 0.99 (0.88–1.13), 1.01 (0.84–1.22) and 1.24 (0.97–1.58) for cancer incidence, and 1.03 (95 % CI 0.86–1.24), 0.95 (0.78–1.16), 1.00 (0.76–1.33), and 1.58 (1.09–2.30) for cancer mortality. Among dialysis patients, there was an excess risk of cancers of the urinary tract (adjusted HR: 2.34; 95 % CI 1.10–4.98) and endocrine cancers (11.65; 95 % CI: 1.30–104.12), and an excess risk of death from digestive tract cancers (2.11; 95 % CI: 1.13–3.99), but a reduced risk of prostate cancers (0.38; 95 % CI: 0.18–0.83). Whilst no association between reduced renal function and the overall risk of cancer was observed, there was evidence among dialysis patients that the risk of cancer was increased (urinary tract, endocrine and digestive tract) or decreased (prostate) at specific sites. Larger studies are needed to characterise these site-specific associations and to identify their pathogenesis.

Efficacy and toxicity of a paediatric protocol in teenagers and young adults with Philadelphia chromosome negative acute lymphoblastic leukaemia: results from UKALL 2003

Abstract: Despite the substantial outcome improvements achieved in paediatric acute lymphoblastic leukaemia (ALL), survival in teenage and young adult (TYA) patients has remained inferior. We report the treatment outcomes and toxicity profiles observed in TYA patients treated on the UK paediatric ALL trial, UKALL2003. UKALL2003 was a multi-centre, prospective, randomized phase III trial, investigating treatment intensification or de-escalation according to minimal residual disease (MRD) kinetics at the end of induction. Of 3126 patients recruited to UKALL2003, 229 (7·3%) were aged 16-24 years. These patients were significantly more likely to have high risk MRD compared to 10-15 year olds (47·9% vs. 36·6%, P = 0·004). Nonetheless, 5-year event-free survival for the TYA cohort (aged 16-24 years) was 72·3% [95% confidence interval (CI): 66·2-78·4] overall and 92·6% (95% CI: 85·5-99·7) for MRD low risk patients. The risk of serious adverse events was higher in patients aged ≥10 years compared to those aged 9 or younger (P < 0·0001) and novel age-specific patterns of treatment-related toxicity were observed. TYA patients obtain excellent outcomes with a risk- and response-adapted paediatric chemotherapy protocol. Whilst those aged 10 years and older have excess toxicity compared with younger patients, the age association is specific to individual toxicities.

Association of green tea consumption with mortality from all-cause, cardiovascular disease and cancer in a Chinese cohort of 165,000 adult men

Abstract: Tea is the most ancient and popular beverage in the world, and its beneficial health effects has attracted tremendous attention worldwide. However, the prospective evidence relating green tea consumption to total and cause-specific mortality is still limited and inconclusive. We recruited 164,681 male participants free of pre-existing disease during 1990-1991, with green tea consumption and other covariates assessed by the standardized questionnaire and mortality follow up continued until 2006 (mean 11 years; total person-years: 1,961,791). Cox regression analyses were used to quantify the associations of green tea consumption with all-cause (n = 32,700), CVD (n = 11,839) and cancer (n = 7002) mortality, adjusting simultaneously for potential confounders. At baseline, 18 % reported regular consumption of green tea. Compared with non-green tea drinkers, regular drinkers had significantly lower all-cause mortality, with adjusted hazard ratios (HRs) being 0.94 (95 % CI 0.89, 0.99) for ≤5 g/day, 0.95 (0.91, 0.99) for 5-10 g/day and 0.89 (0.85, 0.93) for >10 g/day. For CVD mortality, the corresponding HRs were 0.93 (0.85, 1.01) 0.91 (0.85, 0.98) and 0.86 (0.79, 0.93), respectively, while for cancer they were 0.86 (0.78, 0.98), 0.92 (0.83, 1.00) and 0.79 (0.71, 0.88), respectively. The patterns of these associations varied by smoking, alcohol drinking and locality. This large prospective study shows that regular green tea consumption is associated with significantly reduced risk of death from all-cause, CVD and cancer among Chinese adults.

Associations between unprocessed red and processed meat, poultry, seafood and egg intake and the risk of prostate cancer: A pooled analysis of 15 prospective cohort studies

Abstract: Reports relating meat intake to prostate cancer risk are inconsistent. Associations between these dietary factors and prostate cancer were examined in a consortium of 15 cohort studies. During follow-up, 52,683 incident prostate cancer cases, including 4,924 advanced cases, were identified among 842,149 men. Cox proportional hazard models were used to calculate study-specific relative risks (RR) and then pooled using random effects models. Results do not support a substantial effect of total red, unprocessed red and processed meat for all prostate cancer outcomes, except for a modest positive association for tumors identified as advanced stage at diagnosis (advanced(r)). For seafood, no substantial effect was observed for prostate cancer regardless of stage or grade. Poultry intake was inversely associated with risk of advanced and fatal cancers (pooled multivariable RR [MVRR], 95% confidence interval, comparing ≥ 45 vs. <5 g/day: advanced 0.83, 0.70-0.99; trend test p value 0.29), fatal, 0.69, 0.59-0.82, trend test p value 0.16). Participants who ate ≥ 25 versus <5 g/day of eggs (1 egg ∼ 50 g) had a significant 14% increased risk of advanced and fatal cancers (advanced 1.14, 1.01-1.28, trend test p value 0.01; fatal 1.14, 1.00-1.30, trend test p value 0.01). When associations were analyzed separately by geographical region (North America vs. other continents), positive associations between unprocessed red meat and egg intake, and inverse associations between poultry intake and advanced, advanced(r) and fatal cancers were limited to North American studies. However, differences were only statistically significant for eggs. Observed differences in associations by geographical region warrant further investigation.