Publications by authors named "Richard Peto"

193 Publications

Second asymptomatic carotid surgery trial (ACST-2): a randomised comparison of carotid artery stenting versus carotid endarterectomy.

Lancet 2021 Sep 29;398(10305):1065-1073. Epub 2021 Aug 29.

Nuffield Department of Population Health, University of Oxford, Oxford, UK; Medical Research Council Population Health Research Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.

Background: Among asymptomatic patients with severe carotid artery stenosis but no recent stroke or transient cerebral ischaemia, either carotid artery stenting (CAS) or carotid endarterectomy (CEA) can restore patency and reduce long-term stroke risks. However, from recent national registry data, each option causes about 1% procedural risk of disabling stroke or death. Comparison of their long-term protective effects requires large-scale randomised evidence.

Methods: ACST-2 is an international multicentre randomised trial of CAS versus CEA among asymptomatic patients with severe stenosis thought to require intervention, interpreted with all other relevant trials. Patients were eligible if they had severe unilateral or bilateral carotid artery stenosis and both doctor and patient agreed that a carotid procedure should be undertaken, but they were substantially uncertain which one to choose. Patients were randomly allocated to CAS or CEA and followed up at 1 month and then annually, for a mean 5 years. Procedural events were those within 30 days of the intervention. Intention-to-treat analyses are provided. Analyses including procedural hazards use tabular methods. Analyses and meta-analyses of non-procedural strokes use Kaplan-Meier and log-rank methods. The trial is registered with the ISRCTN registry, ISRCTN21144362.

Findings: Between Jan 15, 2008, and Dec 31, 2020, 3625 patients in 130 centres were randomly allocated, 1811 to CAS and 1814 to CEA, with good compliance, good medical therapy and a mean 5 years of follow-up. Overall, 1% had disabling stroke or death procedurally (15 allocated to CAS and 18 to CEA) and 2% had non-disabling procedural stroke (48 allocated to CAS and 29 to CEA). Kaplan-Meier estimates of 5-year non-procedural stroke were 2·5% in each group for fatal or disabling stroke, and 5·3% with CAS versus 4·5% with CEA for any stroke (rate ratio [RR] 1·16, 95% CI 0·86-1·57; p=0·33). Combining RRs for any non-procedural stroke in all CAS versus CEA trials, the RR was similar in symptomatic and asymptomatic patients (overall RR 1·11, 95% CI 0·91-1·32; p=0·21).

Interpretation: Serious complications are similarly uncommon after competent CAS and CEA, and the long-term effects of these two carotid artery procedures on fatal or disabling stroke are comparable.

Funding: UK Medical Research Council and Health Technology Assessment Programme.
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http://dx.doi.org/10.1016/S0140-6736(21)01910-3DOI Listing
September 2021

SARS-CoV-2 Variants and Vaccines.

N Engl J Med 2021 Jul 23;385(2):179-186. Epub 2021 Jun 23.

From the Office of Vaccines Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD (P.R.K., M.G.); the Department of Biostatistics, University of Washington, Seattle (T.R.F.); the Department of Biostatistics, University of Florida, Gainesville (I.M.L.); the Nuffield Department of Population Health, University of Oxford (R.P., V.B.), and the Oxford Vaccine Group, Department of Paediatrics, University of Oxford and National Institute for Health Research Oxford Biomedical Research Centre (M.D.S.), Oxford, and the Global Health Programme, Chatham House (D.L.H.), and the Coalition for Epidemic Preparedness Innovations (J.P.C.), London - all in the United Kingdom; the Howard College School of Law, University of KwaZulu-Natal, Durban (J.A.S.), and the Wits Reproductive Health and HIV Institute, Johannesburg (H.R.) - both in South Africa; the Dalla Lana School of Public Health, University of Toronto, Toronto (J.A.S.); the Clalit Research Institute, Innovation Division, Clalit Health Services, Tel Aviv, Israel (R.D.B.); the Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany (C.M.-F.); the World Health Organization Collaborating Centre for Reference and Research on Influenza, Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia (K.S.); and the World Health Organization, Geneva (S.B., A.-M.R., R.G., M.D.V.K., S.S., M.J.R., A.-M.H.-R.).

Viral variants of concern may emerge with dangerous resistance to the immunity generated by the current vaccines to prevent coronavirus disease 2019 (Covid-19). Moreover, if some variants of concern have increased transmissibility or virulence, the importance of efficient public health measures and vaccination programs will increase. The global response must be both timely and science based.
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http://dx.doi.org/10.1056/NEJMsr2105280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262623PMC
July 2021

Body-mass index, blood pressure, diabetes and cardiovascular mortality in Cuba: prospective study of 146,556 participants.

BMC Public Health 2021 05 27;21(1):963. Epub 2021 May 27.

Nuffield Department of Population Health (NDPH), University of Oxford, Oxford, UK.

Background: Cardiovascular disease accounts for about one-third of all premature deaths (ie, age < 70) in Cuba. Yet, the relevance of major risk factors, including systolic blood pressure (SBP), diabetes, and body-mass index (BMI), to cardiovascular mortality in this population remains unclear.

Methods: In 1996-2002, 146,556 adults were recruited from the general population in five areas of Cuba. Participants were interviewed, measured (height, weight and blood pressure) and followed up by electronic linkage to national death registries until Jan 1, 2017; in 2006-08, 24,345 participants were resurveyed. After excluding all with missing data, cardiovascular disease at recruitment, and those who died in the first 5 years, Cox regression (adjusted for age, sex, education, smoking, alcohol and, where appropriate, BMI) was used to relate cardiovascular mortality rate ratios (RRs) at ages 35-79 years to SBP, diabetes and BMI; RR were corrected for regression dilution to give associations with long-term average (ie, 'usual') levels of SBP and BMI.

Results: After exclusions, there were 125,939 participants (mean age 53 [SD12]; 55% women). Mean SBP was 124 mmHg (SD15), 5% had diabetes, and mean BMI was 24.2 kg/m (SD3.6); mean SBP and diabetes prevalence at recruitment were both strongly related to BMI. During follow-up, there were 4112 cardiovascular deaths (2032 ischaemic heart disease, 832 stroke, and 1248 other). Cardiovascular mortality was positively associated with SBP (>=120 mmHg), diabetes, and BMI (>=22.5 kg/m): 20 mmHg higher usual SBP about doubled cardiovascular mortality (RR 2.02, 95%CI 1.88-2.18]), as did diabetes (2.15, 1.95-2.37), and 10 kg/m higher usual BMI (1.92, 1.64-2.25). RR were similar in men and in women. The association with BMI and cardiovascular mortality was almost completely attenuated following adjustment for the mediating effect of SBP. Elevated SBP (>=120 mmHg), diabetes and raised BMI (>=22.5 kg/m) accounted for 27%, 14%, and 16% of cardiovascular deaths, respectively.

Conclusions: This large prospective study provides direct evidence for the effects of these major risk factors on cardiovascular mortality in Cuba. Despite comparatively low levels of these risk factors by international standards, the strength of their association with cardiovascular death means they nevertheless exert a substantial impact on premature mortality in Cuba.
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http://dx.doi.org/10.1186/s12889-021-10911-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157418PMC
May 2021

Cognitive and social activities and long-term dementia risk - Authors' reply.

Lancet Public Health 2021 05;6(5):e270

Cancer Epidemiology Unit, University of Oxford, Oxford OX3 7LF, UK.

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http://dx.doi.org/10.1016/S2468-2667(21)00072-4DOI Listing
May 2021

Alcohol consumption and cause-specific mortality in Cuba: prospective study of 120 623 adults.

EClinicalMedicine 2021 Mar 17;33:100692. Epub 2021 Mar 17.

Nuffield Department of Population Health (NDPH), University of Oxford, UK.

Background: The associations of cause-specific mortality with alcohol consumption have been studied mainly in higher-income countries. We relate alcohol consumption to mortality in Cuba.

Methods: In 1996-2002, 146 556 adults were recruited into a prospective study from the general population in five areas of Cuba. Participants were interviewed, measured and followed up by electronic linkage to national death registries until January 1, 2017. After excluding all with missing data or chronic disease at recruitment, Cox regression (adjusted for age, sex, province, education, and smoking) was used to relate mortality rate ratios (RRs) at ages 35-79 years to alcohol consumption. RRs were corrected for long-term variability in alcohol consumption using repeat measures among 20 593 participants resurveyed in 2006-08.

Findings: After exclusions, there were 120 623 participants aged 35-79 years (mean age 52 [SD 12]; 67 694 [56%] women). At recruitment, 22 670 (43%) men and 9490 (14%) women were current alcohol drinkers, with 15 433 (29%) men and 3054 (5%) women drinking at least weekly; most alcohol consumption was from rum. All-cause mortality was positively and continuously associated with weekly alcohol consumption: each additional 35cl bottle of rum per week (110g of pure alcohol) was associated with ∼10% higher risk of all-cause mortality (RR 1.08 [95%CI 1.05-1.11]). The major causes of excess mortality in weekly drinkers were cancer, vascular disease, and external causes. Non-drinkers had ∼10% higher risk (RR 1.11 [1.09-1.14]) of all-cause mortality than those in the lowest category of weekly alcohol consumption (<1 bottle/week), but this association was almost completely attenuated on exclusion of early follow-up.

Interpretation: In this large prospective study in Cuba, weekly alcohol consumption was continuously related to premature mortality. Reverse causality is likely to account for much of the apparent excess risk among non-drinkers. The findings support limits to alcohol consumption that are lower than present recommendations in Cuba.

Funding: Medical Research Council, British Heart Foundation, Cancer Research UK, CDC Foundation (with support from Amgen).
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http://dx.doi.org/10.1016/j.eclinm.2020.100692DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980059PMC
March 2021

Abdominal and gluteo-femoral markers of adiposity and risk of vascular-metabolic mortality in a prospective study of 150 000 Mexican adults.

Eur J Prev Cardiol 2021 Mar 9. Epub 2021 Mar 9.

School of Medicine, National Autonomous University of Mexico, Mexico City, Mexico.

Aims: Results of previous studies of abdominal adiposity and risk of vascular-metabolic mortality in Hispanic populations have been conflicting. We report results from a large prospective study of Mexican adults with high levels of abdominal adiposity.

Methods And Results: A total of 159 755 adults aged ≥35 years from Mexico City were enrolled in a prospective study and followed for 16 years. Cox regression, adjusted for confounders, yielded mortality rate ratios (RRs) associated with three markers of abdominal adiposity (waist circumference, waist-hip ratio, and waist-height ratio) and one marker of gluteo-femoral adiposity (hip circumference) for cause-specific mortality before age 75 years. To reduce reverse causality, deaths in the first 5 years of follow-up and participants with diabetes or other prior chronic disease were excluded. Among 113 163 participants without prior disease and aged 35-74 years at recruitment, all adiposity markers were positively associated with vascular-metabolic mortality. Comparing the top versus bottom tenth of the sex-specific distributions, the vascular-metabolic mortality RRs at ages 40-74 years were 2.32 [95% confidence interval (CI) 1.84-2.94] for waist circumference, 2.22 (1.71-2.88) for the waist-hip ratio, 2.63 (2.06-3.36) for the waist-height ratio, and 1.58 (1.29-1.93) for hip circumference. The RRs corresponding to each standard deviation (SD) higher usual levels of these adiposity markers were 1.34 (95% CI 1.27-1.41), 1.31 (1.23-1.39), 1.38 (1.31-1.45), and 1.18 (1.13-1.24), respectively. For the markers of abdominal adiposity, the RRs did not change much after further adjustment for other adiposity markers, but for hip circumference the association was reversed; given body mass index and waist circumference, the RR for vascular-metabolic mortality for each one SD higher usual hip circumference was 0.80 (0.75-0.86).

Conclusions: In this study of Mexican adults, abdominal adiposity (and in particular the waist-height ratio) was strongly and positively associated with vascular-metabolic mortality. For a given amount of general and abdominal adiposity, however, higher hip circumference was associated with lower vascular-metabolic mortality.
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http://dx.doi.org/10.1093/eurjpc/zwab038DOI Listing
March 2021

Low-intensity daily smoking and cause-specific mortality in Mexico: prospective study of 150 000 adults.

Int J Epidemiol 2021 07;50(3):955-964

Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health (NDPH), University of Oxford, Oxford, UK.

Background: Research is needed to determine the relevance of low-intensity daily smoking to mortality in countries such as Mexico, where such smoking habits are common.

Methods: Prospective study of 159 755 Mexican adults recruited from 1998-2004 and followed for cause-specific mortality to 1 January 2018. Participants were categorized according to baseline self-reported smoking status. Confounder-adjusted mortality rate ratios (RRs) at ages 35-89 were estimated using Cox regression, after excluding those with previous chronic disease (to avoid reverse causality).

Results: Among 42 416 men and 86 735 women aged 35-89 and without previous disease, 18 985 men (45%) and 18 072 women (21%) reported current smoking and 8866 men (21%) and 53 912 women (62%) reported never smoking. Smoking less than daily was common: 33% of male current smokers and 39% of female current smokers. During follow-up, the all-cause mortality RRs associated with the baseline smoking categories of <10 cigarettes per day (average during follow-up 4 per day) or ≥10 cigarettes per day (average during follow-up 10 per day), compared with never smoking, were 1.17 (95% confidence interval 1.10-1.25) and 1.54 (1.42-1.67), respectively. RRs were similar irrespective of age or sex. The diseases most strongly associated with daily smoking were respiratory cancers, chronic obstructive pulmonary disease and gastrointestinal and vascular diseases. Ex-daily smokers had substantially lower mortality rates than those who were current daily smokers at recruitment.

Conclusions: In this Mexican population, low-intensity daily smoking was associated with increased mortality. Of those smoking 10 cigarettes per day on average, about one-third were killed by their habit. Quitting substantially reduced these risks.
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http://dx.doi.org/10.1093/ije/dyab013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8271211PMC
July 2021

Changes in the Diagnosis and Management of Diabetes in Mexico City Between 1998-2004 and 2015-2019.

Diabetes Care 2021 04 10;44(4):944-951. Epub 2021 Feb 10.

Faculty of Medicine, National Autonomous University of Mexico, Mexico City, Mexico.

Objective: To investigate the trends in diabetes prevalence, diagnosis, and management among Mexican adults who were participants in a long-term prospective study.

Research Design And Methods: From 1998 to 2004, 159,755 adults from Mexico City were recruited to a prospective study, and from 2015 to 2019, 10,144 survivors were resurveyed. Diabetes was defined as self-reported diagnosis, glucose-lowering medication use, or HbA ≥6.5%. Controlled diabetes was defined as HbA <7%. Prevalence estimates were uniformly standardized for age, sex, and residential district. Cox models explored the relevance of controlled and inadequately controlled diabetes to cause-specific mortality.

Results: During 1998-2004 and 2015-2019, 99,623 and 8,986 participants were aged 45-84 years. Diabetes prevalence had increased from 26% in 1998-2004 to 35% by 2015-2019. Of those with diabetes, the proportion previously diagnosed had increased from 76% to 89%, and glucose-lowering medication use among them had increased from 80% to 94%. Median HbA among those with diabetes had decreased from 8.2% to 7.3%, and the proportion of participants with controlled diabetes had increased from 16% to 37%. Use of blood pressure-lowering medication among those with previously diagnosed diabetes had increased from 35% to 51%, and their use of lipid-lowering therapy had increased from 1% to 14%. The excess mortality risk associated with diabetes accounted for 34% of deaths at ages 35-74 years, of which 5% were attributable to controlled and 29% to inadequately controlled diabetes.

Conclusions: Inadequately controlled diabetes is a leading cause of premature adult death in Mexico. Improvements in diabetes management have increased diagnosis and control, but substantial opportunities remain to improve treatment, particularly with lipid-lowering therapy.
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http://dx.doi.org/10.2337/dc20-2276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985415PMC
April 2021

Cognitive and social activities and long-term dementia risk: the prospective UK Million Women Study.

Lancet Public Health 2021 02;6(2):e116-e123

Cancer Epidemiology Unit, University of Oxford, Oxford, UK.

Background: Although dementia is associated with non-participation in cognitive and social activities, this association might merely reflect the consequences of dementia, rather than any direct effect of non-participation on the subsequent incidence of dementia. Because of the slowness with which dementia can develop, unbiased assessment of any such direct effects must relate non-participation in such activities to dementia detection rates many years later. Prospective studies with long-term follow-up can help achieve this by analysing separately the first and second decade of follow-up. We report such analyses of a large, 20-year study.

Methods: The UK Million Women Study is a population-based prospective study of 1·3 million women invited for National Health Service (NHS) breast cancer screening in median year 1998 (IQR 1997-1999). In median year 2001 (IQR 2001-2003), women were asked about participation in adult education, groups for art, craft, or music, and voluntary work, and in median year 2006 (IQR 2006-2006), they were asked about reading. All participants were followed up through electronic linkage to NHS records of hospital admission with mention of dementia, the first mention of which was the main outcome. Comparing non-participation with participation in a particular activity, we used Cox regression to assess fully adjusted dementia risk ratios (RRs) during 0-4, 5-9, and 10 or more years, after information on that activity was obtained.

Findings: In 2001, 851 307 women with a mean age of 60 years (SD 5) provided information on participation in adult education, groups for art, craft, or music, and voluntary work. After 10 years, only 9591 (1%) had been lost to follow-up and 789 339 (93%) remained alive with no recorded dementia. Follow-up was for a mean of 16 years (SD 3), during which 31 187 (4%) had at least one hospital admission with mention of dementia, including 25 636 (3%) with a hospital admission with dementia mentioned for the first time 10 years or more after follow-up began. Non-participation in cognitive or social activities was associated with higher relative risks of dementia detection only during the first decade after participation was recorded. During the second decade, there was little association. This was true for non-participation in adult education (RR 1·04, 99% CI 0·98-1·09), in groups for art, craft, or music (RR 1·04, 0·99-1·09), in voluntary work (RR 0·96, 0·92-1·00), or in any of these three (RR 0·99, 0·95-1·03). In 2006, 655 118 women provided information on reading. For non-reading versus any reading, there were similar associations with dementia, again with strong attenuation over time since reading was recorded, but longer follow-up is needed to assess this reliably.

Interpretation: Life has to be lived forwards, but can be understood only backwards. Long before dementia is diagnosed, there is a progressive reduction in various mental and physical activities, but this is chiefly because its gradual onset causes inactivity and not because inactivity causes dementia.

Funding: UK Medical Research Council, Cancer Research UK.
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http://dx.doi.org/10.1016/S2468-2667(20)30284-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7848753PMC
February 2021

Repurposed Antiviral Drugs for Covid-19 - Interim WHO Solidarity Trial Results.

N Engl J Med 2021 02 2;384(6):497-511. Epub 2020 Dec 2.

The affiliations of the members of the writing and steering committees are as follows: the Nuffield Department of Population Health and Medical Research Council Population Health Research Unit, University of Oxford, Oxford (H.P., R.P.), and the University of Bristol, Bristol (E.A., S.B., H.B.C.C.-P., D.H., J.K., C.A.R., J.A.C.S.) - both in the United Kingdom; the World Health Organization, Geneva (A.-M.H.-R., M.-P.P., V.S., P. Lydon, M.C.M.-M., K.S., S.S.), the University of Bern, Bern (S.A., M.B., S. McGinty, S.T.), and Lausanne University Hospital, Lausanne (O.M.) - all in Switzerland; the Centre for the AIDS Programme of Research in South Africa, Durban (Q.A.K.), and the University of the Witwatersrand (J.N.) and the Wits Reproductive Health and HIV Institute (H.R.), Johannesburg - all in South Africa; the Institute of National Epidemiology, National Institutes of Health, University of the Philippines, Manila (M.M.A.); the Agency of Medicine and Medical Devices (C.H.G.) and Hospital Clínico San Carlos, Universidad Complutense de Madrid, Spanish Clinical Research Network, Instituto de Investigación Sanitaria San Carlos (A.P.), Madrid; INSERM, Paris (M.-P.K.), and Hospices Civils de Lyon, Lyon (F.A.) - both in France; the Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran (R.M.); the University of British Columbia, Vancouver (S. Murthy), and the Public Health Agency of Canada, Ottawa (M.I.S.) - both in Canada; the Public Health Foundation of India, New Delhi (K.S.R.), and the Indian Council of Medical Research, National AIDS Research Institute, Pune (S.G.) - both in India; the National Academy of Sciences of Buenos Aires (M.R.P.) and Fundación del Centro de Estudios Infectológicos (G.L.), Buenos Aires; Rafic Hariri University Hospital (P.A.H.) and the Ministry of Public Health (R.H.), Beirut, Lebanon; the Ministry of Health (A.M.A.-B.) and Infectious Diseases Hospital (A. Alhasawi), Kuwait City, Kuwait; Universidad Nacional de Colombia and Clinica Colsanitas (C.A.A.-M.) and the Ministry of Health (M.L.M.R.), Bogota, Colombia; the Ministry for Preventive Health, Riyadh, Saudi Arabia (A. Asiri, A. Alotaibi); Oslo University Hospital (P.A., A.B.-D.) and Research Council of Norway (J.-A.R.), Oslo; Secretaria de Salud de Honduras (N. Cerrato) and the National Autonomous University of Honduras (M.T.M.), Tegucigalpa; Penang Hospital, Penang (T.S.C.), and Hospital Sungai Buloh and Jalan Hospital, Selangor (S.K.) - both in Malaysia; University Hospital Center Mother Theresa (N. Como) and the National Agency for Medicines and Medical Devices (N.S.), Tirana, Albania; the HRB Clinical Research Facility, University College Cork, Cork (J.E.), and the Department of Health and Children, Dublin (P. Lennon, T.M.) - both in Ireland; Universidad Peruana Cayetano Heredia, Lima, Peru (P.J.G., E.G.); Vilnius University Hospital Santaros Klinikos (L.G.) and Vilnius University, Institute of Clinical Medicine (L.J.), Vilnius, Lithuania; Shaukat Khanum Memorial Cancer Hospital and Research Center, Lahore, Pakistan (M. Hassan, A.R.); the National Hepatology and Tropical Medicine Research Institute (M. Hassany) and the Ministry of Health and Population (H.Z.), Cairo; the National Institute of Health Research and Development (I.I.) and Rumah Sakit Umum Pusat Persahabatan (M.R.R.), Jakarta, Indonesia; the Italian Medicines Agency, Rome (N.M.), and the University of Verona, Verona (E.T.) - both in Italy; the Ministry of Health (S. Manevska) and the University Clinic of Infectious Diseases and Febrile Conditions (M.S.), Skopje, North Macedonia; the Oswaldo Cruz Foundation, Rio de Janeiro (E.P.N., P.P.S.R.); and the Finnish Institute for Health and Welfare and the University of Finland (M.P.) and Helsinki University Hospital (K.A.O.T.), Helsinki, and South Karelian Central Hospital, Lappeenranta (K.A.O.T.) - all in Finland.

Background: World Health Organization expert groups recommended mortality trials of four repurposed antiviral drugs - remdesivir, hydroxychloroquine, lopinavir, and interferon beta-1a - in patients hospitalized with coronavirus disease 2019 (Covid-19).

Methods: We randomly assigned inpatients with Covid-19 equally between one of the trial drug regimens that was locally available and open control (up to five options, four active and the local standard of care). The intention-to-treat primary analyses examined in-hospital mortality in the four pairwise comparisons of each trial drug and its control (drug available but patient assigned to the same care without that drug). Rate ratios for death were calculated with stratification according to age and status regarding mechanical ventilation at trial entry.

Results: At 405 hospitals in 30 countries, 11,330 adults underwent randomization; 2750 were assigned to receive remdesivir, 954 to hydroxychloroquine, 1411 to lopinavir (without interferon), 2063 to interferon (including 651 to interferon plus lopinavir), and 4088 to no trial drug. Adherence was 94 to 96% midway through treatment, with 2 to 6% crossover. In total, 1253 deaths were reported (median day of death, day 8; interquartile range, 4 to 14). The Kaplan-Meier 28-day mortality was 11.8% (39.0% if the patient was already receiving ventilation at randomization and 9.5% otherwise). Death occurred in 301 of 2743 patients receiving remdesivir and in 303 of 2708 receiving its control (rate ratio, 0.95; 95% confidence interval [CI], 0.81 to 1.11; P = 0.50), in 104 of 947 patients receiving hydroxychloroquine and in 84 of 906 receiving its control (rate ratio, 1.19; 95% CI, 0.89 to 1.59; P = 0.23), in 148 of 1399 patients receiving lopinavir and in 146 of 1372 receiving its control (rate ratio, 1.00; 95% CI, 0.79 to 1.25; P = 0.97), and in 243 of 2050 patients receiving interferon and in 216 of 2050 receiving its control (rate ratio, 1.16; 95% CI, 0.96 to 1.39; P = 0.11). No drug definitely reduced mortality, overall or in any subgroup, or reduced initiation of ventilation or hospitalization duration.

Conclusions: These remdesivir, hydroxychloroquine, lopinavir, and interferon regimens had little or no effect on hospitalized patients with Covid-19, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay. (Funded by the World Health Organization; ISRCTN Registry number, ISRCTN83971151; ClinicalTrials.gov number, NCT04315948.).
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http://dx.doi.org/10.1056/NEJMoa2023184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727327PMC
February 2021

Placebo-Controlled Trials of Covid-19 Vaccines - Why We Still Need Them.

N Engl J Med 2021 Jan 2;384(2):e2. Epub 2020 Dec 2.

The affiliations of the members of the WHO Ad Hoc Expert Group on the Next Steps for Covid-19 Vaccine Evaluation are the Office of Vaccines Research and Review, Food and Drug Administration, Silver Spring (P.R.K.), the School of Medicine, University of Maryland (M.M.L.), and Johns Hopkins University (S.P.), Baltimore, and the National Institute of Allergy and Infectious Diseases, Bethesda (M.N.) - all in Maryland; the Department of Biostatistics (T.R.F.), Fred Hutchinson Cancer Research Center (T.R.F., E.H.), University of Washington, Seattle; the Department of Biostatistics, University of Florida, Gainesville (I.M.L.); the Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom (R.P., V.B.); the Indian Council of Medical Research, New Delhi (B.B.); the Faculty of Medicine of the Universidad Nacional Autónoma de México, Mexico City (A.C.); the Coalition for Epidemic Preparedness Innovations, London (J.P.C.); the University of Pennsylvania, Philadelphia (S.S.E., S.P.); the University of the West Indies, Kingston, Jamaica (J.P.F.); the World Health Organization, Geneva (A.M.H.-R., M.J.R., S.S.); the Department of Health Security, Finnish Institute for Health and Welfare, Helsinki (H.M.N.);and the Wits Reproductive Health and HIV Institute, University of the Witwatersrand, Johannesburg (H.R.), and the Centre for the AIDS Programme of Research in South Africa, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban (J.S.) - both in South Africa.

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http://dx.doi.org/10.1056/NEJMp2033538DOI Listing
January 2021

Childhood Smoking, Adult Cessation, and Cardiovascular Mortality: Prospective Study of 390 000 US Adults.

J Am Heart Assoc 2020 11 28;9(21):e018431. Epub 2020 Oct 28.

Nuffield Department of Population Health (NDPH) University of Oxford United Kingdom.

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http://dx.doi.org/10.1161/JAHA.120.018431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763404PMC
November 2020

Association of Blood Pressure With Cause-Specific Mortality in Mexican Adults.

JAMA Netw Open 2020 09 1;3(9):e2018141. Epub 2020 Sep 1.

Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.

Importance: Elevated blood pressure is a major cause of premature death, but there is little direct evidence demonstrating this association in studies of Hispanic populations.

Objective: To assess the association between blood pressure and cause-specific mortality in a large cohort of Mexican adults with a high prevalence of uncontrolled diabetes.

Design, Setting, And Participants: A total of 159 755 adults aged 35 years or older from 2 districts in Mexico City were recruited to this cohort study between April 1998 and September 2004 and followed up until January 2018. The present analyses focused on 133 613 participants who were aged 35 to 74 years and had no history of chronic disease besides diabetes.

Exposure: Blood pressure.

Main Outcomes And Measures: Cox regression, adjusted for confounders, yielded mortality rate ratios (RRs) for deaths of participants occurring between ages 35 and 74 years.

Results: Of the 133 613 participants (43 263 [32.4%] men; mean [SD] age, 50 [11] years), 16 911 (12.7%) had self-reported previously diagnosed diabetes (including 8435 [6.3%] with uncontrolled diabetes, defined as hemoglobin A1c ≥9%) and 6548 (4.9%) had undiagnosed diabetes. Systolic blood pressure (SBP) was associated with vascular mortality between ages 35 to 74 years, with each 20 mm Hg lower usual SBP associated with 35% lower vascular mortality (RR, 0.65; 95% CI, 0.61-0.68), including 48% lower stroke mortality (RR, 0.52; 95% CI, 0.47-0.59) and 32% lower ischemic heart disease mortality (RR, 0.68; 95% CI, 0.63-0.74). These RRs were broadly similar in those with and without diabetes. Compared with those without diabetes and SBP less than 135 mm Hg at recruitment, the vascular mortality RR was 2.8 (95% CI, 2.4-3.3) for those without diabetes and SBP of 155 mm Hg or greater, 4.7 (95% CI, 4.1-5.4) for those with uncontrolled diabetes and SBP less than 135 mm Hg, and 8.9 (95% CI, 7.2-11.1) for those with uncontrolled diabetes and SBP of 155 mm Hg or greater. Lower SBP was also associated with decreased kidney-related mortality (RR per 20 mm Hg lower usual SBP, 0.69; 95% CI, 0.64-0.74), decreased mortality from infection (RR, 0.81; 95% CI, 0.71-0.91), and decreased mortality from hepatobiliary disease (RR, 0.87; 95% CI, 0.78-0.98), but not decreased neoplastic or respiratory mortality. SBP was more informative for vascular mortality than other blood pressure measures (eg, compared with SBP, diastolic blood pressure was only two-thirds as informative).

Conclusions And Relevance: Blood pressure was most strongly associated with vascular and kidney-related mortality in this Mexican population, with particularly high absolute excess mortality rates among individuals with diabetes. The findings reinforce the need for more widespread use of blood pressure-lowering medication in Mexico, particularly among those with diabetes.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.18141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519421PMC
September 2020

COVID-19 vaccine trials should seek worthwhile efficacy.

Lancet 2020 09 27;396(10253):741-743. Epub 2020 Aug 27.

Nuffield Department of Population Health, University of Oxford, Oxford, UK.

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http://dx.doi.org/10.1016/S0140-6736(20)31821-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832749PMC
September 2020

Quality of primary health care in China: challenges and recommendations.

Lancet 2020 06;395(10239):1802-1812

National Office for Maternal and Child Health Surveillance of China, Department of Obstetrics, West China Second University Hospital, Sichuan University, Chengdu, China.

China has substantially increased financial investment and introduced favourable policies for strengthening its primary health care system with core responsibilities in preventing and managing chronic diseases such as hypertension and emerging infectious diseases such as coronavirus disease 2019 (COVID-19). However, widespread gaps in the quality of primary health care still exist. In this Review, we aim to identify the causes for this poor quality, and provide policy recommendations. System challenges include: the suboptimal education and training of primary health-care practitioners, a fee-for-service payment system that incentivises testing and treatments over prevention, fragmentation of clinical care and public health service, and insufficient continuity of care throughout the entire health-care system. The following recommendations merit consideration: (1) enhancement of the quality of training for primary health-care physicians, (2) establishment of performance accountability to incentivise high-quality and high-value care; (3) integration of clinical care with the basic public health services, and (4) strengthening of the coordination between primary health-care institutions and hospitals. Additionally, China should consider modernising its primary health-care system through the establishment of a learning health system built on digital data and innovative technologies.
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http://dx.doi.org/10.1016/S0140-6736(20)30122-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272159PMC
June 2020

Association of childhood smoking and adult mortality: prospective study of 120 000 Cuban adults.

Lancet Glob Health 2020 06;8(6):e850-e857

National Institute of Cardiology and Cardiovascular Surgery, Havana City, Cuba.

Background: The average age at which people start smoking has been decreasing in many countries, but insufficient evidence exists on the adult hazards of having started smoking in childhood and, especially, in early childhood. We aimed to investigate the association between smoking habits (focusing on the age when smokers started) and cause-specific premature mortality in a cohort of adults in Cuba.

Methods: For this prospective study, adults were recruited from five provinces in Cuba. Participants were interviewed (data collected included socioeconomic status, medical history, alcohol consumption, and smoking habits) and had their height, weight, and blood pressure measured. Participants were followed up until Jan 1, 2017 for cause-specific mortality; a subset was resurveyed in 2006-08. We used Cox regression to calculate adjusted rate ratios (RRs) for mortality at ages 30-69 years, comparing never-smokers with current smokers by age they started smoking and number of cigarettes smoked per day and with ex-smokers by the age at which they had quit.

Findings: Between Jan 1, 1996, and Nov 24, 2002, 146 556 adults were recruited into the study, of whom 118 840 participants aged 30-69 years at recruitment contributed to the main analyses. 27 264 (52%) of 52 524 men and 19 313 (29%) of 66 316 women were current smokers. Most participants reported smoking cigarettes; few smoked only cigars. About a third of current cigarette smokers had started before age 15 years. Compared with never-smokers, the all-cause mortality RR was highest in participants who had started smoking at ages 5-9 years (RR 2·51, 95% CI 2·21-2·85), followed by ages 10-14 years (1·83, 1·72-1·95), 15-19 years (1·56, 1·46-1·65), and ages 20 years or older (1·50, 1·39-1·62). Smoking accounted for a quarter of all premature deaths in this population, but quitting before about age 40 years avoided almost all of the excess mortality due to smoking.

Interpretation: In this cohort of adults in Cuba, starting to smoke in childhood was common and quitting was not. Starting in childhood approximately doubled the rate of premature death (ie, before age 70 years). If this 2-fold mortality RR continues into old age, about half of participants who start smoking before age 15 years and do not stop will eventually die of complications from their habit. The greatest risks were found among adults who began smoking before age 10 years.

Funding: UK Medical Research Council, Cancer Research UK, British Heart Foundation, US Centers for Disease Control and Prevention (CDC) Foundation (with support from Amgen).
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http://dx.doi.org/10.1016/S2214-109X(20)30221-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7248573PMC
June 2020

Tobacco smoking and the risk of Parkinson disease: A 65-year follow-up of 30,000 male British doctors.

Neurology 2020 05 5;94(20):e2132-e2138. Epub 2020 May 5.

From the Clinical Trial Service Unit and Epidemiological Studies Unit (B.M.-K., H.P., S.L., J.K., R.G., R.C., R.P.), Nuffield Department of Population Health, University of Oxford; and Medical Research Council Population Health Research Unit (H.P., S.L.), Nuffield Department of Population Health, University of Oxford, United Kingdom.

Objective: To investigate the causal relevance of current tobacco smoking for the risk of Parkinson disease (PD).

Methods: We compared the risks of death from PD with smoking habits in 30,000 male doctors in the British Doctors cohort study in 1951 and in survivors who had been resurveyed periodically for 5 decades. Cause-specific mortality was monitored for 65 years and included 283 deaths from PD. The relative risks (RRs) of PD (and 95% confidence intervals [CIs]) were estimated using Cox models for smoking habits (smoking status, amount smoked, and years since quitting) at baseline or updated habits at resurvey.

Results: The prevalence of current smoking declined progressively during follow-up from 67% to 8% between 1951 and 1998. The crude rates of PD death were lower in current smokers than in never smokers at baseline (30 vs 46/100,000 persons-years). After adjustment for age at risk, current smokers at baseline had a 30% lower risk of PD (RR 0.71; 95% CI 0.60-0.84), and continuing smokers classified using updated smoking habits at resurvey had a 40% lower risk (RR 0.60; 95% CI 0.46-0.77) of PD compared with never smokers. The risks of PD were inversely associated with the amount of tobacco smoked. The protective effect of current smoking vs never smoking for PD was attenuated by increasing duration since quitting smoking.

Conclusions: In contrast to previous suggestions, the present report demonstrates a causally protective effect of current smoking on the risk of PD, which may provide insights into the etiology of PD.
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http://dx.doi.org/10.1212/WNL.0000000000009437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526668PMC
May 2020

Mortality and recurrent vascular events after first incident stroke: a 9-year community-based study of 0·5 million Chinese adults.

Lancet Glob Health 2020 04;8(4):e580-e590

Medical Research Council Population Health Research Unit, Oxford, UK; Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK. Electronic address:

Background: Stroke is a leading cause of death and disability worldwide. Despite considerable improvements in diagnosis and treatment, little is known about the short-term and long-term prognosis after a first stroke in low-income and middle-income countries, including China. We aimed to assess the short-term and long-term risk of recurrent stroke and mortality after a first stroke for each of the major pathological stroke types.

Methods: This population-based cohort study included adults aged 35-74 years without disability who were recruited to the China Kadoorie Biobank (CKB). A baseline survey was conducted in ten geographical areas (five urban, five rural) in China, and participants had clinical measurements recorded. Participants were followed up by monitoring death registries and by electronic linkage to health registries and health insurance claims databases, with follow-up until Jan 1, 2017. Participants were excluded from analyses if they had a previous history of stroke, transient ischaemic attack, or ischaemic heart disease at baseline. All incidences of fatal and non-fatal stroke during the study period were recorded by type (ischaemic stroke, intracerebral haemorrhage, subarachnoid haemorrhage, and unspecified type). Primary outcome measures were 28-day mortality, recurrent stroke, major vascular events (recurrent stroke, myocardial infarction, or vascular death), vascular mortality, and all-cause mortality.

Findings: Of 512 715 individuals in the CKB, 489 586 participants without previous ischaemic heart disease and stroke at recruitment were included, of whom 45 732 (42 073 [92%] confirmed by brain imaging) had a stroke during the study period. The mean age was 59·3 years (SD 9·8) for participants who had a stroke (54% women) and 50·8 years (10·3) for participants with no stroke (60% women). 36 588 (80%) of the incident cases of stroke were ischaemic stroke, 7440 (16%) were intracerebral haemorrhage, 702 (2%) were subarachnoid haemorrhage, and 1002 (2%) were an unspecified stroke type. 28-day mortality was 3% (95% CI 3-4) for ischaemic stroke, 47% (46-48)for intracerebral haemorrhage, 19% (17-22; 52% for rural areas and 32% for urban areas) subarachnoid haemorrhage, and 24% (22-27) for unspecified stroke. Among participants who survived stroke at 28 days, 41% (41-42) had recurrent stroke at 5 years (ischaemic stroke 41% [41-42], intracerebral haemorrhage 44% [42-46], subarachnoid haemorrhage 22% [18-27], unspecified stroke type 40% [35-44]) and mortality at 5 years was 17% ([17-18] ischaemic stroke 16% [15-16], intracerebral haemorrhage 28% [26-29], subarachnoid haemorrhage 16% [12-20], unspecified stroke type 15% [12-19]). After a first ischaemic stroke, 91% of recurrent strokes were also ischaemic stroke; after an intracerebral haemorrhage, 56% of recurrent strokes were intracerebral haemorrhage, and 41% of recurrent strokes were ischaemic stroke.

Interpretation: After a first stroke, the risk of recurrence or death within 5 years was high among this population of Chinese adults. Urgent improvements to secondary prevention of stroke in China are needed to reduce these risks.

Funding: Wellcome Trust, Medical Research Council, British Heart Foundation, Cancer Research UK, Kadoorie Charitable Foundation, Chinese Ministry of Science and Technology, National Natural Science Foundation of China.

Copyright: © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.
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http://dx.doi.org/10.1016/S2214-109X(20)30069-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7090905PMC
April 2020

The Magic of Randomization versus the Myth of Real-World Evidence.

N Engl J Med 2020 Feb;382(7):674-678

From the Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.

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http://dx.doi.org/10.1056/NEJMsb1901642DOI Listing
February 2020

Cigarette prices, smuggling, and deaths in France and Canada.

Lancet 2020 01;395(10217):27-28

Clinical Trial Service Unit, Richard Doll Building, University of Oxford, UK.

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http://dx.doi.org/10.1016/S0140-6736(19)31291-7DOI Listing
January 2020

Body mass index, diet, physical inactivity, and the incidence of dementia in 1 million UK women.

Neurology 2020 01 18;94(2):e123-e132. Epub 2019 Dec 18.

From the Cancer Epidemiology Unit (S.F., R.F.S., A.B., A.B., A.G., G.K.R., J.G., V.B.) and MRC Population Health Research Unit (S.P.), Nuffield Department of Population Health (R.P.), and Department of Psychiatry (J.G.), University of Oxford; Centre for Medical Informatics (C.S.), Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, UK; Royal Prince Alfred Hospital (P.H.), Sydney, Australia; and Department of Epidemiology (A.H.), Harvard T.H. Chan School of Public Health, Boston, MA.

Objective: To help determine whether midlife obesity is a cause of dementia and whether low body mass index (BMI), low caloric intake, and physical inactivity are causes or merely consequences of the gradual onset of dementia by recording these factors early in a large 20-year prospective study and relating them to dementia detection rates separately during follow-up periods of <5, 5 to 9, 10 to 14, and 15+ years.

Methods: A total of 1,136,846 UK women, mean age 56 (SD 5) years, were recruited in 1996 to 2001 and asked about height, weight, caloric intake, and inactivity. They were followed up until 2017 by electronic linkage to National Health Service records, detecting hospital admissions with mention of dementia. Cox regression yielded adjusted rate ratios (RRs) for first dementia detection during particular follow-up periods.

Results: Fifteen years after the baseline survey, only 1% were lost to follow-up, and 89% remained alive with no detected dementia, of whom 18,695 had dementia detected later, at a mean age of 77 (SD 4) years. Dementia detection during years 15+ was associated with baseline obesity (BMI 30+ vs 20-24 kg/m: RR 1.21, 95% confidence interval 1.16-1.26, < 0.0001) but not clearly with low BMI, low caloric intake, or inactivity at baseline. The latter 3 factors were associated with increased dementia rates during the first decade, but these associations weakened substantially over time, approaching null after 15 years.

Conclusions: Midlife obesity may well be a cause of dementia. In contrast, behavioral changes due to preclinical disease could largely or wholly account for associations of low BMI, low caloric intake, and inactivity with dementia detection during the first decade of follow-up.
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http://dx.doi.org/10.1212/WNL.0000000000008779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6988985PMC
January 2020

Alcohol consumption and vascular disease: other points to consider - Authors' reply.

Lancet 2019 11;394(10209):1618

Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford OX3 7LF, UK.

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http://dx.doi.org/10.1016/S0140-6736(19)31907-5DOI Listing
November 2019

Menopausal hormone therapy and 20-year breast cancer mortality.

Lancet 2019 09 29;394(10204):1139. Epub 2019 Aug 29.

Nuffield Department of Population Health, University of Oxford, Oxford OX3 7LF, UK.

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http://dx.doi.org/10.1016/S0140-6736(19)32033-1DOI Listing
September 2019

Physical Activity, Sedentary Leisure Time, Circulating Metabolic Markers, and Risk of Major Vascular Diseases.

Circ Genom Precis Med 2019 09 28;12(9):386-396. Epub 2019 Aug 28.

Clinical Trial Service Unit and Epidemiological Studies Unit (Y.P., C.K., H.D., I.Y.M., Y.C., L.Y., R.W., F.B., R.P., R. Clarke, R. Collins, D.A.B., L.L., M.V.H., Z.C.), Nuffield Department of Population Health, University of Oxford, United Kingdom.

Background: Physical inactivity and sedentary behavior are associated with higher risk of cardiovascular disease (CVD). Little is known about the relevance of circulating metabolites for these associations.

Methods: A nested case-control study within the prospective China Kadoorie Biobank included 3195 incident CVD cases (2057 occlusive CVD and 1138 intracerebral hemorrhage) and 1465 controls aged 30 to 79 years without prior CVD or statin use at baseline. Nuclear magnetic resonance spectroscopy was used to measure 225 metabolic markers and derived traits in baseline plasma samples. Linear regression was used to relate self-reported physical activity and sedentary leisure time to biomarkers, adjusting for potential confounders. These were contrasted with associations of biomarkers with occlusive CVD risk.

Results: Physical activity and sedentary leisure time were associated with >100 metabolic markers, with patterns of associations generally mirroring each other. Physical activity was inversely associated with very low and low-density and positively with large and very large HDL (high-density lipoprotein) particle concentrations. Physical activity was also inversely associated with alanine, glucose, lactate, acetoacetate, and the inflammatory marker glycoprotein acetyls. In general, associations of physical activity and sedentary leisure time with specific metabolic markers were directionally consistent with the associations of these metabolic markers with occlusive CVD risk. Overall, metabolic markers potentially explained ≈70% of the protective associations of physical activity and ≈50% of the positive associations of sedentary leisure time with occlusive CVD.

Conclusions: Among Chinese adults, physical activity and sedentary behavior have opposing associations with a diverse range of circulating metabolites, which may partially explain their associations with CVD risk.
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http://dx.doi.org/10.1161/CIRCGEN.118.002527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752700PMC
September 2019

General and Abdominal Adiposity and Mortality in Mexico City: A Prospective Study of 150 000 Adults.

Ann Intern Med 2019 09 13;171(6):397-405. Epub 2019 Aug 13.

National Autonomous University of Mexico, Mexico City, Mexico (J.A., R.R., R.T., A.G., C.G., M.S., P.K.).

Background: Some reports suggest that body mass index (BMI) is not strongly associated with mortality in Hispanic populations.

Objective: To assess the causal relevance of adiposity to mortality in Mexican adults, avoiding reverse causality biases.

Design: Prospective study.

Setting: 2 Mexico City districts.

Participants: 159 755 adults aged 35 years and older at recruitment, followed for up to 14 years. Participants with a hemoglobin A1c level of 7% or greater, diabetes, or other chronic diseases were excluded.

Measurements: BMI, waist-to-hip ratio, waist circumference, and cause-specific mortality. Cox regression, adjusted for confounders, yielded mortality hazard ratios (HRs) after at least 5 years of follow-up and before age 75 years.

Results: Among 115 400 participants aged 35 to <75 years at recruitment, mean BMI was 28.0 kg/m2 (SD, 4.1 kg/m2) in men and 29.6 kg/m2 (SD, 5.1 kg/m2) in women. The association of BMI at recruitment with all-cause mortality was J-shaped, with the minimum at 25 to <27.5 kg/m2. Above 25 kg/m2, each 5-kg/m2 increase in BMI was associated with a 30% increase in all-cause mortality (HR, 1.30 [95% CI, 1.24 to 1.36]). This association was stronger at ages 40 to <60 years (HR, 1.40 [CI, 1.30 to 1.49]) than at ages 60 to <75 years (HR, 1.24 [CI, 1.17 to 1.31]) but was not materially affected by sex, smoking, or other confounders. The associations of mortality with BMI and waist-to-hip ratio were similarly strong, and each was weakened only slightly by adjustment for the other. Waist circumference was strongly related to mortality and remained so even after adjustment for BMI and hip circumference.

Limitation: Analyses were limited to mortality.

Conclusion: General, and particularly abdominal, adiposity were strongly associated with mortality in this Mexican population.

Primary Funding Source: Mexican Health Ministry, Mexican National Council of Science and Technology, Wellcome Trust, Medical Research Council, and Kidney Research UK.
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http://dx.doi.org/10.7326/M18-3502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6949137PMC
September 2019

Opposite Associations of Aortic Aneurysm With Blood Glucose and With Diabetes Mellitus.

Circulation 2019 07 15;140(3):264-266. Epub 2019 Jul 15.

Clinical Trial Service Unit and Epidemiological Studies Unit (D.R.M., P.S., R.C., D.P., K.B.H.L., J.C., R.P., S.L., R.B.), University of Oxford, United Kingdom.

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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.040398DOI Listing
July 2019

Conventional and genetic evidence on alcohol and vascular disease aetiology: a prospective study of 500 000 men and women in China.

Lancet 2019 05 4;393(10183):1831-1842. Epub 2019 Apr 4.

Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK. Electronic address:

Background: Moderate alcohol intake has been associated with reduced cardiovascular risk in many studies, in comparison with abstinence or with heavier drinking. Studies in east Asia can help determine whether these associations are causal, since two common genetic variants greatly affect alcohol drinking patterns. We used these two variants to assess the relationships between cardiovascular risk and genotype-predicted mean alcohol intake in men, contrasting the findings in men with those in women (few of whom drink).

Methods: The prospective China Kadoorie Biobank enrolled 512 715 adults between June 25, 2004, and July 15, 2008, from ten areas of China, recording alcohol use and other characteristics. It followed them for about 10 years (until Jan 1, 2017), monitoring cardiovascular disease (including ischaemic stroke, intracerebral haemorrhage, and myocardial infarction) by linkage with morbidity and mortality registries and electronic hospital records. 161 498 participants were genotyped for two variants that alter alcohol metabolism, ALDH2-rs671 and ADH1B-rs1229984. Adjusted Cox regression was used to obtain the relative risks associating disease incidence with self-reported drinking patterns (conventional epidemiology) or with genotype-predicted mean male alcohol intake (genetic epidemiology-ie, Mendelian randomisation), with stratification by study area to control for variation between areas in disease rates and in genotype-predicted intake.

Findings: 33% (69 897/210 205) of men reported drinking alcohol in most weeks, mainly as spirits, compared with only 2% (6245/302 510) of women. Among men, conventional epidemiology showed that self-reported alcohol intake had U-shaped associations with the incidence of ischaemic stroke (n=14 930), intracerebral haemorrhage (n=3496), and acute myocardial infarction (n=2958); men who reported drinking about 100 g of alcohol per week (one to two drinks per day) had lower risks of all three diseases than non-drinkers or heavier drinkers. In contrast, although genotype-predicted mean male alcohol intake varied widely (from 4 to 256 g per week-ie, near zero to about four drinks per day), it did not have any U-shaped associations with risk. For stroke, genotype-predicted mean alcohol intake had a continuously positive log-linear association with risk, which was stronger for intracerebral haemorrhage (relative risk [RR] per 280 g per week 1·58, 95% CI 1·36-1·84, p<0·0001) than for ischaemic stroke (1·27, 1·13-1·43, p=0·0001). For myocardial infarction, however, genotype-predicted mean alcohol intake was not significantly associated with risk (RR per 280 g per week 0·96, 95% CI 0·78-1·18, p=0·69). Usual alcohol intake in current drinkers and genotype-predicted alcohol intake in all men had similarly strong positive associations with systolic blood pressure (each p<0·0001). Among women, few drank and the studied genotypes did not predict high mean alcohol intake and were not positively associated with blood pressure, stroke, or myocardial infarction.

Interpretation: Genetic epidemiology shows that the apparently protective effects of moderate alcohol intake against stroke are largely non-causal. Alcohol consumption uniformly increases blood pressure and stroke risk, and appears in this one study to have little net effect on the risk of myocardial infarction.

Funding: Chinese Ministry of Science and Technology, Kadoorie Charitable Foundation, National Natural Science Foundation of China, British Heart Foundation, Cancer Research UK, GlaxoSmithKline, Medical Research Council, and Wellcome Trust.
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http://dx.doi.org/10.1016/S0140-6736(18)31772-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6497989PMC
May 2019

Causal associations of blood lipids with risk of ischemic stroke and intracerebral hemorrhage in Chinese adults.

Nat Med 2019 04 11;25(4):569-574. Epub 2019 Mar 11.

Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.

Stroke is the second leading cause of death worldwide and accounts for >2 million deaths annually in China. Ischemic stroke (IS) and intracerebral hemorrhage (ICH) account for an equal number of deaths in China, despite a fourfold greater incidence of IS. Stroke incidence and ICH proportion are higher in China than in Western populations, despite having a lower mean low-density lipoprotein cholesterol (LDL-C) concentration. Observational studies reported weaker positive associations of LDL-C with IS than with coronary heart disease (CHD), but LDL-C-lowering trials demonstrated similar risk reductions for IS and CHD. Mendelian randomization studies of LDL-C and IS have reported conflicting results, and concerns about the excess risks of ICH associated with lowering LDL-C may have prevented the more widespread use of statins in China. We examined the associations of biochemically measured lipids with stroke in a nested case-control study in the China Kadoorie Biobank (CKB) and compared the risks for both stroke types associated with equivalent differences in LDL-C in Mendelian randomization analyses. The results demonstrated positive associations of LDL-C with IS and equally strong inverse associations with ICH, which were confirmed by genetic analyses and LDL-C-lowering trials. Lowering LDL-C is still likely to have net benefit for the prevention of overall stroke and cardiovascular disease in China.
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http://dx.doi.org/10.1038/s41591-019-0366-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6795549PMC
April 2019
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