Body mass index and incident coronary heart disease in women: a population-based prospective study

BACKGROUND A high body mass index (BMI) is associated with an increased risk of mortality from coronary heart disease (CHD); however, a low BMI may also be associated with an increased mortality risk. There is limited information on the relation of incident CHD risk across a wide range of BMI, particularly in women. We examined the relation between BMI and incident CHD overall and across different risk factors of the disease in the Million Women Study. METHODS 1.2 million women (mean age=56 years) participants without heart disease, stroke, or cancer (except non-melanoma skin cancer) at baseline (1996 to 2001) were followed prospectively for 9 years on average. Adjusted relative risks and 20-year cumulative incidence from age 55 to 74 years were calculated for CHD using Cox regression. RESULTS After excluding the first 4 years of follow-up, we found that 32,465 women had a first coronary event (hospitalization or death) during follow-up. The adjusted relative risk for incident CHD per 5 kg/m2 increase in BMI was 1.23 (95% confidence interval (CI) 1.22 to 1.25). The cumulative incidence of CHD from age 55 to 74 years increased progressively with BMI, from 1 in 11 (95% CI 1 in 10 to 12) for BMI of 20 kg/m2, to 1 in 6(95% CI 1 in 5 to 7) for BMI of 34 kg/m2. A 10 kg/m2 increase in BMI conferred a similar risk to a 5-year increment in chronological age. The 20 year cumulative incidence increased with BMI in smokers and non-smokers, alcohol drinkers and non-drinkers, physically active and inactive, and in the upper and lower socioeconomic classes. In contrast to incident disease, the relation between BMI and CHD mortality (n=2,431) was J-shaped. For the less than 20 kg/m2 and ≥35 kg/m2 BMI categories, the respective relative risks were 1.27 (95% CI 1.06 to 1.53) and 2.84 (95% CI 2.51 to 3.21) for CHD deaths, and 0.89 (95% CI 0.83 to 0.94) and 1.85 (95% CI 1.78 to 1.92) for incident CHD. CONCLUSIONS CHD incidence in women increases progressively with BMI, an association consistently seen in different subgroups. The shape of the relation with BMI differs for incident and fatal disease.The Million Women Study is funded by Cancer Research UK, the Medical Research Council, and the NHS Breast Screening Programme. The funding organizations were not involved in the study design or conduct, data analysis or interpretation, manuscript preparation or review, final version approval, or decision to submit the manuscript

Body size from birth to middle age and the risk of hip and knee replacement

Background: Information regarding the effects of body size in childhood and early adulthood on the risk of hip and knee replacement in later life is inconsistent. We aimed to assess their effect, taking into account body mass index (BMI) in middle-age. Methods: Prospective cohort (Million Women Study) of 791,034 women with information on birth weight, body size at age 10 and age 20, and current BMI (at mean age 59.5 years) were followed for 6.82 million person-years. Adjusted relative risks (RRs) and absolute risks of hospitalisations for hip or knee replacement surgery for osteoarthritis were estimated. Results: After a mean of 8.6 years follow-up, 17,402 women had a hip replacement and 18,297 a knee replacement. Between the ages of 50 and 79 years, absolute risks for women with current BMIs of <22.5 kg/m2 and 35 + kg/m2 were respectively 5.6 and 13.2 % for hip replacement; and 2.6 and 35.1 % for knee replacement. Within each category of current BMI, increasing body size at age 10 and at age 20 had comparatively small effects; there were no significant associations with birth weight. We estimate that 40 % of UK women with a BMI 35 + kg/m2 have either a hip or knee replacement between the ages of 50–79 years; this compares to just 10 % of UK women with a healthy BMI (<25 kg/m2). Conclusions: The effects of body size in childhood and early adulthood on the absolute risks of either a hip or knee replacement are minimal compared to the effect of adiposity in middle ag

Vascular disease in women: comparison of diagnoses in hospital episode statistics and general practice records in England

BACKGROUND Electronic linkage to routine administrative datasets, such as the Hospital Episode Statistics (HES) in England, is increasingly used in medical research. Relatively little is known about the reliability of HES diagnostic information for epidemiological studies. In the United Kingdom (UK), general practitioners hold comprehensive records for individuals relating to their primary, secondary and tertiary care. For a random sample of participants in a large UK cohort, we compared vascular disease diagnoses in HES and general practice records to assess agreement between the two sources. METHODS Million Women Study participants with a HES record of hospital admission with vascular disease (ischaemic heart disease [ICD-10 codes I20-I25], cerebrovascular disease [G45, I60-I69] or venous thromboembolism [I26, I80-I82]) between April 1st 1997 and March 31st 2005 were identified. In each broad diagnostic group and in women with no such HES diagnoses, a random sample of about a thousand women was selected for study. We asked each woman's general practitioner to provide information on her history of vascular disease and this information was compared with the HES diagnosis record. RESULTS Over 90% of study forms sent to general practitioners were returned and 88% of these contained analysable data. For the vast majority of study participants for whom information was available, diagnostic information from general practice and HES records was consistent. Overall, for 93% of women with a HES diagnosis of vascular disease, general practice records agreed with the HES diagnosis; and for 97% of women with no HES diagnosis of vascular disease, the general practitioner had no record of a diagnosis of vascular disease. For severe vascular disease, including myocardial infarction (I21-22), stroke, both overall (I60-64) and by subtype, and pulmonary embolism (I26), HES records appeared to be both reliable and complete. CONCLUSION Hospital admission data in England provide diagnostic information for vascular disease of sufficient reliability for epidemiological analyses.The Million Women Study is funded by Cancer Research UK and the UK Medical Research Council. The study is registered with the NHS National Institute of Health Research Portfolio (study number 6862). General practices were reimbursed for conducting the data collection through NHS Service Support Cost funding of the National Institute of Health Research

Health impacts and environmental footprints of diets that meet the Eatwell Guide recommendations: analyses of multiple UK studies.

OBJECTIVES: To assess the health impacts and environmental consequences of adherence to national dietary recommendations (the Eatwell Guide (EWG)) in the UK. DESIGN AND SETTING: A secondary analysis of multiple observational studies in the UK. PARTICIPANTS: Adults from the European Prospective Investigation into Cancer - Oxford(EPIC-Oxford), UK Biobank and Million Women Study, and adults and children aged 5 and over from the National Diet and Nutrition Survey (NDNS).Primary and secondary outcome measures risk of total mortality from Cox proportional hazards regression models, total greenhouse gas emissions (GHGe) and blue water footprint (WF) associated with 'very low' (0-2 recommendations), 'low' (3-4 recommendations) or 'intermediate-to-high' (5-9 recommendations) adherence to EWG recommendations. RESULTS: Less than 0.1% of the NDNS sample adhere to all nine EWG recommendations and 30.6% adhere to at least five recommendations. Compared with 'very low' adherence to EWG recommendations, 'intermediate-to-high adherence' was associated with a reduced risk of mortality (risk ratio (RR): 0.93; 99% CI: 0.90 to 0.97) and -1.6 kg CO2eq/day (95% CI: -1.5 to -1.8), or 30% lower dietary GHGe. Dietary WFs were similar across EWG adherence groups. Of the individual Eatwell guidelines, adherence to the recommendation on fruit and vegetable consumption was associated with the largest reduction in total mortality risk: an RR of 0.90 (99% CI: 0.88 to 0.93). Increased adherence to the recommendation on red and processed meat consumption was associated with the largest decrease in environmental footprints (-1.48 kg CO2eq/day, 95% CI: -1.79 to 1.18 for GHGe and -22.5 L/day, 95% CI: -22.7 to 22.3 for blue WF). CONCLUSIONS: The health and environmental benefits of greater adherence to EWG recommendations support increased government efforts to encourage improved diets in the UK that are essential for the health of people and the planet in the Anthropocene

Relationship between body mass index and length of hospital stay for gallbladder disease.

Background: Obesity increases the risk of hospital admission for gallbladder disease but its impact on the length of hospital stay is largely unknown. Methods: Prospective population-based study of 1.3 million women aged 56 years on average, recruited from 1996 to 2001 in England and Scotland and followed-up through NHS hospital admission record databases for gallbladder disease (cholelithiasis, cholecystitis, cholecystectomy) over a total of 7.8 million person-years. Results: During follow-up, 24 953 women were admitted with gallbladder disease, 87% who had a cholecystectomy. After adjusting for age, socioeconomic status and other factors, women with higher BMI at recruitment to the study were more likely to be admitted and spend more days in hospital. For 1000 person-years of follow-up, women in BMI categories of 18.5-24.9, 25-29.9, 30-39.9, 40+ kg/m2 spent, respectively, 16.5[16.0-17.0], 28.6[28.3-28.8], 44.0[43.4-44.5] and 49.4[45.7-53.0] days in hospital for gallbladder disease. Conclusion: On the basis of these estimates, over a quarter of all the days in hospital for gallbladder disease in middle-aged women can be attributed to obesity

Antidepressants, Depression, and Venous Thromboembolism Risk: Large Prospective Study of UK Women

Background: Some investigators have reported an excess risk of venous thromboembolism (VTE) associated with depression and with use of antidepressant drugs. We explored these associations in a large prospective study of UK women. Methods and Results: The Million Women Study recruited 1.3 million women through the National Health Service Breast Screening Programme in England and Scotland. Three years after recruitment, women were sent a second questionnaire that enquired about depression and regular use of medications in the previous 4 weeks. The present analysis included those who responded and did not have prior VTE, cancer, or recent surgery. Follow‐up for VTE was through linkage to routinely collected National Health Service statistics. Cox regression analyses yielded adjusted hazard ratios and 95% CIs. A total of 734 092 women (mean age 59.9 years) were included in the analysis; 6.9% reported use of antidepressants, 2.7% reported use of other psychotropic drugs, and 1.8% reported being treated for depression or anxiety but not use of psychotropic drugs. During follow‐up for an average of 7.3 years, 3922 women were hospitalized for and/or died from VTE. Women who reported antidepressant use had a significantly higher risk of VTE than women who reported neither depression nor use of psychotropic drugs (hazard ratio, 1.39; 95% CI, 1.23–1.56). VTE risk was not significantly increased in women who reported being treated for depression or anxiety but no use of antidepressants or other psychotropic drugs (hazard ratio, 1.19; 95% CI, 0.95–1.49). Conclusions: Use of antidepressants is common in UK women and is associated with an increased risk of VTEThis study was funded by Cancer Research UK, the UK Medical Research Council, and Lifebloo

Paraneoplastic thrombocytosis in ovarian cancer

&lt;p&gt;Background: The mechanisms of paraneoplastic thrombocytosis in ovarian cancer and the role that platelets play in abetting cancer growth are unclear.&lt;/p&gt; &lt;p&gt;Methods: We analyzed clinical data on 619 patients with epithelial ovarian cancer to test associations between platelet counts and disease outcome. Human samples and mouse models of epithelial ovarian cancer were used to explore the underlying mechanisms of paraneoplastic thrombocytosis. The effects of platelets on tumor growth and angiogenesis were ascertained.&lt;/p&gt; &lt;p&gt;Results: Thrombocytosis was significantly associated with advanced disease and shortened survival. Plasma levels of thrombopoietin and interleukin-6 were significantly elevated in patients who had thrombocytosis as compared with those who did not. In mouse models, increased hepatic thrombopoietin synthesis in response to tumor-derived interleukin-6 was an underlying mechanism of paraneoplastic thrombocytosis. Tumorderived interleukin-6 and hepatic thrombopoietin were also linked to thrombocytosis in patients. Silencing thrombopoietin and interleukin-6 abrogated thrombocytosis in tumor-bearing mice. Anti–interleukin-6 antibody treatment significantly reduced platelet counts in tumor-bearing mice and in patients with epithelial ovarian cancer. In addition, neutralizing interleukin-6 significantly enhanced the therapeutic efficacy of paclitaxel in mouse models of epithelial ovarian cancer. The use of an antiplatelet antibody to halve platelet counts in tumor-bearing mice significantly reduced tumor growth and angiogenesis.&lt;/p&gt; &lt;p&gt;Conclusions: These findings support the existence of a paracrine circuit wherein increased production of thrombopoietic cytokines in tumor and host tissue leads to paraneoplastic thrombocytosis, which fuels tumor growth. We speculate that countering paraneoplastic thrombocytosis either directly or indirectly by targeting these cytokines may have therapeutic potential. &lt;/p&gt

Market outlook for satellite-based RE index insurance in agribusiness

In the current report a market outlook for satellite-based RE index insurance is elaborated on. Special thanks for the contributions of Andries Rosema of EARS Earth Environment Monitoring BV and Erik Klaassens of ECORYS Nederland BV. Also the views of experts who were consulted are acknowledged (see for the list of experts Appendix I)

Kinome-Wide Functional Genomics Screen Reveals a Novel Mechanism of TNFα-Induced Nuclear Accumulation of the HIF-1α Transcription Factor in Cancer Cells

Hypoxia-inducible factor-1 (HIF-1) and its most important subunit, HIF-1α, plays a central role in tumor progression by regulating genes involved in cancer cell survival, proliferation and metastasis. HIF-1α activity is associated with nuclear accumulation of the transcription factor and regulated by several mechanisms including modulation of protein stability and degradation. Among recent advances are the discoveries that inflammation-induced cytokines and growth factors affect protein accumulation of HIF-1α under normoxia conditions. TNFα, a major pro-inflammatory cytokine that promotes tumorigenesis is known as a stimulator of HIF-1α activity. To improve our understanding of TNFα-mediated regulation of HIF-1α nuclear accumulation we screened a kinase-specific siRNA library using a cell imaging–based HIF-1α-eGFP chimera reporter assay. Interestingly, this systematic analysis determined that depletion of kinases involved in conventional TNFα signaling (IKK/NFκB and JNK pathways) has no detrimental effect on HIF-1α accumulation. On the other hand, depletion of PRKAR2B, ADCK2, TRPM7, and TRIB2 significantly decreases the effect of TNFα on HIF-1α stability in osteosarcoma and prostate cancer cell lines. These newly discovered regulators conveyed their activity through a non-conventional RELB-depended NFκB signaling pathway and regulation of superoxide activity. Taken together our data allow us to conclude that TNFα uses a distinct and complex signaling mechanism to induce accumulation of HIF-1α in cancer cells. In summary, our results illuminate a novel mechanism through which cancer initiation and progression may be promoted by inflammatory cytokines, highlighting new potential avenues for fighting this disease

Differences in risk factors for three types of stroke: UK prospective study and meta-analyses

OBJECTIVE: To compare associations of behavioral and related factors for incident subarachnoid hemorrhage and intracerebral hemorrhage and ischemic stroke. METHODS: A total of 712,433 Million Women Study participants without prior stroke, heart disease, or cancer reported behavioral and related factors at baseline (1999-2007) and were followed up by record linkage to national hospital admission and death databases. Cox regression yielded adjusted relative risks (RRs) by type of stroke. Heterogeneity was assessed with χ2 tests. When appropriate, meta-analyses were done of published prospective studies. RESULTS: After 12.9 (SD 2.6) years of follow-up, 8,128 women had an incident ischemic stroke, 2,032 had intracerebral hemorrhage, and 1,536 had subarachnoid hemorrhage. In women with diabetes mellitus, the risk of ischemic stroke was substantially increased (RR 2.01, 95% confidence interval [CI] 1.84-2.20), risk of intracerebral hemorrhage was increased slightly (RR 1.31, 95% CI 1.04-1.65), but risk of subarachnoid hemorrhage was reduced (RR 0.43, 95% CI 0.26-0.69) (heterogeneity by stroke type, p < 0.0001). Stroke incidence was greater in women who rated their health as poor/fair compared to those who rated their health as excellent/good (RR 1.36, 95% CI 1.30-1.42). Among 565,850 women who rated their heath as excellent/good, current smokers were at an increased risk of all 3 stroke types, (although greater for subarachnoid hemorrhage [≥15 cigarettes/d vs never smoker, RR 4.75, 95% CI 4.12-5.47] than for intracerebral hemorrhage [RR 2.30, 95% CI 1.94-2.72] or ischemic stroke [RR 2.50, 95% CI 2.29-2.72]; heterogeneity p < 0.0001). Obesity was associated with an increased risk of ischemic stroke and a decreased risk of hemorrhagic stroke (heterogeneity p < 0.0001). Meta-analyses confirmed the associations and the heterogeneity across the 3 types of stroke. CONCLUSION: Classic risk factors for stroke have considerably different effects on the 3 main pathologic types of stroke