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Publication History View all

  • JAMA Internal Medicine 10/2013;
  • Nature Reviews Nephrology 07/2013;
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    ABSTRACT: Forced expiratory volume in one second (FEV1) is inversely associated with mortality in Western populations, but few studies have assessed the associations of peak expiratory flow (PEF) with subsequent cause-specific mortality, or have used populations in developing countries, including China, for such assessments. A prospective cohort study followed ∼170 000 Chinese men ranging in age from 40-69 years at baseline (1990-1991) for 15 years. In the study, height-adjusted PEF (h-PEF), which was uncorrelated with height, was calculated by dividing PEF by height. Hazard ratios (HR) for cause-specific mortality and h-PEF, adjusted for age, area of residence, smoking, and education, were calculated through Cox regression analyses. Of the original study population, 7068 men died from respiratory causes (non-neoplastic) and 22 490 died from other causes (including 1591 from lung cancer, 5469 from other cancers, and 10 460 from cardiovascular disease) before reaching the age of 85 years. Respiratory mortality was strongly and inversely associated with h-PEF. For h-PEF ≥ 250 L/min, the association was log-linear, with a hazard ratio (HR) of 1.29 (95% CI: 1.25-1.34) per 100 L/min reduction in h-PEF. The association was stronger but not log-linear for lower values of h-PEF. Mortality from combined other causes was also inversely associated with h-PEF, and the association was log-linear for all values of h-PEF, declining with follow-up, with HRs per 100 L/min reduction in h-PEF of 1.13 (1.10-1.15), 1.08 (1.06-1.11), and 1.06 (1.03-1.08) in three consecutive 5-year follow-up periods. Specifically, lower values of h-PEF were associated with higher mortality from cardiovascular disease and lung cancer, but not from other cancers. A lower value of h-PEF was associated with increased mortality from respiratory and other causes, including lung cancer and cardiovascular disease, but its associations with the other causes of death declined across the follow-up period.
    International Journal of Epidemiology 06/2013; 42(3):803-15.
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    ABSTRACT: Radiotherapy for breast cancer often involves some incidental exposure of the heart to ionizing radiation. The effect of this exposure on the subsequent risk of ischemic heart disease is uncertain. We conducted a population-based case-control study of major coronary events (i.e., myocardial infarction, coronary revascularization, or death from ischemic heart disease) in 2168 women who underwent radiotherapy for breast cancer between 1958 and 2001 in Sweden and Denmark; the study included 963 women with major coronary events and 1205 controls. Individual patient information was obtained from hospital records. For each woman, the mean radiation doses to the whole heart and to the left anterior descending coronary artery were estimated from her radiotherapy chart. The overall average of the mean doses to the whole heart was 4.9 Gy (range, 0.03 to 27.72). Rates of major coronary events increased linearly with the mean dose to the heart by 7.4% per gray (95% confidence interval, 2.9 to 14.5; P<0.001), with no apparent threshold. The increase started within the first 5 years after radiotherapy and continued into the third decade after radiotherapy. The proportional increase in the rate of major coronary events per gray was similar in women with and women without cardiac risk factors at the time of radiotherapy. Exposure of the heart to ionizing radiation during radiotherapy for breast cancer increases the subsequent rate of ischemic heart disease. The increase is proportional to the mean dose to the heart, begins within a few years after exposure, and continues for at least 20 years. Women with preexisting cardiac risk factors have greater absolute increases in risk from radiotherapy than other women. (Funded by Cancer Research UK and others.).
    New England Journal of Medicine 03/2013; 368(11):987-98.
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    ABSTRACT: Large randomized trials have shown that lowering the concentration of LDL cholesterol with statins reduces vascular morbidity and mortality rapidly, with further benefit emerging during each year of treatment allocation. But, limited evidence is available about the long-term efficacy and safety of statin treatment. Long-term follow-up of surviving trial participants allows direct assessment of the benefits (and any hazards) of a sustained reduction in LDL cholesterol concentration during the post-trial period. Post-trial follow-up of several large statin trials (of which the Heart Protection Study was the largest) confirms that the substantial absolute benefits and cost-effectiveness of statin therapy were, in fact, underestimated in previous analyses restricted to the "in-trial" periods of randomized studies. Reassuringly, no adverse effects on cancer incidence or non-vascular mortality emerged during the extended follow-up of the Heart Protection Study. These findings support the prompt initiation and long-term continuation of statin therapy in individuals at increased vascular risk.
    Current Atherosclerosis Reports 02/2013; 15(2):297.
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    ABSTRACT: BACKGROUND: Few large studies in China have investigated total physical activity and sedentary leisure time and their associations with adiposity. OBJECTIVE: We investigated determinants of physical activity and sedentary leisure time and their associations with adiposity in China. DESIGN: A total of 466,605 generally healthy participants (age: 30-79 y, 60% female) in the China Kadoorie Biobank were included in this cross-sectional analysis. Self-reported information on a range of activities was collected by interviewer-administered questionnaire. Physical activity was calculated as metabolic equivalent task hours per day (MET-h/d) spent on work, transportation, housework, and nonsedentary recreation. Sedentary leisure time was quantified as hours per day. Adiposity measures included BMI, waist circumference, and percentage body fat (by bioimpedance analysis). Associations were estimated by linear and logistic regression. RESULTS: The mean physical activity was 22 MET-h/d, and the mean sedentary leisure time was 3.0 h/d. For each sex, physical activity was about one-third lower among professionals/administrators than among factory workers, with intermediate levels for other occupational categories. A 1-SD (14 MET-h/d) greater physical activity was associated with a 0.15-unit (95% CI: 0.14, 0.16) lower BMI (in kg/m(2)), a 0.58-cm (95% CI: 0.55, 0.61) smaller waist circumference, and 0.48 (95% CI: 0.45, 0.50) percentage points less body fat. In contrast, a 1-SD (1.5 h/d) greater sedentary leisure time was associated with a 0.19-unit higher BMI (95% CI: 0.18, 0.20), a 0.57-cm larger waist circumference (95% CI: 0.54, 0.59), and 0.44 (95% CI: 0.42, 0.46) percentage points more body fat. For any given physical activity level, greater sedentary leisure time was associated with a greater prevalence of increased BMI, as was lower physical activity for any given sedentary leisure time. CONCLUSIONS: In adult Chinese, physical activity varies substantially by occupation, and lack of physical activity and excess sedentary leisure time are independently and jointly associated with greater adiposity.
    American Journal of Clinical Nutrition 01/2013;
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    ABSTRACT: AimsTo examine the independent relevance of plasma concentrations of 25-hydroxyvitamin D [25(OH)D] for vascular and non-vascular mortality.Methods and resultsWe examined associations of plasma concentrations of 25(OH)D and cause-specific mortality in a prospective study of older men living in the UK and included findings in meta-analyses of similar studies identified by a systematic search reporting on vascular and all-cause mortality. In a 13-year follow-up of 5409 men (mean baseline age 77 years), 1358 died from vascular and 1857 from non-vascular causes. Median season-adjusted baseline 25(OH)D concentration was 56 (interquartile range: 45-67) nmol/L. After adjustment for age and seasonality, higher concentrations of 25(OH)D were inversely and approximately linearly (log-log scale) associated with vascular and non-vascular mortality throughout the range 40-90 nmol/L. After additional adjustment for prior disease and cardiovascular risk factors, a doubling in 25(OH)D concentration was associated with 20% [95% confidence interval (CI): 9-30%] lower vascular and 23% (95% CI: 14-31%) lower non-vascular mortality. In meta-analyses of prospective studies, individuals in the top vs. bottom quarter of 25(OH)D concentrations had 21% (95% CI: 13-28%) lower vascular and 28% (95% CI: 24-32%) lower all-cause mortality.Conclusions Despite strong inverse and apparently independent associations of 25(OH)D with vascular and non-vascular mortality, causality remains uncertain. Large-scale randomized trials, using high doses of vitamin D, are required to assess the clinical relevance of these associations.
    European Heart Journal 12/2012;
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    ABSTRACT: Background:Radiation-related heart disease and lung cancer can occur following radiotherapy for breast cancer but the duration of any mortality risk is uncertain.Methods:Mortality ratios, by laterality of breast cancer, were estimated using Poisson regression for 558 871 women recorded with breast cancer during 1973-2008 in the Surveillance, Epidemiology and End Results (SEER) cancer registries and followed until 01 January 2009.Results:For women diagnosed with breast cancer during 1973-1982 and given radiotherapy shortly afterwards, the cardiac mortality ratios, left-sided vs right-sided, were 1.19 (1.03-1.38), 1.35 (1.05-1.73), 1.64 (1.26-2.14) and 1.90 (1.52-2.37) at <10, 10-14, 15-19 and 20+ years since diagnosis (2p for trend: <0.001). The lung cancer mortality ratios, ipsilateral vs contralateral, in these women were 1.05 (0.57-1.94), 2.04 (1.28-3.23) and 3.87 (2.19-6.82) at <10, 10-19 and 20+ years, respectively, (2p for trend: 0.002). For women irradiated during 1983-92 there was evidence of radiation-related mortality for lung cancer, but not for heart disease. For women irradiated since 1993 there is, as yet, little evidence of any radiation-related mortality.Conclusion:In this population, the radiation-related risks were larger in the third decade after exposure than during the first two decades.British Journal of Cancer advance online publication, 20 December 2012; doi:10.1038/bjc.2012.575 www.bjcancer.com.
    British Journal of Cancer 12/2012;
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    ABSTRACT: BACKGROUND: For women with oestrogen receptor (ER)-positive early breast cancer, treatment with tamoxifen for 5 years substantially reduces the breast cancer mortality rate throughout the first 15 years after diagnosis. We aimed to assess the further effects of continuing tamoxifen to 10 years instead of stopping at 5 years. METHODS: In the worldwide Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) trial, 12 894 women with early breast cancer who had completed 5 years of treatment with tamoxifen were randomly allocated to continue tamoxifen to 10 years or stop at 5 years (open control). Allocation (1:1) was by central computer, using minimisation. After entry (between 1996 and 2005), yearly follow-up forms recorded any recurrence, second cancer, hospital admission, or death. We report effects on breast cancer outcomes among the 6846 women with ER-positive disease, and side-effects among all women (with positive, negative, or unknown ER status). Long-term follow-up still continues. This study is registered, number ISRCTN19652633. FINDINGS: Among women with ER-positive disease, allocation to continue tamoxifen reduced the risk of breast cancer recurrence (617 recurrences in 3428 women allocated to continue vs 711 in 3418 controls, p=0·002), reduced breast cancer mortality (331 deaths vs 397 deaths, p=0·01), and reduced overall mortality (639 deaths vs 722 deaths, p=0·01). The reductions in adverse breast cancer outcomes appeared to be less extreme before than after year 10 (recurrence rate ratio [RR] 0·90 [95% CI 0·79-1·02] during years 5-9 and 0·75 [0·62-0·90] in later years; breast cancer mortality RR 0·97 [0·79-1·18] during years 5-9 and 0·71 [0·58-0·88] in later years). The cumulative risk of recurrence during years 5-14 was 21·4% for women allocated to continue versus 25·1% for controls; breast cancer mortality during years 5-14 was 12·2% for women allocated to continue versus 15·0% for controls (absolute mortality reduction 2·8%). Treatment allocation seemed to have no effect on breast cancer outcome among 1248 women with ER-negative disease, and an intermediate effect among 4800 women with unknown ER status. Among all 12 894 women, mortality without recurrence from causes other than breast cancer was little affected (691 deaths without recurrence in 6454 women allocated to continue versus 679 deaths in 6440 controls; RR 0·99 [0·89-1·10]; p=0·84). For the incidence (hospitalisation or death) rates of specific diseases, RRs were as follows: pulmonary embolus 1·87 (95% CI 1·13-3·07, p=0·01 [including 0·2% mortality in both treatment groups]), stroke 1·06 (0·83-1·36), ischaemic heart disease 0·76 (0·60-0·95, p=0·02), and endometrial cancer 1·74 (1·30-2·34, p=0·0002). The cumulative risk of endometrial cancer during years 5-14 was 3·1% (mortality 0·4%) for women allocated to continue versus 1·6% (mortality 0·2%) for controls (absolute mortality increase 0·2%). INTERPRETATION: For women with ER-positive disease, continuing tamoxifen to 10 years rather than stopping at 5 years produces a further reduction in recurrence and mortality, particularly after year 10. These results, taken together with results from previous trials of 5 years of tamoxifen treatment versus none, suggest that 10 years of tamoxifen treatment can approximately halve breast cancer mortality during the second decade after diagnosis. FUNDING: Cancer Research UK, UK Medical Research Council, AstraZeneca UK, US Army, EU-Biomed.
    The Lancet 12/2012;
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    ABSTRACT: AimsStatins reduce LDL cholesterol (LDL-C) and the risk of vascular events, but it remains uncertain whether there is clinically relevant genetic variation in their efficacy. This study of 18 705 individuals aims to identify genetic variants related to the lipid response to simvastatin and assess their impact on vascular risk response.Methods and resultsA genome-wide study of the LDL-C and apolipoprotein B (ApoB) response to 40 mg simvastatin daily was performed in 3895 participants in the Heart Protection Study, and the nine strongest associations were tested in 14 810 additional participants. Selected candidate genes were also tested in up to 18 705 individuals. There was 90% power to detect differences of 2.5% in LDL-C response (e.g. 42.5 vs. 40% reduction) in the genome-wide study and of 1% in the candidate gene study. None of the associations from the genome-wide study was replicated, and nor were significant associations found for 26 of 36 candidates tested. Novel lipid response associations with variants in LPA, CELSR2/PSRC1/SORT1, and ABCC2 were found, as well as confirmatory evidence for published associations in LPA, APOE, and SLCO1B1. The largest and most significant effects were with LPA and APOE, but were only 2-3% per allele. Reductions in the risk of major vascular events during 5 years of statin therapy among 18 705 high-risk patients did not differ significantly across genotypes associated with the lipid response.Conclusions Common genetic variants do not appear to alter the lipid response to statin therapy by more than a few per cent, and there were similar large reductions in vascular risk with simvastatin irrespective of genotypes associated with the lipid response to simvastatin. Consequently, their value for informing clinical decisions related to maximizing statin efficacy appears to be limited.
    European Heart Journal 10/2012;
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