Clinical Trial Service Unit Research Articles

Meet the First Authors

HomeCirculation ResearchVol. 132, No. 4Meet the First Authors Free AccessIn BriefPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessIn BriefPDF/EPUBMeet the First Authors Originally published16 Feb 2023https://doi.org/10.1161/RES.0000000000000596Circulation Research. 2023;132:398–399is related toADAR1 Non-Editing Function in Macrophage Activation and Abdominal Aortic AneurysmApolipoprotein Proteomics for Residual Lipid-Related Risk in Coronary Heart DiseaseCirculating Extracellular Vesicle-Propagated microRNA Signature as a Vascular Calcification Factor in Chronic Kidney DiseaseCNP Promotes Antiarrhythmic Effects via Phosphodiesterase 2CNP Activates PDE2 to Reduce Arrhythmia (p 400)Download figureDownload PowerPointEleder Cachorro is a PhD student at the Institute of Pharmacology and Toxicology (TU Dresden, Germany) under the supervision of Dr Ali El-Armouche and Dr Susanne Kämmerer, where he studies the role of PDE2 in cardiovascular disease. He studied Biochemistry and Molecular Biology at the University of the Basque Country (EHU, Basque Country), where he obtained his BS. He then earned his MS in the Medical Biotechnology department of the Jagiellonian University of Krakow (UJ, Poland). In the laboratory of Dr Jozef Dulak, he collaborated in the generation of isogenic human pluripotent cell lines for in vitro modelling of HNF1A-MODY monogenic diabetes.Macrophage ADAR1 in AAA (p e78)Download figureDownload PowerPointDr Dunpeng Cai is a postdoctoral fellow in the Department of Surgery at the University of Missouri. After graduating from Southern Medical University, he joined Dr Shi-you Chen’s Lab and earned his PhD in 2021 from the Department of Medical Pharmacology and Physiology at the University of Missouri. Dr Cai’s main research interest is the molecular mechanisms underlying the development of cardiovascular diseases, including aortic aneurysm, atherosclerosis and stroke. Through innovation and hardwork, he wishes to establish landmark discoveries which can provide cures for patients. To achieve this goal, he has been developing his skills and capabilities in molecular and cell biology, mouse microsurgery, computer-aided drug design and bioinformatics. Outside of work, he enjoys spending time with family.sEVs Accelerate Vascular Calcification in CKD (p 415)Download figureDownload PowerPointDr Takaaki Koide was born and raised in Tokyo, Japan. He earned his MD from Asahikawa Medical University. He is currently a PhD student in the Department of Nephrology at Tokyo Medical and Dental University (his mentors: Prof. Shinichi Uchida and Shintaro Mandai). His research focuses on the mechanism of vascular calcification caused by chronic kidney disease. He is interested in utilizing non-coding RNAs as a therapeutic modality to treat extra-renal complications of chronic kidney disease. In his leisure time, he enjoys sports, traveling and craft beer.Apolipoprotein Proteomics for Heart Disease Risk (p 452)Download figureDownload PowerPointDr Robert Clarke is a Professor of Epidemiology and Public Health Medicine at the Clinical Trial Service Unit (CTSU), Nuffield Department of Population Health, University of Oxford. He qualified in medicine at the National University of Ireland in 1979. He worked in internal medicine and cardiology in Ireland for 10 years and clinical pharmacology at Vanderbilt University, Nashville, USA for 2 years. He joined University of Oxford in 1991 and specialized in Cardiovascular Epidemiology. Robert leads a research program on observational and genetic analyses assessing the importance of lifestyle factors, blood pressure, blood lipids, genes and proteomic biomarkers for cardiovascular diseases. Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesADAR1 Non-Editing Function in Macrophage Activation and Abdominal Aortic AneurysmDunpeng Cai, et al. Circulation Research. 2023;132:e78-e93Apolipoprotein Proteomics for Residual Lipid-Related Risk in Coronary Heart DiseaseRobert Clarke, et al. Circulation Research. 2023;132:452-464Circulating Extracellular Vesicle-Propagated microRNA Signature as a Vascular Calcification Factor in Chronic Kidney DiseaseTakaaki Koide, et al. Circulation Research. 2023;132:415-431CNP Promotes Antiarrhythmic Effects via Phosphodiesterase 2Eleder Cachorro, et al. Circulation Research. 2023;132:400-414 February 17, 2023Vol 132, Issue 4 Advertisement Article InformationMetrics © 2023 American Heart Association, Inc.https://doi.org/10.1161/RES.0000000000000596PMID: 36795849 Originally publishedFebruary 16, 2023 PDF download Advertisement

Randomized Trials Fit for the 21st Century: A Joint Opinion From the European Society of Cardiology, American Heart Association, American College of Cardiology, and the World Heart Federation.

Randomized Trials Fit for the 21st Century: A Joint Opinion From the European Society of Cardiology, American Heart Association, American College of Cardiology, and the World Heart Federation.

Dairy intake and risk of major cardiovascular events: a prospective cohort study of 0.5 million Chinese adults

Abstract Background Evidence on the association between dairy consumption and risk of cardiovascular disease has been highly inconsistent, with findings suggesting either harmful, neutral or beneficial effects. In addition, a very large majority of the previous studies on this topic were conducted among populations in Europe and North America who usually consume a higher amount of dairy products and very few data, particularly prospective data, come from China where the dairy consumption level is low. Purpose We therefore investigated the associations between intake of dairy products and incidence of several major types of cardiovascular diseases in Chinese adults. Methods During 2004–2008, the prospective China Kadoorie Biobank Study recruited slightly over 0.5 million adults from ten diverse regions (five urban and five rural) across China. Information on the consumption frequency of dairy products was collected at baseline and periodic resurveys, using a validated interviewer-administered laptop-based questionnaire. Over a mean follow-up of 10.9 years, there were 47,128 incident ischaemic heart disease events, 43,481 ischaemic strokes and 9749 intracerebral haemorrhages among 489,595 study participants, who did not report a prior history of cardiovascular disease at baseline. Cox regression analyses were performed to estimate multivariable-adjusted hazard ratios (HRs) for incident events associated with dairy intake. Results Overall, 69.3% of participants reported never or rare consumption (i.e. non-consumers) and 11.3% of them reported regular consumption (i.e. ≥4 days/week) of dairy products, with milk accounting for the largest proportion of total dairy intake (∼77%). Male and female regular dairy consumers had 2.1/1.5 and 1.7/1.1 mmHg lower systolic/diastolic blood pressure, respectively compared to non-consumers. In a subset (∼18,000) of participants with blood lipid levels measured, regular dairy consumers had ∼0.1 mmol/L higher LDL levels than non-consumers. After adjusting for a range of potential confounders, including sociodemographic and lifestyle factors, BMI and other dietary factors, dairy consumption was positively and significantly associated with risk of ischaemic heart disease, with the adjusted HR per 50 g/day increase in usual dairy consumption being 1.11 (95% confidence interval [CI] 1.09–1.14). Dairy consumption was not significantly associated with risk of ischemic stroke but was inversely associated with risk of intracerebral haemorrhage, with each 50 g/day increase in usual dairy consumption being associated with 17% lower risk (HR 0.83, 0.78–0.88). These associations remained significant after additional adjustment for systolic blood pressure. Conclusion In this large study of Chinese adults, higher intake of dairy products was associated with a higher risk of ischaemic heart disease but a lower risk of intracerebral haemorrhage. The exact mechanisms underlying such associations require further investigation. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): The CKB baseline survey and the first re-survey were supported by the Kadoorie Charitable Foundation in Hong Kong. The long-term follow-up has been supported by Wellcome grants to Oxford University (212946/Z/18/Z, 202922/Z/16/Z, 104085/Z/14/Z, 088158/Z/09/Z) and grants from the National Key Research and Development Program of China (2016YFC0900500, 2016YFC0900501, 2016YFC0900504, 2016YFC1303904) and from the National Natural Science Foundation of China (91843302). The UK Medical Research Council (MC_UU_00017/1,MC_UU_12026/2 MC_U137686851), Cancer Research UK (C16077/A29186; C500/A16896) and the British Heart Foundation (CH/1996001/9454), provide core funding to the Clinical Trial Service Unit and Epidemiological Studies Unit at Oxford University for the project.

Associations of red meat, poultry, fish and egg intake with risk of cardiovascular disease: an 11-year prospective study of the China Kadoorie Biobank

Abstract Background Higher red meat intake and lower fish intake have been associated with increased risk of cardiovascular disease (CVD), while the relevance of poultry and egg intake for CVD incidence remains inconclusive. Furthermore, most of the prospective evidence comes from studies in the Western populations, with limited data from China where the CVD patterns are largely different. Purpose We therefore investigated the associations of red meat, poultry, fish and egg intake with risks of several major types of CVD in Chinese adults. Methods The China Kadoorie Biobank is a prospective study which recruited ∼512,000 adult participants from ten diverse localities during 2004–08. At baseline and periodic resurveys, information on the consumption frequency of major food groups was collected using a validated interviewer-administered laptop-based questionnaire, together with medical history, socio-demographic and other lifestyle factors. During an average follow-up of 10.9 years, 47,128 incident ischaemic heart disease events, 43,481 ischaemic strokes and 9749 intracerebral haemorrhages were recorded among 489,595 participants, who did not have a prior history of CVD at baseline. Cox regression was used to calculate adjusted hazard ratios (HRs) relating dietary exposures to CVD risk. Results There were 47.2%, 1.4%, 9.0% and 24.1% of participants at baseline who regularly consumed (i.e. ≥4 days/week) red meat, poultry, fish and eggs, respectively. After adjusting for potential confounders, including body mass index and other dietary factors under study, egg consumption was significantly associated with lower risks of ischaemic heart disease and ischaemic stroke, with each 50 g/day increase in estimated habitual egg consumption being associated with 18% (HR 0.82, 95% confidence interval [CI] 0.75–0.90) and 24% lower risks (HR 0.76, 95% CI 0.69–0.84), respectively. Inverse associations were also observed between intakes of red meat, fish and eggs and risk of intracerebral haemorrhage, with adjusted HRs for 50 g/day higher intake being 0.84 (95% CI 0.74–0.97), 0.86 (95% CI 0.74–0.99) and 0.42 (95% CI 0.34–0.51), respectively. Conclusion This large prospective study of Chinese adults showed that higher intake of eggs was associated with lower risks of ischaemic heart disease and ischaemic stroke. Moreover, higher intakes of red meat, fish and eggs were each associated with a lower risk of intracerebral haemorrhage. Further investigation of the potential mechanisms that underlie the observed associations is required. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): The CKB baseline survey and the first re-survey were supported by the Kadoorie Charitable Foundation in Hong Kong. The long-term follow-up has been supported by Wellcome grants to Oxford University (212946/Z/18/Z, 202922/Z/16/Z, 104085/Z/14/Z, 088158/Z/09/Z) and grants from the National Key Research and Development Program of China (2016YFC0900500, 2016YFC0900501, 2016YFC0900504, 2016YFC1303904) and from the National Natural Science Foundation of China (91843302). The UK Medical Research Council (MC_UU_00017/1,MC_UU_12026/2 MC_U137686851), Cancer Research UK (C16077/A29186; C500/A16896) and the British Heart Foundation (CH/1996001/9454), provide core funding to the Clinical Trial Service Unit and Epidemiological Studies Unit at Oxford University for the project. MG. Kakkoura is supported by the Wellcome Trust, Our Planet Our Health (Livestock, Environment and People - LEAP) (205212/Z/16/Z).

Genetic IL-6R variants and therapeutic inhibition of IL-6 receptor signalling in COVID-19 - Authors' reply.

Genetic IL-6R variants and therapeutic inhibition of IL-6 receptor signalling in COVID-19 - Authors' reply.

Genetic variants mimicking therapeutic inhibition of IL-6 receptor signaling and risk of COVID-19.

Genetic variants mimicking therapeutic inhibition of IL-6 receptor signaling and risk of COVID-19.

Influence of competing risks on estimates of recurrence risk and breast cancer-specific mortality in analyses of the Early Breast Cancer Trialists Collaborative Group.

533 Background: Early stage breast cancer is a curable disease with the majority of patients dying of causes other than breast cancer. The influence of these competing risks of death on the interpretation of Kaplan-Meier(KM)-based analyses such as those performed by the Early Breast Cancer Trialists Collaborative Group (EBCTCG) are unknown. Methods: We searched the Clinical Trial Service Unit and Epidemiological Studies Unit website at Oxford University to identify all meta-analyses published by the EBCTCG between 2005 and 2018. Studies were included if they contained KM curves with risk estimates for either breast cancer mortality and/or breast cancer recurrence. The potential influence of competing risks was estimated using a validated multivariate linear model that predicts the amount that the KM risk estimates are biased relative to outcome risk measured with the cumulative incidence function (CIF). Results: The initial search identified 14 analyses published by the EBCTCG with 10 of the 14 studies (71%) susceptible to competing risk bias cited both the number of events of interest and competing events. Eight of the ten studies (80%) had a relative difference between the KM estimate and the competing risk adjusted estimate of more than 10% while 2 of 10 (20%) had a difference of less than 10%. The relative difference between the KM and adjusted estimates was 28.4% for local recurrence, 16.8% for distant recurrence, and 6.7% for breast cancer-specific mortality. There was 2.2% difference between KM and adjusted analyses between 0-4 years and 18.9% beyond 10 years of follow up. Use of KM and CIF-based analysis did not influence treatment effect in the majority of included studies. Conclusions: This study provides estimates for the overestimation of risk in Kaplan-Meier analyses resulting from failure to address competing risk bias. CIFs are more appropriate to measure outcome risk over time and should be used especially for long-term follow-up studies and for analysis of rare events.

Associations of Changes in Weight and Waist Circumference with Cardiovascular Disease and Mortality in Chinese Adults

Background: The associations of age-related changes in body weight and waist circumferences with cardiovascular disease (CVD) and mortality remain unclear. Methods: We assessed changes in weight and waist circumference from baseline survey and resurvey among 27 964 participants in the China Kadoorie Biobank (CKB, 2004-2008) and Dongfeng-Tongji Cohort (DF-TJ, 2008-2013). We used Cox proportional hazards models to evaluate the associations between adiposity changes and the subsequent risks of incident CVD, CVD mortality and all-cause mortality. Findings: On average, during a median of 3·4 years from baseline to resurvey, participants experienced a weight loss of 0·6 kg, accompanied by a 2·1 cm increase in waist circumference. We identified 3589 incident CVD cases, 485 CVD deaths, and 1283 all-cause deaths during the follow-up in the CKB (2008-2016) and DF-TJ (2013-2016). Weight loss and waist gain were associated with increased risks of those outcomes in the two cohorts. In particular, compared with participants who had stable waist (waist change -2·0 to 7·0 cm) and weight (weight change -2·5 to 2·5 kg), those who gained waist but lost weight (waist circumference change >7·0 cm, weight change ≤ -2·5 kg) had the highest risk of incident CVD, CVD mortality and all-cause mortality, with the pooled multivariate hazard ratios (HRs) of 1·41 (95% CI, 1·13 to 1·75), 2·48 (1·40 to 4·37), and 1·71 (1·16 to 2·51), respectively. Among the weight-stable participants, waist circumference was linearly associated with CVD risk, with 17% higher risk (HR 1·17, 1·04 to 1·32) for those gained waist while 13% lower risk (HR 0·87, 0·77 to 0·99) for those lost waist compared to waist-stable participants. Interpretation: Increased waist circumference with concurrent weight loss is significantly associated with increased risks of CVD morbidity, CVD mortality, and all-cause mortality among Chinese middle-aged and elderly adults. Funding Statement: This work was partly supported by grants from the Foundation of National Key Programs of Research and Development of China (2016YFC0900800, 2016YFC0900500, 2017YFC0907501 and 2017YFC0907504), the National Natural Science Foundation of China (91643202 and 81390540), the 111 Project and the Program for Changjiang Scholars and Innovative Research Team in University. The China Kadoorie Biobank baseline survey and the first resurvey were supported by the Kadoorie Charitable Foundation in Hong Kong. The long-term follow-up has been supported by the UK Wellcome Trust (grants 088158/Z/09/Z, 104085/Z/14/Z), and the Chinese Ministry of Science and Technology (2011BAI09B01). The British Heart Foundation, UK Medical Research Council, and Cancer Research provide core funding to the Clinical Trial Service Unit and Epidemiological Studies Unit at Oxford University for the project. Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: The CKB study was approved by the ethics committees or institutional review boards at the University of Oxford, the Chinese Center for Disease Control and Prevention (China CDC), the Chinese Academy of Medical Sciences. The DF-TJ cohort was approved by the ethics committees of Tongji Medical College and the Sinopharm Dongfeng General Hospital. All participants provided written informed consents.

Influence of Competing Risks on Estimates of Recurrence Risk and Breast Cancer-Specific Mortality in Analyses of the Early Breast Cancer Trialists Collaborative Group

Introduction: Early stage breast cancer is a curable disease with many patients dying of causes other than breast cancer. The influence of these competing risks of death on the interpretation of Kaplan-Meier (KM)-based analyses for other outcomes by the Early Breast Cancer Trialists Collaborative Group (EBCTCG) are unknown. Methods: We searched the Clinical Trial Service Unit and Epidemiological Studies Unit website at Oxford University to identify all meta-analyses published by the EBCTCG between 2005 and 2018. Studies were included if they risk estimates for either breast cancer mortality and/or breast cancer recurrence based on KM analyses and reported competing events. The potential influence of competing risks was estimated using a validated multivariate linear model that predicts the difference between KM and cumulative incidence function (CIF) on estimates of breast cancer-specific outcomes. Results: The initial search identified 14 analyses published by the EBCTCG, 10 of which (71%) reported data on breast cancer and competing events. Eight of the ten studies (80%) had a relative difference between the KM and the competing risk adjusted estimates exceeding 10%. The median (range) relative difference between the KM and adjusted estimates was: 28.4% for local recurrence; 16.8% for distant recurrence, and 6.7% for breast cancer-specific mortality. There was a 2.2% relative difference between KM and CIF adjusted analyses between 0-4 years of follow-up and 18.9% beyond 10 years. Use of KM vs. CIF-based analysis did not influence treatment effect in most included studies. Conclusions: The use of KM-based methods when competing risks are present biases risk estimates in studies of early breast cancer. Future studies should exclusively use the CIF to calculate breast cancer specific outcomes. Funding: N/A Declaration of Interest: Dr. Eitan AMIR reports personal fees from Genentech/Roche, personal fees from Apobiologix, personal fees from Myriad Genetics, personal fees from Agendia, outside the submitted work. Ethical Approval: This study was exempt from institutional review board approval since it used publicly available data exclusively.

Emerging Risk Factors for Stroke: What Have We Learned From Mendelian Randomization Studies?

Establishing new approaches for the prevention and treatment of stroke relies on identifying modifiable risk factors that contribute to the development of this complex disease. Mendelian randomization (MR) studies, analogous to naturally occurring randomized trials, can assess causality of potentially modifiable biomarkers and offer new insights into biological pathways. Stroke is the second leading cause of death worldwide and the chief determinant of long-term disability. Stroke is a heterogeneous disease arising from several distinct underlying pathologies and is typically classified as ischemic or hemorrhagic, and further subclassified using imaging data. Ischemic stroke (IS), including its 3 main subtypes: small vessel disease, large vessel disease, and cardioembolic stroke, accounts for ≈80% of stroke and is the result of an interrupted blood supply, leading to localized areas of ischemia in the brain. Small vessel disease may be a consequence of nonatherosclerotic, as well as atherosclerotic, mechanisms that result in an occlusion of the small perforating arteries, whereas large vessel disease results from occlusions or emboli from plaque rupture in larger vessels, such as a carotid artery. Cardioembolic stroke arises typically from emboli from the heart. By contrast, hemorrhagic stroke is a consequence of intracerebral hemorrhage (bleeding into the brain) or subarachnoid hemorrhage (bleeding into the subarachnoid space). These diverse stroke subtypes have distinct underlying pathologies reflecting different risk factor distributions. MR studies, using genetic variants as instrumental variables, afford a powerful approach to assessing causality of risk factors and avoid biases inherent in observational studies, including confounding and reverse causation. This review considers the contribution of MR studies to stroke epidemiology and their relevance to understanding risk factors and new therapeutic targets for stroke. Meta-analyses of large prospective studies have enhanced our knowledge of classical and emerging risk factors for stroke.1–4 Classical risk factors for stroke include nonmodifiable characteristics, …

Germline exome variation in children with acute lymphoblastic leukemia (ALL): Preliminary Findings

Germline exome variation in children with acute lymphoblastic leukemia (ALL): Preliminary Findings

Nonsteroidal Anti-Inflammatory Drugs and the Heart

Aspirin has been on the market for 115 years. Beginning with the marketing of indomethacin for the treatment of rheumatoid arthritis in 1963, at least 20 other nonsteroidal anti-inflammatory drugs (NSAIDs) with aspirin-like actions have been developed over the past 50 years,1 culminating with the introduction of a new class of selective inhibitors of cyclooxygenase (COX)-2, the coxibs, approximately 15 years ago.2 The NSAIDs represent the single most crowded family of drugs sharing the same therapeutic activities and mechanism of action, perhaps reflecting the unmet therapeutic need in the area of pain management and the large interindividual variability in response to these agents. NSAIDs provide symptomatic relief of pain and inflammation associated with a variety of human disorders, including the rheumatic diseases. Their shared therapeutic actions (ie, analgesic, anti-inflammatory, and antipyretic) are usually accompanied by mechanism-based adverse effects that can, at least in part, be attenuated as a function of individual pharmacokinetic or pharmacodynamic properties.1 Nuances in the tolerability of different NSAIDs had been described in the precoxib era on the basis of clinical trials of a few hundred patients treated for up to a few months with soft end points. More recently, however, important differences in safety have been demonstrated in head-to-head randomized comparisons of individual coxibs and 1 or more traditional NSAIDs that involved tens of thousands of patients treated for up to a few years with hard end points. Even more significantly, the interpretation of the effects of NSAIDs has been greatly enhanced by the availability, for the first time, of large, placebo-controlled trials that aimed to assess the potential for chemoprevention of colorectal cancer by rofecoxib or celecoxib. As a result of these developments, the whole field of NSAIDs has been illuminated during the past 15 years. Although epidemiological studies had previously associated …

Mast cells in the human dura: effects of age and dural bleeding—Authors’ reply

Dear Sir, As Drs. Greeley and Karst point out, the timing of subdural haemorrhage (SDH) is ‘an area which remains opaque and complex’. This is of concern, since oversimplified descriptions of the infant dura have led to clinical diagnoses and timing estimates that do not comport with the neuropathology. The only way to avoid these mistakes is through basic research, such as that presented in our paper. Through such research, we hope to bring clarity not only to the issue of timing of subdural collections, but also to their pathophysiological significance in the infant, which we have addressed separately [1, 2]. As noted, there is nothing new in the demonstration of the inflammatory response to SDH. Indeed, our finding that mast cell density increases with the age of the SDH is consistent with similar studies of eosinophils in adults [3]. We believe, however, that ours is the first study to examine this response in foetal and infant cases. We also agree that what we are observing is part of a generalised inflammatory response, and that the specific cell type involved may be less important than the fact that any inflammation—even an acellular ‘inflammatory soup’—is capable of both stimulating and sensitising dural trigeminal sensory afferent fibres, causing them to be activated by stimuli that previously evoked little or no response [4]. We drew particular attention to mast cells because they are rapid responders in the neurogenic modulation of immunity in host defence [5], and can be accurately identified through tinctorial and immunohistochemical stains, increasing reliability and facilitating counting. With regard to our methods, we noted that ‘[b]linding as to the nature of each slide (age and control versus subdural haemorrhage (SDH)) was maintained as far as possible throughout counting. ’ The assessors (AV, JD, and AG) had no clinical information and did not know whether they were counting control or test sections. While it was not possible to blind them to the presence of SDH, since this can be seen in the dura, the assessors were not neuropathologists and were not in a position to speculate on the age of the bleeding while conducting the counts. The statistical analysis was performed with advice from Professor Sarah Darby at the Clinical Trial Service Unit, University of Oxford. The data were analysed by constructing a variable to indicate the SDH status. The codes for this variable were 1 for controls, 2 for fresh SDH and 3 for chronic SDH. A linear regression analysis was then carried out relating mast cell density to SDH status using the computer program Stata version 12. The significance of the regression coefficient was evaluated using a two-sided t test. Drs. Greeley and Karst correctly note that it is not possible to reach statistical significance in a sample of this size. For this reason, we refrained from making such inferences, instead describing ‘borderline statistical significance’ and indicating that ‘[f]urther studies should more closely examine the relationship between age and mast cell density in the human dura, both in controls and in cases of subdural haemorrhage. ’ Because larger studies are more likely to be statistically reliable, we are not sure it makes sense to reformat our existing data, but if Drs. Greeley and Karst suggest any supplementary analyses we would be happy to run them. Drs. Greeley and Karst refer to an ‘apparent discrepancy’ in our observation that dural samples from older patients (adults, defined arbitrarily as over 200 months) tended to have a lower mast cell density than those from children, infants and A. Varatharaj (*) :W. Squier Department of Neuropathology, John Radcliffe Hospital, Oxford OX3 9DU, UK e-mail: a.varatharaj@gmail.com

Randomised controlled trials: important but overrated?

Practising physicians individualise treatments, hoping to achieve optimal outcomes by tackling relevant patient variables. The randomised controlled trial (RCT) is universally accepted as the best means of comparison. Yet doctors sometimes wonder if particular patients might benefit more from treatments that fared worse in the RCT comparisons. Such clinicians may even feel ostracised by their peers for stepping outside treatments based on RCTs and guidelines. Are RCTs the only acceptable evaluations of how patient care can be assessed and delivered? In this controversy we explore the interpretation of RCT data for practising clinicians facing individualised patient choices. First, critical care anaesthetists John Boylan and Brian Kavanagh emphasise the dangers of bias and show how Bayesian approaches utilise prior probabilities to improve posterior (combined) probability estimates. Secondly, Jane Armitage, of the Clinical Trial Service Unit in Oxford, argues why RCTs remain essential and explores how the quality of randomisation can be improved through systematic reviews and by avoiding selective reporting.

Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12 064 survivors of myocardial infarction: a double-blind randomised trial

SummaryBackgroundLowering of LDL cholesterol reduces major vascular events, but whether more intensive therapy safely produces extra benefits is uncertain. We aimed to establish efficacy and safety of more intensive statin treatment in patients at high cardiovascular risk.MethodsWe undertook a double-blind randomised trial in 12 064 men and women aged 18–80 years with a history of myocardial infarction. Participants were either currently on or had clear indication for statin therapy, and had a total cholesterol concentration of at least 3·5 mmol/L if already on a statin or 4·5 mmol/L if not. Randomisation to either 80 mg or 20 mg simvastatin daily was done centrally using a minimisation algorithm. Participants were assessed at 2, 4, 8, and 12 months after randomisation and then every 6 months until final follow-up. The primary endpoint was major vascular events, defined as coronary death, myocardial infarction, stroke, or arterial revascularisation. Analysis was by intention to treat. This study is registered, number ISRCTN74348595.Findings6031 participants were allocated 80 mg simvastatin daily, and 6033 allocated 20 mg simvastatin daily. During a mean follow-up of 6·7 (SD 1·5) years, allocation to 80 mg simvastatin produced an average 0·35 (SE 0·01) mmol/L greater reduction in LDL cholesterol compared with allocation to 20 mg. Major vascular events occurred in 1477 (24·5%) participants allocated 80 mg simvastatin versus 1553 (25·7%) of those allocated 20 mg, corresponding to a 6% proportional reduction (risk ratio 0·94, 95% CI 0·88–1·01; p=0·10). There were no apparent differences in numbers of haemorrhagic strokes (24 [0·4%] vs 25 [0·4%]) or deaths attributed to vascular (565 [9·4%] vs 572 [9·5%]) or non-vascular (399 [6·6%] vs 398 [6·6%]) causes. Compared with two (0·03%) cases of myopathy in patients taking 20 mg simvastatin daily, there were 53 (0·9%) cases in the 80 mg group.InterpretationThe 6% (SE 3·5%) reduction in major vascular events with a further 0·35 mmol/L reduction in LDL cholesterol in our trial is consistent with previous trials. Myopathy was increased with 80 mg simvastatin daily, but intensive lowering of LDL cholesterol can be achieved safely with other regimens.FundingMerck; The Clinical Trial Service Unit also receives funding from the UK Medical Research Council and the British Heart Foundation.

Smoking kills: the revolutionary life of Richard Doll

Smoking kills: the revolutionary life of Richard Doll

Body-mass index and cause-specific mortality in 900 000 adults: collaborative analyses of 57 prospective studies

SummaryBackgroundThe main associations of body-mass index (BMI) with overall and cause-specific mortality can best be assessed by long-term prospective follow-up of large numbers of people. The Prospective Studies Collaboration aimed to investigate these associations by sharing data from many studies.MethodsCollaborative analyses were undertaken of baseline BMI versus mortality in 57 prospective studies with 894 576 participants, mostly in western Europe and North America (61% [n=541 452] male, mean recruitment age 46 [SD 11] years, median recruitment year 1979 [IQR 1975–85], mean BMI 25 [SD 4] kg/m2). The analyses were adjusted for age, sex, smoking status, and study. To limit reverse causality, the first 5 years of follow-up were excluded, leaving 66 552 deaths of known cause during a mean of 8 (SD 6) further years of follow-up (mean age at death 67 [SD 10] years): 30 416 vascular; 2070 diabetic, renal or hepatic; 22 592 neoplastic; 3770 respiratory; 7704 other.FindingsIn both sexes, mortality was lowest at about 22·5–25 kg/m2. Above this range, positive associations were recorded for several specific causes and inverse associations for none, the absolute excess risks for higher BMI and smoking were roughly additive, and each 5 kg/m2 higher BMI was on average associated with about 30% higher overall mortality (hazard ratio per 5 kg/m2 [HR] 1·29 [95% CI 1·27–1·32]): 40% for vascular mortality (HR 1·41 [1·37–1·45]); 60–120% for diabetic, renal, and hepatic mortality (HRs 2·16 [1·89–2·46], 1·59 [1·27–1·99], and 1·82 [1·59–2·09], respectively); 10% for neoplastic mortality (HR 1·10 [1·06–1·15]); and 20% for respiratory and for all other mortality (HRs 1·20 [1·07–1·34] and 1·20 [1·16–1·25], respectively). Below the range 22·5–25 kg/m2, BMI was associated inversely with overall mortality, mainly because of strong inverse associations with respiratory disease and lung cancer. These inverse associations were much stronger for smokers than for non-smokers, despite cigarette consumption per smoker varying little with BMI.InterpretationAlthough other anthropometric measures (eg, waist circumference, waist-to-hip ratio) could well add extra information to BMI, and BMI to them, BMI is in itself a strong predictor of overall mortality both above and below the apparent optimum of about 22·5–25 kg/m2. The progressive excess mortality above this range is due mainly to vascular disease and is probably largely causal. At 30–35 kg/m2, median survival is reduced by 2–4 years; at 40–45 kg/m2, it is reduced by 8–10 years (which is comparable with the effects of smoking). The definite excess mortality below 22·5 kg/m2 is due mainly to smoking-related diseases, and is not fully explained.FundingUK Medical Research Council, British Heart Foundation, Cancer Research UK, EU BIOMED programme, US National Institute on Aging, and Clinical Trial Service Unit (Oxford, UK).

Pre-referral rectal artesunate to prevent death and disability in severe malaria: a placebo-controlled trial

SummaryBackgroundMost malaria deaths occur in rural areas. Rapid progression from illness to death can be interrupted by prompt, effective medication. Antimalarial treatment cannot rescue terminally ill patients but could be effective if given earlier. If patients who cannot be treated orally are several hours from facilities for injections, rectal artesunate can be given before referral and acts rapidly on parasites. We investigated whether this intervention reduced mortality and permanent disability.MethodsIn Bangladesh, Ghana, and Tanzania, patients with suspected severe malaria who could not be treated orally were allocated randomly to a single artesunate (n=8954) or placebo (n=8872) suppository by taking the next numbered box, then referred to clinics at which injections could be given. Those with antimalarial injections or negative blood smears before randomisation were excluded, leaving 12 068 patients (6072 artesunate, 5996 placebo) for analysis. Primary endpoints were mortality, assessed 7–30 days later, and permanent disability, reassessed periodically. All investigators were masked to group assignment. Analysis was by intention to treat. This study is registered in all three countries, numbers ISRCTN83979018, 46343627, and 76987662.ResultsMortality was 154 of 6072 artesunate versus 177 of 5996 placebo (2·5% vs 3·0%, p=0·1). Two versus 13 (0·03% vs 0·22%, p=0·0020) were permanently disabled; total dead or disabled: 156 versus 190 (2·6% vs 3·2%, p=0·0484). There was no reduction in early mortality (56 vs 51 deaths within 6 h; median 2 h). In patients reaching clinic within 6 h (median 3 h), pre-referral artesunate had no significant effect on death after 6 h or permanent disability (71/4450 [1·6%] vs 82/4426 [1·9%], risk ratio 0·86 [95% CI 0·63–1·18], p=0·35). In patients still not in clinic after more than 6 h, however, half were still not there after more than 15 h, and pre-referral rectal artesunate significantly reduced death or permanent disability (29/1566 [1·9%] vs 57/1519 [3·8%], risk ratio 0·49 [95% CI 0·32–0·77], p=0·0013).InterpretationIf patients with severe malaria cannot be treated orally and access to injections will take several hours, a single inexpensive artesunate suppository at the time of referral substantially reduces the risk of death or permanent disability.FundingUNICEF/UNDP/World Bank Special Programme for Research and Training in Tropical Diseases (WHO/TDR); WHO Global Malaria Programme (WHO/GMP); Sall Family Foundation; the European Union (QLRT-2000-01430); the UK Medical Research Council; USAID; Irish Aid; the Karolinska Institute; and the University of Oxford Clinical Trial Service Unit (CTSU).

WITHDRAWN: Ovarian ablation for early breast cancer.

Among women with early breast cancer, the effects of ovarian ablation on recurrence and death have been assessed by several randomised trials that now have long follow-up. In this report, the Early Breast Cancer Trialists' Collaborative Group present their third 5-yearly systematic overview (meta-analysis), now with 15 years' follow-up. Trial identification procedures for the EBCTCG overviews have been described elsewhere. See under "EBCTCG" in the Breast Cancer Collaborative Review Group module. All properly randomised trials that began recruiting before 1990 which compared the ablation or suppression of ovarian function, sometimes with the addition of prednisone, versus no such adjuvant treatment for women with operable breast cancer. In practice, all the trials that can be reviewed here began before 1980, and all involved surgical or therapeutic ablation. In 1995, information was sought on each patient in any randomised trial of ovarian ablation or suppression versus control that began before 1990. Data were obtained for 12 of the 13 studies that assessed ovarian ablation by irradiation or surgery, all of which began before 1980, but not for the four studies that assessed ovarian suppression by drugs, all of which began after 1985. Menopausal status was not consistently defined across trials; therefore, the main analyses are limited to women aged under 50 (rather than "premenopausal") when randomised. Oestrogen receptors were measured only in the trials of ablation plus cytotoxic chemotherapy versus the same chemotherapy alone. Among 2102 women aged under 50 when randomised, most of whom would have been premenopausal at diagnosis, 1130 deaths and an additional 153 recurrences were reported. 15-year survival was highly significantly improved among those allocated ovarian ablation (52.4 vs 46.1%, 6.3 [SD 2.3] fewer deaths per 100 women, logrank 2p=0.001), as was recurrence-free survival (45.0 vs 39.0%, 2p=0.0007). The numbers of events were too small for any subgroup analyses to be reliable. The benefit was, however, significant both for those with ("node positive") and for those without ("node negative") axillary spread when diagnosed. In the trials of ablation plus cytotoxic chemotherapy versus the same chemotherapy alone, the benefit appeared smaller (even for women with oestrogen receptors detected on the primary tumour) than in the trials in the absence of chemotherapy (where the observed survival improvements were about six per 100 node-negative women and 12 per 100 node-positive women). Among 1354 women aged 50 or over when randomised, most of whom would have been perimenopausal or postmenopausal, there was only a non-significant improvement in survival and recurrence-free survival. In women aged under 50 with early breast cancer, ablation of functioning ovaries significantly improves long-term survival, at least in the absence of chemotherapy. Further randomised evidence is needed on the additional effects of ovarian ablation in the presence of other adjuvant treatments, and to assess the relevance of hormone-receptor measurements.

Combined Effects of Systolic Blood Pressure and Total Cholesterol on Cardiovascular Disease Risk

Half of all adult deaths (and much severe disability) are caused by cardiovascular diseases, and most of these deaths involve ischemic heart disease or stroke. The Asia-Pacific region accounts for about half of the global burden of cardiovascular disease and the proportion is likely to increase during the next few decades.1,2 Smoking and elevated levels of systolic blood pressure (SBP) and total blood cholesterol are major causes of cardiovascular disease,3 yet much of our knowledge about the associations between these risk factors and cardiovascular diseases comes from studies carried out in North American and western European countries. In most Asian countries, however, the mean levels of total cholesterol are lower than those found in Western countries and the incidence of coronary heart disease (CHD) is also lower, whereas the incidence of stroke, particularly hemorrhagic stroke, is higher. Article p 3384 The Asia Pacific Cohort Studies Collaboration report in this issue of Circulation investigates the combined effects of SBP and total cholesterol on risk of cardiovascular disease in a meta-analysis of 36 cohort studies (29 conducted in Asia and 7 from Australia and New Zealand) involving 380 000 individuals.4 This meta-analysis differs from previous studies in several ways: It is the largest study from this region, involving >3000 CHD events and 4000 stroke events; individual records were available for each of the participants in each study, with cause and age of death (if applicable); and information on several thousand repeat measurements of blood pressure and cholesterol made during prolonged follow-up allowed correction for “regression dilution.” These features …